Data Resource Profile: The French Childhood Cancer Observation Platform (CCOP)

Abstract

Childhood cancers are rare diseases, substantially different from adult cancers. They most often develop from embryonal or undifferentiated cells and carcinomas only occur exceptionally. Almost half of childhood cancers occur before the age of 5 years. Intensive protocols used in young people are very effective, altogether resulting in 5-year overall survival to date of ∼80%.1–3 Several dozen thousands of people in France have had a cancer in childhood, sometimes with sequelae, and with various consequences for their education, professional life, lifestyle and overall quality of life (QoL).4–13 Furthermore, large childhood cancer survivors cohorts in North America and Europe14–16 have shown a risk of late adverse effects.17–21 Former patients are exposed to second cancers22–26 and adverse chronic disease conditions (such as cardiovascular,27–37 cerebrovascular38–40 and pulmonary diseases,41–43 endocrine and metabolic disorders,44–48 and neurocognitive disorders49,50) which may occur decades after the end of the treatment. There is thus an essential need for a systematic large-scale and comprehensive long-term surveillance of former childhood cancer cases, in the context of constantly evolving health care management. That is why we have set up the Childhood Cancer Observation Platform (CCOP), a nationwide infrastructure based on the French National Registry of Childhood Cancers (RNCE)3 and medico-administrative databases. Launched in 2013 under the auspices of the French paediatric oncology society (SFCE), the CCOP integrates a large range of standardized data from multiple sources to support observational and interventional research in paediatric oncology. Acronyms used in this paper are listed in Table 1. The CCOP includes all incident cancer or intracranial tumour cases diagnosed in those under 15 years of age in mainland France registered in the RNCE since 2000 (∼1700 new cases per year), amounting to 29 747 cases over the 2000–2016 period, of which 29 546 were primary tumours. A 2-year lag time is necessary for full registration in the RNCE, which means that 2016 is the last complete year in the tables herein. There is no mandatory reporting of childhood cancers in France. RNCE data are manually collected from the medical records by trained clinical research assistants in all French paediatric haematology and oncology departments (∼30 centres). In order to recover missing cases treated in other departments or deceased before any specialized treatment, an annual request is performed for any child diagnosed with a cancer or intracranial tumour from the Information System Medicalization Programme (ISMP) of the University Hospitals and Cancer Centres, from the National health insurance long-term diseases (LTD) files and from the National Registry of medical Causes of Death (CepiDC). The completeness of the RNCE cannot be quantified (e.g. by the capture recapture method) as all valid and reliable sources of information available contribute to RNCE and are therefore not independent sources. The number and quality of sources constitute our guarantee of completeness. The RNCE provides the CCOP with baseline and basic follow-up data, including administrative data, data on initial diagnosis and treatment, relapses and second childhood cancers before the age of 18 years, vital status and causes of death. Four following sets of data are added in the CCOP (Figure 1). Structure and progress of the Childhood Cancer Observation Platform (CCOP). The GEOCAP database (GEOlocation of Pediatric CAncers) GEOCAP includes the spatial coordinates of the residences at the time of diagnosis and, since 2002, that of contemporaneous controls representative of the French paediatric population (5000 controls per year). Addresses are geocoded by the GEOCIBLE company, using the HERE® mapping company street databases and the BD ADRESSE® database from the National Geographic Institute (IGN). We use a geographic information system (GIS) to evaluate residential proximity to sources of environmental and residential exposures. GIS-based exposure assessment relies on models developed and validated by experts in each field. Deprivation scores are also assigned to each residence based on sociodemographic data from the National institute for statistical and economic studies (INSEE) at the smallest census unit in which the residence is located. GEOCAP is used for surveillance and aetiological research on environmental factors, and to appreciate territorial and sociodemographic disparities in incidence and survival. GEOCAP has complete GIS-based data for about 29 500 cases and 60 000 controls. Less than 1% of the addresses are missing. The virtual biobank BIOCAP (BIObank of Pediatric CAncers, BB-0033-00086) BIOCAP aims to provide standardized information on tumour and non-tumour material stored in the hospital biobanks for childhood cancer cases diagnosed from 2011 onwards (since 2009 for the Ile-de-France region), with clinical annotations on diagnosis and follow-up. BIOCAP will eventually support basic and translational research on mechanisms involved in carcinogenesis and tumour spread, and contribute to identifying aetiological and prognostic markers and leads for treatment. Several dozen biobanks contribute to BIOCAP, after local authorizations at various levels (biobank, hospital, clinical research department, paediatric oncology department). Data transfer complies with the legal requirements regarding privacy and security, which are specified in local data transfer agreements. The raw files of the biobanks are securely transferred to the CCOP each year, harmonized and crosschecked with the RNCE to identify the cases, tumours and events associated with each specimen. An interface has been developed to provide investigators with tabulated information on specimens in response to requests relating to clinical and follow-up items. Biobanking data have been collected for 19 698 specimens identified as corresponding to 4944 cases diagnosed over 2009–2016, with at least one tumour specimen (42.9% of the eligible cases) stored in the hospital biobanks. Use in research projects will depend on the real availability of the materials and the consent given for the specimens. The distribution by gender, age at diagnosis and diagnostic group is similar to that of the whole RNCE for 2000–2016 (Table 2). Ile-de-France, as a pilot region between 2009 and 2011, is over-represented. Characteristics of the cases currently included in the Childhood Cancer Observation Platform (primary tumours in those under 15 years of age, mainland France, 2000–2016) Estimation based on 2000–2012 period. Treatments performed and treatment responses A systematic collection of detailed treatments and responses to treatments is ongoing for all cases. These data are collected 5 years after diagnosis by active search in the medical records of departments where the children were treated. They are used for second validation, complementation and enhanced specification of the relapses and second cancers reported in the RNCE. The systematic 5-year follow-up began in 2018 for the cases diagnosed since 2013. For the cases diagnosed before 2013, data are collected retroactively, first for the cases diagnosed in 2005–2012 and then for the cases diagnosed in 2000–2004. So far, the data are complete for 64.1% of the 2005–2012 cases and 29.2% of the 2000–2004 cases, giving a total of 51.0% completion for 2000–2012 (11 511 of 22 611 cases). Table 2 summarizes the main characteristics of the 2000–2012 cases for which data collection is complete, as well as those of all 2000–2016 RNCE cases. The distribution by age at diagnosis, period of diagnosis and diagnostic group reflects the current priorities in retroactive data collection; sympathetic nervous system tumours and germ-cell tumours are slightly over-represented. Figure 2 shows the progress of the retroactive data collection by diagnostic group and period of diagnosis. In all, 2315 cases (20.1%) have had a relapse or second cancer and 2182 (19.0%) had died by 31 December 2018. Additional information on radiotherapies for cases diagnosed since 2013 are provided by a specific database compiled by the French network of paediatric radiotherapy units (PediaRT). The cumulative doses for 641 cases (estimated as 36.8% of the 2013–2016 cases who received radiotherapy) have been provided by PediaRT to date. The cases are described in Table 2. Collection is more advanced in some regions. As expected, central nervous system tumours, bone tumours and soft-tissue sarcomas are more represented and deaths are more frequent in this subgroup of cases who received radiotherapy. Current inclusions in the Childhood Cancer Observation Platform—data collection in medical records 5 years after diagnosis, by diagnosis and period of diagnosis (primary tumours in those under 15 years of age, mainland France, 2000–2012). The COHOPER (COHOrt of the PEdiatric cancer Registry) cohort COHOPER is the key component of the CCOP. Its aims are (i) to evaluate the risk of late complications and (ii) to evaluate lifestyle and individual perceptions of health, with a view to formulating preventive and follow-up recommendations. The cohort ensures systematic follow-up of cases diagnosed since 2000. Relapses and second cancers before the age of 18 years are provided by the RNCE (see above). Health events in adulthood (relapses, second cancers, disabilities and diseases possibly related to treatments) are detected through an annual individual linkage with the National health insurance information system (SNDS) database. The SNDS comprises comprehensive individual data concerning all detailed reimbursements for outpatient and hospital care to the main health insurance schemes beneficiaries (96% of the French population).51 A mapping of the diseases of beneficiaries and their related health care expenditure52 will help compile algorithms for the identification of health events. In addition, adult survivors are eligible to complete online questionnaires on sociodemographic, occupational, lifestyle, health and QoL items at least 5 years after diagnosis. They will be contacted for the first time in fall 2020. Common survey modules will allow comparison of the respondents to the same-aged contemporaneous participants in the French general cohort CONSTANCES.53 To date, 24 130 cases are alive and eligible for long-term follow-up; 10 277 are adults and 10 054 of them were diagnosed at least 5 years ago and are therefore eligible for the administration of questionnaires. Non-respondents and respondents will be compared with regard to baseline data and systematic follow-up information. Most baseline and follow-up data are obtained from medical records and preexisting medico-administrative databases, and active individual participation is not required, except for the questionnaire part of COHOPER. All cases are eligible, provided they have not expressed their opposition to registration in RNCE and CCOP data sets. Information is given to parents in the hospital at diagnosis; parents may opt out of inclusion of their child in RNCE and CCOP (only 10 did so thus far). Once former patients have become adults, they are informed by letter that their data have been included in the RNCE and CCOP databases for research and surveillance purposes, and that their medico-administrative data will be used to ensure follow-up. In compliance with the European General Data Protection Regulation (GDPR 2016/679),54 former patients are informed of our privacy policy relating to personal data protection, and their right to access their personal data, rectify them, and object to their collection or use. This letter is about to be sent and it is not yet possible to assess the number of adult survivors who oppose the collection or use of their data. Vital status is updated every 2 years from the National Registry for the Identification of Individuals (RNIPP) and causes of death are collected from the National Registry of medical Causes of Death (CepiDC). Linkages with PediaRT and BIOCAP databases are annual. Systematic follow-up from medical records is performed continuously, with relapses and second cancers registered at the time of their occurrence and 5 years after the diagnosis. Linkage with the SNDS is annual from 2019 onwards. Online-questionnaires are planned every 2 years depending on financial resources. The catalogue of data is summarized in Table 3. Summary of the catalogue of variables in the Childhood Cancer Observation Platform ADICAP, Association for development of information in cytology and pathology; DNA, deoxyribonucleic acid; FISH, fluorescence in situ hybridization; RNA, ribonucleic acid. Baseline RNCE data include administrative data (identification number, date and place of birth, gender, address at diagnosis); data on initial diagnosis [date, tumour characteristics, diagnostic codes using the WHO (World Health Organisation) international classifications (International Classification of Diseases for Oncology, 3rd edition (ICDO-3), International Classification of Childhood Cancer, 3rd edition (ICCC-3),55 International Classification of Diseases, 10th edition (ICD-10)), stage of extension (following Toronto recommendations56)] and data on initial treatment (treatment protocols, episodes of surgery, chemotherapy, radiotherapy, haematopoietic stem cell transplantation and care pathway). Routine information on family and personal medical history and genetic predisposition syndromes is systematically collected. The GEOCAP database provides the geocoded residential addresses of controls and cases at diagnosis, with allocation of contextual census data (deprivation, degree of urbanization) on the scale of the smallest census units, and indicators of some environmental exposures (roads, power lines, agricultural activities, industrial plants, air pollutants or background ionizing radiation). BIOCAP data include for each material registered: date and sampling method, origin of sample, type of sample, method of storage, existence of derivatives, and existence of signed consent forms appended to the specimens. Table 4 reports the sampling methods by diagnosis for the 4944 cases of 2009–2016 with at least one tumour specimen registered in BIOCAP. For the 1858 haematopoietic malignancies, cytology was reported for 1398 cases (75.2%), biopsy for 279 cases (15.0%) and surgical sample for 228 cases (12.3%). For the 3086 solid tumours, surgical sample was reported for 2442 cases (79.1%), biopsy for 802 cases (26.0%) and cytology for 341 cases (11.0%). Treatments and samples of the Childhood Cancer Observation Platform participants CNS, Central nervous system; IMRT, intensity modulated radiation therapy; SCT, stem cell transplantation; SNS, sympathetic nervous system; VMAT, volumetric modulated arc therapy. Cases can contribute to more than one line. Treatment data include dates and locations of health care delivery units for each therapeutic procedure conducted within 5 years of diagnosis, cumulative doses of each chemotherapy drug, surgical site and result of post-surgical histopathology, type of haematopoietic stem cell transplant, site of radiotherapy and response to each line of treatment. The treatments reported for the 11 511 cases diagnosed in 2000–2012 and retrospectively followed-up at 5 years are shown by diagnosis in Table 4. Almost all 4403 haematopoietic malignancies were treated by chemotherapy (4298 cases, 97.6%); allogenic stem cell transplantation was reported for 405 cases (9.2%) and radiotherapy for 609 cases (13.8%); no treatment was reported for 55 cases (1.2%). Of the 7108 solid tumours, surgery was reported for 5757 cases chemotherapy for cases and radiotherapy for cases no treatment was reported for cases central nervous system tumours. For the cases diagnosed since 2013, the PediaRT database provides cumulative radiation and doses to the and the at The of radiotherapy are reported by diagnosis in Table 4. COHOPER follow-up data include status of the disease years after diagnosis; relapses and second cancers before the age of 18 are described in the as initial tumours in of diagnosis, treatment and response to treatment. The and the provide vital status and causes of death. The SNDS provides indicators of (e.g. full for medical information for for disease outpatient health care and date of all medical or with the corresponding codes in line with the French specific and hospital health care of and medical Causes of and hospital are using A online questionnaire provides information on sociodemographic and characteristics of or insurance health, QoL questionnaire health General Health QoL have been and to and and life, personal disease history and conducted since the end of cancer treatment, and use of The French health are to the with a comprehensive observational infrastructure for childhood cancers, as in the National Cancer The CCOP has been by the French institute of cancer and the National of research for the under the for 10 years. The has obtained a from the cancers to support the CCOP virtual biobank component BIOCAP. Data related to environmental exposures are collected with the support of the French National Health France and the French for and Health the National Registry of Childhood and the National Registry of Childhood that constitute the RNCE, from specific by and The CCOP reports to the French Institute of Health and the CCOP in 2013, with inclusions from 2000 it has yet to relating to and follow-up. the CCOP has provided health health and the with of the risk of relapse and death. The CCOP has been used to identify and specific which may be by new the (e.g. cells in childhood The GEOCAP component of the CCOP and has These include the of an with exposure to a risk of childhood to power and, for a risk of childhood with residential exposure to the of an between and background ionizing and a risk of in most The CCOP is currently to research projects in the of aetiological research factors, factors, genetic observational clinical research survival in the real prognostic in the real of specific in of late of radiotherapy, QoL and disabilities after bone research on of to patients on late of The CCOP is involved in an for Cancer in and on survival after to the European on A of the CCOP is systematic data with the RNCE, for research and The background quality The linkage with the SNDS ensures follow-up of medico-administrative data with statistical The comprehensive set of standardized data collected for each individual is for ensures the and quality of diagnosis and the to respondents and The CCOP thus a for health and health as has been in the of and environmental The CCOP reliable information on chemotherapy and radiotherapy for observational clinical research and provides a baseline for the of clinical The CCOP has time and to ensure compliance with the European The SNDS medico-administrative databases constitute an for the identification of of the of data the of are developed by the SNDS network and the French health which will be an for CCOP The CCOP also has the cohort is and power for long-term follow-up has yet to be the follow-up is more years for half of the more years for only a of the and projects in observational clinical research and research prognostic in the real and of factors, on QoL and disabilities after and on after treatments and of late after current is the of clinical data and in addition, research on sociodemographic, and health has yet to be A of all the consequences of childhood cancers, not only clinical is a necessary care and Former patients are to a range of their it essential to evaluate lifestyle and individual perceptions of health in this These for the most part cannot be by medico-administrative databases and specific COHOPER questionnaire of adult survivors will thus contribute to the long-term and economic consequences of childhood cancer well after treatment and all the survey will be based on the active participation of and therefore to and to participation participants and will be compared for their baseline characteristics, their health and their at inclusion and the using RNCE and SNDS data. of different sources of data will allow of health events in the real and their with and environmental In the CCOP a infrastructure for the support of health surveillance and health in the of childhood cancers. projects with French paediatric and the CCOP can use the clinical data. To access the data, their through the CCOP at Data will be in 2020. The Childhood Cancer Observation Platform (CCOP), based on the French National Registry of Childhood Cancers was in 2013 to up all primary childhood cancers diagnosed in those under 15 years of age in mainland France since 2000. Its is to support clinical and health surveillance and health To date, 29 546 cases are included and eligible for systematic follow-up through a linkage with the National health insurance information system from medical records 5 years after diagnosis is (11 511 cases and online questionnaires will be to adult survivors 054 eligible cases). baseline and basic follow-up RNCE data, the CCOP includes spatial coordinates of the residences at diagnosis, allocation of and environmental exposures indicators for cases diagnosed since 2000 and contemporaneous since information on specimens stored in the hospital biobanks for cases diagnosed since data on including doses of radiotherapy for cases diagnosed since responses to treatment, information on health care from and lifestyle and QoL from to projects will be We are to the French paediatric oncology society and and who were the CCOP for their support of the CCOP and for a for BIOCAP. We to all the clinical research assistants who collected CCOP data from medical and we the and of the paediatric and oncology departments for and and and and and and and and and and of paediatric and We to all the of the French of paediatric who to PediaRT data and and and cancer and and and and and Cancer and We are to and for their support for the BIOCAP We to for in BIOCAP for years, and the and departments and biobanks who provided the CCOP with information and time to their Cancer, of used

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