Childhood cancer survivor cohorts in Europe

Figures & data

Figure 1. Countries in Europe with established national childhood cancer survivor cohorts (black), those in the process of establishing a national cohort (dark gray), as well as countries being data providers to the two European collaborative studies (light gray).

Table I. Characteristics of childhood cancer survivor cohorts in Europe.

Study name (acronym)	Established national survivor cohort				In the process of establishing a national cohort			European collaborative studies
	ALiCCS	BCCSS	DCOG LATER	SCCSS	FCCSS	LEA	OTR	PanCareLIFE	PanCareSurFup
Country	Denmark Finland Iceland Norway Sweden	England Wales Scotland	Netherlands	Switzerland	France (will end up including in addition to the regional cancer registries, all onco-pediatric departments in France)	France (participating pediatric onco-hematology centers cover nearly 75% of all childhood leukemia survivors diagnosed since 1980)	Italy	Czech Republic Denmark France Germany Ireland Italy Netherlands Switzerland	Nordic countries Slovenia France United Kingdom Netherlands Hungary Switzerland Italy
Identification of survivors	Nordic cancer registries	National cancer registration	DCOG LATER registry based on nationwide hospital-based cohorts	Swiss Childhood Cancer Registry	Regional cancer registries, hospital data, clinical trials	Hospital data, clinical trials, and cancer registry (ongoing)	Network of the Italian Association of Paediatric Haematology and Oncology (data to be combined with regional cancer registry data)	Cancer registries and local databases	National and hospital registries
Number of survivors	33 160	17 981 in original cohort; 34 490 in extended cohort	6168	4405	12 000 (6000 more to be enrolled)	3029 (1000 more to be enrolled)	14 201 (16 000 more to be enrolled primarily from regional cancer registries)	About 12 000 to be expected in total cohort	About 100 000 in the cohort studies
Survival at entry	1-year survivors	5-year survivors	5-year survivors	5-year survivors	5-year survivors	2-year survivors	Elective end of therapy	Mostly 5-year survivors	5-year survivors in the case-control studies
Age at cancer diagnosis	0–19	0–14	0–17	0–20	0–19	0–18	0–19	0–20	0–20
Cancer type	All types	All types	All types	All types	All but leukemias	Malignant hemopathies (today only leukemias but lymphomas will also be included)	All types	All types	All types
Calendar years at diagnosis	1943–2008	1940–1991 in original cohort; 1940–2006 in extended cohort	1963–2002	1976–(ongoing)	1946–1999	1980–(ongoing)	1960–2004 (ongoing)	1940s–2000s	1940s–2000s
Maximum age at latest follow-up with respect to death	85 years	80 years	65 years	52 years	74 years	45 years	54 years	NA	85 years
Loss to follow-up	<1%	1.4% in original cohort	<1% for registry data; around 20% for clinical data	8% (mainly survivors emigrated to other countries)	Depend on the outcome	20%	<3%	NA	NA
Funding	Danish Strategic Research Council	Cancer Research UK, Kay Kendall Leukaemia Fund and FP-7	Dutch Cancer Society; the Quality of Life Foundation, KiKa Kinderen Kankervrij	Swiss Cancer League, Swiss National Science Foundation, Swiss Paediatric Oncology Group, Kinderkrebs-hilfe Schweiz, Cancer League Bern, Zurich and Aarau, Swiss Bridge, Stiftung zur Krebsbekämpfung, and FP-7	The French National Cancer Institute (InCA), the French National Research Agency (ANR), the Ligue Nationale Contre le Cancer, and the French Institute for Public Health Research (IRESP)	The French National Research Agency (ANR), the Ligue Nationale Contre le Cancer, the French Institute for Public Health Research (IRESP), the French National Cancer Institute (INCA), the Pfizer Foundation for childhood and adolescent health, and the Programme Hospitalier de Recherche Clinique (PHRC)	Italian ministry of health, Regional Health authorities and partly by the European Union (FP7 project, PanCareSur-Fup)	European Commission; FP7-HEALTH-2013-INNOVATION-1 (Grant Agreement Number 602030)	European Commission; FP7-HEALTH-2010.2.4.1-7 (Grant Agreement Number 257505)
Website	www.aliccs.org	www.bccss.bham.ac.uk	www.skionlaterstudie.nl/english/	www.childhoodcancerregistry.ch	No website	No website	No website	www.pancarelife.eu; www.pancare.eu	www.pancaresurfup.eu; www.pancare.eu

Table II. Design and data collection as well as strengths and limitations of the European childhood cancer survivor cohort studies.

Study name (acronym)	Established national survivor cohort				In the process of establishing a national cohort			European collaborative studies
	ALiCCS	BCCSS	DCOG LATER	SCCSS	FCCSS	LEA	OTR	PanCareLIFE	PanCareSurFup
Study
Design	Cohort and case-cohort studies	Cohort and case-control studies	Cohort and case-control studies	Cohort and case-control studies	Cohort studies	Cohort studies	Cohort studies	Observational studies and molecular genetic investigations	Cohort and case-control studies
Setting	Population-based	Population-based	Nationwide hospital-based	Population-based	Hospital and regional register-based	Hospital and local register-based	Nationwide hospital-based (later also regional register-based)	Population- and hospital-based	Population- and hospital-based
Prospective/retrospective	Retrospective	Retrospective	Retrospective and prospective	Prospective	Retrospective and prospective	Retrospective and prospective	Retrospective and prospective	Retrospective and prospective	Retrospective
Comparisons
Comparison population	Five as many (212 892) randomly selected population comparisons individually matched according to age, sex, and country	Nationwide population-based mortality and cancer incidence rates; National questionnaire surveys and Hospital Episode Statistics database	Matched siblings and population- based controls	Siblings; representative population-based surveys	National statistics	National Database of Health Care	Nationwide population-based mortality and cancer incidence rates	Cohort and case-control design	One control per case nested in the same cohort matched according to age and calendar year of first primary cancer diagnosis and length of follow-up, first primary neoplasm of hereditary/non-hereditary retinoblastoma, and sex
Exposure
Chemotherapy	In case-cohort studies	Crude cohort/comprehensive case-control studies	Complete in detail	Yes	In 50% of the cohort and in case-control studies	Yes	Complete in detail for 80% of the cohort	At least y/n; more detailed for subgroups	In case-control studies
Radiation	In case-cohort studies	Crude cohort/comprehensive case-control studies	Complete in detail	Yes	In 50% of the cohort and in case-control studies	Yes	Complete in detail for 80% of the cohort	At least y/n; more detailed for subgroups	In case-control studies
Surgery	In case-cohort studies	Crude cohort/comprehensive case-control studies	Complete in detail	Yes	In 50% of the cohort and in case-control studies	Yes	Complete in detail for 80% of the cohort	At least y/n; more detailed for subgroups	In case-control studies
Bone marrow transplantation	In case-cohort studies	Not at present, but intend electronic record linkage with the national register	Complete in detail	Yes	In 50% of the cohort and in case-control studies	Yes	Complete in detail for 70% of the cohort	At least y/n; more detailed for subgroups	In case-control studies
Update of data collection	Every 5th to 10th year	Causes of death and cancers every 3rd month; Hospital Episode Statistics database every 5th years	Every 5th year in questionnaire; Clinical visits in 2015–2018	Every 2nd to 5th years	Annual linkage with national hospital data base	Every 2nd year for patients < 20 years; Every 4th year for patients ≥ 20 years	Every 5th to 10th year for vital status and cause of death	NA	NA
Other variables^a
Lifestyle behaviors	No	From questionnaire only	Yes, based on different study designs	Yes	Yes	Yes	No	Yes, in some study designs	No
Co-morbidity	Yes, as medically verified hospital diagnoses	Yes, from national Hospital Episode Statistics database in the future	Yes	Yes	Yes, by questionnaire and as registered in national hospital data base	Yes	Yes, only from treating centers	Yes, in some study designs	Other medical conditions from local study centres
Outcome identification
Data sources	National hospital registers, medical birth registries, prescription registries, psychiatric in-patient registries (except Iceland and Norway), causes of death registries, cancer registries	National death and cancer registries; historically questionnaire; future national Hospital Episode Statistics database	Medical records, national mortality statistics, cancer registries, hospital discharge registry, questionnaires and clinical visits	National mortality statistics; cancer incidence from regional registries; questionnaire survey	National Hospital Register linkage and questionnaires	National Hospital Register linkage and questionnaires	Census bureaus; Causes of death registries; Hospital discharge registries (only for residents of selected regions; later a centralized linkage including all regions)	Population-based and hospital based-data sources; cancer registries; local databases	Population- and hospital-based data sources and medical records
Clinical/physical examination	No	No	Yes	Only for selected patients in nested studies	Long term follow-up consultations for 10% of the cohort	Yes	Yes, if in follow-up clinic	Yes, in some study designs	No
Blood samples	No	No	Yes	No	On-going; Blood in 500 and saliva in 2000 survivors	Yes	No	Yes, in some study designs	No
Medical records	Yes, in case-cohort studies	Yes, in case-control studies	Yes	Yes	50% of the cohort and case-control studies	Yes	Yes	Yes, in some study designs	Yes, in case-control studies
Strengths	Long-term complete follow-up in high quality population- based Nordic registries; Analyses of pattern of morbidity throughout adult life, including after age 50; Medically verified chronic diseases in all organ systems; Robust risk estimates for rare but potentially fatal diseases	Long-term complete follow-up in high quality population-based national registry. Non-cancer non-fatal outcomes ascertained through questionnaires historically, through electronic record linkage with the national Hospital Episode Statistics database in the future	Long-term complete follow-up and complete treatment data. Clinical validation in medical records and in clinical patient visit. Several possibilities for linkage studies. Extensive collaboration between pediatric oncologists, other specialists and epidemiologi-cal investigators	National, including all childhood cancer survivors. Combination of data from questionnaires and records linked with routine data. Ongoing inclusion of survivors	Treatment data and whole body radiation dose reconstruction for 50% of the cohort. Annual linkage with the National Hospital database. Ongoing inclusion of survivors	Clinical examination and self-reported data on life style, quality of life, and relationships with health care system. Ongoing inclusion of survivors	Detailed information on pathological and molecular characteristics of the original tumor; detailed treatment information mainly from medical record abstraction. Ongoing inclusion of survivors	Large dataset enables answers to questions with rare outcomes (fertility, ototoxicity, health-related quality of life). Data from multiple sources in standardized data format allows comparability	Long-term follow-up in population- and hospital-based registries of high quality. Detailed treatment information from medical record abstraction and organ dosimetry included in case-control studies
Limitations	No treatment data in cohort studies; detailed treatment information from medical record abstraction and organ dosimetry in case-cohort studies	Crude treatment only available to cohort studies, detailed and comprehensive treatment information is available in nested case-control studies	Lack of population-based cohort for children with cancer until 2001. However, the expectation is that the cohort is nearly complete for all cancers other than CNS tumors and retinoblastoma	Detailed treatment data need to be abstracted from records. Limited information on non-responders to questionnaire	Not a population- based cohort, because there is no national cancer registry in France. Treatment data only for a part of the cohort	75% of all national cases are included. No economic data.	Registration of an expected 90% of the incident eligible cases at completion of treatment; difficulties in having an extended clinical follow-up of survivors no more in contact with the treating center	Different sources (population- and hospital-based registries); retrospective data which have to be harmonized for a common data format; different logistics per country; different standards	A mixture of population- and hospital- based registries

^aOther variables that might act as a confounder or an intermediate factor.

Table III. Overview of main research areas, ongoing and planned studies, and key publications.

Study name (acronym)	Established national survivor cohort				In the process of establishing a national cohort			European collaborative studies
	ALiCCS	BCCSS	DCOG LATER	SCCSS	FCCSS	LEA	OTR	PanCareLIFE	PanCareSurFup
Main focus areas	Somatic late effects in all organs and organ systems	Comprehensive spectrum of adverse health and social outcomes	Comprehensive spectrum of adverse health and psychosocial outcomes	Somatic and psychosocial late effects, health behaviors and follow-up care	Any long term side effect, role of treatment and genetic predisposition	Late physical effects and psychosocial outcomes (quality of life and social inequality in health)	Mortality, second primary cancers, and somatic late effects	Female fertility, cisplatin-induced ototoxicity and health-related quality of life	Cardiac disease, second sarcomas and second digestive and genito-urinary carcinomas, and late mortality
Publications	Endocrine disorders; Diabetes	Causes of death; Second primary cancers; Use of health services; Educational attainment; Smoking; Alcohol consumption; Marriage; Liveborn	Fertility; methodology of questionnaires; guidelines; single center studies	Cohort profile; Psycho-oncology; Health behaviors; Social outcomes; Asthma; Follow-up care; Quality of life; Education	Diabetes; Age at menopause; Cardiovascular diseases; Mortality, DNA repair capacity and second primary cancers; Second primary cancers	Cohort profile; Bone mineral density; Metabolic syndrome; Sibling's quality of life	Causes of death; Second primary cancers	A manuscript giving a general overview on the PanCare network is close to submission	A manuscript giving a general overview on the PanCare network is close to submission
Selected key publications	[21,22]	[7,23–25]	[8,26–28]	[9,29–31]	[32–35]	[36–39]	[40–42]
Ongoing studies	Cardiovascular, pulmonary, endocrine, renal, gastro-intestinal, autoimmune and neurological disorders, reproductive outcomes, and cohort profile	On-going cohort and case-control studies of subsequent primaries of soft tissue, bone, digestive and genitourinary sites; also of serious cardiac outcomes and strokes. Individual patient electronic record linkage with the national Hospital Episode Statistics database will enable the comparison of observed and expected numbers of a wide spectrum of non-fatal non-neoplastic adverse health outcomes	Questionnaire, cohort and case controls studies on female fertility, second primary cancers, mortality, cardiac diseases, toxicity, quality of life, long-term morbidity and healthcare consumption, adverse health effects of radiotherapy, radiation dosimetry, and breast cancer prediction model	Cardiovascular, pulmonary and endocrine disorders, ototoxicity, reproductive outcomes, late mortality, quality of life, psychosocial outcomes, follow-up care, transition in care, and health behaviors	Cataract, cardiovascu-lar, pulmonary, endocrine, renal, and gastro-intestinal disorders, reproductive and social outcomes	Cardiovascular, pulmonary, and endocrine disorders, reproductive and social outcomes, school performance, quality of life and psychosocial outcomes	Cardiovascular disease, second primary cancers, fertility issues	Fertility, ototoxicity and health-related quality of life	Cardiac disease, second primary cancers, late mortality
Planned studies	Studies of late effects in survivors of ALL, neuroblastoma, retinoblastoma, Wilms, and bone tumors	Establishing the Teenage Young Adult Cancer Survivor Study (TYACSS) cohort of 233 081 individuals who were diagnosed with cancer when aged 15–39 years, in England and Wales, between 1971 and 2006 and survived at least 5 years	Cohort studies including clinical visits to identify risk and risk factors for health problems, new diagnostic tests, and genetic predisposition	Hospitalizations (by linkage to hospital episode statistics)	Genetic predisposition to second cancers and cardiovascular diseases	Genetics, parents’ quality of life, siblings’ outcomes, and social inequalities in health	Cause specific hospitalizations, cause specific mortality, and second cancers	NA	Other second carcinomas than digestive and genito-urinary
Future directions	Late effects in children with other specific cancer types; include information from other Nordic population and health registries; International collaboration	Combined analysis of BCCSS and TYACCS cohorts	International collaboration	Genetics	National screening of breast and thyroid cancer in at risk group	National Level	International collaborations