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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. The Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort includes a large, unselected multi‐center cohort of childhood cancer survivors with an unprecedented combination of detailed, individual‐level data on diagnosis and treatment and highly complete outcome data on various long‐term health outcomes. This Figure gives an overview on inclusion criteria and data collections of part 1 of the DCCSS LATER study.

Background Fatigue is often reported by patients with childhood cancer both during and after cancer treatment. Several instruments to measure fatigue exist, although none are specifically validated for use in childhood cancer survivors (CCS). The aim of the current study was to present norm values and psychometric properties of the Checklist Individual Strength (CIS) and Short Fatigue Questionnaire (SFQ) in a nationwide cohort of CCS. Methods In total, 2073 participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort. Normative data, construct validity, structural validity, and internal consistency were calculated for the CIS and SFQ. In addition, reliability and a cutoff score to indicate severe fatigue were determined for the SFQ. Results Correlations between CIS/SFQ and vitality measures asking about fatigue were high (>0.8). Correlations between CIS/SFQ and measures of different constructs (sleep, depressive emotions, and role functioning emotional) were moderate (0.4–0.6). Confirmatory factor analysis resulted in a four‐factor solution for the CIS and a one‐factor solution for the SFQ with Cronbach's alpha for each (sub)scale showing good to excellent values (>0.8). Test–retest reliability of the SFQ was adequate (Pearson's correlation = 0.88; ICC = 0.946; weighted Cohen's kappa item scores ranged 0.31–0.50) and a cut‐off score of 18 showed good sensitivity and specificity scores (92.6% and 91.3%, respectively). Conclusion The current study shows that the SFQ is a good instrument to screen for severe fatigue in CCS. The CIS can be used as a tool to assess the multiple fatigue dimensions in CCS. Several instruments to measure fatigue exist, although none are specifically validated for use in childhood cancer survivors (CCS). The current study shows that the SFQ is a good instrument to screen for severe fatigue in CCS and that the CIS can be used as a tool to assess the multiple fatigue dimensions in CCS.

Background Adverse late health outcomes after multimodal treatment for pediatric cancer are diverse and of prime interest. Currently available evidence and survivorship care guidelines are largely based on studies addressing side‐effects of two dimensional planned radiotherapy. Aims The Dutch pediatric 3D‐planned radiotherapy (3D‐RT) study aims to gain insight in the long‐term health outcomes among children who had radiotherapy in the 3D era. Here, we describe the study design, data‐collection methods, and baseline cohort characteristics. Methods and Results The 3D‐RT study represents an expansion of the Dutch Childhood Cancer Survivor study (DCCSS) LATER cohort, including pediatric cancer patients diagnosed during 2000–2012, who survived at least 5 years after initial diagnosis and 2 years post external beam radiotherapy. Individual cancer treatment parameters were obtained from medical files. A national infrastructure for uniform collection and archival of digital radiotherapy files (Computed Tomography [CT]‐scans, delineations, plan, and dose files) was established. Health outcome information, including subsequent tumors, originated from medical records at the LATER outpatient clinics, and national registry‐linkage. With a median follow‐up of 10.9 (interquartile range [IQR]: 7.9–14.3) years after childhood cancer diagnosis, 711 eligible survivors were identified. The most common cancer types were Hodgkin lymphoma, medulloblastoma, and nephroblastoma. Most survivors received radiotherapy directed to the head/cranium only, the craniospinal axis, or the abdominopelvic region. Conclusion The 3D‐RT study will provide knowledge on the risk of adverse late health outcomes and radiation‐associated dose‐effect relationships. This information is valuable to guide follow‐up care of childhood cancer survivors and to refine future treatment protocols.

Purpose This study assessed cardiorespiratory fitness (CRF), physical activity (PA), and sedentary behavior (SB), as well as factors associated with these outcomes in children during or shortly after cancer treatment. Methods Cross-sectionally, CRF data, obtained by the cardiopulmonary exercise test, and PA and SB data, obtained by an accelerometer, were assessed in children with cancer (8–18 years old). Linear regression models were used to determine associations between CRF, PA, or SB and patient characteristics. Results Among 60 children with cancer, mean age 12.6 years, 35 boys, 28 % were during cancer treatment. CRF, reported as the z score of VO 2peak , showed that 32 children had a VO 2peak z score which was −2 below the predicted value. CRF was significantly associated with PA and SB: each additional activity count per minute resulted in 0.05 ml/kg/min VO 2peak increase and each additional minute sedentary reduced VO 2peak by 0.06 ml/kg/min. Multiple linear regression models of PA and SB showed that decreased activity was significantly associated with higher age, being fatigued, being during childhood cancer treatment ( p  < 0.001), or having a higher percentage of fat mass. The multiple linear regression model showed that lower CRF was significantly associated with increased fatigue, being during cancer treatment, having a higher percentage of fat mass, and lower belief of own athletic competence ( p  < 0.001). Conclusion This study revealed that children during or shortly after cancer treatment have low CRF scores. The most inactive children had a higher fat mass, were fatigued, older, and during childhood cancer treatment. Unexpectedly, treatment-related factors showed no significant association with activity behavior.

Background Wilms tumors (WT) are the most common kidney tumors in children, with excellent survival rates (90%). However, late adverse effects warrant attention. Limited data exist on musculoskeletal sequelae in WT survivors. We aimed to assess the prevalence and determinants of impaired bone mineral density (BMD) and fractures in a national cohort of Dutch WT survivors. Method This cross‐sectional study includes WT survivors treated between 1963 and 2002, recruited as part of the DCCSS‐LATER cohort between 2016 and 2020. Dual‐energy X‐ray absorptiometry (DXA) scans were used to assess BMD. Low BMD was defined as a Z‐score ≤ 1. From 5 years after diagnosis, fracture prevalence was assessed by questionnaires. Univariable logistic regression was used to analyze associations between impaired BMD as well as fractures with independent variables like patient characteristics, treatments, comorbidities, and lifestyle‐related factors. Results Of 437 invited kidney tumor survivors, 233 WT survivors participated (median age 32.1 years, median follow‐up 27.8 years). DXA scans and fracture data were available for 173 and 221 WT survivors, respectively. Low BMD at any site was observed in 26% (n = 46/173) of survivors and was significantly associated with treatment including ≥ 4 drugs (OR 2.76; 95% CI = 1.13–6.70). Abdominal radiotherapy doses > 30 Gy (OR 4.84; 95% CI = 1.06–22.2) were significantly associated with low lumbar spine BMD. The prevalence of fragility fractures was 16.3% (n = 36/221). The standardized incidence ratio (SIR) of any first fracture was 2.34 for males and 5.38 for females. Conclusion Wilms tumor survivors treated with ≥ 4 drugs or abdominal radiotherapy (> 30 Gy) seem to be at increased risk of impaired BMD; this could indicate the need for surveillance for this subset of Wilms tumor survivors exposed to these treatment regimens in the past.

Background Physical fitness and psychosocial function is often reduced in children during or shortly after cancer treatment. This study evaluates the effect of a combined physical exercise and psychosocial intervention on cardiorespiratory fitness, muscle strength, body composition, psychosocial function and health-related quality of life (HrQoL). In addition, intervention mediators, applicability and adherence were examined. Methods This multicenter randomized controlled trial included 68 children with cancer [mean age 13.2 (SD: 3.1) years; 54% male] during treatment or within 12-months post-treatment. The 12-week intervention consisted of 24 individual physical exercise sessions supervised by a physiotherapist, and 6 psychosocial training sessions for children and 2 for parents. Physical fitness and psychosocial function were assessed at baseline, directly post-intervention and at 12 months’ post-baseline. Generalized estimating equations were used to simultaneously assess intervention effects at short and long-term. Additionally, we evaluated within-group differences over time. Potential physical and psychosocial mediators in the intervention effect on HrQoL were examined using the product-of-coefficient test. Applicability and adherence were assessed by trainer-report. Results This study was able to compare 26 children who received the study intervention, with 33 children who received usual care. No significant differences in the effects of the intervention were found on physical fitness and psychosocial function at short-term. At 12-months follow-up, significantly larger improvements in lower body muscle strength (β = 56.5 Newton; 95% CI: 8.5; 104.5) were found in the intervention group when compared to the control group. Within-group changes showed significant improvements over time in HrQoL and bone density in both groups. Intervention effects on HrQoL were not significantly mediated by physical fitness and psychological function. Intervention applicability was satisfactory with an average session attendance of 67% and 22% dropout (mainly due to disease recurrence). Conclusions This 12-week physical exercise and psychosocial training intervention for children with cancer was applicable and showed satisfactory adherence. We found no significant between-group differences in effect, except for a significant improvement in lower body muscle strength at long-term in the intervention group compared to the control group. Yet, both the intervention and the control group showed improvements in bone mineral density and HrQoL over time. Trial registration The trial was registered at the Dutch Trial Registry ( NTR1531 ). Registered 12 November 2008.

PurposesStudies investigating self-reported long-term morbidity in childhood cancer survivors (CCS) are using heterogeneous outcome definitions, which compromises comparability and include (un)treated asymptomatic and symptomatic outcomes. We generated a Dutch LATER core set of clinically relevant physical outcomes, based on self-reported data. Clinically relevant outcomes were defined as outcomes associated with clinical symptoms or requiring medical treatment.MethodsFirst, we generated a draft outcome set based on existing questionnaires embedded in the Childhood Cancer Survivor Study, British Childhood Cancer Survivor Study, and Dutch LATER study. We added specific outcomes reported by survivors in the Dutch LATER questionnaire. Second, we selected a list of clinical relevant outcomes by agreement among a Dutch LATER experts team. Third, we compared the proposed clinically relevant outcomes to the severity grading of the Common Terminology Criteria for Adverse Events (CTCAE).ResultsA core set of 74 self-reported long-term clinically relevant physical morbidity outcomes was established. Comparison to the CTCAE showed that 36% of these clinically relevant outcomes were missing in the CTCAE.Implications for Cancer SurvivorsThis proposed core outcome set of clinical relevant outcomes for self-reported data will be used to investigate the self-reported morbidity in the Dutch LATER study. Furthermore, this Dutch LATER outcome set can be used as a starting point for international harmonization for long-term outcomes in survivors of childhood cancer.

Childhood cancer patients often remain uninformed regarding their potential risk of gonadal damage. In our hospital we introduced a five step standard oncofertility care plan for all newly diagnosed female patients aiming to identify, inform and triage 100% of patients and counsel 100% of patients at high risk (HR) of gonadal damage. This observational retrospective study (PEARL study) evaluated the use of this standard oncofertility care plan in the first full year in a national cohort. The steps consist of 1)timely (preferably before start of gonadotoxic treatment) identification of all new patients, 2)triage of gonadal damage risk using a standardized gonadal damage risk stratification tool, 3)informing all patients and families, 4)counseling of a selected subset of girls, and 5) fertility preservation including ovarian tissue cryopreservation (OTC) in HR patients using amended Edinburgh criteria. A survey of the medical records of all girls newly diagnosed with cancer the first year (1-1-2019 until 31-12-2019) was conducted. Of 261 girls, 228 (87.4%) were timely identified and triaged. Triage resulted in 151 (66%) low(LR), 32 (14%) intermediate(IR) and 45 (20%) high risk(HR) patients. Ninety-nine families were documented to be timely informed regarding gonadal damage risk. In total, 35 girls (5 LR, 5 IR, 25 HR) were counseled by an oncofertility expert. 16/25 HR patients underwent fertility preservation (1 ovariopexy + OTC, oocyte cryopreservation (1 with and 1 without OTC) and 13 OTC). Fertility preservation did not lead to complications or delay of cancer treatment in any patient. We timely identified and triaged most girls (88%) with cancer with a high risk of gonadal damage to be counseled for fertility preservation. We aim to optimize the oncofertility care plan and the standardized gonadal damage risk stratification tool based on this experience and these may be of value to other pediatric oncology centers.

ObjectiveTo 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.MethodsWe 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.ResultsOf 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.ConclusionsIn 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.

BackgroundWe assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors.MethodsIn this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability.Results16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well.ConclusionA clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell’s criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.