This was a pilot study, in which 55 breast cancer patients were enrolled, to evaluate the alterations of strain and strain-rate parameters in breast cancer patients receiving doxorubicin and compare them with serial conventional echocardiography changes. A week prior to, and a week after, chemotherapy with doxorubicin, left ventricular ejection fraction (LVEF) and strain and strain-rate parameters were measured by conventional 2D echocardiography and tissue Doppler-based imaging, respectively.
Comparison of the results of pre- and post-chemotherapy evaluation demonstrated that strain and strain-rate parameters were significantly reduced. Mean difference (standard deviation) for the strain measurement of basal-septal, basal-lateral, basal-inferior, and basal-anterior values were 2.58% (2.15), 3.20% (1.94), 4.13% (3.48), and 2.86% (2.65), respectively; and for the strain-rate values were 0.18 s–1 (0.17), 0.17 s–1 (0.17), 0.24 s–1 (0.19), and 0.19 s–1 (0.14), respectively; all p values <0.001. There was no significant change in patients’ LVEF after chemotherapy (pre-intervention 61.10 (4.86), post-intervention 61.06 (4.82), p=0.857).
In conclusion, strain/strain-rate significant reduction, in the setting of normal range LVEF, suggests subclinical heart failure. Whether the strain and strain-rate imaging should replace the conventional echocardiography for early monitoring of cardiotoxicity of doxorubicin requires further investigations.
Doxorubicin, which is an antibiotic of the anthracycline group, has a cytotoxic antineoplastic activity and is commonly used in a broad spectrum of malignancies, either alone or in combination with other drugs. Despite its usefulness in chemotherapy of breast cancer, its cardiac side effects, such as cardiomyopathy and congestive heart failure, cause considerable limitations and obstacles for oncologists and cardiologists.2,3
Doxorubicin’s cardiotoxicity is mainly due to oxidative stress, which is induced by the production of reactive oxygen species (ROS) and mitochondrial damage. Other suggested mechanisms include decreased number of contractile cells as a result of damage to mitochondrial and cellular membranes, and extracellular matrix remodelling.4,5
Although it is suggested that anthracycline-related cardiotoxicity is mainly related to cumulative dose of the drug, and the risk of cardiomyopathy increases with a higher cumulative anthracycline dose,6 subclinical cardiac changes have even been reported in patients treated with low-dose anthracycline.7,8 Also, it has been suggested that anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure, and seems to reduce the risk of subclinical cardiac damage, as well.6
Early detection of cardiac damage in still-reversible stage is fundamental because doxorubicin cardiotoxicity will eventually progress into irreversible phase, and detection of subclinical myocardial contractility impairment at a latent stage will allow early treatment and complete recovery.9
Declined left ventricular ejection fraction (LVEF) and shortening fraction at rest, which are found by assessing serial conventional echocardiographs, are the commonly used monitoring parameters for detection of chemotherapy-induced cardiomyopathy. The main drawback of these parameters is that the significant decline is detected when the cardiac dysfunction has become irreversible. In fact, they are not sensitive to early cardiac function alterations.4,10,11 Also, it has been demonstrated that a decline in systolic function may occur while the LVEF is still remaining within the normal range.10,12 Therefore, new echocardiographic methods such as tissue Doppler imaging (TDI) and two-dimensional (2D)-speckle tracking (STE), magnetic resonance imaging (MRI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin I (TnI) are suggested for early detection of cardiac dysfunction.12-17
Recent studies suggest that strain and strain-rate imaging provide more sensitive and reproducible measurement of anthracycline-induced myocardial systolic changes rather than standard echocardiographic parameters, especially early after therapeutic doses of anthracycline chemotherapy when LVEF is still within normal limits.18-23 However, strain and strain-rate parameters have some limitations for patients suffering from obesity, valvular cardiac diseases, myocardial infarction, left ventricle hypertrophy and infiltrative diseases.10
The aim of the present study is to assess the alterations of strain and strain-rate imaging findings and compare them with conventional echocardiographic parameters in breast cancer patients receiving doxorubicin as part of their chemotherapy; and evaluate their efficacy in early identification of anthracycline-induced cardiotoxicity.
Materials and methods
Study settings and approval
This pilot study was conducted at University Hospitals and approved by the Ethics Committee of Mashhad University of Medical Sciences (No. 89233). It is also submitted in Iran Registry of Clinical Trials with the registry number IRCT2014060112924N2. Written informed consent was obtained from all patients.
Fifty-five female patients with pathologically confirmed non-metastatic breast cancer detected between 2010 and 2013 were enrolled in this study. The inclusion criteria were as follows: menstruating women with no cardiac risk factors such as previous cardiac diseases (including ischaemic heart disease, prolonged hypertension, congenital or acquired valvular diseases and any kind of myocardial diseases) and diabetes, no previous chemo/radiotherapy or any kind of cancers, and no contraindication to doxorubicin (hypersensitivity to the drug, pregnancy, lactation, radiotherapy, congestive heart failure, cardiomyopathy, or myelo-suppression). The exclusion criteria were as follows: new-onset cardiac symptoms or atrial fibrillation, unsatisfactory echocardiography and lack of patient’s compliance with the drug or echocardiography.
For all participants, anthropometric parameters including weight and height, as well as vital signs including heart rate, blood pressure, temperature and respiratory rate were measured, using a standard protocol. Height and body weight were measured with the subjects dressed in light clothing after an overnight fast. The body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). Body surface area was calculated using DuBois and DuBois equation (weight [kg]0.425 × height [cm]0.725 × 0.007184). Patients with a BMI over 30 kg/m2 were considered as obese.
Chemotherapy, based on NCCN (National Comprehensive Cancer Network) guideline, was performed using doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) cycled every 21 days for four cycles (cumulative dose of doxorubicin was 240 mg/m2) followed by paclitaxel (175 mg/m2) cycled every 21 days for four cycles. Doxorubicin contraindications were evaluated for all patients prior to commencing the therapy.
Cardiac monitoring and echocardiography
A cardiologist visited each patient every month during the intervention and the exclusion criteria were evaluated. Echocardiography was performed one week before commencing the chemotherapy and one week after the fourth cycle of doxorubicin. Strain and strain-rate parameters, as well as LVEF, were evaluated. In all patients, the agent was discontinued in case of a 10% drop in ejection fraction or a drop to less than 30%.
Conventional 2D echocardiography was performed using commercially available equipment (Vivid-7, General Electric Vingmed, Horten, Norway). Patients were imaged in the left lateral decubitus position and data were acquired with a 3.5 MHz transducer in the parasternal (long- and short-axis views) and apical views (two- and four-chamber and apical long-axis views).
Comprehensive assessment of left ventricular myocardial strain and strain rate was performed using TDI-based imaging by a cardiologist who was blinded to the patients’ information. For this purpose, standard 2D grey-scale images of the left ventricle were acquired at conventional apical two- and four-chamber views, with a mean frame rate of 90 ± 5 frames per second (fps). Basal values are considered to represent the best reproducibility for TDI-based strain assessment, therefore, only this view was evaluated. Data were stored in cine-loop format and analysed by two persons (blinded to patients’ information).
Peak systolic longitudinal strain and strain rate was calculated and derived from the four segments of the two apical views (two- and four-chamber views). Inter-observer variability was not evaluated because one person obtained all images.
All data analysis was performed using Statistical Package for the Social Sciences, 21st release (SPSS Science, Apache Software Foundation, and Chicago, IL, USA). Absolute numbers and percentages were computed to describe data. Also, data were expressed as mean ± standard deviation (SD) for continuous variables. Paired-sample t-test was utilised to compare the alterations of normally distributed parameters before and after the intervention. Also, related-samples Wilcoxon signed-rank test was utilised for non-parametric parameters. A two-sided p value <0.05 was considered significant.
Fifty-five women diagnosed with breast cancer were enrolled in this study from which three patients were excluded due to their refusal to continue participation in the study. Echocardiography was performed for all patients prior to the intervention and after completion of chemotherapy. During regular cardiologist visits, none of the patients presented any kind of cardiac symptoms.
Demographic and baseline characteristics
Patients’ demographic data are summarised in table 1. Neither obese nor hypertensive patients were included, hence, any new-onset cardiac symptom or alteration in echocardiographic values can be roughly considered as due to chemotherapy cardiotoxicity.
There was no abnormality in patients’ diastolic function prior the intervention. A moderate mitral regurgitation (1.9%) and four moderate tricuspid regurgitations (7.7%) were found among the patients from whom none had a history of cardiopulmonary symptoms. Other valvular evaluations were normal. Pulmonary artery pressure was within the normal range in all patients. Echocardiographic baseline characteristics are summarised in table 2.
Comparison of the echocardiographic findings prior to and after intervention clarified that strain and strain-rate parameters were significantly decreased in all four evaluated walls, while there was no considerable change in LVEF. There was no alteration among other parameters after the intervention. For ease of interpretation, the data are presented in table 3.
Early detection of cardiac dysfunction in patients receiving doxorubicin chemotherapy has become an important notable topic for oncologists and cardiologists. Especially because of the fact that it would provide patients with better management and the chance of increased survival with lower additional side effects.
In the present study, data analysis showed that in breast cancer patients receiving 240 mg/m2 of doxorubicin as part of the chemotherapy, strain and strain-rate parameters were significantly reduced after treatment, while there was no significant change in LVEF. These findings suggest that strain and strain-rate parameters evaluated by TDI could be considered as the routine monitoring method in breast cancer patients receiving doxorubicin.
There is controversy among the studies published on assessment and monitoring of anthracycline-induced cardiotoxicity, in terms of using LVEF changes as a definition. Also, there is limited evidence-based consensus due to different chemotherapy regimens, assessment methods, and cut-offs used in different studies.11
This study revealed no significant change in LVEF in breast cancer patients treated with doxorubicin, which is supported by a report by Jurcut et al.20 In contrast with our results, Chung et al. found this alteration significant.24 Their retrospective study showed a considerable decrease in LVEF, especially in patients receiving more than 300 mg/m2 of doxorubicin, which was the case in 39 out of 174 evaluated patients. Since all of our patients received 240 mg/m2 of the drug during chemotherapy, this could be a possible explanation for the more dramatic results observed by Chung et al. Moreover, while patients who were enrolled in the Chung et al. study had different kinds of cardiac risk factors, patients who were enrolled in the present study had no cardiac risk factors. Results considering the LVEF alterations during anthracycline chemotherapy are controversial. Although some studies suggest that monitoring serial LVEF is a reliable measurement for identifying cardiac dysfunction, others believe that this index is not sensitive enough.25
Strain and strain rate
Strain and strain-rate parameters demonstrated a significant decrease in all four evaluated walls in this study. Jurcut et al. found the same results on evaluation of 16 breast cancer patients treated with doxorubicin.20 In contrast, Stoodley et al. reported a significant decrease in strain parameters without any considerable change in strain-rate parameters.12 They set the frame rate of echocardiography between 50 to 70 fps, but our design was to perform the strain and strain-rate imaging within the range of 90 ± 5 fps. Hence, using a more precise and sensitive method for strain-rate assessment lead to detection of even small amounts of reduction in these indices in our study.
This study was unable to evaluate the radial and circumferential strain and strain rate, as well as global, due to limited available software. Also inherent limitations in Doppler-based imaging preclude an accurate assessment. To prevent this, the echocardiography operator in this study tried to get the best image orientation and sample volume position, and as high a frame rate as possible.
Since, following doxorubicin, patients were treated with paclitaxel and radiotherapy, both of which are known to be cardiotoxic, long-term follow-up was not feasible without lots of confounding factors.
Data analysis demonstrated that strain and strain-rate parameters had significant reduction in patients who received doxorubicin as the chemotherapy, while there was no considerable change in LVEF. It seems that strain and strain-rate imaging provide a more sensitive and reliable measurement for early detection of cardiac dysfunction in patients who are under chemotherapy with an anthracycline.
This would not only help in better management of cancer treatment by early detection of cardiac dysfunction, but also would improve the outcome by providing supportive additional therapies in patients who receive cardiotoxic regimens.
The source of funding for this study was Mashhad University of Medical Sciences. We sincerely thank all the employees of the chemotherapy ward of Qaem Hospital for their cooperation. Also we thank Dr Babaei for his help in patient enrolment.
Conflict of interest
- Cancer patients undergoing chemotherapy can develop silent cardiac dysfunction, which can remain undetected by routine echocardiography
- Strain and strain-rate imaging provide a more sensitive and reliable measurement for early detection of cardiac dysfunction in these patients
- These parameters could be considered as the routine monitoring method in breast cancer patients receiving doxorubicin
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