VersKiK: Study protocol of an observational registry-based study on the current state of follow-up care and adherence to follow-up guidelines after cancer in childhood or adolescence.

BACKGROUND: This article describes the study design of the quantitative part of the VersKiK study, The primary objectives of this study are to examine the occurrence of late effects in survivors of childhood or adolescent cancer (module 1), investigate health-related vulnerabilities and medical service utilization within this survivor group (modules 1 and 3), and assess the alignment between documented follow-up care for cardiological and audiological late effects with guideline recommendations, along with evaluating the extent of adherence among paediatric cancer survivors (module 3). METHODS: This is a non-interventional retrospective observational cohort study. It is based on stochastically linked insurance claims data from approximately 150,000 statutory insured persons with information concerning around 25,000-30,000 cancer survivors recorded in the German Childhood Cancer Register (GCCR). To explore adherence to selected follow-up guidelines, intention to treat treatment data from clinical study groups for particular diagnostic entities will be additionally included. DISCUSSION: The growing group of survivors after cancer in childhood and adolescence is representing a special population with an increasing demand for life-long healthcare services through relative high probability of late effects. Currently, there is a limited evidence in Germany on utilization of corresponding medical services and adherence to follow-up guidelines. With this study design, we are aiming to address these gaps and, consequently, suggest improvements to existing follow-up guidelines and follow-up care provision in Germany.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: data from the German CVSS-study.

Aims: The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). Methods and results: In the CVSS-study (NCT02181049), 1002 CCS (age range 23-48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German population-based cohorts. Using log-binomial regression models, an increased risk for occurrence of arterial hypertension [relative risk (RR) 1.38, 95% confidence interval (95% CI 1.21-1.57)] and dyslipidaemia [RR 1.26 (95% CI 1.12-1.42)] was found. This indicates a premature occurrence compared to the general population of approximately 6 and 8 years, respectively [rate advancement period estimator, RAPhypertension 5.75 (95% CI 3.5-8.0) and RAPdyslipidaemia 8.16 (95% CI 4.4-11.9)]. Overall, no differences were observed for obesity and diabetes. Overt CVD was present in 4.5% (95% CI 3.0-6.6%) of CCS [RR 1.89 (95% CI 1.34-2.66), RAPCVD 7.9 (95% CI 4.1-11.7)], of which the most frequent entities were congestive heart failure and venous thromboembolism. Prevalences of CVRF and CVD increased with age without reaching a plateau over time. Conclusion: This large CCS screening examination revealed consistently in comparison to three population samples a considerably increased risk for premature CVD. The findings in these young adult CCS indicate a high burden of cardiovascular morbidity and mortality in the long term. Clinicaltrials. gov-Nr: NCT02181049.

The Krümmel (Germany) Childhood Leukaemia Cluster: a review and update.

The debate surrounding possible adverse health effects from the civil use of nuclear power under normal operating conditions has been on-going since its introduction. It was particularly intensified by the detection of three leukaemia clusters near nuclear installations, i.e. near the reprocessing plants in Sellafield and Dounreay, UK, and near the Krümmel nuclear power plant, Germany, the last of which commenced between 1990 and 1991 and was first described in 1992; it continued until 2003, and an elevated risk up to 2005 has been reported in the literature. A number of expert commissions and working groups were set up by the governments of the German federal states of Lower Saxony and Schleswig-Holstein to investigate the possible causes of the cluster. An overview of the many risk factors that were investigated as a possible explanation of the Krümmel cluster is given here, focussing on radiation, but also including other risk factors. Further, results from related epidemiological and cytogenetic studies are described. In summary, the cause of the occurrence of the Krümmel cluster has to be considered as unknown. Further research on the causes of childhood leukaemia is needed, focussing on epigenetics and on gene-environment interaction. An update of the leukaemia incidence around the Krümmel site shows that the incidence rates are now comparable to the average rate in Germany.

Geographical variability in survival of European children with central nervous system tumours.

Survival for childhood central nervous system (CNS) tumours varies across Europe, partly because of the difficulty of distinguishing malignant from non-malignant disease. This study examines bias in CNS tumours survival analysis to obtain the reliable and comparable survival figures. We analysed survival data for about 15,000 children (age <15) diagnosed with CNS between 2000 and 2007, from 71 population-based cancer registries in 27 countries. We selected high-quality data based on registry-specific data quality indicators and recorded observed 1-year and 5-year survival by countries and CNS entity. We provided age-adjusted survival and used a Cox model to calculate the hazard ratios (HRs) of death, adjusting by age, site and grading by country. Recording of non-malignant lesions, use of appropriate morphology codes and completeness of life status follow-up differed among registries. Five-year survival by countries varied less when non-malignant tumours were included, with rates between 79.5% and 42.8%. The HRs of dying, for registries with good data, adjusting by age and grading, were between 0.7 and 1.2; differences were similar when site (supra- and infra-tentorial) was included. Several sources of bias affect the correct definition of CNS tumours, the completeness of incidence series and the goodness of follow-up. The European Network of Cancer Registries needs to improve childhood cancer registration and stress the need to update the International Classification for Cancer. Since survival differences persisted even when restricting the analysis to registries with satisfactory data, and since diagnosis of CNS tumours is difficult and treatment complex, national plans must aim for the revision of the diagnosis and the coordination of care, with adequate national and international networks.

Incidence, Trends, and Survival of Children With Embryonal Tumors.

BACKGROUND: Central nervous system (CNS) and non-CNS embryonal tumors occur principally in children and are rarely seen in adults. The incidence rates for rare entities such as atypical teratoid/rhabdoid tumors (AT/RT) or primitive neuroectodermal tumors in the CNS are rarely published. Incidence rates for certain subgroups, such as hepatoblastomas, have been increasing in some countries. METHODS: Data of 8337 embryonal tumors, registered in children (0-14 years) between 1991 and 2012 (for AT/RT 2000-2012) in the population-based German Childhood Cancer Registry with complete national coverage were analyzed for incidence rates, time trends, and survival. RESULTS: For most entities, the incidence rates were the highest for children <1 year. An important exception was medulloblastomas, which occurred mainly in 1- to 9-year-olds. Neuroblastomas and ganglioneuroblastomas as well as Wilms tumors (nephroblastomas) had the highest age standardized incidence rates (13.7 and 9.4 per million, respectively). A statistically significant increasing trend for hepatoblastomas (annual average percent change 4.6%) was detected. The survival probabilities varied between the diagnostic groups: primitive neuroectodermal tumors and AT/RT had the lowest and retinoblastomas the highest. The survival was dependent on the age at diagnosis, the most extreme examples being neuroblastomas, for which the survival probability declined steeply for children ≥1 year and medulloblastomas, for which the highest survival was seen for 10- to 14-year-olds. CONCLUSIONS: This study presents a comprehensive overview of pediatric embryonal tumors from a well-established, complete nationwide cancer registry. Significant increasing trend for hepatoblastomas was detected for the first time in Europe.

Childhood leukaemia risks: from unexplained findings near nuclear installations to recommendations for future research.

Recent findings related to childhood leukaemia incidence near nuclear installations have raised questions which can be answered neither by current knowledge on radiation risk nor by other established risk factors. In 2012, a workshop was organised on this topic with two objectives: (a) review of results and discussion of methodological limitations of studies near nuclear installations; (b) identification of directions for future research into the causes and pathogenesis of childhood leukaemia. The workshop gathered 42 participants from different disciplines, extending widely outside of the radiation protection field. Regarding the proximity of nuclear installations, the need for continuous surveillance of childhood leukaemia incidence was highlighted, including a better characterisation of the local population. The creation of collaborative working groups was recommended for consistency in methodologies and the possibility of combining data for future analyses. Regarding the causes of childhood leukaemia, major fields of research were discussed (environmental risk factors, genetics, infections, immunity, stem cells, experimental research). The need for multidisciplinary collaboration in developing research activities was underlined, including the prevalence of potential predisposition markers and investigating further the infectious aetiology hypothesis. Animal studies and genetic/epigenetic approaches appear of great interest. Routes for future research were pointed out.

Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.

[The German cohort of long-term survivors of childhood cancer. A population-based cohort in the German Childhood Cancer Registry]. / Die deutsche Kohorte Langzeitüberlebender nach Krebs im Kindesalter. Eine populationsbezogene Kohorte am Deutschen Kinderkrebsregister.

Due to the considerably improved prognosis of childhood cancer, research regarding the long-term consequences has become highly valuable. The population-based German Childhood Cancer Registry forms the basis of the long-term follow-up of these patients. The cohort comprises over 25,000 patients (with malignant diseases before their 15th birthday) with a current address and who are neither deceased nor lost to follow-up. The current median age is 21 years and 500 individuals are already over 40 years old. All the long-term survivors are contacted every 5 years at the latest and are asked about possible long-term effects. Due to the continued improvement of the prognosis for childhood cancer over the years, such cohorts of long-term survivors have altered in their composition. Corresponding long-term follow-up studies can therefore not easily be compared to one another. This is illustrated by a nested case control study on the possible relationship between the occurrence of second tumors and the therapy undergone for the initial diagnosis. The cohort of long-term survivors in the German Childhood Cancer Registry is highly valuable both for research on long-term effects in Germany as well as for integration into international projects.

Utilization of psychosocial care and oncological follow-up assessments among German long-term survivors of cancer with onset during adolescence.

BACKGROUND: Survivors of pediatric cancer are at increased risk for medical and psychosocial late effects. This study retrospectively investigated the utilization of oncological and psychosocial care by former adolescent cancer patients (≥ 5 years since cancer diagnosis) in Germany. PATIENTS: Based on data of the German Childhood Cancer Registry (N=1 876 survivors of cancer with an age at diagnosis between 15 and 18 years), the study cohort comprised 820 survivors of adolescent cancer (time since diagnosis: M=13.7, SD=6.0, age at follow-up: M=30.4, SD=6.0 years). METHOD: Survivors of adolescent cancer completed standardized questionnaires measuring symptoms of posttraumatic stress, depression and anxiety as well as items on their utilization of medical and psychosocial care. RESULTS: More than a quarter (26.2%) of the survivors was no longer attending regular oncological follow-up assessments. Less than half of the survivors (44.4%) had received psychosocial care, mostly during their in-patient cancer treatment and their post-acute rehabilitation phase. Out of 184 survivors showing clinically relevant symptoms of posttraumatic stress, anxiety and/or depression at time of the study, 12.0% received psychosocial care and 13.6% took psychotropic medication. CONCLUSION: It should be studied further why only a small proportion of the survivors showing clinically relevant symptoms received psychosocial or psychopharmacological treatment. Systematic oncological follow-up assessments should take psychological late effects into greater account.

Strategy for long-term surveillance at the German Childhood Cancer Registry - an update.

BACKGROUND: The objective of this paper is to provide information about the quality (e.g. completeness, response) of long-term surveillance in German paediatric oncology and haematology based on the structures implemented by the German Childhood Cancer Registry (GCCR). METHODS: The GCCR contacts parents or patients to collect and update information on a minimal set of follow-up health status data (e.g. late relapses, subsequent neoplasms, current address) and exchanges this information regularly with the appropriate clinical trials. RESULTS: Between 2006 and 2010, GCCR approached a total of about 20,000 patients (contact at the age of 16 years, inquiry concerning the health status) in the context of long-term surveillance. 11,000 addresses of former patients had to be researched via municipal registrar's offices. The response rates ranged from 56% to 68%, the research in municipal offices provided 93-96% valid addresses. Of 46,115 patients diagnosed between 1980 and 2009, 25,283 are in long-term surveillance in 2010. DISCUSSION: Long-term surveillance requires considerable logistic effort at GCCR and requires that thousands of letters be mailed each year in order to ensure regularly updated information. Long-term surveillance is indispensable for a better understanding of late effects, subsequent neoplasms and quality of life of former childhood cancer patients.

Case-control study on risk factors for leukaemia and brain tumours in children under 5 years in Germany.

In the context of a case control study on the cancer risk for children under five by distance to the nearest nuclear power plant, we collected information on other risk factors in a subset. We present the interview study as if it had been an independent study. Parents of 471 cases with Leukaemia, Lymphoma or CNS (Central Nervous System)-tumour from the German Childhood Cancer Registry, diagnosed at age under 5 in the years 1993-2003, and 1,457 matched controls were to be interviewed. For Leukaemia, 243 cases/604 controls, and for CNS 102 cases/246 controls participated, lymphoma cases were too few. Questions related to social status, ionizing radiation, pregnancy and birth, immune system, and selected toxins. The analysis is exploratory in nature; variables were selected by backward elimination. For leukaemia we found a significant protective effect of social contacts (OR=0.50, 95% CI [0.29;0.87]) and a risk for high birth weight (OR=1.96 95% CI [1.12;3.41] comparing >4,000 g to "normal"). We could not reproduce other associations reported in the literature such as a negative association with allergies. For CNS tumours we found a significant protective effect of social contacts (OR=0.30 95% CI [0.13;0.72]), of pesticides and herbicides (OR=0.39 95% CI [0.18;0.83]) and an increased risk for low birth weight (p=0.0232). This study on risk factors for childhood leukaemia and brain tumours is relatively small and exploratory. We could reproduce some major associations reported in the literature (leukaemia: social contacts and high birth weight) but not others. Some observations may be reporting artefacts or self selection artefacts.

Subtype-specific incidence of testicular cancer in Germany: a pooled analysis of nine population-based cancer registries.

Comparisons of incidence estimates of testicular cancer subtypes beyond seminoma and non-seminoma are virtually missing in the epidemiologic literature. We analysed incidence data from population-based German cancer registries to provide subtype-specific incidences of testicular cancer. We pooled data from nine cancer registries from 1998 to 2003. We estimated incidence and mortality time trends of West and East Germany. Incidence and mortality were standardized by the European standard population. The annual percentage incidence change from 1961 through 1989 was 4.9% in East Germany and 3.0% from 1970 through 2004 in Saarland. Incidence increases were the most pronounced among adolescents and young men aged 15-49 years. In 1998-2003, the seminoma incidence rate was 5.1 per 100,000; among non-seminomas, the rates were the highest for malignant teratoma (1.6 per 100,000), followed by embryonal carcinoma (1.2 per 100,000). Testicular lymphomas were rare (0.1 per 100,000). The incidence of testicular cancer among children aged 0-14 years was nearly constant from 1987 through 2004. Majority of these cancers were yolk sac tumours (0.1 per 100,000). In East and West Germany, rates of embryonal carcinoma in the early periods were considerably lower than the rates of malignant teratoma. In the most recent periods, rates of embryonal carcinoma became quite similar to the rates of malignant teratoma. The mortality decline started in West Germany roughly 12 years earlier than in East Germany. The later start of the mortality decline in East Germany may be because of a later introduction of platinum-based chemotherapy compared to West Germany.

The cohort of long-term survivors at the German childhood cancer registry.

BACKGROUND: With the increasing number of long-term survivors among patients diagnosed with cancer during childhood, questions concerning late effects have become a major research topic. To ascertain late effects, it is necessary to contact former patients. An essential requirement for such studies is a long-term surveillance (LTS) of former childhood cancer patients in their adolescence and their adulthood. The paper describes the role of the German Childhood Cancer Registry (GCCR) in LTS. A cohort of long-term survivors has been built up over the years. The characteristics of this LTS cohort and strategies for further improvement of LTS will be presented. PATIENTS AND METHODS: Since 1980 the GCCR systematically ascertains all malignant neoplasms and benign brain tumours in children under the age of 15 years at diagnosis. Participants are followed up actively by the treating hospitals and the clinical study groups in the first years after diagnosis, and by the GCCR thereafter. Late effects are accessed within the Scientific Society for Paediatric Oncology and Haematology (GPOH) of different groups with different focal points. Those groups are the GCCR (secondary malignant neoplasms), LESS (late effects after chemotherapy), RiSK (late effects after radiotherapy), and the working group on quality of life (quality of life and data on life circumstances). Additionally, the GCCR provides logistics for contacting patients during LTS. The LTS is supported by a recent basic publication ("position paper") by the GPOH. Newly diseased cancer cases are reported to the GCCR very completely. The GCCR contains mainly epidemiological data. Accessorily, the GCCR ascertains a minimum of data for each patient which enables population-based studies involving long-term survivors of childhood cancer. RESULTS: Out of 37 291 children diagnosed with cancer between 1980 and 2004, 8 896 died (until spring 2007). From those not deceased, 21 987 (77.4%) can be followed up further (i.e. current address is known). For about 70% of the patients in the LTS cohort, follow-up data are available and not older than 5 years. Our experience shows that about 80% of former childhood cancer patients agree to continued data storage at the GCCR, 4% explicitly refuse their consent, the remaining do not answer. LTS for patients with leukemia and lymphomas is particularly complete, whereas for patients with brain tumours it is less complete. CONCLUSIONS: The LTS is considered highly relevant concerning aspects of clinical quality assurance and epidemiological research. The GCCR can guarantee a continuing development and improvement of existing procedures for LTS. The GCCR expects to achieve contacting a high percentage of former childhood cancer patients also in future LTS, even after long periods of time.

[Registries for rare diseases. Compliance and data protection]. / Register zu seltenen Krankheiten : Patientencompliance und Datenschutz.

For rare diseases, clinical and epidemiological research suffers from very small numbers of cases. A comprehensive collection of data and information in registries is an essential precondition to improve this situation. To this end, a number of disease specific networks have started collecting data with support from the German Ministry of Research. The past experiences of the German Childhood Cancer Registry show that voluntary participation, based on informed consent, can result in a satisfactory completeness of data collection and, thus, enable successful medical research. There are several ways to build registries and research networks conforming to the data protection rules.

Up-to-date monitoring of childhood cancer long-term survival in Europe: central nervous system tumours.

BACKGROUND: Tumours of the central nervous system (CNS) account for 15-20% of all malignant childhood tumours in developed countries. Steady improvement of survival of children with CNS tumours has been reported for the past decades. However, these results, obtained by cohort analysis of survival, do not reflect the full extent of recent improvement. METHODS: Using selected registries from the database of the Automated Childhood Cancer Information System (ACCIS), we calculated period survival estimates for the years 1995-99 for children diagnosed with a malignant CNS tumour. RESULTS: The overall 10-year period survival estimate for the years 1995-99 was 59% for children with all CNS tumours combined, 73% for children with astrocytoma, 53% for children with ependymoma and 45% for children with primitive neuroectodermal tumours. On average, estimates derived by cohort analysis (pertaining to children diagnosed in 1985-89) were around 4% units lower. Region-specific analysis revealed that recent progress was largest in Eastern Europe, where prognosis nevertheless remained lower than in other European regions. In Northern and Southern Europe, 10-year survival remained essentially unchanged. CONCLUSION: Although period survival of children with CNS tumours is higher than previously reported cohort survival, their long-term prognosis remains modest compared to other childhood malignancies.