Written by : DR. Amiliana M Soesanto, MD, FIHA
Advances of cancer management have improved the outcome and survival rate of patients with malignancy. Hence, longer life of cancer survivors increases their risk of experiencing cancer therapy-related cardiac dysfunction (CTRCD). That condition might cause cardiac injury and increased risk of developing late cardiac events. In recent cardio-oncology practice, echocardiography is the most widely used technique in clinical practice in the detection and surveillance of CTRCD because of its availability, feasibility, and cost-effectiveness. This article highlights the recommendations of the existing guidelines and providing practical guidance on the role of echocardiography in detecting the occurrence of CTRCD.
The definition of Cancer Therapy-related Cardiac Dysfunction
Cardiotoxicity varies by the type of treatment utilized and the mechanisms of cardiac damage involved. It has been classified as follows (figure 1) :
- Type I CTRCD is characterized by anthracyclines (including doxorubicin). It is dose-dependent, leads to cell apoptosis, and is therefore irreversible at the cell level.
- Type II CTRCD is characterized by trastuzumab and pertuzumab. It is not dose-dependent, does not lead to apoptosis by itself, and is often reversible.
There are many varieties of how CTRCD defined. The definition according to the American Society of Echocardiography and the European Association of Cardiovascular Imaging expert consensus in 2014, is a decrease in the LVEF of >10 % points, to a value <53% (2D) echocardiography (2DE).1 The changes should be repeated 2 to 3 weeks after the baseline echocardiography study to detect any decrease in LVEF.
Other definitions of CTRCD depend on the specific anti cancer agent and treatment modality, as well as the clinical setting in which they are observed and approved for use.2 The U.S. Food and Drug Administration (FDA) defines CTRCD is as follows;
- for doxorubicin;
- in adults; 10% decline LVEF below the lower normal level, or absolute LVEF 45%, or 20% decline LVEF at any point.
- In pediatric; a drop in fractional shortening (FS) by an absolute value of >10% or below 29% and a decline in LVEF of 10% or an LVEF below 55%
- for trastuzumab; an absolute LVEF decline of > 16% from pre-treatment values or an LVEF decline of > 10% from pre-treatment values to below the institutional lower level of normal
- for pertuzumab (the newer HER2-targeted antibody); an LVEF decline to 40% or an LVEF of 40% – 45% with > 10% decrease from pre-treatment values
The clinical feature CTRCD may be asymptomatic or symptomatic, and the reversibility may be categorized as;
- Reversible: LVEF improved to within 5 % points of baseline
- Partially reversible: LVEF improved by > 10 % points from the nadir but remaining > 5 % points below the baseline
- Irreversible: improved by <10 % points from the nadir and remaining >5 % points below the baseline
- Indeterminate: patient not available for re-evaluation
Echocardiography evaluation of the LVEF
Since the definitions of CTRCD are based on a quantitative measure of LVEF, accurate data of the LVEF has to be provided during the management of patients with cancer. Echocardiography 2-dimensional (2D) has been the most widely used parameter to evaluate cardiac function in patients during and after potentially cardiotoxic therapy. However, some drawbacks should be understood in calculating LVEF as a parameter of systolic function. Simpson’s method is the method of choice for calculating LVEF. 3 The method used to monitor any changes in LVEF should be consistent whenever possible during treatment and follow up. The images obtained to calculate LVEF during baseline and follow-up echocardiography should be stored to be compared with the previous ones to reduce report variability. The wall motion scoring of 16 segments can be combined with LVEF calculation and has an added value in detecting CTRCD.1
Although LVEF is a robust parameter to assess systolic function, it has some limitation. The LVEF parameter might not be able to detect small changes in LV contractility caused by early myocyte damage.4 Inadequate visualization, geometric assumptions, lack of consideration of subtle regional wall motion abnormalities can cause inaccuracy and variability of the measurements. More advanced echocardiography techniques can overcome those drawbacks and may increase the accuracy in calculating the LVEF. Contrast echocardiography provides better identification of endocardial border for correct tracing, while 3-D echocardiography can minimize the geometrical assumption in calculating the LV. 5 Measuring LVEF by 3-dimensional is more accurate, since it corelate better with cardiac magnetic resonance imaging (MRI) and shows better observer variability.
Another consideration for determining the LV systolic function using LVEF is the load dependency. Changes in loading conditions, which are frequent during chemotherapy, may affect the LVEF calculation. Load changing can occur as volume expansion due to the intravenous administration of chemotherapy or volume depletion due to vomiting or diarrhoea.
Evaluation of the subclinical systolic dysfunction
Strain and strain rate as the parameters of myocardial deformation is more sensitive for earlier detection of slight changes in myocardial function. Speckle tracking–based deformation analysis has become the clinical standard. There are three types of myocardial deformation, including; longitudinal, radial, and circumferential. Among the myocardial deformation indices, global longitudinal strain (GLS) emerged as a highly reproducible and accurate measure of myocardial mechanics and more evidence reporting its value for detecting subclinical myocardial dysfunction and prognosticating subsequent LV dysfunction in patients during and after cancer therapy. 6 Some studies have demonstrated the superiority of GLS to 2D LVEF concerning reproducibility, correlation with MRI-determined EF,7 and prediction of overall outcome in the general population. 8
The ASE/EACVI consensus statement defined a relative percentage decrease in GLS of >15% from baseline as clinically meaningful evidence of subclinical LV dysfunction. Development of LV dysfunction compromises drug delivery in these patients, and changes in GLS have been shown to predict LV dysfunction. Clinically significant changes in GLS during treatment should warrant closer surveillance for signs and symptoms of cardiac dysfunction. However, there is no evidence that changes in strain should prompt changes in oncology treatment at this time.2
Echocardiography detection for diastolic dysfunction
In general, diastolic dysfunction is likely to be the first and sensitive parameter to detect cardiac impairment. This could be driven by oedema or initial fibrosis of the myocardium which stiffens the myocardium. Diastolic dysfunction can occur in patients undergoing cancer therapy. A study reported that changes in mitral E velocity, E/A ratio, pulmonary venous flow, isovolumic relaxation time, and tissue Doppler velocities occurs as early as a few hours after the administration of chemotherapy.9 However, diastolic parameters have not yet demonstrated value in predicting subsequent CTRCD. 1
Evaluation of the right ventricle function
Data regarding the right ventricular (RV) involvement in cancer patients with CTRCD are scarce and conflicting. Right ventricular (RV) abnormalities may occur because of direct neoplastic involvement or due to cardiotoxic effects of chemotherapy. Some study reported that anthracyclines, trastuzumab and cyclophosphamide have been noted to have a negative impact on right ventricular function measured by conventional parameters and more advanced parameter such as strain.10-12 The lack of reproducibility data is also a concern in the application of RV strain for the assessment of cardiotoxicity. The prognostic value of RV dysfunction in oncology patients and its persistence during follow-up still need to be evaluated in further studies. However, the expert consensus mentioned that a quantitative assessment of RV chamber and function should be performed due to possible RV involvement.1
Echocardiography monitoring during Cancer Therapy
If by echocardiography the LVEF is <53%,13 GLS is below the normal limit with or without troponins elevation, the cardiologist and oncologist should discuss the risk and benefit of the situation. However, further cancer treatment is at the discretion of the oncologist. If the quality of the echocardiogram is suboptimal, CMR is recommended. The expert consensus recommends that follow-up echocardiography for monitoring the LV systolic function should consider the specific type of anticancer agent received.1 The evaluation during cancer therapy for type I cancer regiment begin with a baseline evaluation, including measurements of LVEF, GLS, and troponin (figure 2). If any are abnormal, cardiology consultation is recommended. If normal, it is recommended to perform follow-up evaluation after completion of therapy and six months later. Cardiac MRI can be applied to confirm the LVEF. The value of the lower limit of normal (LLN) depends on age and echocardiography machine vendor and application.14 For type II cancer regiment, baseline evaluation including measurements of LVEF, GLS, and troponin is recommended. Measurements of LVEF, GLS, and troponins are recommended every three months during the therapy period. For monitoring subclinical LV dysfunction, baseline GLS data should be compared with the follow-up data during therapy. A relative percentage reduction in GLS of >15% is very likely to be abnormal, whereas a change of <8% appears not to be of clinical significance (figure 3). A repeat study should confirm the abnormal GLS value. The study should be repeated 2 to 3 weeks after the initial abnormal study.1
The LVEF and GLS values are load-dependent measurements. So, it is recommended to report the timing and condition while performing echocardiographic examination concerning the intravenous infusion of chemotherapeutic agents (number of days before or after treatment) as well as the vital signs measured during the test (blood pressure and heart rate), as changes in loading conditions may affect the GLS value.1
Biomarker also has a role in determining the presence of CTRCD. Elevated troponin during therapy is a mark of increased risk for subsequent cardiovascular events. An elevation in NT-proBNP is suggested for increased LV filling pressures in the setting of CTRCD. The negative predictive value of NT-proBNP may be useful, but further studies in this area are needed.
In the field of cardio-oncology, a good collaboration between oncologists and cardiologists is important to conduct prevention, early detection and management of cardiovascular disease in cancer patients. Recent advances in cancer treatment have led to improved survival rates for patients with cancer, which consequently increases the risk of developing cardiovascular complications, including CTRCD. Conventional echocardiography is used to assess the LVEF for detecting CRTCD during cancer therapy. Recently, myocardial deformation imaging with speckle tracking echocardiography shows great potential in detecting early signs of cardiotoxicity.
DR. Amiliana M Soesanto, MD, FIHA serves as lecturer and cardiologist at Department of Cardiology and Vascular Medicine, Faculty of Medicine University of Indonesia, National Cardiovascular Center Harapan Kita
- Plana JP, Galderisi M, Barac A, 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.
- Liu J, Banchs J, Mousavi N, et al. Contemporary Role of Echocardiography for Clinical Decision Making in Patients During and After Cancer Therapy. J Am Coll Cardiol Img 2018; 11: 1122-31.
- Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American society of echocardiography and the European association of cardiovascular imaging. European Heart Journal Cardiovascular Imaging 2015; 16(3): 233-71.
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- Lang RM, Badano LP, Mor-avi V, et al. Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography 2015; 28: 1-39.
- Thavendiranathan P, Poulin F, Lim KD, 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 PtA: 2751–68.
- Brown J, Jenkins C, Marwick TH. Use of myocardial strain to assess global left ventricular function: a comparison with cardiac magnetic resonance and 3-dimensional echocardiography. Am Heart J 2009; 157(102).
- Stanton T, Leano R, TH. M. Prediction ofall-cause mortality from global longitudinalspeckle strain: comparison with ejection fraction and wall motion scoring. Circ Cardiovasc Imaging 2009; 2: 356–64.
- Pudil R, Horacek JM, Strasova A, Jebavy L, Vojacek J. Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines. Exp Oncol 2008; 30: 160-2.
- Chang WT, Shih JY, Feng YH, et al. The early predictive value of right ventricular strain in epirubicin-induced cardiotoxicity in patients with breast cancer. Acta Cardiol Sin 2016; 32: 550-9.
- Calleja A, Poulin F, Khorolsky C, et al. Right ventricular dysfunction in patients experiencing cardiotoxicity during breast cancer therapy. ;2015:609194],. J Oncol 2015; 2015: 609194.
- Grover S LD, Chakrabarty A, , Joerg L, Kotasek D, et al. Left and right ventricular effects of anthracycline and trastuzumab chemotherapy: a prospective study using novel cardiac imaging and biochemical markers. . International journal of cardiology 2013; 168: 5465-7.
- Lancellotti P, Badano LP, Lang RM, et al. Normal Reference Ranges for Echocardiography: rationale, study design, and methodology (NORRE Study). Eur Heart J Cardiovasc Imaging 2013; 14: 303-8.
- Takigiku K TM, Izumi C, Yuda S, Sakata K, Ohte N, et al. Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study. . Circulation journal : official journal of the Japanese Circulation Society 2012; 76: 2623-32