Left ventricular function and its longitudinal change in Swiss childhood cancer survivors – Results from the CardioOnco Study

Left ventricular function and its longitudinal change in Swiss childhood cancer survivors – Results from the CardioOnco Study | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Left ventricular function and its longitudinal change in Swiss childhood cancer survivors – Results from the CardioOnco Study View ORCID Profile Severin Fankhauser , View ORCID Profile Yara Shoman , View ORCID Profile Fabiën N Belle , View ORCID Profile Eva Hägler-Laube , View ORCID Profile Moritz J Hundertmark , View ORCID Profile Gabriela M Kuster , View ORCID Profile Eva Scheler , View ORCID Profile Tomáš Sláma , View ORCID Profile Nicolas von der Weid , View ORCID Profile Claudia E Kuehni , View ORCID Profile Reto D Kurmann , View ORCID Profile Christina Schindera doi: https://doi.org/10.1101/2025.11.20.25340636 Severin Fankhauser 1 Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern , Bern, Switzerland 2 Graduate School for Health Sciences, University of Bern , Bern, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Severin Fankhauser For correspondence: severin.fankhauser{at}unibe.ch Yara Shoman 1 Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern , Bern, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Yara Shoman Fabiën N Belle 1 Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern , Bern, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Fabiën N Belle Eva Hägler-Laube 3 Division of Cardiology, Hospital Baden , Baden, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Eva Hägler-Laube Moritz J Hundertmark 4 Division of Cardiology , Inselspital, University Hospital of Bern , Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Moritz J Hundertmark Gabriela M Kuster 5 Division of Cardiology, University Hospital Basel , Basel, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Gabriela M Kuster Eva Scheler 6 Division of Cardiology, Department of Internal Medicine, Hospital of St. Gallen , St. Gallen, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Eva Scheler Tomáš Sláma 1 Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern , Bern, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tomáš Sláma Nicolas von der Weid 9 Division of Pediatric Oncology/Hematology, University Children’s Hospital Basel, University of Basel , Basel, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nicolas von der Weid Claudia E Kuehni 1 Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern , Bern, Switzerland 7 Pediatric Oncology, Inselspital, Bern University Hospital, University of Bern , Bern, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Claudia E Kuehni Reto D Kurmann 8 Division of Cardiology, Heart Center , Luzerner Kantonsspital, Lucerne, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Reto D Kurmann Christina Schindera 1 Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern , Bern, Switzerland 9 Division of Pediatric Oncology/Hematology, University Children’s Hospital Basel, University of Basel , Basel, Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christina Schindera Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background/Purpose Childhood cancer survivors (CCS) are at risk for cardiac late effects. Echocardiographic assessment of cardiac function by left ventricular ejection fraction (LVEF) is recommended for survivors treated with known cardiotoxic treatments (anthracyclines; heart-relevant radiotherapy). The evidence on cardiotoxicity of other systemic anticancer therapies is conflicting and longitudinal changes in heart function are understudied. We assessed cardiac function in CCS; factors associated with LVEF and longitudinal changes in LVEF. Methods In this prospective, multicenter cohort study, we invited CCS aged ≥18 years, diagnosed <21 years, survived ≥5 years, and received any systemic anticancer therapy or heart-relevant radiotherapy between 1976–2019. We invited them for an echocardiographic assessment including 2-dimensional LVEF (reduced LVEF: <54% for females; <52% for males). We stratified CCS in anthracyclines only, heart-relevant radiotherapy only, both, and a standard risk group exposed to any other systemic anticancer treatment and compared groups using ANOVA- and t-tests. We performed multivariable linear regression to investigate sociodemographic, treatment-, and lifestyle-related factors (hypertension, smoking, dyslipidemia, diabetes, overweight/obesity), and multilevel modelling to assess LVEF changes over time. Results We assessed 487 CCS (median age: 32 years, IQR: 24–39) with a median time since diagnosis of 24 years (IQR 17‒31). Overall prevalence of reduced LVEF was 7.2% (35/487), 7.3% (19/260) for anthracyclines only, 3.6% (1/28) for heart-relevant radiotherapy only, 9.4% (8/85) for both, and 6.1% (7/114) for the standard risk group. Male CCS were at risk for reduced LVEF [β coefficient for male sex = −1.37; 95%CI −2.36, −0.37], and higher cumulative anthracycline dose (per 100 mg/m²) was associated with reduced LVEF (β −0.83; 95%CI −1.20, −0.45). Heart-relevant radiotherapy, other systemic anticancer treatments, and lifestyle were not associated with LVEF. We found a slight annual improvement of LVEF 0.24% among 140 participants followed up for a median of 4.3 years, however, there was no indication of statistical significance (p=0.12). Conclusion This first nationwide study found that a substantial proportion of survivors had reduced LVEF, especially males and those treated with anthracyclines. While cardiac function appeared stable over a four-year period, long-term changes remain uncertain, emphasizing the importance of ongoing cardiac surveillance in this vulnerable population. Introduction Childhood cancer survival has improved significantly over recent decades; it now exceeds 85% in Switzerland 1 . The growing population of childhood cancer survivors (CCS) is at increased risk of long-term morbidity and mortality, with cardiovascular disease representing the leading nonmalignant cause of death 2 . CCS treated with high cumulative doses of anthracyclines or heart-relevant radiotherapy are at the highest risk of developing heart failure 3 . Other cardiovascular risk factors further potentiate their cardiovascular morbidity 4 . For this group of survivors, the International Guideline Harmonization Group (IGHG) recommends regular surveillance of left ventricular ejection fraction (LVEF) by echocardiography 3 . Yet cardiac abnormalities have been reported even in CCS who did not receive anthracyclines or heart-relevant radiation 5 . In comparison with siblings, a two- to three-fold increased risk of cardiac dysfunction has been observed in survivors without exposure to these known cardiotoxic treatments 6 . These findings suggest that other systemic anticancer treatments such as alkylating agents, vincristine, cisplatin, corticosteroids, and hematopoietic stem cell transplantation (HSCT) also contribute to long-term cardiotoxicity. Understanding the late effects of these treatments is essential for improving individual risk prediction and tailoring surveillance strategies. Despite established recommendations, the optimal surveillance strategy for cardiomyopathy in CCS remains uncertain. Most research assessing LVEF in CCS has been based on cross-sectional study designs typically assessing participants only once, many years after treatment 7 . While these studies provide evidence on the prevalence of reduced LVEF, they cannot capture the progression of cardiac dysfunction over time. Whether and how cardiac dysfunction evolves after childhood cancer treatment remains unclear. Moreover, current IGHG recommendations are largely based on data from North America and the Netherlands, which may not be applicable to Swiss CCS due to differences in treatment protocols and lifestyle 6 , 8 – 10 . To address these evidence gaps, we conducted the first longitudinal echocardiography study of adult CCS in Switzerland to 1) assess the prevalence of reduced LVEF and its associated factors including known cardiotoxic and other systemic anticancer treatments, and 2) investigate longitudinal changes of LVEF to better characterize its dynamics after childhood cancer treatment. Methods Study design and participants The CardioOnco study is an ongoing, multicenter longitudinal cohort study assessing cardiovascular health in adult CCS across Switzerland who are registered in the Swiss Childhood Cancer Registry 11 , 12 . Since 1976, the ChCR has included all persons diagnosed with cancer in Switzerland before the age of 20, with cases classified according to the International Classification of Childhood Cancer, Third Edition (ICCC-3) 13 , 14 . The study was launched as a single-center study in 2016 and expanded into a multicenter study, now involving five participating centers. Inclusion criteria are age ≥18 years; treatment in one of the study centers with any chemotherapy, and/or heart-relevant radiotherapy; survival at least five years since diagnosis; registered in the ChCR; and residence in Switzerland 11 , 12 . The exclusion criterion is treatment with only surgery and/or radiotherapy not involving the heart (these survivors are considered at low risk for treatment-related cardiac dysfunction). Study teams at each center identified eligible CCS and sent postal invitations to attend a cardio-oncology outpatient clinic for baseline assessment that included transthoracic echocardiography (TTE) evaluation, physical examination, and taking medical history. Participants exposed to anthracyclines and/or heart-relevant radiotherapy were scheduled for follow-up visits every 2 to 5 years depending on their cumulative doses 3 . Participants not exposed to anthracyclines or heart-relevant radiotherapy but treated with any other systemic anticancer treatments were followed longitudinally if clinically indicated. We collected written informed consent from all participants. The study was conducted in accordance with the Declaration of Helsinki and received ethical approval from the Ethics Committee of the Canton of Bern (KEK-BE: 2017-01612). Detailed information regarding the study design was published previously 15 . This study has the ClinicalTrials.gov identifier NCT03790943 . Explanatory variables Sociodemographics We received information about sex, age, and primary treatment institution from the ChCR. During the visit, we asked patients about their living situation, marital status, and profession. We coded those with a current occupation into the European Socioeconomic Classification (ESeC). We categorized occupational position as low (lower clerical, services and sales workers, skilled workers, and semi-skilled and unskilled workers [ESeC class 7, 8, and 9]), intermediate (small employers and self-employed, farmers, lower supervisors, and technicians [ESeC class 4, 5, and 6]), or high (higher professionals and managers, higher clerical, services, and sales workers [ESeC class 1, 2, and 3]) 16 . Cardiovascular risk factors We asked patients during the visit about cardiovascular risk factors including diabetes mellitus, hypertension, dyslipidemia, and smoking status. We measured blood pressure three times in a sitting position with a break of one minute in between measurements and took the average of the last two readings 17 . We defined hypertension if the mean systolic blood pressure was ≥140 mmHg, the diastolic blood pressure was ≥90 mmHg, or if the patient took prescribed antihypertensive medication 17 . We further measured height and weight to obtain survivor body mass index (BMI), and measured waist-hip-ratio 15 . BMI was calculated as weight in kilograms divided by height in meters squared and classified according to WHO criteria: underweight (<18.5 kg/m²), normal weight (18.5–24.9 kg/m²), overweight (25–29.9 kg/m²), and obese (≥30 kg/m²) 18 . Waist-hip ratio was categorized as nonobese (male <0.9, female <0.85) or obese (male ≥0.9, female ≥0.85) based on established sex-specific thresholds 19 . Cancer history and treatment The ChCR provided clinical information about cancer diagnosis, date of diagnosis, and relapse history. We collected data from the ChCr and from medical records on cancer treatments and doses of anthracyclines, alkylating agents, cisplatin, vincristine, steroids, heart-relevant radiotherapy, and conditioning regimens of HSCT. To quantify anthracycline exposure, we converted doses of daunorubicin, idarubicin, epirubicin, and mitoxantrone into doxorubicin isotoxic equivalents following the latest IGHG recommendations 20 , 21 . We defined heart-relevant radiotherapy as any radiotherapy targeting the chest, abdomen, thoracic or whole spine, and collected the highest reported dose in Grays (Gy) to any of these fields. If total body irradiation (TBI) was additionally administered, we added the respective dose to the highest field dose. We calculated cyclophosphamide equivalent doses based on the total amounts of cyclophosphamide and ifosfamide following COG recommendations 21 . We determined prednisone equivalent doses based on the total amount of prednisone and dexamethasone using a previously published conversion method 22 . Risk groups were defined based on exposure to anthracyclines (including mitoxantrone), heart-relevant radiotherapy, both anthracyclines and heart-relevant radiotherapy, and a standard risk group exposed to any other systemic anticancer treatment including alkylating agents, vincristine, cisplatin, corticosteroids, and HSCT. Outcome measures All echocardiograms were conducted by experienced cardiologists affiliated with the cardiology departments of the participating centers using GE Vivid E9, E90 or E95 (GE Vingmed Ultrasound, Horten, Norway) and Philips EPIQ 7 ultrasound scanners (Philips Ultrasound, Inc., Bothell, Washington, USA). All cardiologists followed standardized imaging protocols to ensure consistency across sites and were blinded with respect to participants cancer treatment whenever possible 23 . To assess LVEF, we used the two-dimensional Simpson’s biplane method 23 , 24 . We defined reduced LVEF with sex-specific cut-off values following international recommendations (men < 52%; women: <54%) 23 . For patients with an LVEF below 50%, we reviewed medical records and extracted information on potential interventions aimed at improving LVEF including prescribed medications and lifestyle modifications. Statistical analysis We summarized continuous variables using the mean (standard deviation) or median (interquartile range), and categorical variables were presented as number (percentages). We reported the prevalence of reduced LVEF for all risk groups. We compared groups using t-tests and analysis of variance (ANOVA), and used univariable and multivariable linear regression models to identify associations between explanatory variables and reduced LVEF. In the multivariable models, we used the a priori factors sex, age, and cumulative doses of radiotherapy and anthracyclines, which have been associated with cardiac dysfunction in CCS 3 . We also chose additional factors that include cancer diagnosis, treatment with cyclophosphamide, vincristine, cisplatin, steroids, and HSCT, and clinical risk factors such as diabetes, dyslipidemia, hypertension, smoking, and waist-hip ratio. These additional factors were included in the multivariable model if they had a p-value < 0.2 in univariable analysis. We also conducted multilevel linear regression modeling to assess changes in LVEF over time (details of the model are provided in Supplementary Materials). To assess potential selection bias, we compared characteristics of our study participants with those of nonparticipants, which in both cases we obtained from the ChCR. This modeling approach allowed us to capture both the average change of LVEF over time and subject-specific deviations from this change. We performed all analyses using R Statistical Software (V-4.5.0.; R Core Team 2024). Results Characteristics of Study Population Between November 2017 and December 2024, we invited 1297 eligible CCS and measured LVEF in 487 (38%) (Supp Figure 1 ). Median age at study was 32 years (IQR 24–39 years) with a median time since diagnosis of 24 years (IQR 17–31 years) ( Tables I and II ). The most frequent cancer diagnoses were leukemias (44%), followed by lymphomas (21%), malignant bone tumors (7%), and renal tumors (7%). Among all participants, 64% had received anthracyclines with a median cumulative dose of 154mg/m2 (standard deviation [SD] 145mg/m2), 23% had received heart-relevant radiotherapy with a median cumulative dose of 26 Gy (SD 13Gy), 7% received autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and 23% had none of these. Download figure Open in new tab Figure 1: Distribution of left ventricular ejection fraction among CardioOnco Study participants stratified by risk group Note: Each point represents an individual childhood cancer survivor (CSS). Red points indicate the group mean LVEF, with error bars representing the 95% confidence intervals . Abbreviations: LVEF, left ventricular ejection fraction; AC, anthracyclines; RT, radiotherapy; CCS, childhood cancer survivor a Survivors exposed to anthracyclines and heart-relevant radiotherapy. View this table: View inline View popup Table I: Socio-demographic and cardiovascular risk factors of CardioOnco study participants View this table: View inline View popup Table II: Cancer history and treatment of CardioOnco study participants Cardiovascular risk factors were common: 30% were former or current smokers, 17% had hypertension, and 6% had dyslipidemia. A diagnosis of type 1 or type 2 diabetes mellitus was reported in 2% of participants. Median BMI was 23.9 kg/m², and 39% of participants were classified as overweight or obese. To assess potential selection bias, we compared study participants with nonparticipants (those invited but who did not participate). Both groups were largely comparable in terms of age, sex, diagnosis, and treatment characteristics, with statistically significant differences observed only in the proportion of survivors who received chemotherapy and in the distribution of germ cell and other tumors (Supplementary Table I). Echocardiographic characteristics The mean LVEF across all participants was 59.5% (SD 5.7%) ( Figure 1 & Supp. Table II). When stratified by risk groups, patients treated with anthracycline only exhibited the lowest mean LVEF (58.8±5.6%), while the highest mean LVEF was observed among survivors in the standard risk group (61.2±5.1%). When we compared individual risk groups against the standard risk group, the survivors treated with anthracyclines only (58.8±5.6%, p<0.01) and those treated with a combination of anthracyclines and heart-relevant radiotherapy (58.8±5.9%, p<0.01) had lower mean LVEF. Prevalence of reduced LVEF Among all participants, 7.2% had a reduced LVEF (Supp Table II ). Reduced LVEF was most common in survivors treated with both anthracyclines and heart-relevant radiotherapy (9.4%), and least common in survivors treated with heart-relevant radiotherapy alone (3.6%) ( Figure 2 ). Among survivors in the standard risk group, most reduced LVEF values were clustered near the lower limit of normal. The prevalence of reduced LVEF did not differ significantly between risk groups (ANOVA, p=0.68). Download figure Open in new tab Figure 2: Prevalence of abnormal left ventricular ejection fraction among CardioOnco study participants stratified by risk group Note : Bars represent the proportion of survivors with abnormal LVEF in each group; error bars indicate 95% confidence intervals . Abbreviations: LVEF, left ventricular ejection fraction; AC anthracyclines; RT radiotherapy; CCS, childhood cancer survivors a Survivors exposed to anthracyclines and heart-relevant radiotherapy. Factors associated with LVEF Survivors treated with anthracyclines and male survivors were at risk for lower LVEF (unstandardized coefficient (β) for cumulative dose of anthracyclines = −0.83; 95% CI −1.20.– −0.45; per 100mg/m 2 ; β for male sex= −1.37; 95%CI −2.36, −0.37) ( Table III ). Survivors treated with heart-relevant radiotherapy, other systemic anticancer treatments, and the presence of cardiovascular risk factors were not associated with LVEF. View this table: View inline View popup Download powerpoint Table III: Factors associated with left ventricular ejection fraction among CardioOnco participants using multivariable linear regression (n=480) Longitudinal assessment of LVEF using multilevel modelling Among 140 patients followed longitudinally, 133 (95%) received anthracyclines, heart-relevant radiotherapy or both (Supp. Table III). Overall, we observed an average annual increase of LVEF 0.24%, with no indication of statistical significance (p=0.12) ( Figure 3 ). We found no evidence of a meaningful change in LVEF over time and no significant differences between individual patients were detected. Download figure Open in new tab Figure 3: Longitudinal assessment of left ventricular ejection fraction among CardioOnco study participants (n=140) Note : In total, 140 participants were assessed longitudinally with a median follow-up time of 4.3 years. The mean LVEF at baseline assessment was 59.2% and improved by 0.24% LVEF per year, although not statistically significant (p=0.12). Abbreviations: LVEF, left ventricular ejection fraction; n, number; Among 15 patients with LVEF below 50%, we observed potential interventions that may have improved LVEF during follow-up. Cardiologists started heart failure medication in CCS with LVEF <40%, addressed modifiable cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia, and provided lifestyle counselling including engagement in physical activity, weight reduction, and smoking cessation when appropriate. Discussion Summary of findings This nationwide, longitudinal cohort study assessing cardiac function among adult CCS in Switzerland found that 7.2% of survivors showed signs of cardiac dysfunction assessed as reduced LVEF, especially male survivors and those treated with higher cumulative anthracycline doses. We found no evidence of a change in LVEF over time. Prevalence of reduced LVEF In population-based cohorts of healthy adults, reduced LVEF has been reported in 1.7–3.6%, according to LVEF cut-offs of <50% and <55% respectively 25 . These prevalences are derived from older populations (mean age ∼ 61 years), underscoring the importance of the 7.2% observed in our young CCS cohort 25 . This prevalence is comparable to the 5.8% reported in the largest CCS study to date, the St. Jude Lifetime Cohort (n = 1820) 8 . However, reported prevalences in the literature vary substantially, ranging from 0.8% to 24.2% across seven studies published since 2012 6 , 8 , 9 , 26 – 29 . These differences may in part reflect different intervals between cancer diagnosis and outcome assessment. The study reporting the lowest prevalence (0.8%) had the shortest follow-up period (9 years), while the highest prevalence (24.2%) was reported by the study with the longest time since diagnosis (27 years) 6 , 9 . These observations suggest that cardiotoxic effects may become more apparent with longer follow-up, which emphasizes the importance of extended cardiac surveillance in this population. Another factor contributing to the variability is the use of different cut-off values for defining reduced LVEF. Although sex-specific thresholds (<54% for females, <52% for males) were introduced by ASE/EACVI in 2016, not all studies have adopted them, with earlier research often using general cut-offs between 50% and 55% 8 , 9 , 26 – 30 . To improve comparability, future studies should consistently apply these standardized criteria. Factors associated with reduced LVEF CCS treated with higher cumulative anthracycline dose had higher risk for reduced LVEF, which is consistent with evidence from the St. Jude Lifetime Cohort study and the Dutch LATER study, the only two studies that used regression analysis to assess factors associated with LVEF 6 , 8 . Anthracyclines induce myocyte apoptosis through complex formation with topoisomerase-IIβ and DNA, providing a mechanistic explanation for their cardiotoxic effect 31 . The IGHG and European Society of Cardiology guidelines acknowledge the crucial role of anthracyclines in cardiac dysfunction and recommend more frequent surveillance for CCS exposed to high cumulative doses 3 , 32 . Although the IGHG also recommends screening for CCS exposed to heart-relevant radiotherapy, we found no association with reduced LVEF. Both the St. Jude and Dutch studies reported stronger associations between survivors treated with chest-directed radiotherapy and abnormal global longitudinal strain (GLS) than with LVEF 6 , 8 , suggesting GLS may be more sensitive in detecting radiotherapy-induced cardiotoxicity. Another explanation for our findings may lie in how we defined radiotherapy exposure. We used the highest reported dose to heart-relevant fields, whereas the St. Jude and Dutch study applied organ-specific dose reconstruction – a method that accounts for radiation orientation, field size, and patient anatomy, which is crucial since the proximity of radiation field to relevant organs can vary substantially with body size 6 , 8 , 21 , 33 . Our approach likely introduced uncertainty in cardiac dose estimation, possibly contributing to the low prevalence of reduced LVEF (3.6%) in the radiotherapy group. Furthermore, we found no association between CCS exposed to other systemic anticancer treatments and LVEF. Evidence regarding cardiac effects of these treatments is conflicting. Subtle cardiac changes that included increased left ventricular mass and wall thickness were observed in 201 CCS survivors not exposed to treatments known to be cardiotoxic compared to siblings⁵. The clinical relevance of these cardiac changes remains questionable because most studies have not shown an association between CCS exposed to these treatments and heart failure 34 , 35 . Further research is needed to determine whether these subtle changes represent silent residuals or may progress to clinically manifest disease. We identified male CCS as being at higher risk for reduced LVEF. This is surprising since female CCS have been linked to heart failure 34 . The St. Jude study also found increased risk in males, while the Dutch study reported female sex as a risk factor 6 , 8 . This inconsistency may reflect differences in LVEF definitions: both studies conducted nonlinear regression models with reduced LVEF defined as <50% by the St. Jude study and a sex-specific cut-off by the Dutch study (<52% for males, <54% for females) 6 , 8 . The sex-specific cut-off is recommended by the ASE/EACVI and reflects normal physiological differences, with females having slightly higher LVEF values than males 30 . Since we used LVEF as a continuous outcome in a linear model, our finding may reflect these physiological sex differences and should be interpreted with caution. We did not identify an association between survivors with modifiable cardiovascular risk factors and reduced LVEF. Similarly, both the St. Jude and Dutch study found no association with reduced LVEF, with the exception of hypertension, which was associated with lower LVEF in the St. Jude study 6 , 8 . However, both studies reported stronger and more consistent associations between modifiable risk factors and abnormal GLS. Because the median age in these cohorts is ∼30 years, the impact of modifiable cardiovascular risk factors may emerge later in life, and GLS, as a more sensitive marker, may already detect subtle dysfunction not yet evident in LVEF. Further studies with longer follow-up are needed to clarify the long-term impact of modifiable risk factors. Longitudinal assessment We observed no changes in LVEF over time. Although there was a slight annual increase in LVEF, it was not statistically significant. While regression to the mean cannot be entirely excluded, it is unlikely to have influenced the findings on this study. Cardiotoxicity is known to progress slowly, and the median follow-up duration of 4.3 years in our cohort may have been too short to detect a decline in LVEF. Interventions prescribed by cardiologists are more likely to show effects within this timeframe and may have contributed to the observed increase in LVEF in some patients during longitudinal follow-up 36 . Longitudinal data on LVEF after childhood cancer remain limited since most studies are cross-sectional. Studies with repeated measurements often focus on prediction modeling rather than assessing changes over time 37 , 38 . One exception is a US study, which examined longitudinal cardiac changes in a young cohort with a median age of 4.8 years at treatment initiation, which was followed for a median of 11.8 years 39 . The study did not assess LVEF but focused on LV dimensions and contractility, reporting progressive cardiac abnormalities over time 39 . Whether comparable clinical interventions were implemented is unclear and comparability with our findings is limited. Longer follow-up is needed to better understand LVEF changes over time, and the impact of cardiac surveillance and interventions. Strengths & limitations Our nationwide, population-based cohort represents a broad sample of CCS in Switzerland, which overcomes limitations of previous single-center studies and those restricted to specific cancer types or treatments 9 , 28 , 29 . We used medical data from the ChCR, allowing for detailed and accurate characterization of cancer diagnoses and treatments. The longitudinal design provides insight into temporal changes in LVEF, an area with limited existing evidence. Nevertheless, as with any long-term follow-up study, survival bias may have distorted our results. CCS who experienced severe early cardiotoxicity leading to cardiac death before study inclusion are not represented in our cohort. However, since heart failure in CCS increases linearly over time, it is unlikely that we missed a substantial number of early cases. Selection bias may also be present, although comparison of participants and nonparticipants using ChCR data showed them to be largely comparable. While most participants (133/140) were followed in accordance with IGHG recommendations, a subset of individuals from the standard risk group (7/140) were monitored based on clinical indication. These individuals may represent a less healthy subgroup, introducing potential selection bias. Furthermore, the lack of a healthy control group limits comparisons to the general population. Due to the observational design, causal inferences between identified factors and reduced LVEF cannot be made. Finally, echocardiographic images were not independently reviewed. Nonetheless, all measurements were obtained using standardized protocols and comparable ultrasound equipment ensure consistency in image acquisition and interpretation. Conclusion At a median of 32 years after the end of treatment a substantial proportion of CCS who received known cardiotoxic treatments had reduced cardiac function. Male survivors and those exposed to higher cumulative anthracycline doses were at higher risk for reduced LVEF, while neither other systemic anticancer therapies nor modifiable cardiovascular risk factors were associated. Cardiac function remained stable over a four-year time period but longer follow-up is needed to determine long-term trajectories to inform optimal surveillance strategies. Conflict of interest statement CS reports a relationship to Swedish Orphan Biovitrum AB that includes travel reimbursement. This relationship has no association with the current study. Funding We received funding for our study from the Swiss Cancer Research foundation (KFS-5027-02-2020; Bern, Switzerland), Stiftung fuer krebskranke Kinder - Regio Basiliensis (Basel, Switzerland), University of Basel Research Fund for Excellent Junior Researchers (Basel, Switzerland), and Kinderkrebs Schweiz (Basel, Switzerland). Data availability statement The datasets analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval statement Ethical approval was granted by the Ethics Committee of Canton Bern (KEK-BE: 2017-01612). Acknowledgement We thank all survivors for participating in our study, the study team of the Childhood Cancer Research Group and the team of the Swiss Childhood Cancer Registry. Footnotes ↵ * shared first authors ↵ + shared last authors References 1. ↵ Schindler M , Belle FN , Grotzer MA , von der Weid NX , Kuehni CE . Childhood cancer survival in Switzerland (1976–2013): Time-trends and predictors . Int J Cancer 2017 ; 140 ( 1 ): 62 – 74 . OpenUrl CrossRef PubMed 2. ↵ Schindler M , Spycher BD , Ammann RA , Ansari M , Michel G , Kuehni CE . Cause-specific long-term mortality in survivors of childhood cancer in Switzerland: A population-based study . Int J Cancer 2016 ; 139 ( 2 ): 322 – 33 . OpenUrl CrossRef PubMed 3. ↵ Ehrhardt MJ , Leerink JM , Mulder RL , et al. Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group . Lancet Oncol . 2023 ; 24 ( 3 ): e108 – 20 . OpenUrl CrossRef PubMed 4. ↵ Armstrong GT , Oeffinger KC , Chen Y , et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer . Journal of Clinical Oncology 2013 ; 31 ( 29 ): 3673 – 80 . OpenUrl Abstract / FREE Full Text 5. ↵ Lipshultz SE , Landy DC , Lopez-Mitnik G , et al. Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy . Journal of Clinical Oncology 2012 ; 30 ( 10 ): 1050 – 7 . OpenUrl Abstract / FREE Full Text 6. ↵ Merkx R , Leerink JM , Feijen E (Lieke) AM , et al. Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study . JACC CardioOncol 2023 ; 5 ( 4 ): 472 – 85 . OpenUrl PubMed 7. ↵ Merkx R , Leerink JM , De Baat EC , et al. Asymptomatic systolic dysfunction on contemporary echocardiography in anthracycline-treated long-term childhood cancer survivors: a systematic review . Journal of Cancer Survivorship [Internet] Available from : doi: 10.1007/s11764-021-01028-4 OpenUrl CrossRef 8. ↵ Armstrong GT , Joshi VM , Ness KK , et al. Comprehensive Echocardiographic Detection of Treatment-Related Cardiac Dysfunction in Adult Survivors of Childhood Cancer Results From the St . Jude Lifetime Cohort Study. JACC: Cardiology 2015 ; 9. ↵ Slieker MG , Fackoury C , Slorach C , et al. Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer . Circ Cardiovasc Imaging 2019 ; 12 ( 12 ). 10. ↵ Belle FN , Schindera C , Ansari M , et al. Risk factors for overweight and obesity after childhood acute lymphoblastic leukemia in North America and Switzerland: A comparison of two cohort studies . Cancer Med 2023 ; 12 ( 20 ): 20423 – 36 . OpenUrl PubMed 11. ↵ The Swiss Childhood Cancer Registry website, www.childhoodcancerregistry.ch , accessed 20 November 2025 . 12. ↵ The CardioOnco study website, www.cardiosurvivor.ch , accessed 20 November 2025 . 13. ↵ Steliarova-Foucher E , Stiller C , Lacour B , Kaatsch P . International classification of childhood cancer, third edition . Cancer 2005 ; 103 ( 7 ): 1457 – 67 . OpenUrl CrossRef PubMed Web of Science 14. ↵ Ly WK , Michel G , Von Der Weid NX , et al. The Swiss Childhood Cancer Registry: rationale, organisation and results for the years 2001-2005 1 [Internet] . Available from: www.asrt.ch 15. ↵ Schindera C , Kuehni CE , Pavlovic M , et al. Diagnosing preclinical cardiac dysfunction in Swiss childhood cancer survivors: Protocol for a single-center cohort study . JMIR Res Protoc 2020 ; 9 ( 6 ). 16. ↵ Harrison E , Rose D . ESeC Colchester , UK : Institute for Social and Economic Research, University of Essex ; 2006 [Available from: https://www.iser.essex.ac.uk/archives/esec/user-guide . 17. ↵ Williams B , Mancia G , Spiering W , et al. 2018 ESC/ESH Guidelines for themanagement of arterial hypertension . Eur Heart J . 2018 ; 39 ( 33 ): 3021 – 104 . OpenUrl CrossRef PubMed 18. ↵ Obesity: preventing and managing the global epidemic . Report of a WHO consultation . World Health Organ Tech Rep Ser . 2000 ; 894 : i-xii , 1-253. OpenUrl PubMed 19. ↵ Organization WH . Waist circumference and waist-hip ratio: report of a WHO expert consultation , Geneva , 8 – 11 December 2008 . 20. ↵ Kouwenberg TW , van Dalen EC , Mulder RL , et al. IGHG Recommendations for Anthracycline and Anthraquinone Cardiac Dysfunction Equivalence Ratios After Childhood Cancer: JACC: CardioOncology Expert Panel . JACC CardioOncol . 2025 ; 21. ↵ Children’s Oncology Group . Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers, Version 6.0. Monrovia, CA: Children’s Oncology Group ; October 2023 ; Available on-line: www.survivorshipguidelines.org . 22. ↵ Inaba H , Pui CH . Glucocorticoid use in acute lymphoblastic leukaemia . Lancet Oncol . 2010 ; 11 ( 11 ): 1096 – 106 . OpenUrl CrossRef PubMed Web of Science 23. ↵ 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 . Eur Heart J Cardiovasc Imaging 2015 ; 16 ( 3 ): 233 – 71 . OpenUrl CrossRef PubMed 24. ↵ Mitchell C , Rahko PS , Blauwet LA , et al. Guidelines for Performing a Comprehensive Transthoracic Echocardiographic Examination in Adults: Recommendations from the American Society of Echocardiography . Journal of the American Society of Echocardiography 2019 ; 32 ( 1 ): 1 – 64 . OpenUrl CrossRef PubMed 25. ↵ Yeboah J , Rodriguez CJ , Qureshi W , et al. Prognosis of Low Normal Left Ventricular Ejection Fraction in an Asymptomatic Population-Based Adult Cohort: The Multiethnic Study of Atherosclerosis . J Card Fail 2016 ; 22 ( 10 ): 763 – 8 . OpenUrl PubMed 26. ↵ Armenian SH , Rinderknecht D , Au K , et al. Accuracy of a novel handheld wireless platform for detection of cardiac dysfunction in anthracycline-exposed survivors of childhood cancer . Clinical Cancer Research 2018 ; 24 ( 13 ): 3119 – 25 . OpenUrl Abstract / FREE Full Text 27. Ichikawa N , Hasegawa D , Nagase K , et al. Echocardiographic parameters and risk factors for cardiomyopathy in Japanese childhood cancer survivors: a report from St. Luke’s lifetime cohort study . J Cardiol [Internet] 2025 ;Available from: https://linkinghub.elsevier.com/retrieve/pii/S091450872500142X 28. ↵ Yu AF , Raikhelkar J , Zabor EC , et al. Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer . Biomed Res Int 2016 ; 2016 . 29. ↵ Christiansen JR , Hamre H , Massey R , et al. Left ventricular function in long-term survivors of childhood lymphoma . American Journal of Cardiology 2014 ; 114 ( 3 ): 483 – 90 . OpenUrl CrossRef PubMed 30. ↵ Lang RM , Badano LP , Victor MA , 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 ): 1 – 39 .e14. OpenUrl CrossRef PubMed 31. ↵ Zhang S , Liu X , Bawa-Khalfe T , et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity . Nat Med 2012 ; 18 ( 11 ): 1639 – 42 . OpenUrl CrossRef PubMed 32. ↵ Lyon AR , López-Fernánde T , Couch LS , et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) . Eur Heart J 2022 ; 43 ( 41 ): 4229 – 361 . OpenUrl CrossRef PubMed 33. ↵ Howell RM , Smith SA , Weathers RE , Kry SF , Stovall M . Adaptations to a Generalized Radiation Dose Reconstruction Methodology for Use in Epidemiologic Studies: An Update from the MD Anderson Late Effect Group . Radiat Res 2019 ; 192 ( 2 ): 169 – 88 . OpenUrl PubMed 34. ↵ Mulrooney DA , Yeazel MW , Kawashima T , et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: Retrospective analysis of the childhood cancer survivor study cohort . BMJ (Online ) 2009 ; 339 ( 7736 ): 34 . OpenUrl 35. ↵ Lieke Feijen EAM , Font-Gonzalez A , van der Pal HJH , et al. Risk and temporal changes of heart failure among 5-year childhood cancer survivors: A DCOG-LATER study . J Am Heart Assoc 2019 ; 8 ( 1 ). 36. ↵ Tang J , Wang P , Liu C , Peng J , Liu Y , Ma Q . Pharmacotherapy in patients with heart failure with reduced ejection fraction: A systematic review and meta-analysis . Chin Med J (Engl ) 2025 ; 138 ( 8 ): 925 – 33 . OpenUrl PubMed 37. ↵ Leerink JM , van der Pal HJH , Kremer LCM , et al. Refining the 10-Year Prediction of Left Ventricular Systolic Dysfunction in Long-Term Survivors of Childhood Cancer . JACC CardioOncol 2021 ; 3 ( 1 ): 62 – 72 . OpenUrl CrossRef PubMed 38. ↵ Border WL , Sachdeva R , Stratton KL , et al. Longitudinal Changes in Echocardiographic Parameters of Cardiac Function in Pediatric Cancer Survivors . JACC CardioOncol 2020 ; 2 ( 1 ): 26 – 37 . OpenUrl PubMed 39. ↵ Lipshultz SE , Lipsitz SR , Sallan SE , et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia . Journal of Clinical Oncology 2005 ; 23 ( 12 ): 2629 – 36 . OpenUrl Abstract / FREE Full Text View the discussion thread. Back to top Previous Next Posted November 21, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Left ventricular function and its longitudinal change in Swiss childhood cancer survivors – Results from the CardioOnco Study Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. 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