Inter-individual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: We aimed to discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SUBJECTS: A discovery cohort of adult female childhood cancer survivors, from the pan-European PanCareLIFE cohort (n=743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-based St. Jude Lifetime Cohort (n=391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure. INTERVENTION: No intervention was performed. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0x10-8) and 16 genome-wide suggestive (<5.0x10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10-6), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): -0.484 (0.091), p-value= 9.39×10-8). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity and as well as fertility preservation options for childhood cancer survivors.

Different subtypes of chronic fatigue in childhood cancer survivors: A DCCSS LATER study.

INTRODUCTION: The aim of the current study was to investigate whether subtypes of chronic fatigue (CF) can be identified in childhood cancer survivors (CCS), and if so, to determine the characteristics of participants with a specific subtype. METHODS: Participants were included from the nationwide DCCSS LATER cohort. The Checklist Individual Strength (CIS) was completed to assess fatigue. Participants with CF (scored ≥35 on the fatigue severity subscale and indicated to suffer from fatigue for ≥6 months) were divided into subgroups using two-step cluster analysis based on the CIS concentration, motivation, and physical activity subscales. Differences between groups on demographics, psychosocial, lifestyle, and treatment-related variables were determined using ANOVA and chi-square analyses (univariable) and multinomial regression analysis (multivariable). RESULTS: A total of 1910 participants participated in the current study (n = 450 with CF; n = 1460 without CF). Three CF subgroups were identified: Subgroup 1 (n = 133, 29% of participants) had CF with problems in physical activity; Subgroup 2 (n = 111, 25% of participants) had CF with difficulty concentrating; and Subgroup 3 (n = 206, 46% of participants) had multi-dimensional CF. Compared to Subgroup 1, Subgroup 2 more often reported sleep problems, limitations in social functioning, and less often have more than two comorbidities. Subgroup 3 more often reported depression, sleep problems, a lower self-esteem, and limitations in social functioning and a lower educational level compared to Subgroup 1. CONCLUSION: Different subgroups of CCS with CF can be identified based on fatigue dimensions physical activity, motivation and concentration. Results suggest that different intervention strategies, tailored for each subgroup, might be beneficial.

Unhealthy lifestyle behaviors, overweight, and obesity among childhood cancer survivors in the Netherlands: A DCCSS LATER study.

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/m2), 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/m2 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.

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors.

BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In 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. RESULTS: 16% 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. CONCLUSION: A 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%.

Reproductive outcomes and reproductive health care utilization among male survivors of childhood cancer: A DCCSS-LATER study.

BACKGROUND: Treatment-related gonadal dysfunction leading to fertility problems is a frequently encountered late effect in childhood cancer survivors (CCSs). This study evaluated reproductive outcomes and reproductive health care utilization among male CCSs compared with male siblings. METHODS: A nationwide cohort study was conducted as part of the Dutch Childhood Cancer Survivor LATER study part 1, a questionnaire and linkage study. A questionnaire addressing reproductive outcomes and reproductive health care was completed by 1317 male CCSs and 407 male siblings. A total of 491 CCSs and 185 siblings had a previous or current desire for children and were included in this study. RESULTS: Fewer CCSs had biological children compared with siblings (65% vs. 88%; p < .001). The type of conception by men who fathered a child was comparable between CCSs and siblings (spontaneous conception of 90% of both groups; p = .86). The percentage of men who had consulted a reproductive specialist because of not siring a pregnancy was higher in CCSs compared with siblings (34% vs. 12%; p < .001). Following consultation, fewer CCSs underwent assisted reproductive techniques (ART) compared with siblings (41% vs. 77%; p = .001). After ART, fewer CCSs fathered a child compared with siblings (49% vs. 94%; p = .001). CONCLUSIONS: More male survivors consult a reproductive specialist, but fewer survivors undergo ART and father a child after ART compared with siblings. This insight is important for understanding potential problems faced by survivors regarding family planning and emphasizes the importance of collaboration between oncologists and reproductive specialists.

The cumulative burden of self-reported, clinically relevant outcomes in long-term childhood cancer survivors and implications for survivorship care: A DCCSS LATER study.

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.

The Value of IgM Memory B-Cells in the Assessment of Splenic Function in Childhood Cancer Survivors at Risk for Splenic Dysfunction: A DCCSS-LATER Study.

Background: Childhood cancer survivors (CCS) who received radiotherapy involving the spleen or total body irradiation (TBI) might be at risk for splenic dysfunction. A comprehensive screening test for examining splenic dysfunction is lacking. Objective: We investigated whether IgM memory B-cells could be used to assess splenic dysfunction in CCS who received a splenectomy, radiotherapy involving the spleen, or TBI. Methods: All CCS were enrolled from the DCCSS-LATER cohort. We analyzed differences in IgM memory B-cells and Howell-Jolly bodies (HJB) in CCS who had a splenectomy (n = 9), received radiotherapy involving the spleen (n = 36), or TBI (n = 15). IgM memory B-cells < 9 cells/µL was defined as abnormal. Results: We observed a higher median number of IgM memory B-cells in CCS who received radiotherapy involving the spleen (31 cells/µL, p=0.06) or TBI (55 cells/µL, p = 0.03) compared to CCS who received splenectomy (20 cells/µL). However, only two CCS had IgM memory B-cells below the lower limit of normal. No difference in IgM memory B-cells was observed between CCS with HJB present and absent (35 cells/µL vs. 44 cells/µL). Conclusion: Although the number of IgM memory B-cells differed between splenectomized CCS and CCS who received radiotherapy involving the spleen or TBI, only two CCS showed abnormal values. Therefore, this assessment cannot be used to screen for splenic dysfunction.

Prevalence, risk factors, and optimal way to determine overweight, obesity, and morbid obesity in the first Dutch cohort of 2338 long-term survivors of childhood cancer: a DCCSS-LATER study.

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-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.

Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study.

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 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 long-term 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).

Psychosocial functioning of adult siblings of Dutch very long-term survivors of childhood cancer: DCCSS-LATER 2 psycho-oncology study.

OBJECTIVE: To describe psychosocial outcomes among adult siblings of very long-term childhood cancer survivors (CCS), to compare these outcomes to reference populations and to identify factors associated with siblings' psychosocial outcomes. METHODS: Siblings of survivors (diagnosed <18 years old, between 1963 and 2001, >5 years since diagnosis) of the Dutch Childhood Cancer Survivor Study DCCSS-LATER cohort were invited to complete questionnaires on HRQoL (TNO-AZL Questionnaire for Adult's HRQoL), anxiety/depression (Hospital Anxiety and Depression Scale), post-traumatic stress (Self-Rating Scale for Post-traumatic Stress Disorder), self-esteem (Rosenberg Self-Esteem Scale) and benefit and burden (Benefit and Burden Scale for Children). Outcomes were compared to a reference group if available, using Mann-Whitney U and chi-Square tests. Associations of siblings' sociodemographic and CCS' cancer-related characteristics with the outcomes were assessed with mixed model analysis. RESULTS: Five hundred five siblings (response rate 34%, 64% female, mean age 37.5, mean time since diagnosis 29.5) of 412 CCS participated. Siblings had comparable HRQoL, anxiety and self-esteem to references with no or small differences (r = 0.08-0.15, p < 0.05) and less depression. Proportions of symptomatic PTSD were very small (0.4%-0.6%). Effect sizes of associations of siblings' sociodemographic and CCS cancer-related characteristics were mostly small to medium (ß = 0.19-0.67, p < 0.05) and no clear trend was found in the studied associated factors for worse outcomes. CONCLUSIONS: On the very long-term, siblings do not have impaired psychosocial functioning compared to references. Cancer-related factors seem not to impact siblings' psychosocial functioning. Early support and education remain essential to prevent long-term consequences.

Psychosexual development, sexual functioning and sexual satisfaction in long-term childhood cancer survivors: DCCSS-LATER 2 sexuality substudy.

OBJECTIVES: Childhood 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. METHODS: From 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. RESULTS: One 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. CONCLUSIONS: Emerging 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.

Positive and negative survivor-specific psychosocial consequences of childhood cancer: the DCCSS-LATER 2 psycho-oncology study.

PURPOSE: Numerous studies investigated generic psychosocial outcomes in survivors of childhood cancer (CCS). The present study aimed to describe survivor-specific psychosocial consequences in CCS, and to identify socio-demographic and medical associated factors. METHODS: CCS from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (diagnosed 1963-2001) part 2 (age ≥ 18 years, diagnosed < 18 years, ≥ 5 years since diagnosis) completed the Benefit & Burden Scale (BBSC) and the Impact of Cancer-Childhood Cancer (IOC-CS). Items were scored on a 5-point Likert scale (range 1-5). We examined outcomes with descriptive statistics, and socio-demographic and medical associated factors with regression analyses, corrected for multiple testing (p < 0.004). RESULTS: CCS, N = 1713, age mean (M) 36 years, 49% female, ≥ 15 years since diagnosis, participated. On average, CCS reported 'somewhat' Benefit (M = 2.9), and 'not at all' to 'a little' Burden (M = 1.5) of childhood cancer. Average scores on IOC-CS' positive impact scales ranged from 2.5 (Personal Growth) to 4.1 (Socializing), and on the negative impact scales from 1.4 (Financial Problems) to 2.4 (Thinking/Memory). Apart from cognitive problems, CCS reported challenges as worries about relationship status, fertility, and how cancer had affected siblings. Female sex was associated with more Personal Growth, and more negative impact. CCS more highly educated, partnered, and employed had higher positive and lower negative impact. CCS older at diagnosis reported more positive impact. CNS tumor survivors and those who had head/cranium radiotherapy had higher negative impact. CNS tumor survivors reported less positive impact. CONCLUSION AND IMPLICATIONS: The majority of CCS reported positive impact of cancer while most CCS reported little negative impact. While this may indicate resiliency in most CCS, health care providers should be aware that they can also experience survivor-specific challenges that warrant monitoring/screening, information provision and psychosocial support.

Frailty and sarcopenia within the earliest national Dutch childhood cancer survivor cohort (DCCSS-LATER): a cross-sectional study.

BACKGROUND: Childhood cancer survivors appear to be at increased risk of frailty and sarcopenia, but evidence on the occurrence of and high-risk groups for these aging phenotypes is scarce, especially in European survivors. The aim of this cross-sectional study was to assess the prevalence of and explore risk factors for pre-frailty, frailty, and sarcopenia in a national cohort of Dutch childhood cancer survivors diagnosed between 1963 and 2001. METHODS: Eligible individuals (alive at the time of study, living in the Netherlands, age 18-45 years, and had not previously declined to participate in a late-effects study) from the Dutch Childhood Cancer Survivor Study (DCCSS-LATER) cohort were invited to take part in this cross-sectional study. We defined pre-frailty and frailty according to modified Fried criteria, and sarcopenia according to the European Working Group on Sarcopenia in Older People 2 definition. Associations between these conditions and demographic and treatment-related as well as endocrine and lifestyle-related factors were estimated with two separate multivariable logistic regression models in survivors with any frailty measurement or complete sarcopenia measurements. FINDINGS: 3996 adult survivors of the DCCSS-LATER cohort were invited to participate in this cross-sectional study. 1993 non-participants were excluded due to lack of response or a decline to participate and 2003 (50·1%) childhood cancer survivors aged 18-45 years were included. 1114 (55·6%) participants had complete frailty measurements and 1472 (73·5%) participants had complete sarcopenia measurements. Mean age at participation was 33·1 years (SD  7·2). 1037 (51·8%) participants were male, 966 (48·2%) were female, and none were transgender. In survivors with complete frailty measurements or complete sarcopenia measurements, the percentage of pre-frailty was 20·3% (95% CI 18·0-22·7), frailty was 7·4% (6·0-9·0), and sarcopenia was 4·4% (3·5-5·6). In the models for pre-frailty, underweight (odds ratio [OR] 3·38 [95% CI 1·92-5·95]) and obesity (OR 1·67 [1·14-2·43]), cranial irradiation (OR 2·07 [1·47-2·93]), total body irradiation (OR 3·17 [1·77-5·70]), cisplatin dose of at least 600 mg/m2 (OR 3·75 [1·82-7·74]), growth hormone deficiency (OR 2·25 [1·23-4·09]), hyperthyroidism (OR 3·72 [1·63-8·47]), bone mineral density (Z score ≤-1 and >-2, OR 1·80 [95% CI 1·31-2·47]; Z score ≤-2, OR 3·37 [2·20-5·15]), and folic acid deficiency (OR 1·87 [1·31-2·68]) were considered significant. For frailty, associated factors included age at diagnosis between 10-18 years (OR 1·94 [95% CI 1·19-3·16]), underweight (OR 3·09 [1·42-6·69]), cranial irradiation (OR 2·65 [1·59-4·34]), total body irradiation (OR 3·28 [1·48-7·28]), cisplatin dose of at least 600 mg/m2 (OR 3·93 [1·45-10·67]), higher carboplatin doses (per g/m2; OR 1·15 [1·02-1·31]), cyclophosphamide equivalent dose of at least 20 g/m2 (OR 3·90 [1·65-9·24]), hyperthyroidism (OR 2·87 [1·06-7·76]), bone mineral density Z score ≤-2 (OR 2·85 [1·54-5·29]), and folic acid deficiency (OR 2·04 [1·20-3·46]). Male sex (OR 4·56 [95%CI 2·26-9·17]), lower BMI (continuous, OR 0·52 [0·45-0·60]), cranial irradiation (OR 3·87 [1·80-8·31]), total body irradiation (OR 4·52 [1·67-12·20]), hypogonadism (OR 3·96 [1·40-11·18]), growth hormone deficiency (OR 4·66 [1·44-15·15]), and vitamin B12 deficiency (OR 6·26 [2·17-1·81]) were significantly associated with sarcopenia. INTERPRETATION: Our findings show that frailty and sarcopenia occur already at a mean age of 33 years in childhood cancer survivors. Early recognition and interventions for endocrine disorders and dietary deficiencies could be important in minimising the risk of pre-frailty, frailty, and sarcopenia in this population. FUNDING: Children Cancer-free Foundation, KiKaRoW, Dutch Cancer Society, ODAS Foundation.

Psychosocial outcomes in long-term Dutch adult survivors of childhood cancer: The DCCSS-LATER 2 psycho-oncology study.

BACKGROUND: This study compares a comprehensive range of psychosocial outcomes of adult childhood cancer survivors (CCS) to general population-based references and identifies sociodemographic and medical risk factors. METHODS: CCS from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (diagnosed 1963-2001) part 2 (attained age ≥18 years, diagnosed <18 years, ≥5 years since diagnosis) completed the Rosenberg Self-Esteem Scale, Hospital Anxiety and Depression Scale, Distress Thermometer, Self-Rating Scale for Post-Traumatic Stress Disorder, and the Short Form-36 (Health Related Quality of Life). CCS' scores were compared with references using analysis of variances and logistic regression analysis, controlling for age and sex (p < .05). Risk factors for worse psychosocial outcomes were assessed with regression analyses (p < .05). RESULTS: CCS, N = 1797, mean age 35.4 years, 49.0% female, all ≥15 years since diagnosis, participated. Three percent reported posttraumatic stress disorder because of childhood cancer and 36.6% experienced clinical distress. CCS did not differ from references on self-esteem and anxiety but were less depressed (d = -.25), and scored poorer on all health-related quality of life scales, except for bodily pain (.01 ≤ d  ≥  -.36). Female sex, lower educational attainment, not being in a relationship, and being unemployed were negatively associated with almost all psychosocial outcomes. Except for a central nervous system tumor diagnosis, few medical characteristics were associated with psychosocial outcomes. CONCLUSION: CCS appear resilient regarding mental health but have slightly poorer health-related quality of life than references. Sociodemographic characteristics and central nervous system tumors were related to most psychosocial outcomes, but no clear pattern was observed for other medical factors. Future studies should address additional factors in explaining CCS' psychosocial functioning, such as coping, social support, and physical late effects.

Desire for children among male survivors of childhood cancer: A DCCSS LATER study.

BACKGROUND: Knowledge of the desire for children among childhood cancer survivors (CCSs) is scarce. This study evaluated the desire for children in male CCSs in comparison with male siblings. METHODS: A nationwide cohort study was conducted as part of the Dutch Childhood Cancer Survivor Study LATER study: 1317 male CCSs and 407 male sibling controls completed a questionnaire addressing the desire for children. Logistic regression analyses were used to explore the independent association between survivorship status and the desire for children. Furthermore, additional analyses were performed to identify which cancer-related factors were associated with the desire for children in male CCSs. RESULTS: After adjustments for the age at assessment, the percentage of men who had a desire for children was significantly lower among CCSs compared with the siblings (74% vs. 82%; odds ratio [OR], 0.61; 95% CI, 0.46-0.82; p = .001). The association between survivorship status and the desire for children was attenuated after adjustments for marital status, level of education, and employment status (OR, 0.83; 95% CI, 0.61-1.14; p = .250). The percentage of men who had an unfulfilled desire for children remained significantly higher among CCSs compared with the siblings after adjustments for sociodemographic factors (25% vs. 7%; OR, 5.14; 95% CI, 2.48-10.64; p < .001). CONCLUSIONS: The majority of male CCSs have a desire for children. The likelihood of having to deal with an unfulfilled desire for children is 5 times higher among CCSs compared with their siblings. This insight is important for understanding the needs and experienced problems of CCSs regarding family planning and fertility issues.

Reproductive ability in survivors of childhood, adolescent, and young adult Hodgkin lymphoma: a review.

BACKGROUND: Owing to a growing number of young and adolescent Hodgkin lymphoma (HL) survivors, awareness of (long-term) adverse effects of anticancer treatment increases. The risk of impaired reproductive ability is of great concern given its impact on quality of life. There is currently no review available on fertility after childhood HL treatment. OBJECTIVE AND RATIONALE: The aim of this narrative review was to summarize existing literature on different aspects of reproductive function in male and female childhood, adolescent, and young adult HL survivors. SEARCH METHODS: PubMed and EMBASE were searched for articles evaluating fertility in both male and female HL survivors aged <25 years at diagnosis. In females, anti-Müllerian hormone (AMH), antral follicle count, premature ovarian insufficiency (POI), acute ovarian failure, menstrual cycle, FSH, and pregnancy/live births were evaluated. In males, semen-analysis, serum FSH, inhibin B, LH, testosterone, and reports on pregnancy/live births were included. There was profound heterogeneity among studies and a lack of control groups; therefore, no meta-analyses could be performed. Results were presented descriptively and the quality of studies was not assessed individually. OUTCOMES: After screening, 75 articles reporting on reproductive markers in childhood or adolescent HL survivors were included. Forty-one papers reported on 5057 female HL survivors. The incidence of POI was 6-34% (median 9%; seven studies). Signs of diminished ovarian reserve or impaired ovarian function were frequently seen (low AMH 55-59%; median 57%; two studies. elevated FSH 17-100%; median 53%; seven studies). Most survivors had regular menstrual cycles. Fifty-one studies assessed fertility in 1903 male HL survivors. Post-treatment azoospermia was highly prevalent (33-100%; median 75%; 29 studies). Long-term follow-up data were limited, but reports on recovery of semen up to 12 years post-treatment exist. FSH levels were often elevated with low inhibin B (elevated FSH 0-100%; median 51.5%; 26 studies. low inhibin B 19-50%; median 45%; three studies). LH and testosterone levels were less evidently affected (elevated LH 0-57%, median 17%; 21 studies and low testosterone 0-43%; median 6%; 15 studies). In both sexes, impaired reproductive ability was associated with a higher dose of cumulative chemotherapeutic agents and pelvic radiotherapy. The presence of abnormal markers before treatment indicated that the disease itself may also negatively affect reproductive function (Females: AMH

Adverse late health outcomes among children treated with 3D radiotherapy techniques: Study design of the Dutch pediatric 3D-RT study.

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.

Clinical evaluation of late outcomes in Dutch childhood cancer survivors: Methodology of the DCCSS LATER 2 study.

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 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.

Risk and determinants of low and very low bone mineral density and fractures in a national cohort of Dutch adult childhood cancer survivors (DCCSS-LATER): a cross-sectional study.

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 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 (64·8%) of 6165 individuals from the DCCSS LATER cohort were invited to participate, of whom 2003 (50·1%) were enrolled (mean age at participation was 33·1 years [SD 7·2], 966 [48·2%] were female, and 1037 [51·8%] were male [data on ethnicity and race were not available due to national policies]). 1548 (77·3%) had evaluable DXA scans for assessment of BMD, 1892 (94·5%) provided medical history of fractures, and 249 (12·4%) were assessed for vertebral fractures. 559 (36·1%) of 1548 had low BMD at any site, and 149 (9·6%) had very low BMD at any site. The standardised incidence ratio of any first fracture was 3·53 (95% CI 3·06-4·06) for male participants and 5·35 (4·46-6·52) for female participants. 33 (13·3%) 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. FUNDING: Children Cancer-free Foundation (KiKa), KiKaRoW, and ODAS foundation.

Questionnaire- and linkage-based outcomes in Dutch childhood cancer survivors: Methodology of the DCCSS LATER study part 1.

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.