Cardiovascular Imaging in Cardio-Oncology: Have we made progress?

Cancer screening and advances in treatment have led to a burgeoning population of cancer survivors. It is estimated there will be 22.5 million cancer survivors in the United States alone by 2032 (1) While health care should be encouraged by these advancements, less attention has been paid to the potential short and long-term toxicity of cancer treatments, including cardiotoxicity. Post-menopausal women, several years after a breast cancer diagnosis, are more likely to die of cardiovascular disease than recurrent cancer (2). Cardio-Oncology has emerged as a sub-specialty of medicine to ensure that patients with cancer receive optimal cancer therapy without compromising cardiovascular health. Cardiovascular (CV) imaging in patients with cancer has largely been driven by the need to assess left ventricular (LV) function in patients treated with anthracyclines and/or HER-2 targeted therapies, who are at risk of LV dysfunction or heart failure. Alexander, et al (3) demonstrated decades ago, the benefit of multigated acquisition (MUGA) radionuclide imaging to assess LV ejection fraction (LVEF) in patients with heart failure symptoms from anthracyclines; while more recently Plana and colleagues have recognized the utility of echocardiographic evaluation with 3D LVEF and strain (4) to detect LV dysfunction prior to and during potentially cardiotoxic chemotherapy. Importantly, Daniela Cardinale and colleagues have demonstrated that early identification of LV dysfunction and introduction of anti-remodeling medications can mitigate cardiotoxicity in patients exposed to these agents (5) However, patients with cancer are not only at risk of LV dysfunction or heart failure - modern cancer treatments are associated with a number of potential cardiovascular toxicities including, myocarditis, valvular heart disease, coronary artery disease and pericardial disease. In the American Heart Association (AHA) scientific statement titled "Uses of Cardiovascular Imaging in Contemporary Cardio-Oncology" (6) Addison and colleagues summarize the current data of CV imaging modalities in cardio-oncology including the most appropriate modality to consider based on the cancer treatment related CV toxicity.

Cardiovascular imaging with modern cancer therapies.

The American Heart Association (AHA) statement presented by Addison and colleagues (6) focuses on the specific utility of CV imaging techniques with different classes of anti-cancer drugs and their respective toxicities, as well as optimal CV imaging based on cardiac disease presentation (e.g. acute coronary syndrome). The use of CV imaging along the spectrum of cancer treatment, including before, during, and after treatment is included.

In this AHA scientific statement, Addison et al. suggest recommend suggest echocardiography as the first line imaging test to assess for LV dysfunction as part of a baseline assessment, prior to cardiotoxic treatment, in pediatric patients and in adult patients with at least one cardiac risk factor. This is similar to the recently published European Society of Cardiology (ESC) guidelines which recommends echocardiography, preferably 3-D LVEF with global longitudinal strain(GLS), as the first-line modality for the assessment of cardiac function at baseline and during therapy for patients treated with anti-cancer drugs, who are at risk of LV dysfunction/heart failure (7). Both the ESC guideline and the AHA statement recommend suggest repeating an echocardiogram after 250 mg/m2 of doxorubicin-equivalent dose in patients with higher risk of LV dysfunction and in patients treated with HER2-targeting therapies. Addison et al endorse cardiac imaging surveillance during therapy in high-risk patients treated with MEK or VEGF inhibitors, (6) and both the ESC and AHA statements recommend support an echocardiogram in the year following completion of treatment with anthracycline or anti-HER2 therapy. While LV dysfunction is reported with other classes of cancer therapies, there is less robust evidence to support routine cardiac imaging surveillance in the absence of clinical symptoms. The AHA statement does not recommend promote obtaining a routine echocardiogram in asymptomatic patients treated with an immune checkpoint inhibitor (ICI), while the ESC guideline recommends a baseline echocardiogram in patients at high risk of cardiac toxicity. There is less robust evidence to support routine imaging during ICI therapy in the absence of heart failure (HF) symptoms or suspected myocarditis. For patients receiving CAR-T cell therapy, trials have reported decreases in LVEF associated with cytokine release syndrome, however the role of echocardiogram is yet to be established. Addison, et al. support recommend pre-treatment echocardiograms in patients with more than one risk factor receiving CAR-T cell treatment and post-treatment within 12 months. Pre-treatment echocardiograms are also suggested in those patients with one or more cardiac risk factors receiving BTK inhibitors, VEGF inhibitors, stem cell transplant, or thoracic radiation. There is limited data supporting the role of surveillance cardiac imaging in adults after completion of cancer treatment. The AHA statement recommends supports consideration of post-treatment screening echocardiogram (beyond 12 months) every 2-5 years for anthracyclines and HER-2 targeted therapy, while the ESC guideline recommendations are based on baseline risk of cardiovascular toxicity: high/very high-risk patients – echocardiogram at 1,3, 5 years and then every 5 years; moderate risk – echocardiogram every 5 years. Further research is needed to demonstrate the optimal frequency of echocardiograms in ‘at risk' patient populations and to determine if such strategies lead to improved clinical outcomes.

Cardiac Magnetic Imaging (CMR) is a second-line modality, after echocardiography, for the screening and monitoring of LV systolic function in patients treated with potential cardiotoxic cancer therapy, particularly in cases where the echocardiography windows are sub-optimal. CMR has an established role in patients presenting with a diagnosis of cardiomyopathy by echocardiogram, and in certain cardio-oncology patients it has significant impact in clinical diagnosis and management (8). Addison, et al. (6) endorses CMR in patients that have a complex differential for etiology of cardiomyopathy to simplify diagnostic pathways and avoid invasive studies when possible. CMR has a supportive role for the diagnosis of ICI-related myocarditis, but as established by Zhang L, et al. (9) a negative CMR does not exclude ICI-myocarditis. CMR is prognostic for cardiac tumor assessment (10). There are several limitations when considering the role of CMR in patients with cancer including, availability, resources, and time on machine for patients. New CMR imaging techniques such as fast-SENC can be acquired in less than 10 minutes and have been shown to establish cardiac safety in patients undergoing therapy with anthracyclines. (11)

The role of Cardiac CT (CCT) in cardio-oncology continues to evolve. CCT has a principal role in ruling out obstructive coronary atherosclerosis in stable chest pain per recent guidelines. (12) For patients with cancer at high risk of bleeding, cardiovascular tomography angiography (CCTA) provides a noninvasive option to assess for coronary artery disease. Coronary artery calcium (CAC) score is an important prognosticator in the general population. CAC score assessment in non-gated non-cardiac scans is feasible and useful to identify subclinical atherosclerosis from chest CT for oncologic imaging purposes. (13) For structural procedural planning (e.g., transcatheter aortic valve replacement), CCT is part of the current standard of care.

Addison, et al. (6) acknowledge that although MUGA scan was a legacy imaging technique for LVEF assessment (3) in patients exposed to cardiotoxic cancer therapy, in current practice it should only be utilized when echocardiography and other prior mentioned techniques are unavailable due to increased radiation, and highly reproducible alternatives (i.e. Echo-GLS, CMR). The role of stress SPECT and PET-CT in cardio-oncology currently may lie in long term surveillance for ischemia. Although there is some recent data suggesting that coronary microvascular dysfunction may be associated with an increased cancer incidence in patients with non-obstructive CAD, (14) there are no defined evidence-based recommendations for the use of cardiac PET-CT in current cardio-oncology guidelines, other than for cardiac tumor assessment or as a second line modality for detection of ICI-related myocarditis. (7)

Knowledge Gaps and the Future of CV imaging in Cardio-Oncology

While there have been great gains in our understanding of the value of cardiac imaging in patients treated with cancer therapy, Addison, et al.⁶ highlight several important knowledge gaps. There are clear limitations of LVEF as a prognosticator and predictor of HF in patients treated with cancer therapeutics. 3-D echocardiogram with GLS, may provide more sensitive detection of early LV dysfunction, however, does this lead to improvement in patient outcomes? In the SUCCOUR trial, GLS was not shown to be superior to an LVEF guided strategy to start anti-remodeling treatment in patients undergoing treatment with anthracyclines. (15) The expanding list of novel cancer therapeutics and respective cardiovascular toxicities (e.g., ICI induced myocarditis) mandates the need for further research to determine the most sensitive and specific CV imaging strategy for detection and surveillance. The role of imaging biomarkers to assess toxicities of anti-cancer drugs such as oral tyrosine kinase inhibitors, which may cause subclinical metabolic and vascular effects, needs further study. Despite recommendations on cardiac imaging in cardio-oncology from several societies, evidence to date would suggest a sub-optimal adoption of current recommendations into clinical practice. Education of health care providers and patients on the importance of CV imaging in the early detection and subsequent prevention of cancer therapy related cardiovascular toxicity is needed. Ongoing collaboration with researchers, CV imaging societies, as well as organizations such as ESC, American College of Cardiology, European Society of Medical Oncology, the International Society of Cardio-Oncology and the current scientific statement is essential for implementation of the current recommendations for CV imaging, particularly among oncologist/hematologists and primary care providers. Yes, we have made progress, but there is still more to learn. Future research will determine the optimal use and timing of CV imaging techniques across the spectrum of anti-cancer drugs and CV diseases in patients with cancer.