Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or muscle damage, wherein the heart becomes weaker and is unable to efficiently pump and circulate blood. This can manifest as a complication of cancer therapies, and recent immune-oncology study data with trastuzumab reports cardiotoxicity rates ranging from 4.1 – 10%.1
There are several imaging modalities commonly used to provide detailed information on cardiac anatomy (e.g., vessel stenosis) and function (e.g. left ventricular ejection fraction, wall motion, etc.). These techniques include echocardiography (Echo), CT angiography (CTA), X-ray coronary angiography, Cardiac MRI (CMR), SPECT, MUGA and PET.
Several algorithms and professional society recommendations exist for cardiac monitoring in routine oncology clinical practice. In fact, the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging have provided a consensus statement for multimodality imaging evaluation of patients during and after cancer therapy.2 These imaging recommendations facilitate cardiac assessment and diagnosis of cardiotoxicity, especially when combined with other available clinical tools such as:
- Electrocardiograms (ECG) to measure conduction disturbances or arrhythmias;
- Cardiac biomarkers, such as cardiac troponin or the myocardial band of creatine kinase (CK-MB); and
- Other markers like brain natriureteric peptide (BNP) or serum anti-striated muscle antibodies.3
Recent immuno-oncology clinical trials have focused on the early detection of myocardial injury relative to pre-treatment risk assessments based on patient age, disease comorbidities (e.g., hypertension, diabetes), cardiovascular disease (e.g., coronary artery disease, atrial fibrillation), cardiac biomarkers, and results from advanced imaging technologies (e.g., 3D Echo, myocardial strain measurements). Several imaging methods may be used to measure cardiac ejection fraction (EF), with Cardiac MRI and Echo being equal to or more accurate when compared to MUGA scans. Let’s review a few here.
Echo is the preferred method for assessing EF due to its wide availability, low cost, and lack of radiation exposure. Left ventricular ejection fraction (LVEF) may be measured in 2 or 3 imaging planes (2D- or 3D-echo), and is considered a surrogate indicator of myocardial contractility. Further, 3D-echo techniques have been shown to provide superior accuracy and reproducibility over time.
Myocardial Strain Imaging
Myocardial strain imaging measures the amount of myocardial deformation or change in length of a myocardial segment from the contracted and relaxed states. This advanced 3D imaging technique has been reported to be more sensitive than 2D Echo LVEF and comparable to MUGA imaging for detecting the onset of heart failure. Strain imaging has been included in the previously mentioned industry consensus guidelines, and is starting to be included in clinical trial designs.
The consensus threshold for defining myocardial abnormality is that any Global Longitudinal Strain (GLS) value less negative than -19 may be considered abnormal [note that the cardiology literature has removed the negative sign and consider anything <19 as abnormal and >19 as normal].4
Cardiac Magnetic Resonance (CMR)
With the emergence of immuno therapy (e.g immune checkpoint inhibitors upregulation of T-cell activity) for treating advanced cancers, the potential for immune-related cardiotoxicity (e.g., myocarditis) is very real. In addition to traditional clinical endpoints and biomarkers, Cardiac Magnetic Resonance (CMR) plays an important role in detecting myocarditis.
The International Consensus Group on Diagnosis of Myocarditis recently released the “Lake Louise Criteria,” which defines CMR protocol standards (pulse sequences), reporting terminology, and diagnostic criteria.5 Given the ability of CMR to detect tissue changes associated with myositis, the consensus group recommends a combination of markers for tissue edema, inflammation (hyperemia or early-gadolinium enhancement), and necrosis or fibrosis (late-gadolinium replacement), because the combined use of these three markers result in optimal accuracy for detecting myocarditis.
How Imaging Core Labs Make a Difference
Imaging core labs play an important role in ensuring these advanced imaging techniques are appropriately evaluated for incorporation into a study protocol, and for deciding how they should be implemented within the study’s imaging documentation. Additionally, image acquisition standardized across clinical sites will help ensure the consistent collection of high quality cardiac imaging data for the assessment of treatment-related cardiotoxicity as a study safety endpoint.
The inclusion of these cardiac endpoints in oncology clinical trials helps identify at-risk patients and provide the treating oncologists and cardiologists with important information that they can use to make treatment-related decisions. The overall goal is to balance survival benefits and reduce cardiac risk relative to a patient’s quality of life.
Click here to learn more about potential treatment-related CV issues and the practical approaches sponsors should consider when creating drug development plans ─ including the incorporation of appropriate imaging endpoints into clinical study protocols.
- Matthias FG, Sechtem U, Schultz-Menger J, Holmvang G, Alakija P, et al; Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper J Am Coll Cardiol. 2009; 53(17): 1475–1487
- Henry, ML, Niu J, Zhang N, Giodano SH, Chavez-MacGregor M. Cardiotoxicity and Cardiac Monitoring Among Chemotherapy-Treated Breast Cancer Patients. JACC – Cardiovascular Imaging 2018:11 (8),1084-93
- Asnani, A. Cardiotoxicity of Immunotherapy: Incidence, Diagnosis, and Management. Curr Oncol Rep 2018; 20:44
- Plana, JC, Galderisi M, Barac A, Ewer MS, Ky B et al. Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014;27:911-39
- Thavendiranathan,P, Poulin F, Ki-Ding L, Plana JC, Woo A, Marwick TH. Use of Myocardial Strain Imaging by Echocardiography for the Early Detection of Cardiotoxicity in Patients During and After Cancer Chemotherapy A Systematic Review. J Am Coll Cardiol 2014;63:2751–68