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.

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.

Feasibility and potential effectiveness of nurse-led video-coaching interventions for childhood, adolescent, and young adult cancer survivors: the REVIVER study.

BACKGROUND: Childhood, adolescent, and young adult (CAYA) cancer survivors, at risk for late effects, including cancer-related fatigue, cardiovascular issues, and psychosocial challenges, may benefit from interventions stimulating behaviour adjustments. Three nurse-led eHealth interventions (REVIVER) delivered via video calls and elaborating on person-centred care, cognitive behaviour therapy and/or motivational interviewing were developed. These interventions target: 1) fatigue management, 2) healthier lifestyle behaviours, and 3) self-efficacy and self-management. This study aimed to assess the feasibility and potential effectiveness of the REVIVER interventions for CAYA cancer survivors and healthcare professionals. METHODS: In a single-group mixed methods design, CAYA cancer survivors aged 16-54, more than five years post-treatment, were enrolled. Feasibility, assessed via Bowen's outcomes for feasibility studies, included acceptability, practicality, integration and implementation, demand and adherence. Qualitative data from semi-structured interviews and a focus group interview with survivors and healthcare professionals supplemented the evaluation. Paired sample t-tests assessed changes in self-reported quality of life, fatigue, lifestyle, self-management, and self-efficacy at baseline (T0), post-intervention (T1), and 6-month follow-up (T2). RESULTS: The interventions and video consults were generally acceptable, practical, and successfully integrated and implemented. Success factors included the nurse consultant (i.e., communication, approach, and attitude) and the personalised approach. Barriers included sustainability concerns, technical issues, and short intervention duration. Regarding demand, 71.4%, 65.4%, and 100% of eligible CAYA cancer survivors engaged in the fatigue (N = 15), lifestyle (N = 17) and empowerment (N = 3) intervention, respectively, with 5, 5 and 2 participants interviewed, correspondingly. Low interest (demand) in the empowerment intervention (N = 3) and dropout rates of one-third for both fatigue and empowerment interventions were noted (adherence). Improvements in quality of life, fatigue (fatigue intervention), lifestyle (lifestyle intervention), self-efficacy, and self-management were evident among survivors who completed the fatigue and lifestyle interventions, with medium and large effect sizes observed immediately after the intervention and six months post-intervention. CONCLUSIONS: Our study demonstrates the feasibility of nurse-led video coaching (REVIVER interventions) despite lower demand for the empowerment intervention and lower adherence to the fatigue and empowerment interventions. The medium and high effect sizes found for those who completed the interventions hold potential clinical significance for future studies investigating the effectiveness of the REVIVER interventions.

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.

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.

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.

Psychosocial functioning of parents of Dutch long-term survivors of childhood cancer.

OBJECTIVE: To describe health-related quality of life (HRQoL), post-traumatic stress and post-traumatic growth of parents of long-term survivors of childhood cancer (CCS) and study associated factors. METHODS: Parents of survivors of the Dutch Childhood Cancer Survivor Study LATER cohort below 30 years and diagnosed 1986-2001 were invited to complete the TNO-AZL Questionnaire for Adult's HRQoL (e.g., sleep and aggressive emotions), Self-Rating Scale for Post-traumatic Stress Disorder, Post-traumatic Growth Inventory, and Illness Cognition Questionnaire. HRQoL domain scores were compared to references using Mann-Whitney U tests. Correlations between post-traumatic stress, growth and HRQoL were evaluated. Medical characteristics of their child and illness cognitions were studied as associated factors of HRQOL, post-traumatic stress and growth. p < 0.05 was considered statistically significant. RESULTS: Parents (n = 661 of n = 448 survivors, 56% female, mean time since child's diagnosis: 21.3 [SD: 3.3] years) reported better HRQoL in social functioning and aggressive emotions than references (r = .08-0.17). Mothers additionally reported better HRQoL in pain, daily activities, sexuality, vitality, positive and depressive emotions (r = .07-0.14). Post-traumatic stress was symptomatic in 3%, and associated with worse HRQoL (r = -0.27-0.48). Post-traumatic growth was positively associated to post-traumatic stress and better HRQoL (r = 0.09-0.12). Cancer recurrence was associated to better HRQoL (ß = 0.37-0.46). Acceptance illness cognitions were associated to better (ß = 0.12-0.25), and helplessness to worse outcomes (ß = 0.14-0.38). CONCLUSIONS: HRQoL of parents of young adult survivors of CCS is comparable to references or slightly better. Only a small proportion reports symptomatic post-traumatic stress. Improving acceptance and reducing feelings of helplessness may provide treatment targets for parents with psychosocial problems.

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.

Self-reported outcomes on oral health and oral health-related quality of life in long-term childhood cancer survivors-A DCCSS-LATER 2 Study.

PURPOSE: The 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). METHODS: Patient 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. RESULTS: A 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. CONCLUSION: Though 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.

The Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 kidney analysis examined long-term glomerular dysfunction in childhood cancer survivors.

This investigation aimed to evaluate glomerular dysfunction among childhood cancer survivors in comparison with matched controls from the general population. In the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, 1024 survivors five or more years after diagnosis, aged 18 or more years at study, treated between 1963-2001 with nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation participated. In addition, 500 age- and sex-matched controls from Lifelines, a prospective population-based cohort study in the Netherlands, participated. At a median age of 32.0 years (interquartile range 26.6-37.4), the glomerular filtration rate was under 60 ml/min/1.73m2 in 3.7% of survivors and in none of the controls. Ten survivors had kidney failure. Chronic kidney disease according to age-thresholds (glomerular filtration rate respectively under 75 for age under 40, under 60 for ages 40-65, and under 40 for age over 65) was 6.6% in survivors vs. 0.2% in controls. Albuminuria (albumin-to-creatinine ratio over3 mg/mmol) was found in 16.2% of survivors and 1.2% of controls. Risk factors for chronic kidney disease, based on multivariable analyses, were nephrectomy (odds ratio 3.7 (95% Confidence interval 2.1-6.4)), abdominal radiotherapy (1.8 (1.1-2.9)), ifosfamide (2.9 (1.9-4.4)) and cisplatin over 500 mg/m2 (7.2 (3.4-15.2)). For albuminuria, risk factors were total body irradiation (2.3 (1.2-4.4)), abdominal radiotherapy over 30 Gy (2.6 (1.4- 5.0)) and ifosfamide (1.6 (1.0-2.4)). Hypertension and follow-up 30 or more years increased the risk for glomerular dysfunction. Thus, lifetime monitoring of glomerular function in survivors exposed to these identified high risk factors is warranted.

Prevalence and risk factors of cancer-related fatigue in childhood cancer survivors: A DCCSS LATER study.

BACKGROUND: Cancer-related fatigue is a debilitating late effect after treatment for childhood cancer. The prevalence of fatigue in childhood cancer survivors (CCSs) and associated factors for fatigue has varied widely in previous studies. Two important aspects of cancer-related fatigue, its severity and chronicity, are often not assessed. This study investigated the prevalence of, and risk factors for, severe chronic fatigue (CF) in a national cohort of Dutch CCSs. METHODS: In this study, 2810 CCSs (5-year survivors of all childhood malignancies diagnosed between 1963 and 2001 with a current age of 12-65 years) and 1040 sibling controls were included. CF was assessed with the Short Fatigue Questionnaire and was defined as a score ≥ 18 and persistence of fatigue for ≥6 months. Cancer- and treatment-related characteristics, current health problems, and demographic and lifestyle variables were assessed as potential risk factors for CF via multivariable logistic regression analyses. RESULTS: In adult CCSs and sibling controls (≥18 years old), the prevalence of CF was 26.1% and 14.1%, respectively (P < .001). In adolescent CCSs and sibling controls (<18 years old), the prevalence of CF was 10.9% and 3.2%, respectively. Female gender (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.73-2.62), unemployment (OR, 2.18; 95% CI, 1.67-2.85), having 1 or more health problems (OR for 1-2, 1.48; 95% CI, 1.18-1.87; OR for >2, 2.20; 95% CI, 1.50-3.21), and a central nervous system diagnosis (OR, 1.74; 95% CI, 1.17-2.60) were significantly associated with CF in adult CCSs. CONCLUSIONS: This study shows that CCSs, regardless of their cancer diagnosis, report CF more often than sibling controls. This study provides new evidence for the prevalence of fatigue in CCSs.

Increased health-related quality of life impairments of male and female survivors of childhood cancer: DCCSS LATER 2 psycho-oncology study.

BACKGROUND: The objective of this study was to compare the health-related quality of life (HRQOL) of Dutch adult male and female childhood cancer survivors (CCSs) to general population references and to study medical determinants. METHODS: CCSs from the Dutch Childhood Cancer Survivor Study LATER cohort (1963-2001) part 2, who were 18 years old or older (time since diagnosis ≥ 5 years), were invited to complete the TNO-AZL Questionnaire for Adult Health-Related Quality of Life. Domain scores and proportions of CCSs with impaired HRQOL (score < 25th percentile of the reference scores) were compared with references via Mann-Whitney U tests and logistic regression analyses corrected for age and sex (P < .004). Interactions of group with sex were included if they were significant (P < .05). Moreover, medical determinants were analyzed with multivariable logistic regression analyses. RESULTS: HRQOL scores for 1766 CCSs (mean age, 35.9 years [standard deviation, 9.4 years]; male, 51%; response rate, 71%) differed from references on most domains with small effect sizes. Both male and female CCSs were more often impaired in gross and fine motor functioning, cognitive functioning, sleep, and vitality with odds ratios (ORs) > 1.4. In addition, female CCSs were more often impaired in daily activities, pain, and sexuality (ORs, 1.4-1.9) and were less often aggressive (OR, 0.6). CCCs of central nervous system (CNS) tumors, bone tumors, and retinoblastoma and those with cranial, abdominopelvic, or lower extremity radiotherapy were at increased risk of impairment in 1 or more domains. CONCLUSIONS: Dutch adult CCSs, especially females, have impaired HRQOL in several domains; this is most pronounced in cognitive functioning. The vulnerabilities of subgroups at risk, such as CCSs of CNS tumors, were confirmed. Surveillance of HRQOL and multidisciplinary survivor care are recommended. LAY SUMMARY: The health-related quality of life in a Dutch nationwide cohort of 1766 survivors of childhood cancer was studied. Survivors of childhood cancer were found to have lower health-related quality of life in several domains (eg, motor functioning and vitality) in comparison with the general population. They most often reported low cognitive functioning (eg, memory and attention). Females had low health-related quality of life in more domains than males. Survivors of brain tumors had low health-related quality of life in most domains. Monitoring health-related quality of life regularly and collaborating between disciplines in survivor care is recommended.

Late Mortality in Childhood Cancer Survivors according to Pediatric Cancer Diagnosis and Treatment Era in the Dutch LATER Cohort.

This multi-center cohort-study examined late mortality among 6,165 Dutch five-year childhood cancer survivors diagnosed 1963-2001. Clinical details and cause of death were based on medical records. Mortality was 12-fold that of the general population, with 51.3 additional deaths per 10,000 person-years (21.9 yrs median follow-up). Cumulative mortality 15 yrs post-diagnosis was 6.9%, predominantly from late recurrences; thereafter the absolute contribution of other health outcomes increased. Cumulative all-cause and recurrence-related mortality were highest for Central Nervous System and bone tumor survivors. All-cause, but not subsequent tumor and circulatory disease-related cumulative mortality, was highest for patients diagnosed 1963-1979 vs. later (p-trend <0.001).

Long-term cognitive, psychosocial, and neurovascular complications of unilateral head and neck irradiation in young to middle-aged adults.

BACKGROUND: With a growing, younger population of head and neck cancer survivors, attention to long-term side-effects of prior, often radiotherapeutic, treatment is warranted. Therefore, we studied the long-term cognitive effects in young adult patients irradiated for head and neck neoplasms (HNN). METHODS: Young to middle-aged adults with HNN (aged 18-40 years) and treated with unilateral neck irradiation ≥ 5 years before inclusion underwent cardiovascular risk and neuropsychological assessments and answered validated questionnaires regarding subjective cognitive complaints, fatigue, depression, quality of life, and cancer-specific distress. Additionally, magnetic resonance imaging (MRI) of the brain was performed to assess white matter hyperintensities (WMH), infarctions, and atrophy. RESULTS: Twenty-nine patients (aged 24-61, 13 men) median 9.2 [7.3-12.9] years post-treatment were included. HNN patients performed worse in episodic memory (Z-score = -1.16 [-1.58-0.34], p < 0.001) and reported more fatigue symptoms (Z-score = 1.75 [1.21-2.00], p < 0.001) compared to normative data. Furthermore, patients had a high level of fear of tumor recurrence (13 patients [44.8%]) and a heightened speech handicap index (13 patients [44.8%]). Only a small number of neurovascular lesions were found (3 infarctions in 2 patients and 0.11 [0.00-0.40] mL WMH), unrelated to the irradiated side. Cognitive impairment was not associated with WMH, brain atrophy, fatigue, or subjective speech problems. CONCLUSIONS: HNN patients showed impairments in episodic memory and an increased level of fatigue ≥ 5 years after radiotherapy compared to normative data. Cognitive impairments could not be explained by WMH or brain atrophy on brain MRI or psychological factors. TRIAL REGISTRATION: Clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT04257968 ).

Psychosocial developmental milestones of young adult survivors of childhood cancer.

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 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.

Shrunken pore syndrome in childhood cancer survivors treated with potentially nephrotoxic therapy.

Childhood cancer survivors (CCS) are at risk of kidney dysfunction. Recently, the shrunken pore syndrome (SPS) has been described, which is characterized by selectively impaired filtration of larger molecules like cystatin C, while filtration of smaller molecules like creatinine is unaltered. It has been associated with increased mortality, even in the presence of a normal estimated glomerular filtration rate (eGFR). The aim of this study was to evaluate the prevalence of SPS in CCS exposed to potentially nephrotoxic therapy. In the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 Renal study, a nationwide cross-sectional cohort study, 1024 CCS ≥5 years after diagnosis, aged ≥18 years at study, treated between 1963-2001 with nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation participated, and 500 age- and sex-matched controls form Lifelines. SPS was defined as an eGFRcys/eGFRcr ratio <0.6 in the absence of non-GFR determinants of cystatin C and creatinine metabolism (i.e. hyperthyroidism, corticosteroids, underweight). Three pairs of eGFR-equations were used; CKD-EPIcys/CKD-EPIcr, CAPA/LMR, and FAScys/FASage. Median age was 32 years. Although an eGFRcys/eGFRcr ratio <0.6 was more common in CCS (1.0%) than controls (0%) based on the CKD-EPI equations, most cases were explained by non-GFR determinants. The prevalence of SPS in CCS was 0.3% (CKD-EPI equations), 0.2% (CAPA/LMR) and 0.1% (FAS equations), and not increased compared to controls. CCS treated with nephrotoxic therapy are not at increased risk for SPS compared to controls. Yet, non-GFR determinants are more common and should be taken into account when estimating GFR.

Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function.

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Diagnostic tools for early detection of cardiac dysfunction in childhood cancer survivors: Methodological aspects of the Dutch late effects after childhood cancer (LATER) cardiology study.

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 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.

Clinical characteristics and survival patterns of subsequent sarcoma, breast cancer, and melanoma after childhood cancer in the DCOG-LATER cohort.

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, 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.