Characterization of Cardiac, Vascular, and Metabolic Changes in Young Childhood Cancer Survivors

Background: Childhood cancer survivors (CCS) are at an increased risk for cardiovascular diseases (CVD). It was the primary aim of this study to determine different measures of cardiac, carotid, lipid, and apolipoprotein status in young adult CCS and in healthy controls.Methods: Cardiac and common carotid artery (CCA) structure and function were measured by ultrasonography. Lipids and apolipoproteins were measured in the blood. Peripheral arterial endothelial vasomotor function was assessed by measuring digital reactive hyperemia index (PAT-RHI) using the Endo-PAT 2000.Results: Fifty-three CCS (20–30 years, 35 men) and 53 sex-matched controls were studied. The CCS cohort was divided by the median dose of anthracyclines into a low anthracycline dose (LAD) group (50–197 mg/m2, n = 26) and a high anthracycline dose (HAD) group (200–486 mg/m2, n = 27). Carotid distensibility index (DI) and endothelial function determined by PAT-RHI were both lower in the CCS groups compared with controls (p < 0.05 and p = 0.02). There was no difference in carotid intima media thickness. Atherogenic apolipoprotein-B (Apo-B) and the ratio between Apo-B and Apoliprotein-A1 (Apo-A1) were higher in the HAD group compared with controls (p < 0.01). Apo-B/Apo-A1-ratio was over reference limit in 29.6% of the HAD group, in 15.4% of LAD group, and in 7.5% of controls (p = 0.03). Measured lipid markers (low density lipoprotein and total cholesterol and triglycerides) were higher in both CCS groups compared with controls (p < 0.05). Systolic and diastolic function were measurably decreased in the HAD group, as evidenced by lower EF (p < 0.001) and lower é-wave (p < 0.005) compared with controls. CCA DI correlated with Apo-B/Apo-A1-ratio and Apo-A1. Follow-up time after treatment correlated with decreased left ventricular ejection fraction (p = 0.001).Conclusion: Young asymptomatic CCS exhibit cardiac, vascular, lipid, and apolipoprotein changes that could account for increased risk for CVD later in life. These findings emphasize the importance of cardiometabolic monitoring even in young CCS.

Development and Validation of a Risk Score Model for Predicting the Cardiovascular Outcomes After Breast Cancer Therapy: The CHEMO‐RADIAT Score

Background Cardiovascular disease is an important cause of mortality among survivors of breast cancer (BC). We developed a prediction model for major adverse cardiovascular events after BC therapy, which is based on conventional and BC treatment‐related cardiovascular risk factors. Methods and Results The cohort of the study consisted of 1256 Asian female patients with BC from 4 medical centers in Korea and was randomized in a 1:1 ratio into the derivation and validation cohorts. The outcome measures comprised cardiovascular mortality, myocardial infarction, congestive heart failure, and transient ischemic attack/stroke. To correct overfitting, a penalized Cox proportional hazards regression was performed with a cross‐validation approach. Number of cardiovascular diseases (myocardial infarction, peripheral artery disease, heart failure, and transient ischemic attack/stroke), number of baseline cardiovascular risk factors (hypertension, age ≥60, body mass index ≥30 kg/m 2 , estimated glomerular filtration rate <60 mL/min per 1.73 m 2 , dyslipidemia, and diabetes mellitus), radiation to the left breast, and anthracycline dose per 100 mg/m 2 were included in the risk prediction model. The time‐dependent C‐indices at 3 and 7 years after BC diagnosis were 0.876 and 0.842, respectively, in the validation cohort. Conclusions A prediction score model, including BC treatment‐related risk factors and conventional risk factors, was developed and validated to predict major adverse cardiovascular events in patients with BC. The CHEMO‐RADIAT (congestive heart failure, hypertension, elderly, myocardial infarction/peripheral artery occlusive disease, obesity, renal failure, abnormal lipid profile, diabetes mellitus, irradiation of the left breast, anthracycline dose, and transient ischemic attack/stroke) score may provide overall cardiovascular risk stratification in survivors of BC and can assist physicians in multidisciplinary decision‐making regarding the BC treatment.

Characterization of subclinical diastolic dysfunction by cardiac magnetic resonance feature-tracking in adult survivors of non-Hodgkin lymphoma treated with anthracyclines

Background The use of anthracycline-based chemotherapy is associated with the development of heart failure, even years after the end of treatment. Early detection of cardiac dysfunction could identify a high-risk subset of survivors who would eventually benefit from early intervention. Cardiac magnetic resonance feature-tracking (CMR-FT) analysis offers a practical and rapid method to calculate systolic and diastolic strains from routinely acquired cine images. While early changes in systolic function have been described, less data are available about late effects of chemotherapy in diastolic parameters by CMR-FT. The main goal of this study was to determine whether left ventricular (LV) early diastolic strain rates (GDSR-E) by CMR-FT are impaired in long-term adult survivors of non-Hodgkin lymphoma (NHL). Our secondary objective was to analyze associations between GDSR-E with cumulative anthracycline dose, systolic function parameters and myocardial tissue characteristics. Methods This is a single center cross-sectional observational study of asymptomatic patients in remission of NHL who previously received anthracycline therapy. All participants underwent their CMR examination on a 3.0-T scanner, including cines, T2 mapping, T1 mapping and late gadolinium enhancement imaging. Derived myocardial extracellular volume fraction was obtained from pre- and post-contrast T1 maps. CMR-FT analysis was performed using Trufi Strain software. The data obtained were compared between anthracycline group and volunteers without cardiovascular disease or neoplasia. Results A total of 18 adult survivors of NHL, 14 (77.8%) males, at mean age of 57.6 (± 14.7) years-old, were studied 88.2 (± 52.1) months after exposure to anthracycline therapy (median 400 mg/m2). Compared with controls, anthracycline group showed impaired LV global early diastolic circumferential strain rate (GCSR-E) [53.5%/s ± 19.3 vs 72.2%/s ± 26.7, p = 0.022], early diastolic longitudinal strain rate (GLSR-E) [40.4%/s ± 13.0 vs 55.9%/s ± 17.8, p = 0.006] and early diastolic radial strain rate (GRSR-E) [− 114.4%/s ± 37.1 vs − 170.5%/s ± 48.0, p < 0.001]. Impaired LV GCSR-E, GLSR-E and GRSR-E correlated with increased anthracycline dose and decreased systolic function. There were no correlations between GDSR-E and myocardial tissue characteristics. Conclusions Left ventricular early diastolic strain rates by CMR-FT are impaired late after anthracycline chemotherapy in adult survivors of non-Hodgkin lymphoma.

Cardiotoxic Effect of Modern Anthracycline Dosing on Left Ventricular Ejection Fraction: A Systematic Review and Meta‐Analysis of Placebo Arms From Randomized Controlled Trials

Background Anthracyclines are a key chemotherapeutic agent used against hematological and solid organ malignancies. However, their benefits in cancer survival are limited by cumulative, dose‐related cardiotoxicity. The impact of anthracyclines on left ventricular ejection fraction (LVEF), in the era of modern chemotherapy regimens, remains unclear. Methods and Results Three databases (CENTRAL, MEDLINE, and SCOPUS) were systematically searched for randomized trials evaluating cardioprotective agents against placebo, in preventing cardiotoxicity. Echocardiography or magnetic resonance measured LVEF pre‐ and post‐anthracycline‐based chemotherapy was abstracted from placebo trial arms. The key terms included “anthracycline,” “cardiotoxicity” and “randomized.” A doxorubicin equivalent anthracycline dose metric was calculated to compare different anthracyclines. A random‐effects model was used to pool mean difference in LVEF after anthracycline. Meta‐regressions were calculated to identify variation sources. We included 660 patients from 19 trials. The weighted mean baseline LVEF across studies was 62.6%, and follow‐up LVEF assessment was performed at 6 months. The pooled mean decline in LVEF among placebo arms was 5.4% (95% CI, 3.5%–7.3%) with a doxorubicin equivalent anthracycline dose of 385 mg/m 2 . Meta‐regression analysis showed no significant difference in LVEF against doxorubicin equivalent anthracycline dose as continuous ( P =0.29) or against published cut‐offs for cardiotoxicity (250 mg/m 2 , P =0.21; 360 mg/m 2 , P =0.40; and 400 mg/m 2 , P =0.66). The differences in mean LVEF were not associated with sex, adjunct chemotherapy, or cancer type. Conclusions The magnitude of LVEF impairment post‐anthracycline therapy appears less than previously described with modern dosing regimens. This may improve the accuracy of power calculation for future clinical trials assessing the role of cardioprotective therapy.

Anthracycline-related acute cardiotoxicity in a very young Omani patient with acute myeloid leukaemia

Anthracycline-related cardiomyopathy is of concern in children treated for acute myeloid leukemia (AML). Risk is dose-dependent, increasing with higher doses. We aim to highlight the risk of early-onset cardiotoxicity with low-cumulative anthracycline dose in a young Omani boy with AML. We conclude in the presence of other known risk factors for cardiac dysfunction, there is probably no risk-free anthracycline dose.

Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients from Southern Sri Lanka: An Echocardiographic Analysis

Anthracycline-induced cardiotoxicity has never been investigated in Sri Lanka. Therefore, this study was conducted to determine the prevalence of anthracycline-induced cardiotoxicity in breast cancer patients using echocardiographic findings. A prospective cohort study was performed. All newly diagnosed breast cancer patients who were administered with anthracycline and cyclophosphamide (AC schedule) for the first time were enrolled in the study. In the hospital setting, anthracycline is administered only as a combination therapy, and only this combination was selected to limit the effect of other cardiotoxic chemotherapy agents. Records of echocardiography were obtained: one day before anthracycline chemotherapy (baseline), one day after the first chemotherapy dose, one day after the last chemotherapy dose, and six months after the completion of anthracycline chemotherapy. Following parameters were recorded from the echocardiography results: ejection fraction (EF, %), fractioning shortening (FS, %), posterior wall thickness, left ventricle (PWT, mm), the thickness of interventricular septum (IVS, mm), left ventricular end-diastolic diameter (LVEDD, mm), and left ventricular end-systolic diameter (LVESD, mm). Statistical analysis of the echocardiography results was performed using ANOVA at four stages. A p value <0.05 was considered significant. Subclinical cardiac dysfunction was defined as a fall of EF >10% during the follow-up echocardiography. There was no significant change ( p > 0.05 ) between the baseline echocardiographic parameters and one day after the 1st anthracycline dose. However, significant differences ( p < 0.05 ) were observed between the baseline echocardiographic parameters and one day after the last anthracycline dose and six months after the completion of anthracycline therapy with a gradual and progressive deterioration in functional parameters including EF, FS, PWT, and IVS over time. There were 65 patients out of 196 (33.16%) who developed subclinical cardiac dysfunction six months after the completion of anthracycline chemotherapy. The prevalence of subclinical anthracycline-induced cardiotoxicity was relatively higher in these patients. An equation was also developed based on left ventricular ejection fraction (LVEF) to predict the anthracycline-induced cardiotoxicity of a patient six months after the completion of anthracycline chemotherapy. We believe that this will help in the monitoring of patients who undergo anthracycline therapy for cardiotoxicity. It is recommended to carry out a long-term follow-up to detect early-onset chronic progressive cardiotoxicity in all patients who were treated with anthracycline therapy.

Biomarkers for detection of anthracycline-induced cardiomyopathy in childhood cancer survivors: a case-control study in the Dutch LATER cohort study

Introduction Plasma biomarkers may aid in the surveillance for anthracycline-induced cardiomyopathy (ACM) in long-term childhood cancer survivors and provide insight into the pathophysiological mechanisms involved. In this pilot study, we aimed to identify new plasma markers associated with ACM. Methods A case-control study within the Dutch Late Effects After Childhood Cancer Cohort study (Dutch LATER) was conducted. We compared 184 plasma markers (Olink) between ACM cases (LVEF&lt;45%) and anthracycline treated controls (LVEF≥53%), matched on sex, time since cancer diagnosis and anthracycline dose. Associations of plasma markers with ACM were assessed with conditional logistic regression. Pathway analysis was performed with STRING (string-db.org). Significant markers were evaluated in multivariable models next to anthracyclines dose, sex and time after cancer. Results In total, 28 ACM cases (median anthracycline dose 351 mg/m2; median age at study 38 years, 29% chest radiotherapy) and 29 controls (median anthracycline dose 300 mg/m2; median age at study 44 years, 7% chest radiotherapy) were included. Eight markers were significantly associated with ACM (Table 1) and were implicated in ventricular wall stress, apoptosis, inflammation and endothelial dysfunction (Figure 1). The AUC of the model including only the clinical variables was 0.73 (95% confidence interval (CI) 0.60–0.86), and improved to 0.82 (95% CI 0.71–0.94) with the addition of NT-proBNP and further to 0.86 (95% CI 0.76–0.97) with the addition of all 8 markers. Conclusion In this biomarker discovery study, 8 markers related to ventricular wall stress, apoptosis, inflammation and endothelial dysfunction were associated with ACM. We intend to validate these markers quantitatively in the Dutch LATER cohort study. Figure 1. Pathway analysis of significant markers Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Heart Foundation Grant; Amsterdam University Funding

Long-term echocardiographic assessment of descendants of gestational breast cancer patients exposed to anthracycline-based chemotherapy

Background Breast cancer is the most common cancer in women and the leading cause of cancer death in women. Although gestational breast cancer (GBC) accounts only for a small amount of diagnosis, the incidence is increasing due to delayed childbearing. Treating GBC is a significant challenge, having to maintain a balance between effective treatment for the patient and safety for the descendants. Anthracycline-based chemotherapy (AC) remains to be the systemic treatment of choice in many GBC patients. Although AC in GBC appears to be safe for the descendants, data on the long-term cardiotoxic effects of AC are scarce. Purpose To evaluate long-term cardiotoxicity on descendants of GBC patients exposed to AC during pregnancy or breastfeeding. Methods We retrospectively recruited descendants of GBC patients and classified them according to AC exposure (case group and non-exposed control group). We performed a thorough echocardiographic assessment. Results We identified 7 GBC patients that received AC during pregnancy (n=6) or breastfeeding (n=1). All of them were diagnosed during the second or third trimester. Median cumulative anthracycline dose was 508mg/m2. A total of 8 cases and 5 controls were recruited. Median age at echocardiographic assessment was 10 years in cases and 8 years in controls. None of them had known prior cardiac disease. Echocardiographic parameters were within normal values in both groups (Table 1). Conclusion A long-term echocardiographic assessment showed no abnormalities in a series of descendants of GBC exposed to AC during pregnancy or breastfeeding. This study may contribute to a better understanding of the safety for the descendants of AC during pregnancy or breastfeeding. Funding Acknowledgement Type of funding source: None