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.

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.

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.

[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.

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.

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.

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.

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.

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.

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.

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.

Cancer in children and adolescents in Europe: developments over 20 years and future challenges.

This special issue contains 18 articles describing population-based analyses of incidence and survival for cancer among children and adolescents in Europe over the period 1978-1997. The analyses were derived from the large database of the ACCIS project (Automated Childhood Cancer Information System), which was built through collaboration of 62 population-based cancer registries in 19 European countries. Data on 88,465 cancers in children and 15,369 in adolescents (age 15-19 yrs) were included in the various analyses, making this the largest database on cancer in these age-groups in the world. National data were grouped into five European regions to allow comparisons of incidence and survival, for all cancers and by tumour type, including analysis of trends in both over time. This overview paper focuses on the comparability of the data from multiple registries and describes the potential confounding factors. Age-standardised annual incidence rates of many, but not all, cancers in children and adolescents are clearly rising. There are geographical differences in survival for the majority of tumour types. Survival rates increased for nearly all types of cancer in children and adolescents. The implications of these findings for aetiological factors and treatment delivery for cancer in children and adolescents are discussed.

Quality, comparability and methods of analysis of data on childhood cancer in Europe (1978-1997): report from the Automated Childhood Cancer Information System project.

In collaboration with 62 population-based cancer registries contributing to the Automated Childhood Cancer Information System (ACCIS), we built a database to study incidence and survival of children and adolescents with cancer in Europe. We describe the methods and evaluate the quality and internal comparability of the database, by geographical region, period of registration, type of registry and other characteristics. Data on 88,465 childhood and 15,369 adolescent tumours registered during 1978-1997 were available. Geographical differences in incidence are caused partly by differences in definition of eligible cases. The observed increase in incidence rates cannot be explained by biases due to the selection of datasets for analyses, and only partially by the registration of non-malignant or multiple primary tumours. Part of the observed differences in survival between the regions may be due to variable completeness of follow-up, but most is probably explained by resource availability and organisation of care. Further standardisation of data and collection of additional variables are required so that this study may continue to yield valuable results with reliable interpretation.

Incidence of skin lymphoma in Germany.

PURPOSE: Population-based analyses of the incidence of skin lymphoma in Europe are very sparse. We analyzed German population-based incidence data on skin lymphoma to study the descriptive epidemiology of these tumors. METHODS: We extracted skin lymphoma cases from the registry files of the East German National Cancer Registry (1976-1989) and registries of three new federal states (1998-2002) (Sachsen, Brandenburg, Mecklenburg-Vorpommern), the Cancer Registry Schleswig-Holstein, Lübeck (1998-2002), and the Epidemiological Cancer Registry Münster (1998-2002). We calculated age-standardized incidence rates (world standard population) and compared these figures with international data. RESULTS: From 1976 through 1989, 619 cases of skin lymphoma were registered in the former German Democratic Republic. During this period, the incidence among men increased from 2.0 to 2.5 per million and decreased among women from 1.5 to 0.8 per million. Current age-standardized incidence rates of skin lymphoma (1998-2002) varied by sex and registry and were about 3.2-6.0 per million among men and 1.6-2.6 per million among women. CONCLUSIONS: The current incidence rates among the registries of Germany are fairly similar but are considerably lower than incidence rates from the United States and Israel. Several methodological issues hamper the analysis of population-based incidence data of skin lymphoma.

[Name-based identification of cases of Turkish origin in the childhood cancer registry in Mainz]. / Namensbasierte Identifizierung von Fällen mit türkischer Herkunft im Kinderkrebsregister Mainz.

Until now few analyses of routine data relating to the health of migrants have been conducted in Germany. A major obstacle is that most data sources do not provide reliable information on the origin of migrants. While some sources contain the nationality of persons registered, this information does not allow one to identify migrants who have taken up German citizenship, i.e., a substantial part of second-generation migrants. In this paper we demonstrate how a computer-aided, name-based algorithm can be used to identify persons of Turkish origin in the German Childhood Cancer Registry in Mainz, Germany. The performance of the algorithm, as assessed against the gold standard of assessing names manually, was very good (sensitivity and specificity > or = 0.975). In total, we identified 1774 of the 37,259 cases in the registry as being of Turkish origin. The name algorithm proved to be a useful tool to identify Turkish migrants in routine data sources, thus avoiding potential bias due to changes in citizenship. This approach aims at improving migrant-sensitive health reporting and research in Germany. In future, additional information on migrant status should be obtained already during primary data collection so that health data for all migrant groups can be provided.