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.

Subsequent primary neoplasms after childhood cancer therapy - design and description of the German nested case-control study STATT-SCAR.

BACKGROUND: Subsequent primary neoplasms (SPN) are among the most severe late effects and the second most frequent cause of death in childhood cancer patients. In this paper we introduce method and properties of the STATT-SCAR study (Second Tumor After Tumor Therapy, Second Cancer After Radiotherapy), which is a joint nested matched case-control study to evaluate the impact of chemotherapy (STATT) as well as radiotherapy (SCAR) on the risk of developing a SPN. METHODS: Based on the cohort of the German childhood cancer registry (GCCR), we selected patients diagnosed with a first neoplasm before age 15 or younger between 1980 and 2014. We selected those with a SPN at least half a year after the first neoplasm, and matched up to four controls to each case. Therapy data were acquired from various sources, including clinical study centers and treating hospitals. To analyze the impact of radiotherapy, organ doses were estimated by using reconstructed treatment plans. The effect of chemotherapy was analyzed using substance groups summarized after isotoxic dose conversion. RESULTS: 1244 cases with a SPN were identified and matched with 4976 controls. Treatment data were acquired for 83% of all match groups (one case and at least one control). Based on preliminary analyses, 98% of all patients received chemotherapy and 54% of all patients were treated with radiotherapy. CONCLUSIONS: Based on our data, detailed analyses of dose response relationships and treatment element combinations are possible, leading to a deeper insight into SPN risks after cancer treatments. TRIAL REGISTRATION: The study is registered at the German clinical trial register (DRKS) under number DRKS00017847 [45].

Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide. METHODS: The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCareSurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression. RESULTS: Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4-1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9-2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1-10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7-5.7), leukemia (SIR, 2.8; 95% CI, 1.8-4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4-5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2-3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7-2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8-1.5). CONCLUSIONS: In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy.

Risk of subsequent primary oral cancer in a cohort of 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Survivors of childhood cancer are at risk of subsequent primary malignant neoplasms (SPNs), but the risk for rarer types of SPNs, such as oral cancer, is uncertain. Previous studies included few oral SPNs, hence large-scale cohorts are required to identify groups at risks. METHODS: The PanCareSurFup cohort includes 69,460 5-year survivors of childhood cancer across Europe. Risks of oral SPNs were defined by standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence. RESULTS: One hundred and forty-five oral SPNs (64 salivary gland, 38 tongue, 20 pharynx, 2 lip, and 21 other) were ascertained among 143 survivors. Survivors were at 5-fold risk of an oral SPN (95% CI: 4.4-5.6). Survivors of leukaemia were at greatest risk (SIR = 19.2; 95% CI: 14.6-25.2) followed by bone sarcoma (SIR = 6.4, 95% CI: 3.7-11.0), Hodgkin lymphoma (SIR = 6.2, 95% CI: 3.9-9.9) and soft-tissue sarcoma (SIR = 5.0, 95% CI: 3.0-8.5). Survivors treated with radiotherapy were at 33-fold risk of salivary gland SPNs (95% CI: 25.3-44.5), particularly Hodgkin lymphoma (SIR = 66.2, 95% CI: 43.6-100.5) and leukaemia (SIR = 50.5, 95% CI: 36.1-70.7) survivors. Survivors treated with chemotherapy had a substantially increased risk of a tongue SPN (SIR = 15.9, 95% CI: 10.6-23.7). CONCLUSIONS: Previous radiotherapy increases the risk of salivary gland SPNs considerably, while chemotherapy increases the risk of tongue SPNs substantially. Awareness of these risks among both health-care professionals and survivors could play a crucial role in detecting oral SPNs early.

Disclosing a history of childhood cancer to romantic partners.

OBJECTIVE: To describe young adult childhood cancer survivors' disclosure of their cancer history (i.e., disclosure behavior, difficulty, and timing), perceived partner responses, and associations with relationship status satisfaction. METHODS: German long-term survivors of childhood cancer (N = 509; response rate: 31.3%, age 21-26, 59.7% female) completed a registry-based nationwide survey (embedded mixed methods design, including closed and open-ended questions) on measures about disclosure history (behavior, difficulty, and timing), partner responses, and relationship status satisfaction. Statistical (χ2 -, t-, or F-tests) and qualitative analyses were conducted. RESULTS: Half of all survivors always disclosed their cancer history to romantic partners. Thereby, three themes for considering (non-)disclosure were identified: Survivors' attitudes, having integrated cancer as part of their identity, and anticipated effects on romantic relationships. About 40% indicated having no difficulties with disclosing their cancer history. The timing of disclosure varied, with most survivors disclosing after a few dates. Facilitators of disclosure were the visibility of their former illness (e.g., scars), having trust in a (potential) partner, getting older/mature, and previous positive experiences with disclosure. Few survivors (13.8%) had ever experienced negative responses from dating partners. Yet, those who had negative experiences, found it more difficult to disclose their cancer history. Survivors were overall rather satisfied with their relationship status, with partnered survivors reporting greater satisfaction than singles (Hedge's g = 1.68); and particularly partnered survivors with past positive responses being most satisfied. CONCLUSIONS: Young adult childhood cancer survivors appear rather open in disclosing their cancer history to (potential) romantic partners, and few experienced negative responses. Psycho-educational programs may emphasize such findings in helping to prevent fear of disclosure or avoidance of dating and disclosure among survivors.

Contraceptive methods and fertility testing in young adult survivors of childhood cancer.

PURPOSE: Reproductive health is important, but often neglected in cancer survivorship care. This study explored contraceptive use and factors associated with fertility testing among young adult survivors of childhood cancer in Germany. METHODS: Young adult survivors of childhood cancer were identified through the German Childhood Cancer Registry and completed a mailed survey. Survivors were queried regarding contraceptive use, reproductive goals, uncertainty about fertility, and completion or interest in fertility testing. Multivariable stepwise logistic regression models were used to calculate Odds Ratios (OR) and 95% confidence intervals (CI) as a means of identifying factors associated with completion of and interest in fertility testing. RESULTS: Survivors (N = 472; 57.8% female; aged 23.3 ± 1.5 years, and 14.9 ± 5.0 years from diagnosis), reported high rates of contraceptive use, including 61.2% using a single method, 30.6% dual methods, and 8.1% no/less effective methods. Few survivors had completed fertility testing (13.0%), although 58.8% were interested. Having been diagnosed during adolescence (OR = 2.66, 95%CI: 1.39-5.09), greater uncertainty about fertility (OR = 1.16, 95%CI: 1.03-1.31), and use of dual contraceptive methods (OR = 1.94, 95%CI: 1.02-3.69) were associated with having completed fertility testing. Factors associated with interest in fertility testing included goals of wanting to have children (OR = 7.76, 95%CI: 3.01-20.04) and greater uncertainty about fertility (OR = 1.19 95%CI: 1.06-1.33). CONCLUSION: In this sample of young adults who survived childhood cancer, most reported contraceptive use. Few survivors had completed fertility testing, although more than half were interested. Interventions are needed to address potential barriers to fertility testing and help survivors manage fertility-related uncertainty.

Impact of era of diagnosis on cause-specific late mortality among 77 423 five-year European survivors of childhood and adolescent cancer: The PanCareSurFup consortium.

Late mortality of European 5-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 and 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95% CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95% CI 6.32-6.62). At 60 to 68 years of attained age all-cause mortality was still higher than expected (SMR = 2.41, 95% CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95% CI 16.5-20.4) to 7.3% (95% CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960 to 1969, the mortality hazard ratio declined for first neoplasms (P for trend <.0001) and for infections (P < .0001); declines in relative mortality from second neoplasms and cardiovascular causes were less pronounced (P = .1105 and P = .0829, respectively). PanCareSurFup is the largest study with the longest follow-up of late mortality among European childhood and adolescent cancer 5-year survivors, and documents significant mortality declines among European survivors into modern eras. However, continuing excess mortality highlights survivors' long-term care needs.

Secondary malignant neoplasms after bone and soft tissue sarcomas in children, adolescents, and young adults.

BACKGROUND: Increased survival in young sarcoma patients comes along with a higher incidence of second malignant neoplasms (SMNs). The incidence, latency, histiotype, and outcome of these patients were analyzed because this information is essential to design evidence-based long-term follow-up care programs for young sarcoma survivors. METHODS: Patients entered on clinical trials or registered in registries with a primary sarcoma in 1 of the cooperative sarcoma study groups in the framework of the Society for Pediatric Oncology and Hematology (GPOH) were screened for SMNs. Descriptive analysis, the Kaplan-Meier method, the Gray model, the Fine-Gray model, and the Cox regression model were used for the statistical analyses. RESULTS: A total of 159 out of 7079 (2.2%) patients were registered with a SMN. Among them, 104 solid SMNs (65%) and 56 hematologic SMNs (35%) occurred. Median latency from first diagnosis of sarcoma to the diagnosis of SMN was 6.8 years (range, 0-26.7 years). Cumulative incidence of SMN was 8.8% after 30 years. Five-year-survival was 67.1% (95% confidence interval [CI], 66.0-68.2) for the 7079 patients and it was 45.1% (95% CI, 36.2-53.6) after the diagnosis of a SMN (subcohort of n = 159 patients). CONCLUSIONS: There is a remarkable high cumulative incidence of SMNs after bone and soft tissue sarcomas in children, adolescents, and young adults. Therefore, effective transition as well as risk adapted long-term follow-up care programs should be developed and offered to young sarcoma survivors. LAY SUMMARY: Bone sarcomas and soft tissue tumors are rare tumors in children, adolescents, and young adults. The treatment varies, but may comprise chemotherapy, surgery, and/or radiotherapy. Developing a subsequent malignant tumor is a long-term risk for the patients. To better characterize this risk, we analyzed the data of 7079 patients (up to 21 years old) with bone sarcomas or soft tissue tumors. Our findings provide a basis to counsel young sarcoma survivors on their individual risk of subsequent malignant tumors. Moreover, these data can help to establish recommendations for aftercare in young sarcoma survivors.

Psychosexual Development and Sexual Functioning in Young Adult Survivors of Childhood Cancer.

BACKGROUND: Childhood cancer and its treatment can impair survivors' development throughout life, particularly psychosexual development, which can be affected in complex ways and is crucial for survivors' well-being. Yet, research is scarce. AIM: This study assessed psychosexual development (milestone attainment, age at attainment, perceived timing) in young adult survivors of childhood cancer. It further examined sexual satisfaction and sexual functioning, and whether survivors' perceived timing of sexual debut was related to satisfaction or functioning. METHODS: A registry-based nationwide survey was completed by N = 492 German survivors of childhood cancer (age 21-26 years, 6-26 years postdiagnosis). They completed standardized measures of psychosexual milestones (eg, first kiss, sexual debut), sexual satisfaction, and sexual functioning. Psychosexual development was compared to normative data (N = 1,533). OUTCOMES: Psychosexual development, sexual satisfaction, and sexual functioning were the primary outcome measures. Psychosexual development was characterized in three ways: milestone attainment (yes/no), age at attainment, perceived timing ("right" time, too early/late). RESULTS: Milestone attainment was comparable to normative data, except for sexual debut: Survivors were less often experienced (82.5% vs 88%; P = .002) and older at sexual debut (17.4 vs 16.2 years; g = 0.55), but most survivors (58.3%) perceived their timing as "right." Survivors of brain tumors were least likely to have had their sexual debut, but if experienced age at sexual debut was similar to other survivors. Female survivors were somewhat more experienced than males (eg, first kiss, first relationship; <10% difference), but they were somewhat older when they first kissed (g = 0.26). Age at diagnosis was unrelated to milestone attainment. Perceived early/late sexual debut was related to lower satisfaction in female survivors (P = .026), but unrelated to sexual dysfunction. Instead, partnered men reported particularly low dysfunction whereas women reported similar levels of sexual dysfunction irrespective of their relationship status (P = .049). Overall, sexual functioning was favorable (60.2%: not/barely problematic). CLINICAL IMPLICATIONS: Most survivors reported favorable sexual satisfaction and functioning, but a minority of survivors may need supportive services. STRENGTHS & LIMITATIONS: This project represents one of few large-scale studies on psychosexual development in childhood cancer survivors relative to normative data, and is the first to link development to sexual satisfaction/functioning. Assessing satisfaction/functioning with validated, but brief measures limits detailed insights, but was inclusive of any sexual orientation. Medical background information based on registry data was limited. CONCLUSION: Results showed normative psychosexual development (except for sexual debut) in most survivors. A self-determined attitude toward sexuality (ie, engaging in sexual activities at the "right" time) may generally determine positive sexual experiences. Lehmann V, Gerhardt CA, Baust K, et al. Psychosexual Development and Sexual Functioning in Young Adult Survivors of Childhood Cancer. J Sex Med 2022;19:1645-1654.

[The 41,000 long-term survivor cohort of the German Childhood Cancer Registry]. / Die Kohorte der 41.000 Langzeitüberlebenden des Deutschen Kinderkrebsregisters.

BACKGROUND AND OBJECTIVES: One-third of childhood cancer long-term survivors suffer from severe late effects (e.g., secondary cancer and cardiovascular diseases). The German Childhood Cancer Registry (GCCR) holds approximately 70,000 registered cancer cases, of which more than 41,000 are long-term survivors, with recent follow-up and contact information that can be used for scientific studies on late effects. The characteristics of this cohort are presented, previous late effects studies with the support of the GCCR are described, and the respective participation rates are reported. METHODS: For all patients who developed cancer between 1980 and 2019 and were in long-term observation at the GCCR, the distribution of diagnoses, current age, observation time, and number of secondary cancers as of 16 July 2021 was determined. The rates of patients who responded to history queries were computed. The influence of determinants on the participation rate were calculated using generalized estimating equations. RESULTS: The cohort comprises 41,466 long-term survivors. Of these, 10% are older than 40 years and 40% had their cancer diagnosis more than 20 years ago. The participation rates range between 30 and 60% and depend on age at diagnosis, the complexity of the study, and the number of previously conducted surveys. A time interval of at least four years between two consecutive contacts seems optimal. CONCLUSIONS: Our unique cohort enables population-based research on late effects after childhood cancer. To define a sensible time interval for contacting survivors is essential. In order to ensure that survivors are not contacted too frequently, the number of survivors included in research projects should be as small as possible.

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.

Mental health and health-related quality of life in preschool-aged childhood cancer survivors. Results of the prospective cohort study ikidS-OEVA.

OBJECTIVES: Long-term survivors of childhood cancer are at increased risk for sequelae such as poor mental health (MH) or impaired health-related quality of life (HrQoL). We aimed to evaluate early adverse effects on MH and HrQoL in young childhood cancer survivors (YCCS) before school entry. METHODS: In a nationwide prospective cohort study, children with cancer other than brain tumors diagnosed at preschool age and completed cancer treatments were identified from the German Childhood Cancer Registry. The comparison group was children of the same age without a cancer diagnosis who participated in the prospective population-based health survey ikidS. MH problems and HrQoL were assessed by parental versions of the Strengths and Difficulties Questionnaire (SDQ) and the questionnaire for health-related quality of life in children (KINDL), respectively. Associations between cancer and MH as well as HrQoL were analyzed by multivariable linear regression. RESULTS: Of 382 YCCS contacted, 145 were enrolled (mean age 6.6 years) and 124 analyzed. Compared to children without a cancer diagnosis (3683 contacted, 2003 enrolled, 1422 analyzed), YCCS had more MH problems (13% vs. 3%) and slightly worse HrQoL (median 78.7 vs. 80.2 points). In the adjusted analysis, YCCS had higher SDQ scores (2.2 points, 95% confidence interval [CI] 1.3, 3.0) and lower KINDL scores (-2.4 points, 95% CI -3.7, -1.1) compared to children without cancer diagnosis. CONCLUSION: Already at preschool age, YCCS may be at increased risk of MH problems and impaired HrQoL. This could have impacts on subsequent school performance and educational attainment. Follow-up health care for YCCS may include early screening for MH problems and reasons for HrQoL deficits.

Risk of digestive cancers in a cohort of 69 460 five-year survivors of childhood cancer in Europe: the PanCareSurFup study.

BACKGROUND: Survivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide. METHODS: The PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence. RESULTS: 427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN-comparable to the risk among members of the general population with at least two first-degree relatives affected. CONCLUSIONS: Colonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.

Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study.

Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10-7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.

Changing geographical patterns and trends in cancer incidence in children and adolescents in Europe, 1991-2010 (Automated Childhood Cancer Information System): a population-based study.

BACKGROUND: A deceleration in the increase in cancer incidence in children and adolescents has been reported in several national and regional studies in Europe. Based on a large database representing 1·3 billion person-years over the period 1991-2010, we provide a consolidated report on cancer incidence trends at ages 0-19 years. METHODS: We invited all population-based cancer registries operating in European countries to participate in this population-based registry study. We requested a listing of individual records of cancer cases, including sex, age, date of birth, date of cancer diagnosis, tumour sequence number, primary site, morphology, behaviour, and the most valid basis of diagnosis. We also requested population counts in each calendar year by sex and age for the registration area, from official national sources, and specific information about the covered area and registration practices. An eligible registry could become a contributor if it provided quality data for all complete calendar years in the period 1991-2010. Incidence rates and the average annual percentage change with 95% CIs were reported for all cancers and major diagnostic groups, by region and overall, separately for children (age 0-14 years) and adolescents (age 15-19 years). We examined and quantified the stability of the trends with joinpoint analyses. FINDINGS: For the years 1991-2010, 53 registries in 19 countries contributed a total of 180 335 unique cases. We excluded 15 162 (8·4%) of 180 335 cases due to differing practices of registration, and considered the quality indicators for the 165 173 cases included to be satisfactory. The average annual age-standardised incidence was 137·5 (95% CI 136·7-138·3) per million person-years and incidence increased significantly by 0·54% (0·44-0·65) per year in children (age 0-14 years) with no change in trend. In adolescents, the combined European incidence was 176·2 (174·4-178·0) per million person-years based on all 35 138 eligible cases and increased significantly by 0·96% (0·73-1·19) per year, although recent changes in rates among adolescents suggest a deceleration in this increasing trend. We observed temporal variations in trends by age group, geographical region, and diagnostic group. The combined age-standardised incidence of leukaemia based on 48 458 cases in children was 46·9 (46·5-47·3) per million person-years and increased significantly by 0·66% (0·48-0·84) per year. The average overall incidence of leukaemia in adolescents was 23·6 (22·9-24·3) per million person-years, based on 4702 cases, and the average annual change was 0·93% (0·49-1·37). We also observed increasing incidence of lymphoma in adolescents (average annual change 1·04% [0·65-1·44], malignant CNS tumours in children (average annual change 0·49% [0·20-0·77]), and other tumours in both children (average annual change 0·56 [0·40-0·72]) and adolescents (average annual change 1·17 [0·82-1·53]). INTERPRETATION: Improvements in the diagnosis and registration of cancers over time could partly explain the observed increase in incidence, although some changes in underlying putative risk factors cannot be excluded. Cancer incidence trends in this young population require continued monitoring at an international level. FUNDING: Federal Ministry of Health of the Federal German Government, the European Union's Seventh Framework Programme, and International Agency for Research on Cancer.

Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol.

BACKGROUND: Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment  as the primary outcome in CCS. METHODS: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort. DISCUSSION: This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.

The PanCareSurFup cohort of 83,333 five-year survivors of childhood cancer: a cohort from 12 European countries.

Childhood cancer survivors face risks from a variety of late effects, including cardiac events, second cancers, and late mortality. The aim of the pan-European PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) Consortium was to collect data on incidence and risk factors for these late effects among childhood cancer survivors in Europe. This paper describes the methodology of the data collection for the overall PanCareSurFup cohort and the outcome-related cohorts. In PanCareSurFup 13 data providers from 12 countries delivered data to the data centre in Mainz. Data providers used a single variable list that covered all three outcomes. After validity and plausibility checks data was provided to the outcome-specific working groups. In total, we collected data on 115,596 patients diagnosed with cancer from 1940 to 2011, of whom 83,333 had survived 5 years or more. Due to the eligibility criteria and other requirements different numbers of survivors were eligible for the analysis of each of the outcomes. Thus, 1014 patients with at least one cardiac event were identified from a cohort of 39,152 5-year survivors; for second cancers 3995 survivors developed at least one second cancer from a cohort of 71,494 individuals, and from the late mortality cohort of 79,441 who had survived at least 5 years, 9247 died subsequently. Through the close cooperation of many European countries and the establishment of one central data collection and harmonising centre, the project succeeded in generating the largest cohort of children with cancer to date.

[Long-Term Follow-Up in Childhood Cancer Survivors - Position paper 2018 of the working group "long-term follow-up" of the Society of Pediatric Oncology and Hematology (GPOH) on long-term surveillance, long-term follow-up and late effect evaluation in pediatric oncology patients]. / Langzeitbeobachtung ehemaliger krebskranker Kinder und Jugendlicher.

Nowadays, childhood cancer patients survive much more often than they did 40 years ago. Therefore, the cure rates rise over 80%. Approximately 33,000 cured childhood cancer patients are documented by the German Childhood Cancer Registry (GCCR) for long-term follow-up in Germany. But does that mean, they are healthy, too? When compared to the normal population, it can be seen that morbidity and mortality are significantly higher among former childhood cancer patients. In two out of three survivors, the cancer and its treatments can lead to treatment-related late complications 30 years later; in about one-third, these late complications are classified as severe. A structured long-term follow-up is needed to detect and to treat new diseases early. The purpose of this position paper is to update the first position paper from 2007. Current developments are described, how appropriate aftercare structures and aftercare facilities should be planned, taking into account existing structures and increasing needs.

Return and Disclosure of Research Results: Parental Attitudes and Needs Over Time in Pediatric Oncology.

OBJECTIVES: To explore parental attitudes regarding the return and disclosure of research findings in pediatric cancer trials over time. STUDY DESIGN: Two surveys were set up to evaluate the stability of parental attitudes. One survey was carried out among 581 parents whose child was diagnosed recently (response rate, 53.5%). A second, population-based survey was set up with a time interval of 4 years between first cancer diagnosis and survey in which 1465 parents were included (response rate, 55.1%). RESULTS: Almost all surveyed parents stated a parental right to receive aggregate research results. Fifty-five percent of the parents who recently participated in trials and 62% of those asked after a multiyear time interval thought that disclosure of individual findings is in any case necessary (P = .0034). The respondents wanted to restrict the duty to disclose study results to the child according to their notion of the child's well-being, composed of child's maturity, impairment of the parent-child relationship, and the quality of the results. CONCLUSIONS: Attitudes of parents regarding the return of research findings change over time. Shortly after diagnosis, parents are mainly interested in aggregate findings. Interest in individual findings appeared to increase as more time elapsed between cancer diagnosis and survey.

Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology.

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.