Acta Oncologica, 2015; 54: 655–668

REVIEW

Childhood cancer survivor cohorts in Europe Jeanette F. Winther1, Line Kenborg1, Julianne Byrne2, Lars Hjorth3, Peter Kaatsch4, Leontien C. M. Kremer5, Claudia E. Kuehni6, Pascal Auquier7, Gérard Michel8, Florent de Vathaire9, Riccardo Haupt10, Roderick Skinner11, Laura M. Madanat-Harjuoja12, Laufey Tryggvadottir13,14, Finn Wesenberg15,16,17, Raoul C. Reulen18, Desiree Grabow4, Cecile M. Ronckers5, Eline van Dulmen-den Broeder5, Marry M. van den Heuvel-Eibrink5, Matthias Schindler6, Julie Berbis7, Anna S. Holmqvist3, Thorgerdur Gudmundsdottir1, Sofie de Fine Licht1, Trine G. Bonnesen1,19, Peter H. Asdahl1,19, Andrea Bautz1, Anja K. Kristoffersen1, Liselotte Himmerslev1, Henrik Hasle19, Jørgen H. Olsen1 & Mike M. Hawkins18 1Danish

Cancer Society Research Center, Copenhagen, Denmark, 2Boyne Research Institute, Drogheda, Ireland, Oncology and Haematology, Skåne University Hospital, Lund University, Lund, Sweden, 4German Childhood Cancer Registry (GCCR), Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Mainz, Germany, 5on behalf of the DCOG LATER group The Netherlands, Emma Children’s Hospital/AMC, Amsterdam, VU University Medical Center, Amsterdam, EMC-Sophia Children’s Hospital, Rotterdam, Princess Maxima Center for Paediatric Oncology, Utrecht, 6Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Switzerland, 7Aix-Marseille University, EA 3279 Research Unit, Department of Public Health, University Hospital, Marseille, France, 8Departement of Paediatric Onco-haematology, APHM, La Timone Hospital, Marseilles, France, 9Centre for Research in Epidemiology and Population Health (CESP), U1018 Inserm, Radiation Epidemiology Group, Villejuif, France, 10Epidemiology and Biostatistics Unit, G. Gaslini Institute, Genoa, on behalf of the AIEOP-OTR study group, Italy, 11Department of Paediatric and Adolescent Haematology and Oncology, Great North Children’s Hospital, Royal Victoria Infirmary, Newcastle Upon Tyne, UK, 12The Finnish Cancer Registry, Helsinki, Finland, 13The Icelandic Cancer Registry, Reykjavik, Iceland, 14Faculty of Medicine, University of Iceland, Reykjavik, Iceland, 15Department of Paediatrics, Oslo University Hospital, Oslo, Norway, 16Faculty of Medicine, University of Oslo, Oslo, Norway, 17Norwegian Cancer Registry, Oslo, Norway, 18Centre for Childhood Cancer Survivor Studies, School of Health and Population Sciences, University of Birmingham, UK and 19Department of Paediatrics, Aarhus University Hospital, Aarhus, Denmark 3Paediatric

Abstract With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for

Correspondence: J. F. Winther, Consultant, MD, DMSc, Head of research group Childhood Cancer Survivorship, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark. Tel: 45 35 257670. Fax: 45 35 271811. E-mail: [email protected] (Received 19 December 2014; accepted 12 January 2015) ISSN 0284-186X print/ISSN 1651-226X online © 2015 Informa Healthcare DOI: 10.3109/0284186X.2015.1008648

656 J. F. Winther et al. childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia – PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers.

“Paediatric cancer seen in perspective, then, puts us almost at the end of a long tunnel. Looking back in one direction towards the blackness of ‘no hope’ and ‘no cure’. Looking forward, we see a wide and open road with well-spaced way-stops en route to our final destination. Some of these way-stops surely are the development of ever more refined and precisely targeted methods of treatment, so that the increasing numbers of successfully treated children of today do not become the chronically ill adults of tomorrow.” This is how Professor Emeritus Giulio J. D’Angio described the ‘road of childhood cancer’ in his paper on pediatric cancer in perspective in 1975 with the end of the road being reached when childhood cancer is forever eliminated stressing that ‘indeed, cure is not enough’ [1]. The treatment of childhood cancer is a success story of modern medicine, as effective regimens have been identified for many previously untreatable diseases. The survival rates from childhood cancer have improved at a remarkable pace over the past half century, with multidisciplinary, centralized treatment and high-quality supportive care. Survival rates have reached 80% at five years from diagnosis in developed European countries [2]. It has been estimated that the number of survivors of cancer diagnosed during childhood and adolescence in Europe are between 300 000 and 500 000 with approximately one in every 640 young adults being a survivor of childhood cancer [3]. The price of this remarkable success, however, has been high. To varying degrees, these former patients experience a wide spectrum of long-term adverse health consequences of the live-saving treatments that can affect almost any organ or body system [4]. Unique possibilities exist to study late effects in a European setting including the complementary advantages of large population-based cancer registries with the oldest going back to the 1940s and 1950s together with rich and detailed hospital-based cohorts. Here we present both established and developing national survivor cohorts within Europe to study late effects in those treated as children for cancer highlighting the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCare-

SurFup and PanCareLIFE. Both projects have their origin in the PanCare Network (www.pancare.eu) inspired by the Erice Statement from 2007 [5]. Childhood cancer survivor cohorts in Europe This paper describes the established large national survivor cohorts, cohorts in the process of becoming established and national, and the two large European consortia totaling more than 100 000 former childhood cancer patients. We present an overview of studies of late effects focusing on differences and similarities in design and methods. Countries in Europe with established national childhood cancer survivor cohorts, countries in the process of establishing a national cohort, as well as countries being data providers to the two European collaborative studies are mapped in Figure 1 with detailed characteristics presented in Table I. Details on study designs and methods and information on main research areas are presented in Tables II and III. Established national childhood cancer survivor cohorts The Nordic Adult Life after Childhood Cancer in Scandinavia (ALiCCS). The ALiCCS cohort comprises 33 160 children diagnosed with cancer below the age of 20; identification of children started at the establishment of the five national Nordic cancer registries in the 1940s and 1950s through 2008; children had to be at least one-year survivors. The ALiCCS cohort also includes 212 892 population comparison subjects randomly selected from Nordic civil registration systems. Large-scale record linkage techniques provide accurate follow-up information on childhood cancer survivors, and enable comparisons with the general population to be accomplished. Such methods provide comprehensive knowledge of risks of treatmentinduced late effects. Nationwide hospital registers in all five countries (Denmark, Finland, Norway, Iceland and Sweden) allow follow-up for a wide range of somatic late effects measured as medically verified



Childhood cancer survivor cohorts in Europe  657

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).

diagnoses. In ongoing retrospective cohort studies, late effects in different organ systems are being studied. Morbidity among cohort members is analyzed on the basis of person-years at risk. Observed numbers of first-time hospitalizations for a broad range of sub-acute and chronic diseases in survivors are compared with that expected based on hospitalization rates derived from the population comparison cohort with relative and absolute risks estimated for specific chronic diseases. There has been linkage with several other registries for the ALiCCS study, allowing investigations for a broad variety of other outcomes, such as adverse events during pregnancy and birth as well as drug prescriptions. Subsequent clinical case-cohort studies are designed to investigate associations, including doseresponse effects, between specific elements of treatment regimens and the risk of late effects, and will include study subjects selected from the ALiCCS cohort including, however, only five-year survivors diagnosed from 1970. Cases are defined as those affected with a selected disease outcome (late effect) observed in the cohort studies. For cases and 600 sub-cohort members randomly selected from the cohort of five-year survivors representing cancer treatment in the entire five-year survivor cohort, information on cancer treatment is being abstracted

from medical records, including drug names and cumulative doses as well as radiation field and doses. Organ dose reconstruction from pediatric radiation therapy including dosimetry for a variety of organs is being performed at the M.D. Anderson Cancer Center in Houston, USA [6]. ALiCCS contributes data to PanCareSurFup and Denmark is contributing data to PanCareLIFE. Our Nordic approach and choice of epidemiological designs allow systematic ascertainment of late effects in organ systems and will strengthen knowledge of all types of late sequelae that these patients encounter as they age. The main limitation is lack of treatment information; this aspect will be addressed in the clinical case-cohort studies. The British Childhood Cancer Survivor Study (BCCSS). The BCCSS cohort originally comprised 17 981 individuals diagnosed with childhood cancer before aged 15 years, between 1940 and 1991 in England, Wales or Scotland and who survived at least five years from diagnosis [7]. The cohort has recently been extended to include an additional 16 509 individuals diagnosed between 1992 and 2006, but otherwise satisfying the criteria defining the original cohort. Causes of deaths and incident cancers occurring subsequent to five-year survival are obtained through

658 J. F. Winther et al. Table I. Characteristics of childhood cancer survivor cohorts in Europe. Study name (acronym) Country

Established national survivor cohort ALiCCS Denmark Finland Iceland Norway Sweden

BCCSS England Wales Scotland

DCOG LATER Netherlands

In the process of establishing a national cohort SCCSS

Switzerland

Identification Nordic cancer of registries survivors

DCOG LATER Swiss Childhood National Cancer Registry registry based cancer on registration nationwide hospitalbased cohorts

Number of survivors

33 160

Survival at entry

1-year survivors

17 981 in original cohort; 34 490 in extended cohort 5-year survivors

6168

4405

5-year survivors

5-year survivors

FCCSS

LEA

OTR

European collaborative studies PanCareLIFE Czech Republic Denmark France Germany Ireland Italy Netherlands Switzerland

PanCareSurFup Nordic countries Slovenia France United Kingdom Netherlands Hungary Switzerland Italy National and hospital registries

France (will end France (participating Italy pediatric up including onco-hematology in addition to centers cover the regional nearly 75% of all cancer childhood registries, all leukemia onco-pediatric survivors departments diagnosed since in France) 1980) Network of the Regional cancer Hospital data, Italian clinical trials, registries, Association of and cancer hospital data, Paediatric registry clinical trials Haematology (ongoing) and Oncology (data to be combined with regional cancer registry data) 3029 (1000 more to 14 201 (16 000 12 000 (6000 be enrolled) more to be more to be enrolled enrolled) primarily from regional cancer registries) 5-year survivors 2-year survivors Elective end of therapy

Mostly 5-year survivors

0–20

5-year survivors in the case-control studies 020

Cancer registries and local databases

About 12 000 to be About 100 000 in the cohort expected in total studies cohort

Age at 019 cancer diagnosis Cancer type All types

0–14

0–17

020

019

018

All types

All types

All types

All but leukemias

All types

All types

Calendar 19432008 years at diagnosis

1940–1991 in 1963–2002 original cohort; 1940–2006 in extended cohort 80 years 65 years

1976(ongoing)

19461999

All types Malignant hemopathies (today only leukemias but lymphomas will also be included) 1980(ongoing) 19602004 (ongoing)

1940s–2000s

1940s–2000s

52 years

74 years

45 years

NA

85 years

85 years Maximum age at latest follow-up with respect to death Loss to 1% follow-up

Funding

Danish Strategic Research Council

Website

www.aliccs. org

019

54 years

Depend on the 20% NA NA 3% 1% for registry 8% (mainly outcome survivors data; around emigrated to 20% for other countries) clinical data European European The French National Italian ministry The French Swiss Cancer Dutch Cancer Cancer Commission; Commission; of health, Research Agency National League, Swiss Society; the Research FP7FP7-HEALTHRegional (ANR), the Ligue Cancer National Science Quality of UK, Kay HEALTH2013Health Nationale Contre Institute Foundation, Life Kendall 2010.2.4.1-7 INNOVATION-1 authorities le Cancer, the (InCA), the Swiss Paediatric Foundation, Leukaemia (Grant (Grant and partly by French Institute French Oncology Group, KiKa Fund and Agreement Agreement the European for Public Health National Kinderkrebs-hilfe Kinderen FP-7 Number Number Union Research Research Schweiz, Cancer Kankervrij 257505) 602030) (FP7 project, (IRESP), the Agency League Bern, PanCareSurFrench National (ANR), the Zurich and Fup) Cancer Institute Ligue Aarau, Swiss (INCA), the Nationale Bridge, Stiftung Pfizer Foundation Contre le zur for childhood and Cancer, and Krebsbekämpfung, adolescent health, the French and FP-7 and the Institute for Programme Public Health Hospitalier de Research Recherche (IRESP) Clinique (PHRC) No website No website No website www.pancare­life.eu; www. www. www. www.bccss. www.pancare.eu pancaresurfup. childhoodcanc­ skionlaterstudie. bham. eu; erregistry.ch nl/english/ ac.uk www.pancare.eu 1.4% in original cohort



Childhood cancer survivor cohorts in Europe  659

Table II. Design and data collection as well as strengths and limitations of the European childhood cancer survivor cohort studies. Study name (acronym) Study Design

Established national survivor cohort ALiCCS

BCCSS

Populationbased

Hospital and regional register-based

Hospital and local registerbased

Retrospective

Retrospective and prospective

Prospective

Retrospective and prospective

Retrospective and prospective

Five as many Nationwide population(212 892) based randomly mortality and selected cancer population incidence comparisons rates; individually National matched questionnaire according surveys and to age, sex, Hospital and Episode country Statistics database

Matched siblings and populationbased controls

Siblings; representative populationbased surveys

National statistics National Database of Health Care

In case-cohort Crude cohort/ studies comprehensive case-control studies In case-cohort Crude cohort/ studies comprehensive case-control studies In case-cohort Crude cohort/ studies comprehensive case-control studies In case-cohort Not at present, studies but intend electronic record linkage with the national register Every 5th to Causes of death 10th year and cancers every 3rd month; Hospital Episode Statistics database every 5th years

Complete in detail

Yes

Complete in detail

Yes

Complete in detail

Yes

Complete in detail

Yes

In 50% of the cohort and in case-control studies In 50% of the cohort and in case-control studies In 50% of the cohort and in case-control studies In 50% of the cohort and in case-control studies

Populationbased

Prospective/ retrospective

Retrospective

Surgery

Bone marrow transplantation

Update of data collection

Other variablesa Lifestyle behaviors No

Co-morbidity

LEA

Population-based Nationwide hospitalbased

Setting

Radiation

FCCSS

Cohort studies

Cohort and case-control studies

Exposure Chemotherapy

SCCSS

Cohort studies Cohort and case-control studies

Cohort and casecohort studies

Comparisons Comparison population

In the process of establishing a national cohort

DCOG LATER

Yes, as medically verified hospital diagnoses

From questionnaire only Yes, from national Hospital Episode Statistics database in the future

Cohort and case-control studies

Yes

Yes

Yes

Yes

OTR

European collaborative studies PanCareLIFE

PanCareSurFup

Cohort and Observational case-control studies and studies molecular genetic investigations Population- and Population- and Nationwide hospital-based hospitalhospital-based based (later also regional registerbased) Retrospective Retrospective Retrospective and and prospective prospective Cohort studies

Cohort and Nationwide case-control populationdesign based mortality and cancer incidence rates

Complete in detail for 80% of the cohort Complete in detail for 80% of the cohort Complete in detail for 80% of the cohort Complete in detail for 70% of the cohort

At least y/n; more detailed for subgroups At least y/n; more detailed for subgroups At least y/n; more detailed for subgroups At least y/n; more detailed for subgroups

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 In case-control studies

In case-control studies

In case-control studies

In case-control studies

Every 2nd to Every 5th year 5th years in questionnaire; Clinical visits in 2015–2018

Annual linkage with national hospital data base

Every 2nd year Every 5th to 10th year for for vital status patients  20 and cause of years; Every death 4th year for patients  20 years

NA

NA

Yes Yes, based on different study designs Yes Yes

Yes

Yes

No

No

Yes, by questionnaire and as registered in national hospital data base

Yes

Yes, only from treating centers

Yes, in some study designs Yes, in some study designs

Other medical conditions from local study centres

(Continued)

660 J. F. Winther et al. Table II. (Continued) Study name (acronym)

Established national survivor cohort ALiCCS

BCCSS

DCOG LATER

In the process of establishing a national cohort SCCSS

FCCSS

LEA

OTR

European collaborative studies PanCareLIFE

PanCareSurFup

Outcome identification Data sources

Clinical/physical examination

Blood samples

Medical records

Strengths

Limitations

aOther

National Medical records, National National death National Hospital mortality national and cancer hospital Register statistics; mortality registries; registers, linkage and cancer statistics, historically medical questionnaires incidence cancer questionnaire; birth from regional registries, future registries, registries; hospital national prescription questionnaire discharge Hospital registries, survey registry, Episode psychiatric questionnaires Statistics in-patient and clinical database registries visits (except Iceland and Norway), causes of death registries, cancer registries Long term No No Yes Only for follow-up selected consultations patients in for 10% of the nested cohort studies No No Yes No On-going; Blood in 500 and saliva in 2000 survivors Yes Yes 50% of the Yes, in Yes, in cohort and case-control casecase-control studies cohort studies studies Treatment data National, Long-term Long-term Long-term and whole including all complete complete complete body radiation childhood follow-up follow-up in follow-up in dose cancer and complete high quality high quality reconstruction survivors. treatment populationpopulationfor 50% of the Combination data. based national based cohort. of data from Clinical registry. Nordic Annual questionnaires validation in Non-cancer registries; linkage with and records medical non-fatal Analyses of the National linked with records and outcomes pattern of Hospital routine data. in clinical ascertained morbidity database. Ongoing patient visit. through throughout Ongoing inclusion of Several questionnaires adult life, inclusion of survivors possibilities historically, including survivors for linkage through after age 50; studies. electronic Medically Extensive record linkage verified collaboration with the chronic between national diseases in pediatric Hospital all organ oncologists, Episode systems; other Statistics Robust risk specialists and database in estimates for epidemiologithe future rare but cal potentially investigators fatal diseases Detailed No treatment Crude treatment Lack of Not a treatment populationonly available data in populationdata need to based cohort to cohort cohort based cohort, be abstracted for children studies, studies; because there from records. with cancer detailed and detailed is no national Limited until 2001. comprehensive treatment cancer registry information However, the treatment information in France. on expectation is information is from Treatment nonthat the cohort available in medical data only for a responders is nearly nested record part of the to complete for case-control abstraction cohort questionnaire all cancers studies and organ other than dosimetry CNS tumors in and case-cohort retinoblastoma studies

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

Census bureaus; National Causes of Hospital death Register registries; linkage and Hospital questionnaires discharge registries (only for residents of selected regions; later a centralized linkage including all regions)

Populationbased and hospital based-data sources; cancer registries; local databases

Population- and hospital-based data sources and medical records

Yes

Yes, if in follow-up clinic

Yes, in some study designs

No

Yes

No

Yes, in some study designs

No

Yes

Yes

Yes, in some study designs

Yes, in case-control studies

Long-term Large dataset Detailed Clinical follow-up in enables information examination population- and answers to on and hospital-based questions pathological self-reported registries of with rare and molecular data on life high quality. outcomes characteristics style, quality Detailed (fertility, of the original of life, and treatment ototoxicity, tumor; relationships information health-related detailed with health from medical quality of treatment care system. record life). Data information Ongoing abstraction and from mainly from inclusion of organ multiple medical survivors dosimetry sources in record included in standardized abstraction. case-control data format Ongoing studies allows inclusion of comparability survivors

Different sources A mixture of Registration of 75% of all population- and (populationan expected national hospital- based and 90% of the cases are registries hospital-based incident included. No registries); eligible cases economic retrospective at completion data. data which of treatment; have to be difficulties in harmonized having an for a extended common data clinical format; follow-up of different survivors no logistics per more in country; contact with different the treating standards center



Childhood cancer survivor cohorts in Europe  661

Table III. Overview of main research areas, ongoing and planned studies, and key publications. Study name (acronym)

Established national survivor cohort ALiCCS

BCCSS

DCOG LATER

In the process of establishing a national cohort SCCSS

FCCSS

LEA

OTR

Mortality, Late physical Any long term Somatic and second effects and side effect, role psychosocial primary psychosocial of treatment late effects, cancers, and outcomes and genetic health behaviors somatic late (quality of life predisposition and follow-up effects and social care inequality in health)

European collaborative studies PanCareLIFE PanCareSurFup Cardiac Female disease, fertility, second cisplatinsarcomas induced and second ototoxicity digestive and and healthgenitorelated urinary quality of carcinomas, life and late mortality

Main focus areas

Somatic late effects in all organs and organ systems

Comprehensive Comprehensive spectrum of spectrum of adverse health adverse health and and social psychosocial outcomes outcomes

Publications

Endocrine disorders; Diabetes

Causes of death; Second primary cancers; Use of health services; Educational attainment; Smoking; Alcohol consumption; Marriage; Liveborn

Diabetes; Age at Cohort profile; Cohort profile; Fertility; Bone mineral menopause; Psychomethodology density; Cardiovascular oncology; of Metabolic diseases; Health questionnaires; syndrome; Mortality, behaviors; guidelines; Sibling’s DNA repair Social single center quality of life capacity and outcomes; studies second Asthma; primary Follow-up care; cancers; Quality of life; Second Education primary cancers

Causes of death; A manuscript A manuscript giving a giving a Second primary general general cancers overview on overview the PanCare on the network is PanCare close to network is submission close to submission

Selected key [21,22] publications

[7,23–25]

[8,26–28]

[40–42]

Ongoing studies

Cardiovascular Cardiovascular, Cataract, Cardiovascular, On-going cohort Questionnaire, disease, pulmonary, cardiovascupulmonary and cohort and and second and endocrine lar, pulmonary, endocrine case controls case-control primary disorders, endocrine, disorders, studies on studies of cancers, reproductive renal, and ototoxicity, female fertility, subsequent fertility issues and social gastroreproductive second primaries of outcomes, intestinal outcomes, late primary soft tissue, school disorders, mortality, cancers, bone, performance, reproductive quality of life, mortality, digestive and quality of life and social psychosocial cardiac genitourinary and outcomes outcomes, diseases, sites; also of psychosocial follow-up care, toxicity, quality serious outcomes transition in of life, cardiac care, and health long-term outcomes and behaviors morbidity and strokes. healthcare Individual consumption, patient adverse health electronic effects of record linkage radiotherapy, with the radiation national dosimetry, and Hospital breast cancer Episode prediction Statistics model database will enable the comparison of observed and expected numbers of a wide spectrum of non-fatal nonneoplastic adverse health outcomes

Cardiovascular, pulmonary, endocrine, renal, gastrointestinal, autoimmune and neurological disorders, reproductive outcomes, and cohort profile

[9,29–31]

[32–35]

[36–39]

Cardiac Fertility, disease, ototoxicity second and primary healthcancers, late related mortality quality of life

(Continued)

662 J. F. Winther et al. Table III. (Continued) Study name (acronym) Planned studies

Future directions

Established national survivor cohort ALiCCS

BCCSS

DCOG LATER

In the process of establishing a national cohort SCCSS

FCCSS

Genetic Hospitalizations Cohort studies Establishing the Studies of late predisposition (by linkage to including Teenage Young effects in to second hospital episode clinical visits to Adult Cancer survivors of cancers and statistics) identify risk Survivor Study ALL, cardiovascular and risk (TYACSS) neuroblastoma, diseases factors for cohort of 233 retinoblastoma, health 081 individuals Wilms, and problems, new who were bone tumors diagnostic diagnosed with tests, and cancer when genetic aged 15–39 predisposition years, in England and Wales, between 1971 and 2006 and survived at least 5 years International Genetics National Combined Late effects in collaboration screening of analysis of children with breast and BCCSS and other specific thyroid cancer TYACCS cancer types; in at risk cohorts include group information from other Nordic population and health registries; International collaboration

individual patient electronic record linkage with the national population-based death and cancer registries. Historically, between 2002 and 2007, a questionnaire was sent to 14 836 survivors aged over 16 years and 10 483 (71%) returned it completed. The questionnaire included several questions which had been included in the ‘General Household Survey’ which was undertaken on a probability sample of the national general population; these included frequency use of health services, educational attainment, occupational status, smoking, and alcohol consumption history. The extent to which survivors marry and produce liveborn offspring has also been compared with that expected from the national marriage and birth registries. The BCCSS contributes data to PanCareSurFup. Nested case-control studies have been undertaken to evaluate the association between increased cumulative exposure to different types of chemotherapy or radiotherapy and the increased risk of development of subsequent primary leukemia, bone cancer, soft tissue sarcoma, and central nervous system tumors. The Dutch Childhood Oncology Group Program on longterm adverse effects after childhood cancer (DCOG LATER). The DCOG LATER program is responsible for optimal care and research related to Dutch childhood cancer survivors. In recent years, the DCOG LATER group developed the DCOG LATER guidelines, set up seven outpatient clinics for survivors in The Netherlands, and designed the DCOG LATER study program consisting of two parts.

LEA

OTR

European collaborative studies PanCareLIFE PanCareSurFup

NA Cause specific Genetics, hospitalizations, parents’ cause specific quality of life, mortality, and siblings’ second outcomes, and cancers social inequalities in health

National Level

Other second carcinomas than digestive and genitourinary

International collaborations

In the first part, all five-year survivors of childhood cancer treated in one of seven pediatric oncology centers between 1963 and 2002 for cancer before the age of 18 years have been identified and ascertained. The DCOG LATER nationwide hospital-based cohort consists of 6168 five-year survivors; baseline demographics about their first cancer diagnosis and treatment have been collected in a web-based database. In addition, a questionnaire focusing on risk factors, lifestyle, and health conditions was sent to the survivors in 2013 with questionnaire outcomes to be validated by information retrieved from general physicians and medical records. The first results of several observational studies on mortality, symptomatic cardiac disease, secondary primary malignancies and female reproductive function in the entire DCOG-LATER cohort are expected in 2015. In the second part of the DCOG LATER study program, all 5545 living survivors will be invited for a visit to the research clinic for a physical examination, laboratory tests, diagnostic tests, and additional questionnaires. This clinical evaluation will provide a unique opportunity to validate the questionnaire outcomes and the results of linkage studies, to collect data on asymptomatic outcomes, and to gain insight in the additional value of screening tests. Furthermore, DNA collection will allow future analyses of genetic predisposition for specific treatment-related health problems. As all clinical data are collected within one visit, the burden for survivors is minimized substantially [8]. The research project-specific questions within the projects are based

on gaps in knowledge as identified during the establishment of the DCOG LATER guidelines for patient care. In 2007 the DCOG LATER VEVO study was initiated to evaluate female reproductive function in the DCOG LATER cohort. This study established the feasibility of similar studies in the Netherlands. The DCOG LATER contributes data to both PanCareSurFup and PanCareLIFE. The Swiss Childhood Cancer Survivor Study (SCCSS). The Swiss Childhood Cancer Survivor Study (SCCSS) comprises all Swiss residents diagnosed with cancer before age 21 from 1976 until the present and registered in the Swiss Childhood Cancer Registry (SSCR), i.e. 7600 persons with 6100 still being alive and 4405 being five-year survivors. Depending on the outcome under study, different comparisons are made: with the general population, representative population surveys, and siblings. Different methods are used to collect long-term outcome data: prospective data collection by hospitals during clinical follow-up visits; data linkages to Swiss routine statistics (population, birth and mortality registers, census data, hospital statistics); and questionnaire surveys to patients [9]. Clinical follow-up is continued for 5–10 years after diagnosis in all nine Swiss pediatric cancer centers, and information on remissions, relapses, changes in therapy, and late effects is forwarded to the SCCR. Vital status, information about migration and current address are continuously updated via population registers and causes of death from Swiss mortality statistics. Observed mortality and cancer incidence are compared to that expected from the general population. Patient-reported outcomes on psychological and somatic morbidity, treatments, quality of life, health behaviors, follow-up care, and socio-economic outcomes are assessed in questionnaire surveys for all five-year survivors. The first questionnaires were mailed in 2007 and the first follow-up questionnaire has been sent to a sub-population. The content of the SCCSS questionnaire is similar to that of CCSS (the US Childhood Cancer Survivor Study) [10] and BCCSS. The Swiss questionnaire is developed in different versions for three age groups (0–15, 16–19,  19 years) and in three languages (French, German, and Italian). By December 2013, about 3500 patients diagnosed from 1976 to 2005 had received a questionnaire, and 72% had replied. Patients diagnosed between 2006 and 2010 will be contacted in 2015. Focused studies (for subgroups of patients and controls defined by outcomes or treatments of interest and often in international collaborations) include detailed treatment information and validated outcomes from hospital charts and general practitioner

Childhood cancer survivor cohorts in Europe  663 notes. DNA collection is currently ongoing for subgroups but is to be extended to the whole cohort. The SCCSS study contributes data to both PanCareSurFup and PanCareLIFE. The main limitation of SCCSS is the relatively small size reflecting the population size of Switzerland. Strengths include the inclusive representative design with an ongoing study of national coverage, involvement of all pediatric oncologists, a broad range of data collected in a standardized way thus allowing pooling with other studies. Childhood cancer survivor cohorts developing towards becoming established and national The French Childhood Cancer Survivor Study (FCCSS). The FCCSS cohort is coordinated by the Centre for Research in Epidemiology and Population Health (CESP) of the National Institute for Health and Medical Research (INSERM) and aims to include about 18 000 individuals diagnosed with a malignant tumor (except leukemias), below the age of 20 years between 1946 and 1999 in France, and who survived at least five years from diagnosis. Today the cohort includes about 12 000 survivors. The establishment of a national cohort is expected in 2016. In FCCSS, detailed treatment information is collected from medical records for all patients. Additionally, whole body dose reconstruction is planned for all patients who received radiation therapy, using software developed by INSERM CESP in collaboration with Gustav Roussy Institute [11,12]. Information on vital status and causes of deaths are obtained each year through individual patient electronic record linkage with the national population-based cause of death register. Between 2000 and 2010, a questionnaire was sent to the first sub-cohort of survivors (‘Euro2K’) including 3172 patients treated before 1986 in five centers, with a response rate of 76% among those still alive. Based on these survey data, investigations have been undertaken concerning the role of dose of specific type of chemotherapy and of radiation dose to specific bodily organs in subsequent primary neoplasms, early menopause, cardiovascular diseases, and diabetes. In 2010, a biobank of constitutional DNA was set up, now including 2500 patients, and since 2014, yearly linkages to the national hospital database of France (linkage at individual level since 2006) has been performed to ascertain late effects. The FCCSS study contributes data to PanCareSurFup. The Rhône-Alpes region (ARCERRA) is contributing data to PanCareLIFE. The French Childhood Cancer Survivor Study for Leukaemia (LEA). The LEA project aims to study

664 J. F. Winther et al. determinants (medical, socio-economic, behavioral, and environmental) of medium- and long-term health and quality of life of patients treated for a childhood acute leukemia. The cohort includes patients with an acute leukemia diagnosis after January 1980, below the age of 19, surviving 2 years after diagnosis for myeloblastic acute leukemia patients or lymphoblastic acute leukemia patients grafted in first complete remission or four years after diagnosis for lymphoblastic acute leukemia patients not grafted in first complete remission. As of 31 October 2014, 3029 survivors constitute the cohort in the 14 participating French pediatric onco-hematology centers. Information collected comprises medical data, relating to acute leukemia and physical late effects, and personal data, such as socioeconomic status, schooling, psycho-cognitive data or quality of life, for which age- and sex-matched population norms are available. Data are collected every two years until the patient is 20 years old and has had a 10-year follow-up duration from diagnosis or relapse. Thereafter, assessments are planned every four years. Studies in progress are focusing on sparsely explored physical late effects, such as thyroid tumors, metabolic syndrome, and fertility. The risk of sequelae in survivors of childhood standard-risk lymphoblastic acute leukemia is explored. The survivor’s professional outcome is compared to that in general population. Risk factors relating to school performance are analyzed. Molecular explorations are planned involving a whole-genome scan to identify variations associated with the risk of survivor’s sequelae. In addition, the LEA study will use a nested case-control design to study the objective and subjective health of survivors, comparing survivors from the most disadvantaged backgrounds with those of other backgrounds for whom access to suitable examinations is facilitated by their socioeconomic status or geographic proximity to healthcare providers. Long-term outcome of healthy siblings (with a particular focus on hematopoietic stem cell donors) will be explored, as a control group for some sequelae. The major strength of the LEA cohort is to undertake dedicated clinical examinations and laboratory exams to document the occurrence of late side effects. At present the participating pediatric oncohematology centers cover nearly 75% of all French childhood leukemia survivors diagnosed since 1980. The ongoing extension of the cohort (inclusion of new pediatric onco-hematology centers and continuous inclusion of incident cases in the active centers) should ensure a higher representation. The Italian Study on off-Therapy Childhood Cancer Survivors (OTR). A national Italian cohort of

childhood cancer survivors will be set up in the near future in Italy. The Off-Therapy Registry (OTR) of the Italian Association of Paediatric Haematology and Oncology (AIEOP) originally started up in 1980 enrolling children with cancer prospectively when they had completed therapy. At the start of this register prevalent cases were also included with the first patient being diagnosed in 1960. Since 1987, a more systematic enrolment of patients from the clinical centers was established. Today, the clinical OTR register is almost complete for children below 15 (92% recruitment rate of expected cases), whereas the register is less complete for those aged 15–19 years (covers only around 25% of all cases). Detailed information on treatment is available mainly from abstraction of medical records. The clinical OTR register will be merged with data on children diagnosed with cancer from provincial and regional cancer registries (AIRTUM) with complete registration of all cancers within that specific geographical area [13]. The AIRTUM registries cover cancer registration in about 50% of the Italian population. An agreement between the AIEOP network and AIRTUM about pooling data will allow the establishment of a large national Italian cohort of childhood cancer survivors that become eligible at the off-therapy stage. Nationwide hospital- and regional cancer register-based data will be entered into an updated version of the original OTR register. The register will include more than 30 000 survivors covering more than 95% of all childhood cancer survivors in Italy. Based on record linkage to national health data (combined data from regional hospital registries), the aim of this updated register is to study cause-specific hospitalizations, second primary cancers, and mortality. Both PanCareSurFup and PanCareLIFE receive data from Italian population-based registries and from hospital-based records. The EU-funded collaborative research projects PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup). PanCareSurFup is a five-year project that started in 2011. The PanCareSurFup cohort comprises more than 100 000 children and adolescents diagnosed with cancer below the age of 21 from 1940s to 2000s identified in both national and hospital-based registries in the Nordic countries, Slovenia, UK, France, the Netherlands, Hungary, Switzerland, and Italy. The project aims to establish a single retrospective panEuropean cohort of long-term survivors of childhood and adolescent cancer with systematic ascertainment of at least one of the following endpoints: cardiac

disease, subsequent primary neoplasms, and late mortality. From this cohort a virtual pan-European database will be constructed storing characteristics of these patients as available in individual databases. Currently case-control studies are being undertaken to explore the relationship between previous cancer therapy and the risk of development of subsequent primary neoplasms and serious cardiac outcomes. Ascertainment of these cases will be done by questionnaire, by linkage to hospital registries, or by clinical visit, depending on the data provider. Besides the partners named in the project, some of whom are data providers, a number of other institutions will also provide data to the PanCareSurFup cohort and casecontrol studies (see Acknowledgments). An estimated number of 600 cardiac cases are expected including survivors with heart failure, cardiac ischemia, pericarditis, valvular disease, and arrhythmia. For the subsequent primary neoplasm studies, focus will be on bone cancer, soft-tissue sarcoma, digestive, and genitourinary carcinomas with an estimated number of 300 cases in each of these four studies and a similar number of matched controls. For all cases and controls, information on cancer treatment is being abstracted from medical records, including cumulative drug doses and radiation field and doses. Radiotherapy organ dose reconstruction will be performed at the Institut Gustave Roussy in France [11,12]. Strengths include long-term follow-up in high quality registries together with detailed treatment information from medical record abstraction and organ dosimetry. A potential limitation relates to data being provided from a mixture of population- and hospital-based registries. However, a large number of individuals is included in both the underlying cohorts and in the case-control studies and will provide the largest ever studies of the relevant outcomes. PanCareSurFup has also identified a need for pan-European guidelines for long-term follow-up of childhood cancer survivors [14]. The information obtained about the risks factors for serious cardiac disease and subsequent primary neoplasms will be incorporated into evidence-based guidelines by PanCareSurFup. PanCareLIFE. PanCareLIFE is a five-year project that started in 2013. PanCareLIFE studies the risks of impairments in female fertility, in hearing following cisplatin therapy, and in quality of life, both independently and in relation to impairments in fertility and hearing. Additionally, biospecimens will be collected for related genetic studies. PanCareLIFE comprises a number of different studies with non-overlapping patient and survivor populations. Besides the partners named in the project, some of

Childhood cancer survivor cohorts in Europe  665 whom are data providers, a number of other institutions will also provide data for PanCareLIFE’s studies (see Acknowledgments). PanCareLIFE’s research team includes investigators from eight European countries who will enrol as many as 12 000 well-characterized research subjects into observational studies and molecular genetic investigations to identify risk factors, both genetic and non-genetic, linked to decrements in fertility and ototoxicity. Quality-of-life studies will evaluate the impact of fertility and ototoxicity. PanCareLIFE will advance the state-of-the-art in survivorship studies by evaluation of large cohorts with observational and genetic tools that will provide better knowledge of individual risk factors. Survivors can then be stratified into groups benefitting from personalized, evidence-based care. Information from PanCareLIFE studies will be incorporated into new guidelines for fertility preservation and will disseminate the results from this project widely to clinicians, scientists, and survivors and their families. Discussion A growing number of large national childhood cancer survivor cohorts have been established in Europe over recent decades evaluating a broad range of late effects. Other cohorts are being developed with the goal of becoming established and national. Several of these cohorts take advantage of large populationbased cancer registries with the oldest registries in Europe going back to the 1940s providing unrivalled opportunities to study lifetime risks. By systematic ascertainment of organ dysfunctions and subsequent primary neoplasms, these studies will provide information on all types of late effects with estimations of relative and absolute risks for specific disorders. Furthermore, information on the cumulative risk for childhood cancer survivors of being diagnosed with a subsequent primary neoplasm or hospitalized for a somatic disease will be provided in different phases of life compared to that in the general population. As study subjects are identified from large populationbased registries, access to information on all patients and comparisons with virtually complete follow-up of study populations will be available. Thus, such data are less susceptible to participation and response biases. As information on disease outcomes will be obtained from health registries and not from selfreports, data will not be influenced by recall or reporting bias. Using the unique resources in several of the European countries for conducting epidemiological research by linkage to a variety of different population and health registries going long back in time will further strengthen the knowledge of both

666 J. F. Winther et al. secondary carcinogenesis and risk of organ dysfunction that these patients encounter as they age, filling out the gaps in knowledge about very late disease outcomes that emerge up to and beyond the age of 60. Although population- and register-based retrospective cohort studies will constitute a comprehensive, powerful surveillance instrument for estimating risks for medically verified diseases in survivors, the main limitation of such studies, however, might be lack of treatment information – a limitation that will be addressed in clinical case-cohort or case-control studies including the collection of detailed information on all past cancer treatments. In several of the cohort studies, a ‘gold standard’ approach for exposure assessment is implemented, in which organ dose reconstruction from radiation therapy and administrated chemotherapy received will be quantified from medical records and radiotherapy schemes and related to late effects. Computation of individual organ radiation doses and drug doses will make it possible to interpret the epidemiological results in the light of dose-response evaluations. Cohort studies with study subjects and outcomes based solely on population-based registries are limited by the information available in these administrative health registries. Some of the register-based cohorts and those recruiting patients at the pediatric oncological wards, however, have the possibility to define data needed for ongoing and future studies and to obtain high quality data from thorough clinical examinations of survivors. Additional data on health behaviors, such as smoking, diet, and physical activity that may modify the risks associated with treatment [4] can be obtained in some studies, and several are able to store biosamples to test future hypotheses as they emerge. Within Europe complementing the large-scale cohort studies using population-based registries are the well-established hospital-based cohort studies which benefit from detailed information measured on individual patients which is rarely available to population-based cohort studies. This detailed information includes: comprehensive treatment information, genotypic information from blood or saliva samples, and outcomes of clinical tests which need to be undertaken in a clinic setting. In recent years great strides have been taken to coordinate efforts to exploit these advantages in the European context through the establishment of two large EU-funded collaborative research projects by investigators from several European countries focusing on cardiac toxicity, subsequent primary neoplasms, and late mortality (PanCareSurFup) and female infertility, cisplatin-induced ototoxicity, and quality of life (PanCareLIFE). These two large

consortia have several advantages including very large cohort studies combining both register- and hospital-based data with data from surveys, clinical case-control studies with detailed treatment information and dosimetry evaluation, as well as genetic evaluations. New survivor cohorts are emerging and some of these cohorts are already contributing data to the European collaborative studies. As an example of a new cohort that is based in a cancer registry, the VIVE study was developed out of the German Childhood Cancer Registry. The first survey of the VIVE cohort is on-going and will be finalised in 2015 (Principal Investigator: Dr. G. Calaminus, Münster). The therapeutic challenge of today is to reduce the treatment-related complications, while maintaining the high survival rate. To fully understand the health risks resulting from treatment and to adjust future treatment regimens, the first step is to characterize the morbidity among survivors and to identify those with the highest risk for late effects [4]. Complementary advantages of ongoing European studies using different designs and methodologies will all contribute to important new knowledge about late effects. Published findings on late effects all stress that childhood cancer survivors need tailored follow-up care to identify health problems after treatment at an early stage. Furthermore, coordination of complex care is needed. Thus pediatric oncologists and other healthcare providers need to work together to achieve optimal models of care. A risk-stratified approach to health surveillance was proposed by the Scottish Intercollegiate Guidelines Network in 2004 identifying three different groups of survivors who required an increasing intensity of follow-up [15]. Since then, several groups in Europe and the US have developed guidelines [16]. In 2010 the guideline groups started the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) (www. ighg.org) with the overall aim of establishing a common vision and integrated strategy for the surveillance of chronic health problems and subsequent primary neoplasms in childhood, adolescent, and young adult cancer survivors and to reduce duplication of effort, optimize the quality of care, and improve quality of life for this group of survivors [16]. Recently, the first set of guidelines for breast cancer and cardiomyopathy surveillance from this worldwide collaboration have been published, with substantial input from Work Package (WP) 6 in PanCareSurFup [17,18]. PanCareSurFup and IGHG have also collaborated in the development of surveillance guidelines for female and male gonadotoxicity (manuscripts in preparation), and are currently working on guidelines for secondary thyroid cancer



Childhood cancer survivor cohorts in Europe  667

and central nervous system neoplasms. This collaboration will continue to develop surveillance guidelines for several other important and large topics, including metabolic syndrome, vasculopathy, and growth hormone deficiency, whilst WP 6 will develop guidelines for many other smaller topics (e.g. dental, hepatic). In addition, responding to a recent European survey showing great variability in the provision of long-term follow-up [19], WP 6 is developing evidence-based guidelines for the delivery of such follow-up, including the important issues of age-appropriate transition of care from pediatric to adult services, models by which longterm follow-up care can be provided effectively, and the provision of health promotion information for survivors and their families. A recent PanCare survey [20] highlighted the urgent need for fertility preservation guidelines, which is one of the major elements of the PanCareLIFE study. The European Network for research on Cancer in Children and Adolescents (ENCCA) is another European project working in parallel with PanCareSurFup and PanCareLIFE. The Survivorship Passport is being developed within ENCCA and is intended to be an electronic tool containing comprehensive information on the medical history of each patient ending cancer therapy. The passport includes recommendations for tailored follow-up based on up-to-date clinical guidelines developed with PanCareSurFup and IGHG to facilitate the prevention, early detection and treatment of potential late effects or relapses. The passport is generated through a secured web-based platform being patient oriented, accessible in multiple languages by patients, and clinicians among others and can be integrated with national, hospital, and clinical trials databases. It will also help in making survivors, general practitioners, and healthcare professionals aware of the potential risks or late effects stemming from the previous disease and treatment received. The overall goal of these large survivor cohorts and collaborative studies in Europe is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers. Declaration of interest:  The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] D’Angio GJ. Pediatric cancer in perspective: Cure is not enough. Cancer 1975;35(3 Suppl):866–70.

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