A Biomarker-Based Diagnostic Model for Cardiac Dysfunction in Childhood Cancer Survivors.

Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested. Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors. Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics. Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%). Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).

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.

Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. METHODS: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940-2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. RESULTS: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. DISCUSSION: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms.

Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.

PURPOSE: Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study. METHODS: Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area. RESULTS: Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected). CONCLUSION: We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk.

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.

A User's Guide and Summary of Pediatric Normal Tissue Effects in the Clinic (PENTEC): Radiation Dose-Volume Response for Adverse Effects After Childhood Cancer Therapy and Future Directions.

Pediatric Normal Tissue Effects in the Clinic (PENTEC) is an international multidisciplinary effort that aims to summarize normal-tissue toxicity risks based on published dose-volume data from studies of children and adolescents treated with radiation therapy (RT) for cancer. With recognition that children are uniquely vulnerable to treatment-related toxic effects, our mission and challenge was to assemble our group of physicians (radiation and pediatric oncologists, subspecialists), physicists with clinical and modeling expertise, epidemiologists, and other scientists to develop evidence-based radiation dosimetric guidelines, as affected by developmental status and other factors (eg, other cancer therapies and host factors). These quantitative toxicity risk estimates could serve to inform RT planning and thereby improve outcomes. Tandem goals included the description of relevant medical physics issues specific to pediatric RT and the proposal of dose-volume outcome reporting standards to inform future studies. We created 19 organ-specific task forces and methodology to unravel the wealth of data from heterogeneous published studies. This report provides a high-level summary of PENTEC's genesis, methods, key findings, and associated concepts that affected our work and an explanation of how our findings may be interpreted and applied in the clinic. We acknowledge our predecessors in these efforts, and we pay homage to the children whose lives informed us and to future generations who we hope will benefit from this additional step in our path forward.

Risk of Subsequent Neoplasms in Childhood Cancer Survivors After Radiation Therapy: A Comprehensive PENTEC Review.

PURPOSE: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors. METHODS AND MATERIALS: A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated. RESULTS: The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs. CONCLUSIONS: This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors.

Modeling the Risk of Hearing Loss From Radiation Therapy in Childhood Cancer Survivors: A PENTEC Comprehensive Review.

PURPOSE: The Pediatric Normal Tissue Effects in the Clinic (PENTEC) hearing loss (HL) task force reviewed investigations on cochlear radiation dose-response relationships and risk factors for developing HL. Evidence-based dose-response data are quantified to guide treatment planning. METHODS AND MATERIALS: A systematic review of the literature was performed to correlate HL with cochlear dosimetry. HL was considered present if a threshold exceeded 20 dB at any frequency. Radiation dose, ototoxic chemotherapy exposure, hearing profile including frequency spectra, interval to HL, and age at radiation therapy (RT) were analyzed. RESULTS: Literature was systematically reviewed from 1970 to 2021. This resulted in 739 abstracts; 19 met inclusion for meta-analysis, and 4 included data amenable to statistical modeling. These 4 studies included 457 cochleas at risk in patients treated with RT without chemotherapy, and 398 cochlea treated with chemotherapy. The incidence and severity of cochlear HL from RT exposure alone is related to dose and age. Risk of HL was <5% in cochlea receiving a mean dose ≤35 Gy but increased to 30% at 50 Gy. HL risk ranged from 25% to 40% in children under the age of 5 years at diagnosis, declining to 10% in older children for any radiation dose. Probability of similar severe HL occurred at doses 18.3 Gy higher for children <3 versus >3 years of age. High-frequency HL was most common, with average onset occurring 3.6 years (range, 0.4-13.2 years) after RT. Exposure to platinum-based chemotherapies added to the rates of HL at a given cochlear dose level, with 300 mg/m2 shifting the dose response by 7 Gy. CONCLUSIONS: In children treated with RT alone, risk of HL was low for cochlear dose <35 Gy and rose when dose exceeded 35 Gy without clear RT dose dependence. High-frequency HL was most prevalent, but all frequencies were affected. Children younger than 5 years were at highest risk of developing HL, although independent effects of dose and age were not fully elucidated. Future reports with more granular data are needed to better delineate time to onset of HL and the effects of chemoradiotherapy.

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.

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.

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 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 ≥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 ≥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 ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

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).

Updated International Guidelines for Survivorship Care after Pediatric Cancer: Practice Implications in a German and Austrian Comprehensive Care Network.

BACKGROUND: Timely diagnosis of treatment-related chronic health conditions in childhood cancer survivors (CCS) may result in reduced long-term morbidity and mortality. Evidence-based guidelines serve as a tool to implement risk-adapted screening examinations in long-term follow-up (LTFU) of CCS. SUMMARY: New international LTFU guidelines from the last 3 years have been reviewed and included into a practical LTFU tool in order to provide an updated summary of LTFU recommendations. The inclusion of 13 new LTFU guidelines as well as 25 pragmatic recommendations resulted in an updated LTFU plan for implantation in daily practice. Special consideration of psychosocial and mental health aspects as well as recommendations for pregnant CCS complement holistic LTFU care. KEY MESSAGES: Risk-adapted LTFU in CCS offers the possibility for early detection and treatment of late effects. As these LTFU recommendations aim at asymptomatic individuals, benefits and potential risks of regular screening examinations have to be carefully balanced. Implementation of current evidence-based guidelines in clinical practice as well as the development of new application tools such as the Survivorship Passport can contribute to an individualized LTFU approach in order to ensure long-term health and quality of life in CCS.

Liver Late Effects in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: A pediatric normal tissue effects in the clinic (PENTEC) comprehensive review of patients with childhood cancer who received radiation therapy (RT) to the liver was performed to develop models that may inform RT dose constraints for the liver and improve risk forecasting of toxicities. METHODS AND MATERIALS: A systematic literature search was performed to identify published data on hepatic toxicities in children. Treatment and outcome data were extracted and used to generate normal tissue complication probability (NTCP) models. Complications from both whole and partial liver irradiation were considered. For whole liver irradiation, total body irradiation and non-total body irradiation treatments were considered, but it was assumed that the entire liver received the prescribed dose. For partial liver irradiation, only Wilms tumor flank field RT could be analyzed. However, a prescribed dose assumption could not be applied, and there was a paucity of analyzable liver dosimetry data. To associate the dose-volume exposures with the partial volume complication data from flank irradiation, liver dose-volume metrics were reconstructed for Wilms tumor flank RT using age-specific computational phantoms as a function of field laterality and superior extent of the field. RESULTS: The literature search identified 2103 investigations pertaining to hepatic sinusoidal obstructive syndrome (SOS) and liver failure in pediatric patients. All abstracts were screened, and 241 articles were reviewed in full by the study team. A model was developed to calculate the risk of developing SOS after whole liver RT. RT dose (P = .006) and receipt of nonalkylating chemotherapy (P = .01) were significant. Age <20 years at time of RT was borderline significant (P = .058). The model predicted a 2% risk of SOS with zero RT dose, 6.1% following 10 Gy, and 14.5% following 20 Gy to the whole liver (modeled as the linear-quadratic equivalent dose in 2-Gy fractions [α/ß = 3 Gy]). Patients with Wilms tumor treated with right flank RT had a higher observed rate of SOS than patients receiving left flank RT, but data were insufficient to generate an NTCP model for partial liver irradiation. From the phantom-based dose reconstructions, mean liver dose was estimated to be 2.16 ± 1.15 Gy and 6.54 ± 2.50 Gy for left and right flank RT, respectively, using T10-T11 as the superior field border and a prescription dose of 10.8 Gy (based on dose reconstruction). Data were sparse regarding rates of late liver injury after RT, which suggests low rates of severe toxicity after treatment for common pediatric malignancies. CONCLUSIONS: This pediatric normal tissue effects in the clinic (PENTEC) review provides an NTCP model to estimate the risk of hepatic SOS as a function of RT dose following whole liver RT and quantifies the range of mean liver doses from typical Wilms tumor flank irradiation fields. Patients treated with right flank RT had higher rates of SOS than patients treated with left flank RT, but data were insufficient to develop a model for partial liver irradiation. Risk of SOS was estimated to be approximately ≤6% in pediatric patients receiving whole liver doses of <10 Gy.

Central Endocrine Complications Among Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Children who receive cranial radiation therapy (RT) as a component of treatment for malignancy are often at risk of long-term central endocrine toxicity secondary to radiation to the hypothalamic-pituitary axis (HPA). A comprehensive analysis was performed of central endocrine late effects in survivors of childhood cancer treated with RT as part of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium. METHODS AND MATERIALS: A systematic review of the risk of RT-related central endocrine effects was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 4629 publications were identified, of which 16 met criteria for inclusion in dose modeling analysis, with a total of 570 patients in 19 cohorts. Eighteen cohorts reported outcomes for growth hormone deficiency (GHD), 7 reported outcomes for central hypothyroidism (HT), and 6 reported outcomes for adrenocorticotropic hormone (ACTH) deficiency. RESULTS: Normal tissue complication probability modeling for GHD (18 cohorts, 545 patients) yielded D50 = 24.9 Gy (95% CI, 20.9-28.0) and γ50 = 0.5 (95% CI, 0.27-0.78). The normal tissue complication probability model fit for whole brain irradiation in children with a median age of >5 years indicated a 20% risk of GHD for patients who receive a mean dose of 21 Gy in 2-Gy fractions to the HPA. For HT, among 7 cohorts (250 patients), D50 = 39 Gy (95% CI, 34.1-53.2) and γ50 = 0.81 (95% CI, 0.46-1.35), with a 20% risk of HT in children who receive a mean dose of 22 Gy in 2-Gy fractions to the HPA. For ACTH deficiency (6 cohorts, 230 patients), D50 = 61 Gy (95% CI, 44.7-119.4) and γ50 = 0.76 (95% CI, 0.5-1.19); there is a 20% risk of ACTH deficiency in children who receive a mean dose of 34 Gy in 2-Gy fractions to the HPA. CONCLUSIONS: RT dose to the HPA increases the risk of central endocrine toxicity, including GHD, HT, and ACTH deficiency. In some clinical situations, these toxicities may be difficult to avoid, and counseling of patients and families with respect to anticipated outcomes is important.

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.

Temporal patterns of childhood cancer survival 1991 to 2016: A nationwide register-study based on data from the German Childhood Cancer Registry.

Childhood cancer is the leading disease-related cause of death among under 15 year olds in Europe. Since primary preventive measures are lacking, improving survival probabilities and long-term well-being remain primary goals. With this report, we provide the first long-term assessment and interpretation of patterns in childhood cancer survival in Germany, covering a period of 30 years. Using data from the German Childhood Cancer Registry, we assessed temporal patterns of cancer survival among children (0-14 years) diagnosed in Germany from 1991 to 2016, by cancer type, age at diagnosis and sex. We calculated overall survival (OS) and average annual percentage changes of the respective 5-year OS estimates. OS improved across all cancer types, age groups as well as for boys and girls over time. Five-year OS for all childhood cancers combined increased from 77.8% in 1991-1995 to 86.5% in 2011-2016, with stronger improvements during the early 1990s. The most pronounced survival improvement was seen for acute myeloid leukaemia, at 2% annually and 5-year OS recently reaching 81.5%. Survival improvements for some diagnoses such as neuroblastoma, renal tumours and bone tumours have flattened out. Tremendous enhancements in diagnostics, treatment and supportive care have affected average survival improvements for most cancer types. Recently, survival improvements have decelerated overall and for some cancer types, it plateaued at an unsatisfactory level. As not all children benefited equally from the survival improvements, personal factors (eg, socioeconomic circumstances, health literacy, access to care) likely affect individual prognosis and warrant further investigation.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.