Background: Overweight and obesity are common challenges among childhood cancer survivors. Overweight may be disguised, as survivors can have normal weight but high fat percentage (fat%) on dual... Show moreBackground: Overweight and obesity are common challenges among childhood cancer survivors. Overweight may be disguised, as survivors can have normal weight but high fat percentage (fat%) on dual-energy X-ray absorptiometry (DXA). We aimed to assess prevalence, identify determinants and biomarkers, and assess which method captures overweight best, in a nationwide cohort.Methods: The prevalence of overweight and obesity, primarily defined by body mass index (BMI), was assessed in the DCCSS-LATER cohort of adult survivors treated from 1963-2002, with the LifeLines cohort as reference. The associations between risk factors and overweight metrics were investigated using logistic regression. Additional overweight metrics included DXA fat%, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and high-molecular-weight (HMW) adiponectin.Results: A total of 2338 (mean age 35.5 years, follow-up 28.3 years) survivors participated. The overweight prevalence was 46.3% in men and 44.3% in women (obesity 11.2% and 15.9%, morbid obesity 2.4% and 5.4%), with highest rates among brain tumor survivors. Compared to controls, there was no overall increased overweight rate, but this was higher in women > 50 years, morbid obesity in men > 50 years. Overweight at cancer diagnosis (adjusted odds ratio [aOR] = 3.83, 95% CI 2.19-6.69), cranial radiotherapy (aOR = 3.21, 95% CI 1.99-5.18), and growth hormone deficiency (separate model, aOR = 1.61, 95% CI 1.00-2.59) were associated with overweight. Using BMI, WC, WHR, and WHtR, overweight prevalence was similar. Low HMW adiponectin, present in only 4.5% of survivors, was an insensitive overweight marker. Dual-energy X-ray absorptiometry-based classification identified overweight in an additional 30%, particularly after abdominal radiotherapy, total body irradiation, anthracyclines, and platinum.Conclusions: Overweight occurs in almost half of long-term survivors. There was no overall increased incidence of overweight compared to controls. We identified factors associated with overweight, as well as subgroups of survivors in whom DXA can more reliably assess overweight. Show less
Penson, A.; Walraven, I.; Bronkhorst, E.; Grootenhuis, M.A.; Maurice-Stam, H.; Beijer, I. de; ... ; utch LATER Study Grp 2023
Background: The purpose of this study was to determine factors associated with chronic fatigue (CF) in childhood cancer survivors (CCS). Patients and methods: Participants were included from the... Show moreBackground: The purpose of this study was to determine factors associated with chronic fatigue (CF) in childhood cancer survivors (CCS). Patients and methods: Participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort, a nationwide cohort of CCS (>= 5 years after diagnosis) and siblings as controls. Fatigue severity was assessed with the 'fatigue severity subscale' of the Checklist Individual Strength ('CIS-fatigue'). CF was defined as scoring >35 on the 'CIS-fatigue' and having fatigue symptoms for >6 months. Twenty-four parameters were assessed, categorized into assumed fatigue triggering, maintaining and moderating factors. Multivariable logistic regression analyses were carried out to investigate the association of these factors with CF. Results: A total of 1927 CCS participated in the study (40.7% of invited cohort), of whom 23.6% reported CF (compared with 15.6% in sibling controls, P < 0.001). The following factors were associated with CF: obesity [versus healthy weight, odds ratio (OR) 1.93; 95% confidence interval (CI) 1.30-2.87], moderate physical inactivity (versus physical active, OR 2.36; 95% CI 1.67-3.34), poor sleep (yes versus no, OR 2.03; 95% CI 1.54-2.68), (sub)clinical anxiety (yes versus no, OR 1.55; 95% CI 1.10-2.19), (sub)clinical depression (yes versus no, OR 2.07; 95% CI 1.20-3.59), pain (continuous, OR 1.49; 95% CI 1.33-1.66), self-esteem (continuous, OR 0.95; 95% CI 0.92-0.98), helplessness (continuous, OR 1.13; 95% CI 1.08-1.19), social functioning (continuous, OR 0.98; 95% CI 0.97-0.99) and female sex (versus male sex, OR Conclusion: CF is a prevalent symptom in CCS that is associated with several assumed maintaining factors, with lifestyle and psychosocial factors being the most prominent. These are modifiable factors and may therefore be beneficial to prevent or reduce CF in CCS. Show less
Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early... Show moreAnthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with & GE;200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for & GE;400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received & GE;200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.In a pooled analysis of six international studies involving about 17,900 female survivors of childhood cancer, the use of doxorubicin was associated with a dose-dependent risk of subsequent breast cancer, irrespective of prior chest radiotherapy exposure. Show less
BACKGROUND Childhood cancer survivors (CCS) are at risk for cardiotoxicity.OBJECTIVES We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by... Show moreBACKGROUND Childhood cancer survivors (CCS) are at risk for cardiotoxicity.OBJECTIVES We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors.METHODS This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397 $5-year CCS and 277 siblings. Of CCS, n = 1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n = 143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression.RESULTS CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as < 52% in men, < 54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunction grade $II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors.CONCLUSIONS Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among longterm CCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained risk of cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATER study; NTR7481) (J Am Coll Cardiol CardioOnc 2023;5:472-485) (c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). Show less
Priboi, C.; Gorp, M. van; Maurice-Stam, H.; Michel, G.; Kremer, L.C.M.; Tissing, W.J.E.; ... ; Grootenhuis, M. 2023
ObjectivesChildhood cancer may negatively impact childhood cancer survivors' (CCS) sexuality. However, this is an understudied research area. We aimed to describe the psychosexual development,... Show moreObjectivesChildhood cancer may negatively impact childhood cancer survivors' (CCS) sexuality. However, this is an understudied research area. We aimed to describe the psychosexual development, sexual functioning and sexual satisfaction of CCS, and identify determinants for these outcomes. Secondarily, we compared the outcomes of a subsample of emerging adult CCS to the Dutch general population. MethodsFrom the Dutch Childhood Cancer Survivor Study LATER cohort (diagnosed 1963-2001), 1912 CCS (18-71 years, 50.8% male) completed questions on sexuality, psychosocial development, body perception, mental and physical health. Multivariable linear regressions were used to identify determinants. Sexuality of CCS age 18-24 (N = 243) was compared to same-aged references using binomial tests and t-tests. ResultsOne third of all CCS reported hindered sexuality due to childhood cancer, with insecure body the most often reported reason (44.8%). Older age at study, lower education, surviving central nervous system cancer, poorer mental health and negative body perception were identified as determinants for later sexual debut, worse sexual functioning and/or sexual satisfaction. CCS age 18-24 showed significantly less experience with kissing (p = 0.014), petting under clothes (p = 0.002), oral (p = 0.016) and anal sex (p = 0.032) when compared to references. No significant differences with references were found for sexual functioning and sexual satisfaction, neither among female CCS nor male CCS age 18-24. ConclusionsEmerging adult CCS reported less experience with psychosexual development, but similar sexual functioning and sexual satisfaction compared to references. We identified determinants for sexuality, which could be integrated in clinical interventions for CCS at risk for reduced sexuality. Show less
PurposeThe present study aimed to determine the prevalence of self-reported oral problems and the oral health-related quality of life (OHRQoL) in childhood cancer survivors (CCS).MethodsPatient and... Show morePurposeThe present study aimed to determine the prevalence of self-reported oral problems and the oral health-related quality of life (OHRQoL) in childhood cancer survivors (CCS).MethodsPatient and treatment characteristics of CCS have been collected in a cross-sectional study, part of the multidisciplinary DCCSS-LATER 2 Study. To assess self-reported oral health problems and dental problems, CCS filled out the 'Toegepast-Natuurwetenschappelijk Onderzoek' (TNO) oral health questionnaire. OHRQoL was assessed by the Dutch version of the Oral Health Impact Profile-14 (OHIP-14). Prevalences were compared with two comparison groups from the literature. Univariable and multivariable analyses were performed.ResultsA total of 249 CCS participated in our study. The OHIP-14 total score had a mean value of 1.94 (sd 4.39), with a median score of 0 (range 0-29). The oral problems 'oral blisters/aphthae' (25.9%) and 'bad odor/halitosis' (23.3%) were significantly more often reported in CCS than in comparison groups (12% and 12%, respectively). The OHIP-14 score was significantly correlated with the number of self-reported oral health problems (r = .333, p<0.0005) and dental problems (r = .392, p <0.0005). In multivariable analysis, CCS with a shorter time since diagnosis (10-19 years vs. >= 30 years) had a 1.47-fold higher risk of >= 1 oral health problem.ConclusionThough the perceived oral health is relatively good, oral complications following childhood cancer treatment are prevalent in CCS. This underlines that attention to impaired oral health and awareness on this topic is mandatory and regular visits to the dentist should be a part of long-term follow-up care. Show less
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... Show moreBackground: 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. Show less
Feijen, E.A.M.; Teepen, J.C.; Dulmen-den Broeder, E. van; Heuvel-Eibrink, M. van den; Heiden-van der Loo, M. van der; Pal, H.J.H. van der; ... ; Kremer, L.C.M. 2023
Background: Childhood cancer survivors face late health problems; despite advances in research, details on risk remain unclear. We describe the methodological aspects of the Dutch Childhood Cancer... Show moreBackground: Childhood cancer survivors face late health problems; despite advances in research, details on risk remain unclear. We describe the methodological aspects of the Dutch Childhood Cancer Survivor Study (DCCSS) cross-sectional clinical study (LATER 2 study). Procedure: From the multi-center DCCSS LATER cohort of 6165 five-year survivors diagnosed during 1963-2001, we invited 4735 eligible survivors in 2016, as well as siblings and parents of survivors. Gaps in evidence identified during development of surveillance guidelines were translated into clinical research questions for 16 outcome-specific subprojects. The regular care visit to the LATER outpatient clinic forms the backbone of outcome assessment complemented with research-defined measurements (physical examination, clinical tests, questionnaires). Furthermore, blood/saliva samples were taken for deoxyribonucleic acid (DNA) extraction. Results: In total, 2519 (53.2%) survivors participated in the LATER 2 study. When comparing participants with nonparticipants, we observed that males, CNS survivors, and those treated with surgery only were less likely to participate. Of the participating survivors, 49.3% were female. Median time since childhood cancer diagnosis was 26.9 years (range 14.8-54.7 years) and median attained age was 34.4 years (range 15.4-66.6 years). Conclusions: The high-quality data generated in the LATER 2 study will provide valuable insights into risks of and risk factors for clinical and physical and psychosocial health outcomes and factors for early recognition of those health outcomes in long-term childhood cancer survivors. This will contribute to fill in important gaps in knowledge and improve the quality of life and care for childhood cancer survivors. Show less
Atteveld, J.E. van; Winter, D.T.C. de; Pluimakers, V.G.; Fiocco, M.; Nievelstein, R.A.J.; Hobbelink, M.G.G.; ... ; Dutch LATER Study Grp 2022
Background: Childhood cancer survivors are at risk of developing skeletal comorbidities later in life. We aimed to assess risk factors for low and very low bone mineral density (BMD), and the risk... Show moreBackground: Childhood cancer survivors are at risk of developing skeletal comorbidities later in life. We aimed to assess risk factors for low and very low bone mineral density (BMD), and the risk of and risk factors for any fractures and vertebral fractures in a national cohort of Dutch adult childhood cancer survivors.Methods: In this cross-sectional study, we used data from the DCCSS LATER cohort, which comprised individuals who were alive for at least 5 years after diagnosis of childhood cancer (ie, histologically confirmed malignancies or Langerhans cell histiocytosis), were diagnosed before the age of 19 years, and who had been treated at one of seven Dutch paediatric oncology centres between 1963 and 2002 (hereafter referred to as survivors). For this study, we invited survivors aged 18-45 years, who were alive as of Oct 10, 2016, living in the Netherlands, and who were deemed eligible by their treating physician to participate. We assessed BMD using dual-energy x-ray absorptiometry (DXA). Self-reported fractures that occurred at least 5 years after cancer diagnosis were assessed using available medical history and compared with population-level data from the Swedish national registry. We assessed vertebral fractures in a subset of participants using a vertebral fracture assessment. We assessed associations between the occurrence of low (Z-score of <=-1) or very low (Z-score of <=-2) BMD, fractures, and vertebral fractures and demographic, treatment -related, endocrine, and lifestyle-related factors using logistic regression analysis. Findings: Between April 29, 2016, and Jan 22, 2020, 3996 (64 center dot 8%) of 6165 individuals from the DCCSS LATER cohort were invited to participate, of whom 2003 (50 center dot 1%) were enrolled (mean age at participation was 33 center dot 1 years [SD 7 center dot 2], 966 [48 center dot 2%] were female, and 1037 [51 center dot 8%] were male [data on ethnicity and race were not available due to national policies]). 1548 (77 center dot 3%) had evaluable DXA scans for assessment of BMD, 1892 (94 center dot 5%) provided medical history of fractures, and 249 (12 center dot 4%) were assessed for vertebral fractures. 559 (36 center dot 1%) of 1548 had low BMD at any site, and 149 (9 center dot 6%) had very low BMD at any site. The standardised incidence ratio of any first fracture was 3 center dot 53 (95% CI 3 center dot 06-4 center dot 06) for male participants and 5 center dot 35 (4 center dot 46-6 center dot 52) for female participants. 33 (13 center dot 3%) of 249 participants had vertebral fractures. Male sex, underweight, high carboplatin dose, any dose of cranial radiotherapy, hypogonadism, hyperthyroidism, low physical activity, and severe vitamin D deficiency were associated with low BMD at any site and male sex, underweight, cranial radiotherapy, growth hormone deficiency, and severe vitamin D deficiency were associated with very low BMD at any site. Additionally, male sex, former and current smoking, and very low lumbar spine BMD were associated with any fractures, whereas older age at follow-up, previous treatment with platinum compounds, growth hormone deficiency, and low physical activity were specifically associated with vertebral fractures. Interpretation: Survivors of childhood cancer are at increased risk of any first fracture. Very low lumbar spine BMD was associated with fractures, highlighting the importance of active BMD surveillance in high-risk survivors (ie, those treated with cranial, craniospinal, or total body irradiation). Moreover, our results indicate that intensive surveillance and timely interventions for endocrine disorders and vitamin deficiencies might improve bone health in childhood cancer survivors, but this needs to be assessed in future studies. Show less
Teepen, J.C.; Kok, J.L.; Feijen, E.A.M.; Loonen, J.J.; Heuvel-Eibrink, M.M. van den; Pal, H.J. van der; ... ; DCCSS LATER Study Grp 2022
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... Show moreBackground: 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. Show less
Atteveld, J.E. van; Winter, D.T.C. de; Pluimakers, V.G.; Fiocco, M.; Nievelstein, R.A.J.; Hobbelink, M.G.G.; ... ; Heuvel-Eibrink, M.M. van den 2022
Background: Anthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential car-diotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine... Show moreBackground: Anthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential car-diotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine-treated >5-year child-hood cancer survivors (CCS). Methods and results: We cross-sectionally compared echocardiograms of 101 vincristine-treated CCS (median age 35 years [range: 17-53], median vincristine dose 63 mg/m2) from the national Dutch Childhood Cancer Survivor Study, LATER cohort, to 101 age-and sex-matched controls. CCS treated with anthracyclines, radiotherapy involving the heart region, cyclophosphamide or ifosfamide were excluded. Twelve CCS (14%) versus four controls (4%; p 0.034) had a decreased left ventricular ejection fraction (LVEF; men <52%, women <54%). Mean LVEF was 58.4% versus 59.7% (p 0.050). Global longitudinal strain (GLS) was abnormal in nineteen (24%) CCS versus eight controls (9%; p 0.011). Mean GLS was 19.0% versus 20.1% (p 0.001). No >= grade 2 diastolic dysfunction was detected. In multivariable logistic regression analysis CCS had higher risk of abnormal GLS (OR 3.55, p 0.012), but not abnormal LVEF (OR 3.07, p 0.065), than controls. Blood pressure and smoking history contributed to variation in LVEF, whereas obesity and diastolic blood pressure contributed to variation in GLS. Cumulative vincristine dose was not associated with either abnormal LVEF or abnormal GLS in multivariable models corrected for age and sex (OR per 50 mg/m2: 0.88, p 0.85 and 1.14, p 0.82, respectively). Conclusions: Vincristine-treated long-term CCS showed an abnormal GLS more frequently than controls. Their risk for future clinical cardiac events and the role of risk factor modification should be further elucidated. Show less
Maurice-Stam, H.; Erp, L.M.E. van; Maas, A.; Oers, H.A. van; Kremer, L.C.M.; Dulmen-den Broeder, E. van; ... ; Dutch LATER Study Grp 2022
Purpose The study aimed to compare the psychosocial development of young adult survivors of childhood cancer (YACCS) with a norm group of young adults from the general population. Methods From 2017... Show morePurpose The study aimed to compare the psychosocial development of young adult survivors of childhood cancer (YACCS) with a norm group of young adults from the general population. Methods From 2017 to 2020, 558 YACCS (18-30 years, 51% female, 10.9% CNS cancer) who participated in the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort (diagnosed 1963-2001) part 2 completed the Course of Life Questionnaire (CoLQ), assessing the achievement of milestones. Items were grouped into the scales autonomy, psychosexual, and social development. Differences between YACCS and norm group were examined with ANOVA and Cohen's d (CoLQ scales) and with logistic regression analysis and odds ratio (OR) (CoLQ items), for the total group and YACCS of CNS cancer. Results The total group of YACCS did not report a less favorable psychosocial development than the norm group. YACCS of CNS cancer scored lower than the norm group (p < 0.001) on the scales autonomy (d = - 0.36) and psychosexual (d = - 0.46). Additionally, on half of the items of autonomy (0.25 <= OR <= 0.34), psychosexual (0.30 <= OR <= 0.48), and social (0.23 <= OR <= 0.47) development, YACCS of CNS cancer were less likely (p < 0.01) than the norm group to have achieved the milestones. Conclusion Overall, psychosocial development of YACCS was as favorable as the norm, but YACCS of CNS cancer were at risk of an unfavorable psychosocial development in all domains. Monitoring psychosocial development should be included in the standards of psychosocial care, especially for CNS cancer patients and survivors, to be able to trace delay. Personalized interventions should be offered to improve the psychosocial development in an early stage. Show less
Wang, Z.Y.; Virgolin, M.; Balgobind, B.V.; Dijk, I.W.E.M. van; Smith, S.A.; Howell, R.M.; ... ; Alderliesten, T. 2022
Purpose: Our purpose was to validate and compare the performance of 4 organ dose reconstruction approaches for historical radiation treatment planning based on 2-dimensional radiographs.Methods and... Show morePurpose: Our purpose was to validate and compare the performance of 4 organ dose reconstruction approaches for historical radiation treatment planning based on 2-dimensional radiographs.Methods and materials: We considered 10 patients with Wilms tumor with planning computed tomography images for whom we developed typical historic Wilms tumor radiation treatment plans, using anteroposterior and posteroanterior parallel-opposed 6 MV flank fields, normalized to 14.4 Gy. Two plans were created for each patient, with and without corner blocking. Regions of interest (lungs, heart, nipples, liver, spleen, contralateral kidney, and spinal cord) were delineated, and dose-volume metrics including organ mean and minimum dose (Dmean and Dmin) were computed as the reference baseline for comparison. Dosimetry for the 20 plans was then independently reconstructed using 4 different approaches. Three approaches involved surrogate anatomy, among which 2 used demographic-matching criteria for phantom selection/building, and 1 used machine learning. The fourth approach was also machine learning-based, but used no surrogate anatomies. Absolute differences in organ dose-volume metrics between the reconstructed and the reference values were calculated.Results: For Dmean and Dmin (average and minimum point dose) all 4 dose reconstruction approaches performed within 10% of the prescribed dose (≤1.4 Gy). The machine learning-based approaches showed a slight advantage for several of the considered regions of interest. For Dmax (maximum point dose), the absolute differences were much higher, that is, exceeding 14% (2 Gy), with the poorest agreement observed for near-beam and out-of-beam organs for all approaches.Conclusions: The studied approaches give comparable dose reconstruction results, and the choice of approach for cohort dosimetry for late effects studies should still be largely driven by the available resources (data, time, expertise, and funding). Show less
Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of... Show moreBackground: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up.Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [beta-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin).Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers beta-CTX and PINP remained stable.Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Show less
Aim: To investigate the health-related quality of life (HRQOL) of Dutch adult childhood cancer survivors (CCS) and to identify risk factors of impaired HRQOL.Methods: Adult CCS (age >18,... Show moreAim: To investigate the health-related quality of life (HRQOL) of Dutch adult childhood cancer survivors (CCS) and to identify risk factors of impaired HRQOL.Methods: Adult CCS (age >18, diagnosed <18, >= 5 years since diagnosis) from the Dutch LATER registry completed the Medical Outcome Study Short Form 36 (SF-36) to measure HRQOL and provided sociodemographic characteristics. Age-adjusted mean SF-36 scale scores of CCS were compared to the Dutch general population for men and women separately using t-tests, with effect size d. Multivariate logistic regression models were built to identify sociodemographic and cancer-related risk factors for impaired physical and mental HRQOL.Results: Both male and female CCS (N = 2301, mean age = 35.4 years, 49.6% female) reported significantly (p <= .005) worse HRQOL than the general population on almost all scales of the SF-36 (-.11 <= d <= -.56). Largest differences were found on vitality and general health perceptions. Significant risk factors (p <= .05) for impaired physical HRQOL were female sex, older age at diagnosis, not having a partner, low educational attainment, disease recurrence and exposure to radiotherapy, specifically to lower extremity radiation. Odds ratios (ORs) ranged from 1.6 to 3.7. Significant risk factors for impaired mental HRQOL were age 26-35 years, male sex, not having a partner and low educational attainment. ORs ranged from 1.3 to 2.0.Conclusion: Adult CCS had worse HRQOL than the general population. CCS most at risk were those with low educational attainment and without a partner. Adult CCS could benefit from routine surveillance of their HRQOL. Special attention for CCS' vitality and health perceptions and beliefs is warranted. (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Merkx, R.; Leerink, J.M.; Feijen, E.A.M.; Kremer, L.C.M.; Baat, E.C. de; Bellersen, L.; ... ; Dutch LATER Study Grp 2021
Background Cardiotoxicity is a well-known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation... Show moreBackground Cardiotoxicity is a well-known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation of echocardiographic measurements for early identification of CCS at highest risk of developing heart failure. This paper describes the design, feasibility, and reproducibility of the echocardiography protocol.Methods Echocardiograms from CCS and sibling controls were prospectively obtained at the participating centers and centrally analyzed. We describe the image acquisition, measurement protocol, and software-specific considerations for myocardial strain analyses. We report the feasibility of the primary outcomes of systolic and diastolic function, as well as reproducibility analyses in 30 subjects.Results We obtained 1,679 echocardiograms. Biplane ejection fraction (LVEF) measurement was feasible in 91% and 96% of CCS and siblings, respectively, global longitudinal strain (GLS) in 80% and 91%, global circumferential strain (GCS) in 86% and 89%, and >= 2 diastolic function parameters in 99% and 100%, right ventricle free wall strain (RVFWS) in 57% and 65%, and left atrial reservoir strain (LASr) in 72% and 79%. Intra-class correlation coefficients for inter-observer variability were 0.85 for LVEF, 0.76 for GLS, 0.70 for GCS, 0.89 for RVFWS and 0.89 for LASr. Intra-class correlation coefficients for intra-observer variability were 0.87 for LVEF, 0.82 for GLS, 0.82 for GCS, 0.85 for RVFWS and 0.79 for LASr.Conclusion The DCCSS LATER 2 CARD study includes a protocolized echocardiogram, with feasible and reproducible primary outcome measurements. This ensures high-quality outcome data for prevalence estimates and for reliable comparison of cardiac function parameters. Show less
Nies, M.; Cantineau, A.E.P.; Arts, E.G.J.M.; Berg, M.H. van den; Leeuwen, F.E. van; Kobold, A.C.M.; ... ; Links, T.P. 2020
Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to... Show moreBackground: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Mullerian hormone (AMH) levels (a marker of ovarian reserve).Methods: Female survivors of childhood DTC, diagnosed at <= 18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of I-131 administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) mu g/L vs. 1.6 (IQR 0.6-3.1) mu g/L, respectively, p = 0.244]. The cumulative dose of I-131 was not associated with AMH levels in DTC survivors (r(s) = 0.210, p = 0.130).Conclusions: Female survivors of DTC who received I-131 treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure. Show less
Leerink, J.M.; Feijen, E.L.A.M.; Pal, H.J.H. van der; Kok, W.E.M.; Mavinkurve-Groothuis, A.M.C.; Kapusta, L.; ... ; LATER Study Grp 2020
Background Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and... Show moreBackground Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure.Objective To describe the methodology of the Dutch LATER cardiology study (LATER CARD).Methods The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings.Conclusions The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure. Show less
Teepen, J.C.; Kremer, L.C.; Heiden-van der Loo, M. van der; Tissing, W.J.; Pal, H.J. van der; Heuvel-Eibrink, M.M. van den; ... ; DCOG-LATER Study Grp 2019
Purpose Childhood cancer survivors are at increased risk of developing subsequent malignant neoplasms (SMNs). We compared survival and clinical characteristics of survivors with SMNs (sarcoma,... Show morePurpose Childhood cancer survivors are at increased risk of developing subsequent malignant neoplasms (SMNs). We compared survival and clinical characteristics of survivors with SMNs (sarcoma, breast cancer, or melanoma) and a population-based sample of similar first malignant neoplasm (FMN) patients. Methods We assembled three case series of solid SMNs observed in a cohort of 5-year Dutch childhood cancer survivors diagnosed 1963-2001 and followed until 2014: sarcoma (n = 45), female breast cancer (n = 41), and melanoma (n = 17). Each SMN patient was sex-, age-, and calendar year-matched to 10 FMN patients in the population-based Netherlands Cancer Registry. We compared clinical and histopathological characteristics by Fisher's exact tests and survival by multivariable Cox regression and competing risk regression analyses. Results Among sarcoma-SMN patients, overall survival [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.23-2.87] and sarcoma-specific mortality (HR 1.91, 95% CI 1.16-3.13) were significantly worse compared to sarcoma-FMN patients (foremost for soft-tissue sarcoma), with 15-year survival rates of 30.8% and 61.6%, respectively. Overall survival did not significantly differ for breast-SMN versus breast-FMN patients (HR 1.14, 95% CI 0.54-2.37), nor for melanoma-SMN versus melanoma-FMN patients (HR 0.71, 95% CI 0.10-5.00). No significant differences in tumor characteristics were observed between breast-SMN and breast-FMN patients. Breast-SMN patients were treated more often with mastectomy without radiotherapy/chemotherapy compared to breast-FMN patients (17.1% vs. 5.6%). Conclusions Survival of sarcoma-SMN patients is worse than sarcoma-FMN patients. Although survival and tumor characteristics appear similar for breast-SMN and breast-FMN patients, treatment differs; breast-SMN patients less often receive breast-conserving therapy. Larger studies are necessary to substantiate these exploratory findings. Show less
