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Background: The aim of this study is to evaluate how cumulative burden of clinically relevant, self‐reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. Methods: The authors invited 5925 5‐year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete a questionnaire on health outcomes. Health outcomes were validated by self‐reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30‐year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30‐year MCC, and compared the ranking to levels of care according to existing risk stratifications. Results: At median 18.5 years after 5‐year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30‐year MCC = 0.79; 95% confidence interval [CI], 0.74–0.85 vs. 30‐year MCC = 0.29; 95% CI, 0.25–0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30‐year MCC often did not correspond with levels of care in existing risk stratifications. Conclusions: CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity. Survivors of childhood cancer experience a high cumulative burden of clinically relevant outcomes. Choices for survivorship care should extend beyond primary tumor and treatment parameters and should also consider including the current morbidity of childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors are at risk for developing long‐term adverse health outcomes. To identify the risk of and risk factors for specific health outcomes, well‐established cohorts are needed with detailed information on childhood cancer diagnosis, treatment, and health outcomes. We describe the design, methodology, characteristics, and data availability of the Dutch Childhood Cancer Survivor Study LATER cohort (1963–2001) part 1; questionnaire and linkage studies. Methods: The LATER cohort includes 5‐year childhood cancer survivors, diagnosed in the period 1963–2001, and before the age of 18 in any of the seven former pediatric oncology centers in the Netherlands. Information on health outcomes from survivors and invited siblings of survivors was collected by questionnaires and linkages to medical registries. Results: In total, 6165 survivors were included in the LATER cohort. Extensive data on diagnosis and treatment have been collected. Information on a variety of health outcomes has been ascertained by the LATER questionnaire study and linkages with several registries for subsequent tumors, health care use, and hospitalizations. Conclusion: Research with data of the LATER cohort will provide new insights into risks of and risk factors for long‐term health outcomes. This can enhance risk stratification for childhood cancer survivors and inform surveillance guidelines and development of interventions to prevent (the impact of) long‐term adverse health outcomes. The data collected will be a solid baseline foundation for future follow‐up studies. [ABSTRACT FROM AUTHOR]

Background: Insight in hospitalizations in long-term childhood cancer survivors (CCS) is useful to understand the impact of long-term morbidity. We aimed to investigate hospitalization rates and underlying types of diagnoses in CCS compared to matched controls, and to investigate the determinants. Methods: We linked 5,650 five-year CCS from the Dutch nationwide Dutch LATER cohort and 109,605 age- and sex-matched controls to the Dutch Hospital Discharge register, which contained detailed information on inpatient hospitalizations from 1995–2016. Relative hospitalization rates (RHRs) were calculated using a Poisson regression model. Adjusting for multiple hospitalizations per person via a Poisson model for generalized estimated equations, we investigated determinants for hospitalizations for all types of underlying diagnoses among CCS. Results: CCS were twice as likely to be hospitalized as reference persons (hospitalization rate 178 and 78 per 1,000 person-years respectively; RHR 2.0, 95% confidence interval (CI) 1.9–2.2). Although CCS had more hospitalizations for 17 types of underlying diagnoses, they were especially more likely to be hospitalized for endocrine conditions (RHR: 6.0, 95% CI 4.6–7.7), subsequent neoplasms (RHR: 5.6, 95% CI 4.6–6.7) and symptoms without underlying diagnoses (RHR: 5.2, 95% CI 4.6–5.8). For those types of underlying diagnoses, female sex and radiotherapy were determinants. Conclusion: This study provides new insights in the high risk of hospitalizations for many types of underlying diagnoses in CCS and treatment related determinants. CCS are especially at high risk for hospitalizations for endocrine conditions, subsequent neoplasms and symptoms without an underlying diagnosis. This new knowledge is important for survivorship care and to identify possible preventable hospitalizations among CCS. [ABSTRACT FROM AUTHOR]

Objective: To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines.Methods: We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, <29% or <30%. Contingency tables were created to assess diagnostic accuracies of biomarkers for diagnosing LV dysfunction.Results: Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63-125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions.Conclusions: In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors are at risk of subsequent primary soft-tissue sarcomas (STS), but the risks of specific STS histological subtypes are unknown. We quantified the risk of STS histological subtypes after specific types of childhood cancer.Methods: We pooled data from 13 European cohorts, yielding a cohort of 69 460 five-year survivors of childhood cancer. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated.Results: Overall, 301 STS developed compared with 19 expected (SIR = 15.7, 95% confidence interval [CI] = 14.0 to 17.6). The highest standardized incidence ratios were for malignant peripheral nerve sheath tumors (MPNST; SIR = 40.6, 95% CI = 29.6 to 54.3), leiomyosarcomas (SIR = 29.9, 95% CI = 23.7 to 37.2), and fibromatous neoplasms (SIR = 12.3, 95% CI = 9.3 to 16.0). SIRs for MPNST were highest following central nervous system tumors (SIR = 80.5, 95% CI = 48.4 to 125.7), Hodgkin lymphoma (SIR = 81.3, 95% CI = 35.1 to 160.1), and Wilms tumor (SIR = 76.0, 95% CI = 27.9 to 165.4). Standardized incidence ratios for leiomyosarcoma were highest following retinoblastoma (SIR = 342.9, 95% CI = 245.0 to 466.9) and Wilms tumor (SIR = 74.2, 95% CI = 37.1 to 132.8). AERs for all STS subtypes were generally low at all years from diagnosis (AER < 1 per 10 000 person-years), except for leiomyosarcoma following retinoblastoma, for which the AER reached 52.7 (95% CI = 20.0 to 85.5) per 10 000 person-years among patients who had survived at least 45 years from diagnosis of retinoblastoma.Conclusions: For the first time, we provide risk estimates of specific STS subtypes following childhood cancers and give evidence that risks of MPNSTs, leiomyosarcomas, and fibromatous neoplasms are particularly increased. While the multiplicative excess risks relative to the general population are substantial, the absolute excess risk of developing any STS subtype is low, except for leiomyosarcoma after retinoblastoma. These results are likely to be informative for both survivors and health care providers. [ABSTRACT FROM AUTHOR]

Background and Aim: Childhood cancer survivors are at high risk of long-term adverse effects of cancer and its treatment, including cardiac events. The pan-European PanCareSurFup study determined the incidence and risk factors for cardiac events among childhood cancer survivors. The aim of this article is to describe the methodology of the cardiac cohort and nested case-control study within PanCareSurFup. Methods: Eight data providers in Europe participating in PanCareSurFup identified and validated symptomatic cardiac events in their cohorts of childhood cancer survivors. Data on symptomatic heart failure, ischemia, pericarditis, valvular disease and arrhythmia were collected and graded according to the Criteria for Adverse Events. Detailed treatment data, data on potential confounders, lifestyle related risk factors and general health problems were collected. Results: The PanCareSurFup cardiac cohort consisted of 59,915 5-year childhood cancer survivors with malignancies diagnosed between 1940 and 2009 and classified according to the International Classification of Childhood Cancer 3. Different strategies were used to identify cardiac events such as record linkage to population/ hospital or regional based databases, and patient- and general practitioner-based questionnaires. Conclusion: The cardiac study of the European collaborative research project PanCareSurFup will provide the largest cohort of 5-year childhood cancer survivors with systematically ascertained and validated data on symptomatic cardiac events. The result of this study can provide information to minimize the burden of cardiac events in childhood cancer survivors by tailoring the follow-up of childhood cancer survivors at high risk of cardiac adverse events, transferring this knowledge into evidence-based clinical practice guidelines and providing a platform for future research studies in childhood cancer patients.  [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to examine the prevalence of unhealthy lifestyle behaviors, overweight, and obesity in Dutch childhood cancer survivors (CCSs) compared with sibling controls and the Dutch general population. Other aims were to assess associated factors of unhealthy lifestyle behaviors, overweight, and obesity and to identify subgroups of CCSs at risk for these unhealthy statuses., Methods: The authors included 2253 CCSs and 906 siblings from the Dutch Childhood Cancer Survivor Study-Late Effects After Childhood Cancer cohort, part 1, and added data from the Dutch general population. Questionnaire data were collected on overweight and obesity (body mass index >25.0 kg/m 2 ), meeting physical activity guidelines (>150 minutes per week of moderate or vigorous exercises), excessive alcohol consumption (>14 and >21 alcoholic consumptions per week for women and men, respectively), daily smoking, and monthly drug use. Multivariable logistic regression analyses and two-step cluster analyses were performed to examine sociodemographic-related, health-related, cancer-related, and treatment-related associated factors of unhealthy lifestyle behaviors and to identify subgroups of CCSs at risk for multiple unhealthy behaviors., Results: CCSs more often did not meet physical activity guidelines than their siblings (30.0% vs. 19.3%; p < .001). Married as marital status, lower education level, nonstudent status, and comorbidities were common associated factors for a body mass index ≥25.0 kg/m 2 and insufficient physical activity, whereas male sex and lower education were shared associated factors for excessive alcohol consumption, daily smoking, and monthly drug use. A subgroup of CCSs was identified as excessive alcohol consumers, daily smokers, and monthly drug users., Conclusions: The current results emphasize the factors associated with unhealthy behaviors and the potential identification of CCSs who exhibit multiple unhealthy lifestyle behaviors., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested., Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors., Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics., Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%)., Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641)., Competing Interests: This research was supported by the Dutch Heart Foundation (CVON2015-21) and Stichting Kinderen Kankervrij/ODAS Stichting. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Purpose: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy., Methods: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship., Results: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation ( P < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m trend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m 2 , the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer., Conclusion: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m 2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Purpose: Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines., Methods: This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors., Results: The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m 2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses., Conclusion: Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m 2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

Purpose: The purpose of this study is to assess the available literature on the prevalence and risk factors of electrocardiographic (ECG) abnormalities after cardiotoxic treatment in childhood cancer survivors (CCS)., Methods: A literature search was performed within MEDLINE, EMBASE, and CENTRAL (1966-11/2020) and reference lists of relevant studies. Studies were eligible for inclusion if they reported ECG abnormalities ≥2 years after cancer diagnosis in ≥50 CCS treated with anthracyclines, RT involving the heart region and/or mitoxantrone. Information about population, treatment, outcome, and risk factors were extracted and risk of bias was assessed., Results: Of 934 identified publications, 10 studies were included. Outcome definitions, treatment regimens, follow-up period, and risk of bias varied. These ECG abnormalities and prevalences were reported: major (5%-23%) and minor (12%) abnormalities according to the Minnesota Code, rhythm abnormalities (0%-12%), conduction abnormalities (0.3%-7.1%), depolarization abnormalities (0%), and repolarization abnormalities (0%-65%). The reported risk factors of ECG abnormalities (two studies) are male sex, anthracyclines, RT involving the heart region, and hypertension, although results were not univocal between studies and abnormalities., Conclusions: Multiple ECG abnormalities have been described in CCS ≥2 years from diagnosis, some of which can have important implications. Future research is needed to evaluate the exact long-term incidence and risk factors, and to investigate their clinical relevance and relation with cardiac dysfunction or future cardiac events. This could improve cardiac surveillance for CCS., (© 2022 Wiley Periodicals LLC.)

As in other cardiomyopathies, extracellular matrix (ECM) remodeling plays an important role in anthracycline-induced cardiomyopathy. To understand the pattern and timing of ECM remodeling pathways, we conducted a systematic review in which we describe protein and mRNA markers for ECM remodeling that are differentially expressed in the hearts of animals with anthracycline-induced cardiomyopathy. We included 68 studies in mice, rats, rabbits, and pigs with follow-up of 0.1-8.2 human equivalent years after anthracycline administration. Using meta-analysis, we found 29 proteins and 11 mRNAs that were differentially expressed in anthracycline-induced cardiomyopathy compared to controls. Collagens, matrix metalloproteinases (MMPs), inflammation markers, transforming growth factor ß signaling markers, and markers for cardiac hypertrophy were upregulated, whereas the protein kinase B (AKT) pro-survival pathway was downregulated. Their expression patterns over time from single time point studies were studied with meta-regression using human equivalent years as the time scale. Connective tissue growth factor showed an early peak in expression but remained upregulated at all studied time points. Brain natriuretic peptide (BNP) and MMP9 protein levels increased in studies with longer follow-up. Significant associations were found for higher atrial natriuretic peptide with interstitial fibrosis and for higher BNP and MMP2 protein levels with left ventricular systolic function., (© 2021. The Author(s).)

Background: In childhood cancer survivors (CCS) at risk for heart failure, echocardiographic surveillance recommendations are currently based on anthracyclines and chest-directed radiotherapy dose. Whether the ejection fraction (EF) measured at an initial surveillance echocardiogram can refine these recommendations is unknown., Objectives: The purpose of this study was to assess the added predictive value of EF at >5 years after cancer diagnosis to anthracyclines and chest-directed radiotherapy dose in CCS, for the development of left ventricular dysfunction with an ejection fraction <40% (LVD40)., Methods: Echocardiographic surveillance was performed in 299 CCS from the Emma Children's Hospital in the Netherlands. Cox regression models were built including cardiotoxic cancer treatment exposures with and without EF to estimate the probability of LVD40 at 10-year follow-up. Calibration, discrimination, and reclassification were assessed. Results were externally validated in 218 CCS., Results: Cumulative incidences of LVD40 at 10-year follow-up were 3.7% and 3.6% in the derivation and validation cohort, respectively. The addition of EF resulted in an integrated area under the curve increase from 0.74 to 0.87 in the derivation cohort and from 0.72 to 0.86 in the validation cohort (likelihood ratio p < 0.001). Reclassification of CCS without LVD40 improved significantly (noncase continuous net reclassification improvement 0.50; 95% confidence interval [CI]: 0.40 to 0.60). A predicted LVD40 probability ≤3%, representing 75% of the CCS, had a negative predictive value of 99% (95% CI: 98% to 100%) for LVD40 within 10 years. However, patients with midrange EF (40% to 49%) at initial screening had an incidence of LVD40 of 11% and a 7.81-fold (95% CI: 2.07- to 29.50-fold) increased risk of LV40 at follow-up., Conclusions: In CCS, an initial surveillance EF, in addition to anthracyclines and chest-directed radiotherapy dose, improves the 10-year prediction for LVD40. Through this strategy, both the identification of low-risk survivors in whom the surveillance frequency may be reduced and a group of survivors at increased risk of LVD40 could be identified., Competing Interests: This study was funded by a Dutch Heart Foundation Grant (CVON2015-21). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Advances in cancer treatments have improved clinical outcomes, leading to an increasing population of cancer survivors. However, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach that includes expertise in oncology, cardiology and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and management, and long-term follow-up strategies for patients at risk of cancer therapy-related cardiotoxicities. Research to better define strategies for early identification, follow-up and management is highly necessary. Although the academic cardio-oncology community may be the best vehicle to foster awareness and research in this field, additional stakeholders (industry, government agencies and patient organizations) must be involved to facilitate cross-discipline interactions and help in the design and funding of cardio-oncology trials. The overarching goals of cardio-oncology are to assist clinicians in providing optimal care for patients with cancer and cancer survivors, to provide insight into future areas of research and to search for collaborations with industry, funding bodies and patient advocates. However, many unmet needs remain. This document is the product of brainstorming presentations and active discussions held at the Cardiovascular Round Table workshop organized in January 2020 by the European Society of Cardiology., (© 2020 European Society of Cardiology.)

Cardiac diseases in the growing population of childhood cancer survivors are of major concern. Cardiotoxicity as a consequence of anthracyclines and chest radiotherapy continues to be relevant in the modern treatment era. Mitoxantrone has emerged as an important treatment-related risk factor and evidence on traditional cardiovascular risk factors in childhood cancer survivors is accumulating. International surveillance guidelines have been developed with the aim to detect and manage cardiac diseases early and prevent symptomatic disease. There is growing interest in risk prediction models to individualize prevention and surveillance. This State-of-the-Art Review summarizes literature from a systematic PubMed search focused on cardiac diseases after treatment for childhood cancer. Here, we discuss the prevalence, risk factors, prevention, risk prediction, and surveillance of cardiac diseases in survivors of childhood cancer., (© 2020 The Authors.)

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF., Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public., Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors., Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose: Radiotherapy involving the thoracic region is associated with cardiotoxicity in long-term childhood cancer survivors. We quantified heart volume changes during radiotherapy in children (<18 years) and investigated correlations with patient and treatment related characteristics., Material and Methods: Between 2010 and 2016, 34 children received radiotherapy involving the thoracic region. We delineated heart contours and measured heart volumes on 114 CBCTs. Relative volume changes were quantified with respect to the volume on the first CBCT (i.e., 100%). Cardiac radiation dose parameters expressed as 2 Gy/fraction equivalent doses were calculated from DVHs. Chemotherapy was categorized as treatment with anthracyclines, alkylating agents, vinca-alkaloids, and other., Results: The overall median heart volume reduction from the first to the last CBCT was 5.5% (interquartile range1.6-9.7%; p < 0.001). Heart volumes decreased significantly between the baseline measurement and the first week (Bonferroni's adjusted p = 0.002); volume changes were not significant during the following weeks. Univariate analysis showed a significant correlation between heart volume reduction and alkylating agents; however, no multivariate analyses could be done to further confirm this., Conclusions: We found a significant heart volume reduction in children during radiotherapy. Elucidation of underlying mechanisms, clinical relevance, and possible long-term consequences of early heart volume reduction require a prospective follow-up study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Childhood cancer survivors are at risk of subsequent primary soft-tissue sarcomas (STS), but the risks of specific STS histological subtypes are unknown. We quantified the risk of STS histological subtypes after specific types of childhood cancer., Methods: We pooled data from 13 European cohorts, yielding a cohort of 69 460 five-year survivors of childhood cancer. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated., Results: Overall, 301 STS developed compared with 19 expected (SIR = 15.7, 95% confidence interval [CI] = 14.0 to 17.6). The highest standardized incidence ratios were for malignant peripheral nerve sheath tumors (MPNST; SIR = 40.6, 95% CI = 29.6 to 54.3), leiomyosarcomas (SIR = 29.9, 95% CI = 23.7 to 37.2), and fibromatous neoplasms (SIR = 12.3, 95% CI = 9.3 to 16.0). SIRs for MPNST were highest following central nervous system tumors (SIR = 80.5, 95% CI = 48.4 to 125.7), Hodgkin lymphoma (SIR = 81.3, 95% CI = 35.1 to 160.1), and Wilms tumor (SIR = 76.0, 95% CI = 27.9 to 165.4). Standardized incidence ratios for leiomyosarcoma were highest following retinoblastoma (SIR = 342.9, 95% CI = 245.0 to 466.9) and Wilms tumor (SIR = 74.2, 95% CI = 37.1 to 132.8). AERs for all STS subtypes were generally low at all years from diagnosis (AER < 1 per 10 000 person-years), except for leiomyosarcoma following retinoblastoma, for which the AER reached 52.7 (95% CI = 20.0 to 85.5) per 10 000 person-years among patients who had survived at least 45 years from diagnosis of retinoblastoma., Conclusions: For the first time, we provide risk estimates of specific STS subtypes following childhood cancers and give evidence that risks of MPNSTs, leiomyosarcomas, and fibromatous neoplasms are particularly increased. While the multiplicative excess risks relative to the general population are substantial, the absolute excess risk of developing any STS subtype is low, except for leiomyosarcoma after retinoblastoma. These results are likely to be informative for both survivors and health care providers.