Edited by: Zahra K. Motamed, McMaster University, Canada
Reviewed by: Ankush Gupta, Military Hospital Jaipur, India; Alexander E. Berezin, Zaporizhia State Medical University, Ukraine
This article was submitted to Cardiovascular Imaging, a section of the journal Frontiers in Cardiovascular Medicine
†These authors have contributed equally to this work and share first authorship
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As one of the important treatment methods for cancer patients, radiotherapy may lead to incidental irradiation of the heart, resulting in radiotherapy-induced heart disease (RIHD) arising many years after radiotherapy. While, there are few studies on early subclinical cardiac damage, which may be essential for the protection of late RIHD. To detect and predict RIHD and early subclinical cardiac damage induced by thoracic radiation therapy, based on two-dimensional speckle tracking echocardiography (2D STE) combined with multiple circulating biomarkers and accurate heart dosimetry.
This is a monocentric prospective cohort study in which 104 patients treated for malignant tumors and with cardiac radiation exposure will be included. All participants will be followed for 12 months after radiotherapy. Echocardiography, 2D STE, and blood samples will be underwent at 5-time points (baseline; after completion of RT; 2, 6, and 12 months after RT). Left ventricular ejection fraction (LVEF); global longitudinal, radial, and circumferential strain; diastolic function parameters; creatine kinase (CK); creatine kinase isoenzyme (CK-MB); cardiac troponin T (cTnT); N-terminal pro-B-type natriuretic peptide (NT-proBNP) and hypersensitive C-reactive protein (hs-CRP) will be measured at baseline and every follow-up time. The incidence of major adverse cardiovascular events will be recorded.
This study details the protocol and presents the primary limits and advantages of this single-center project. The inclusion of patients began in 2021, and the results are expected to be published in 2023. This study will be allowed to enhance knowledge on detection and prediction of early subclinical cardiac dysfunction induced by thoracic radiation therapy, based on two-dimensional speckle tracking echocardiography (2D STE) combined with circulating biomarkers and accurate heart dosimetry. Furthermore, we will evaluate risk factors of subtle cardiac damage and identify high-risk groups for early heart damage.
Cancer is expected to rank as the most critical barrier to increasing life expectancy and the leading cause of death in the world in the twenty-first century. Data from global cancer statistics indicate that there will be about 18.1 million new cancer patients all over the world in 2018 (
Heart is inevitably affected during thoracic radiation therapy, resulting in radiotherapy-induced heart damage. Thoracic radiation therapy is associated with long-term increased risk of coronary artery disease, heart failure, myocardial infarction, valvular disease, arrhythmias, pericarditis, and major adverse cardiovascular events many years after RT (
Long before the onset of clinically cardiac events occurring, subclinical cardiac changes may occur during the process, after completion, over weeks, months, or first years after RT, that can be detected based on functional dysfunction (
As an essential tool for the assessment of cardiac structure and function, echocardiography has been widely used. However, left ventricular ejection fraction (LVEF) is a relatively insensitive index for detecting subclinical cardiac damage at an early stage (
Traditional circulating biomarkers, such as creatine kinase (CK), creatine kinase isoenzyme (CK-MB), cardiac troponin T (cTnT), and cardiac troponin I (cTnI) may play an essential role in the detection of acute and late RIHD (
A large number of studies have shown that many chemotherapy drugs can lead to cardiac toxicity (
It is a monocenter, prospective cohort study that will include patients who will receive RT. All patients will be followed 12 months after RT. 2D STE parameters and circulating biomarkers will be collected. MACEs were defined as a diagnosis of unstable angina [
One hundred and four patients with thoracic radiotherapy will be included in Peking University Third Hospital from June 21, 2020 to December 31, 2021. Participants will be recruited based on the eligibility criteria presented in
Inclusion and exclusion criteria.
| With malignant tumors | Satisfactory echocardiographic images could not be obtained |
| Will receive radiotherapy | Moderate or severe valvular disease |
| With cardiac exposure during the radiotherapy process | Cardiomyopathy |
| Could receive regular follow-up for 12 months | Congenital heart disease |
| Written informed consent | Refractory hypertension |
| Coronary artery disease |
|
| Heart failure | |
| Arrhythmia requiring intervention | |
| Pericarditis | |
| Acute myocarditis | |
| Participating in other clinical studies of drug intervention | |
| Severe liver and kidney dysfunction | |
| Autoimmune disease | |
| Pulmonary hypertension |
Oncologist and cardiologist will present the study to the eligible patients, explaining the study, offering participation, and requesting written informed consent. All patients will be informed that they have no obligation to participate, and they can stop participating at any time and without any consequences for therapeutic schedule and medical follow up.
Before radiotherapy, echocardiography, 2D STE, CK, CK-MB, cTnT, NT-proBNP, ECG, hs-CRP, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine will be detected, and eligible patients will be enrolled. All participants will be followed up after completion of RT (post-RT), 2 months after RT (2-months post-PT), 6 months after RT (6-months post-PT), and 12 months after RT (12-months post-PT). During subsequent follow-up, echocardiography, 2D STE, CK, CK-MB, cTnT, NT-proBNP, ECG, and hs-CRP will be collected at every follow-up time.
A precise description of cancer, treatments for cancer, and information about the main risk factors of a cardiac event is collected at inclusion; details will be shown in
Baseline characteristics.
| Age | ||
| Hight | ||
| Weight | ||
| Body mass index (BMI) | ||
| Systolic blood pressure (SBP) | ||
| Diastolic blood pressure (DBP) | ||
| Smoking status | ||
| Hypertension | ||
| Diabetes | ||
| Hyperlipidemia | ||
| Arrhythmia | ||
| Cancer | Type | |
| Size | ||
| Chemotherapy history | ||
| Mean heart dose |
Parameters of echocardiography, 2D STE, ECG and circulating biomarkers.
| LVEF measured by the modified Simpson or the modified Quinones method |
| LV mass index calculated by the Devereux formula |
| The degree of aortic and mitral regurgitation classified according to the guidelines of the American Society of Echocardiography |
| E/A wave ratio |
| E/e' ratio |
| Left atrium volume index calculated using the area-length method |
| Systolic pulmonary arterial pressure |
| Global longitudinal strain (GLS) |
| Global radial strain (GRS) |
| Global circumferential strain (GCS) |
| S' |
| Heart rate |
| rhythm |
| P-R intervals |
| QRS wave |
| QTC |
| S-T segment changes |
| CK |
| CK-MB |
| cTnT |
| NT-proBNP |
| HsCRP |
All of the patients will be treated with stereotactic body radiotherapy (SBRT). Before radiotherapy, the chest CT examination will be carried out to locate the target area. According to the location of CT, the treatment target area is gross tumor volume and planning target volume is appropriately expanded on the basis of the anterior target. The treatment plan was made by multiplan 4.6 planning system. After the plan was completed, the plan was verified first, and then the stereotactic radiotherapy robot was used. In the treatment, we use the Xsight-Spinal tracking system, synchronous respiratory tracking mode, or the six-dimensional bed system to control the patient's position and focus perfectly, so as to achieve the effect of precise radiotherapy. According to the treatment plan, the minimum, average and maximum doses of the heart and the V5, V10, V20 and V30 of the heart are counted. To evaluate the effect of radiotherapy dose on heart more accurately, we converted all maximum and mean cardiac doses to the biologically effective doses (BED), assuming an α/β ratio of 3 for the heart, with conversion to an equivalent dose in 2-Gy fractions (EQD2) using the linear quadratic model (
The primary endpoint is an at least 10% decrease in the global longitudinal, radial, and circumferential strain or strain rate, determined using cardiac 2D STE, compared with the baseline, which can be considered clinically pertinent based on those observed in the previous studies (
CK, CKMB, cTnT and NT proBNP were within the range of normal reference values at baseline, but exceeded the upper limit of normal reference values at follow-up.
ECG indicates new arrhythmia.
Patients had symptoms and signs of heart failure with LVEF decreased by at least 5% and less than 55%, or LVEF decreased by at least 10% and less than 55% without symptoms and signs, or LVEF <50%, measured by echocardiography (
Study data will be managed by two study investigators using a predesigned casereport form (Microsoft Office Excel and Word) with double data-entry. Data checks will be regularly performed to ensure data quality. The number of eligible, included and excluded of patients will be recorded. Withdrawals will also record as detailed as possible.
The sample size was based on a statistical power of 80%, an alpha-risk of 5%, the definition of the primary endpoint (a decrease in the global longitudinal, radial, circumferential strain or strain rate of at least 10%). The baseline value was derived from the literature: mean global longitudinal strain before RT = the post-RT value was derived from the literature: mean global longitudinal strain after RT in patients without a history of chemotherapy = −17.5 ± 1.7%, mean global longitudinal strain after RT in patients with a history of chemotherapy = −16.1 ± 1.9% (
Continuous variables will be expressed as means ± standard deviation or median (interquartile range) where appropriate. Categorical variables will be expressed as counts (percentages). Changes regarding early subclinical cardiac damage and biomarkers between the baseline and the follow-up in two groups will be tested with repeated measures analysis of variance. For within-group comparisons, changes in the GLS, GCS, GRS, S', LVEF, and circulating biomarkers between the baseline and the follow-up time points will be analyzed using paired t-test for parametric variables, and Wilcoxon signed-rank test for non-parametric variables. Chi-square test will be used to compare the occurrence and progression of early subclinical cardiac damage and changes in circulating biomarkers between the two groups. Mixed regression models will be used to investigate the correlation between RIHD and age, blood pressure, BMI, smoking status, hypertension, hypercholesterolemia and heart dose. All statistical analyses will be performed using SPSS 24.0 statistical software, and a
This population-based cohort study aims to estimate the value of 2D STE combined with multiple circulating biomarkers in the detection and prediction of early subclinical cardiac damage induced by thoracic radiation therapy in patients with SBRT. Furthermore, we want to find the risk factors of subtle cardiac damage and to determine the prevalence of MACE within 12 months post-RT.
The study has far-reaching clinical significance. Firstly, the subclinical heart damage reduced by radiotherapy can be identified early by combining 2D STE, echocardiography and a variety of circulating biomarkers. Secondly, the risk factors of RIHD were further identified by prospective cohort study, so as to achieve the early identification of high-risk groups before radiotherapy in the future. Moreover, after detection of RIHD, we will further explore the occurrence mechanism of early RIHD, and explore the prevention and treatment measures through randomized controlled trials, in order to achieve early intervention before the occurrence of clinical symptoms, reduce the incidence of RIHD, alleviate a patient's suffering, improve the quality of patients' life and reduce the economic burden on patients and society. Meanwhile, this study will also provide reference clinical research data for the formulation of guidelines and the detection and protection of RIHD.
Meanwhile, there are some limitations to this study. First, the sample size was small,which might represent a beta error. Second, as the follow-up in this study was limited to 12 months, subclinical cardiac changes may not produce during this period. A larger study with a longer duration of follow-up would be required to validate our current observations and to determine its impact on long-term adverse outcomes. Although these hindrances should be acknowledged, we believe the findings from this study will provide important data, which will help focus on “high-risk” patients for longer follow-ups and take up protective measures.
This study will allow evaluating the advantages of 2D STE combined with circulating biomarkers in early detection and prediction of RIHD and validate risk factors and high-risk groups of subclinical cardiac damage, which will be important for proposing primary and secondary preventive measures and improving patient care and quality of life.
To summarize, this study will elucidate concerns and problems related to RIHD and risk foctors.The findings will form a basis for developing early detection method for subclinical cardiac damage and interventions to alleviate RIHD in people who will receive thoracic radiotherapy in the shaort and long term.
Ethical approval has been obtained for the study procedures by the Ethics Committee of Peking University Third Hospital, China (IRB00006761-M2020074). Any protocol amendments will be submitted to the Ethics Committee of Peking University Third Hospital for ethical approval. Written informed consent will be collected from all participants before entering this study.
MC: conceptualization, supervision, and writing—review and editing. HZ and TL: data curation and formal analysis. DZ and TL: writing—original draft. All authors have read and agreed to the published version of the manuscript.
This study is funded by Peking University Third Hospital (BYSYLXHG2020003). The Peking University Third Hospital has no direct role in the design, conduct, or analysis of this study.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
We thank the Department of Cardiology, Peking University Third Hospital for the technical supports. We thank the patients and all the investigators who are participating in this study.