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Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007. We analysed survival data for 157 499 children (age 0–14 years) diagnosed between Jan 1, 1978 and Dec 31, 2007. They came from 74 population-based cancer registries in 29 countries. We calculated observed, country-weighted 1-year, 3-year, and 5-year survival for major cancers and all cancers combined. For comparison between countries, we used the corrected group prognosis method to provide survival probabilities adjusted for multiple confounders (sex, age, period of diagnosis, and, for all cancers combined without CNS cancers, casemix). Age-adjusted survival differences by area and calendar period were calculated with period analysis and were given for all cancers combined and the major cancers. We analysed 59 579 cases. For all cancers combined for children diagnosed in 2000–07, 1-year survival was 90·6% (95% CI 90·2–90·9), 3-year survival was 81·0 % (95% CI 80·5–81·4), and 5-year survival was 77·9% (95% CI 77·4–78·3). For all cancers combined, 5-year survival rose from 76·1% (74·4–77·7) for 1999–2001, to 79·1% (77·3–80·7) for 2005–07 (hazard ratio 0·973, 95% CI 0·965–0·982, p<0·0001). The greatest improvements were in eastern Europe, where 5-year survival rose from 65·2% (95% CI 63·1–67·3) in 1999–2001, to 70·2% (67·9–72·3) in 2005–07. Europe-wide average yearly change in mortality (hazard ratio) was 0·939 (95% CI 0·919–0·960) for acute lymphoid leukaemia, 0·959 (0·933–0·986) for acute myeloid leukaemia, and 0·940 (0·897–0·984) for non-Hodgkin lymphoma. Mortality for all of Europe did not change significantly for Hodgkin's lymphoma, Burkitt's lymphoma, CNS tumours, neuroblastoma, Wilms' tumour, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Disparities for 5-year survival persisted between countries and regions, ranging from 70% to 82% (for 2005–07). Several reasons might explain persisting inequalities. The lack of health-care resources is probably most important, especially in some eastern European countries with limited drug supply, lack of specialised centres with multidisciplinary teams, delayed diagnosis and treatment, poor management of treatment, and drug toxicity. In the short term, cross-border care and collaborative programmes could help to narrow the survival gaps in Europe. Italian Ministry of Health, European Commission, Compagnia di San Paolo Foundation.

Background Ganglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of patients. Methods Clinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010. Results Of 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p < 0.001), less frequently with adrenal tumors (31 % vs. 43 %, p = 0.001) and positive mIBG-uptake (34 % vs. 90 %, p < 0.001), and had less often elevated urine catecholamine metabolites (homovanillic acid 39 % vs. 62 %, p < 0.001, vanillylmandelic acid 27 % vs. 64 %, p < 0.001). Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001). Complete tumor resection was achieved at diagnosis in 70 % of 162 GN and 67 % of 55 GNBI, and after 4 to 32 months of observation in 4 GN (2 %) and 5 GNBI (9 %). Eleven patients received chemotherapy without substantial effect. Fifty-five residual tumors (42 GN, 13 GNBI) are currently under observation (median: 44 months). Five patients (3 GN, 2 GNBI) showed local progression; all had tumor residuals > 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression. Conclusions GN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment. Trial registration ClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006)

Cancer is rare before age 20 years. We aimed to use the European database of childhood and adolescent cancer cases, within the Automated Childhood Cancer Information System project, to estimate patterns and trends of incidence and survival within Europe. Comparable, high-quality data from 63 European population-based cancer registries consisted of 113000 tumours in children and 18 243 in adolescents diagnosed in 1970–99. Incidence rates and survival were compared by region (east vs west), period, and malignant disease. In the 1990s, age-standardised incidence rates were 140 per million for children (0–14 years) and 157 per million for ages 0–19 years. Over the three decades, overall incidence increased by 1·0% per year (p<0·0001) in children (increases for most tumour types), and by 1·5% (p<0·0001) in adolescents (15–19 years; notable increases were recorded for carcinomas, lymphomas, and germ-cell tumours). Overall 5-year survival for children in the 1990s was 64% in the east and 75% in the west, with differences between regions for virtually all tumour groups; 5-year survival was much the same in adolescents. Survival has improved dramatically since the 1970s in children and adolescents, more so in the west than in the east. Our results are clear evidence of an increase of cancer incidence in childhood and adolescence during the past decades, and of an acceleration of this trend. Geographical and temporal patterns suggest areas for further study into causes of these neoplasms, as well as providing an indicator of progress of public-health policy in Europe.

Background Epidemiological research on late effects of therapy shows the necessity to aggregate chemotherapy agents to substance classes. This requires using conversion factors by substance classes. Aims The aim of this study was to identify previously used conversion factors from the literature, to present a novel approach for additional factors, and to compare these approaches. Methods and Results A literature review was performed, which identified two main principles of deriving conversion factors: effect‐equivalence and equimolar. Thirty‐five articles presenting effect equivalence‐based factors in the widest sense were found in the literature. Ten articles presented the equimolar approach which can be applied to almost all chemotherapy substances. Based on a comprehensive list of treatment protocols used in German pediatric oncology, we derived alternative conversion factors from typical doses. We compared the conversion factors using Pearson correlation coefficients and linear regression. At least two types of conversion factor were available for each of the 49 substances included. The equivalent effect‐based and the typical dose‐based factors were highly correlated with a regression coefficient close to 1. The equimolar factors are independent. Conclusions For substances for which no conversion factor based on some type of effect equivalence has been published so far, a factor based on a typical doses‐approach may be used in epidemiological late effects research. Doses aggregated based on the equimolar approach may not be compatible with doses aggregated based on equivalent effects.

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.

Despite a significant number of studies on female fertility following childhood, adolescent, and young adult (CAYA) cancer, studies establishing precise (dose-related) estimates of treatment-related risks are still scarce. Previous studies have been underpowered, did not include detailed treatment information, or were based on self-report only without any hormonal assessments. More precise assessments of who is at risk for sub- or infertility are needed. The objective of our study is to describe the design and methods of 2 studies on female fertility (a cohort study and a nested case-control study) among female survivors of CAYA cancer performed within the European PanCareLIFE project. For the cohort study, which aims to evaluate the overall risk of fertility impairment, as well as the risk for specific subgroups of female CAYA cancer survivors, 13 institutions from 9 countries provide data on fertility impairment. Survivors are defined as being fertility impaired if they meet at least one of 8 different criteria based on self-reported and hormonal data. For the nested case-control study, which aims to identify specific treatment-related risk factors associated with fertility impairment in addition to possible dose-response relationships, cases (fertility impaired survivors) are selected from the cohort study and matched to controls (survivors without fertility impairment) on a 1:2 basis. Of the 10,964 survivors invited for the cohort study, data are available from 6619 survivors, either questionnaire-based only (n=4979), hormonal-based only (n=72), or both (n=1568). For the nested case-control study, a total of 450 cases and 882 controls are identified. Results of both PanCareLIFE fertility studies will provide detailed insight into the risk of fertility impairment following CAYA cancer and diagnostic- or treatment-related factors associated with an increased risk. This will help clinicians to adequately counsel both girls and young women, who are about to start anticancer treatment, as well as adult female CAYA cancer survivors, concerning future parenthood and to timely refer them for fertility preservation. Ultimately, we aim to empower patients and survivors and improve their quality of life. RR1-10.2196/10824.

Background A comprehensive clinical long-term survey over the complete spectrum of neuroblatoma disease is lacking in the literature. Objective Our objective was to describe the incidence, risk profiles, therapies, and outcomes for the total cohort of German patients with neuroblastoma including all clinical stages and risk groups. Methods Epidemiological, clinical, and outcome data of neuroblastoma patients who participated in one of the six consecutive national trials between 1979 and 2015 were analyzed retrospectively. Results Of all German neuroblastoma patients known to the national childhood cancer registry, ninety seven percent enrolled in one of the trials. The absolute neuroblastoma rate has increased slightly, whereas the median age at diagnosis has decreased. Except for the screening period (1995–2000), the risk factors lactate dehydrogenase (LDH), ferritin, chromosome 1p, and the MYCN oncogene have remained largely constant, with the exception of an increase in MYCN amplification at stage 4 for those aged ≥18 months between trials NB97 (27%) and NB2004 (35%). The 10-year overall survival increased in patients with stage 1–3 neuroblastoma from 83 to 91%, for stage 4S from 80 to 85%, and for stage 4 aged ≥18 months from 2 to 38%. The fraction of patients in stages 1–3 who never received chemotherapy (neither for frontline nor at recurrence) increased from 35 to 60%. The proportion of macroscopically complete surgical resections of the primary tumor decreased for the total population as well as for patients with stage 4 aged ≥18 months. The impact of chemotherapy response on the outcome was trial dependent. The overall proportion of toxic death during the time of the protocol therapy was 6% for stage 4 patients aged ≥18 months and 2% for low-/intermediate-risk patients. The most frequently reported late sequelae in stage 4 patients aged ≥18 months were renal dysfunctions, hypothyroidism, major hearing impairment, and second malignancies. Conclusion The body of data for incidences, risk profiles, and survival rates from this survey of more than 37 years provides a useful perspective for future studies on neuroblastoma sub-cohorts.

Therapy for a first primary neoplasm (FPN) in childhood with high doses of ionizing radiation is an established risk factor for second primary neoplasms (SPN). An association between exposure to low doses and childhood cancer is also suggested; however, results are inconsistent. As only subgroups of children with FPNs develop SPNs, an interaction between radiation, genetic, and other risk factors is presumed to influence cancer development. Therefore, the population-based, nested case-control study KiKme aims to identify differences in genetic predisposition and radiation response between childhood cancer survivors with and without SPNs as well as cancer-free controls. We conducted a population-based, nested case-control study KiKme. Besides questionnaire information, skin biopsies and saliva samples are available. By measuring individual reactions to different exposures to radiation (eg, 0.05 and 2 Gray) in normal somatic cells of the same person, our design enables us to create several exposure scenarios for the same person simultaneously and measure several different molecular markers (eg, DNA, messenger RNA, long noncoding RNA, copy number variation). Since 2013, 101 of 247 invited SPN patients, 340 of 1729 invited FPN patients, and 150 of 246 invited cancer-free controls were recruited and matched by age and sex. Childhood cancer patients were additionally matched by tumor morphology, year of diagnosis, and age at diagnosis. Participants reported on lifestyle, socioeconomical, and anthropometric factors, as well as on medical radiation history, health, and family history of diseases (n=556). Primary human fibroblasts from skin biopsies of the participants were cultivated (n=499) and cryopreserved (n=3886). DNA was extracted from fibroblasts (n=488) and saliva (n=510). This molecular-epidemiological study is the first to combine observational epidemiological research with standardized experimental components in primary human skin fibroblasts to identify genetic predispositions related to ionizing radiation in childhood and SPNs. In the future, fibroblasts of the participants will be used for standardized irradiation experiments, which will inform analysis of the case-control study and vice versa. Differences between participants will be identified using several molecular markers. With its innovative combination of experimental and observational components, this new study will provide valuable data to forward research on radiation-related risk factors in childhood cancer and SPNs. DERR1-10.2196/32395.

Purely intracranial soft tissue sarcomas (ISTS) are very rare among children. A retrospective database analysis of the Cooperative Weichteilsarkom Studiengruppe (CWS) and brain tumor (HIT) registries was conducted to describe treatment and long-term outcome of children and adolescents with ISTS. Nineteen patients from Germany, Austria and Switzerland were reported between 1988 and 2009. Median age at diagnosis was 9.7 years (range, 0.5–17.8). Central pathological review was performed in 17 patients. Eleven patients underwent a total and five a subtotal tumor resection. A biopsy was done in one patient. In two patients no data concerning extent of initial resection was available. Radiotherapy was performed in 15 patients (first-line, n  = 11; following progression, n  = 4). All but one patient received chemotherapy (first-line, n  = 7, following progression, n  = 5; first-line and following progression, n  = 6). With a median follow-up of 5.8 years (range, 0.6–19.8) ten patients were alive in either first or second complete remission. Seven patients died due to relapse or progression and two were alive with progressive disease. Estimated progression-free and overall survival at 5 years were 47 % (±12 %) and 74 % (±10 %), respectively. About 50 % of patients with ISTS remain relapse-free after 5 years. Multimodality treatment including complete tumor resection and radio-/chemotherapy is required to achieve sustained tumor control in patients with ISTS. Early initiation of postoperative non-surgical treatment seems to be important to prevent recurrence. Due to the intracranial localization local therapy should follow the recommendations used in brain tumors rather than in soft tissue sarcomas, whereas chemotherapy should be guided by histological subtype.

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. 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. 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]). 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. Federal Ministry of Health of the Federal German Government, the European Union's Seventh Framework Programme, and International Agency for Research on Cancer.