Sweden (Åsa Klint & Jan Adolfson)

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1 MINUTES ANCR BOARD MEETING Time Monday January 18 th 2010, time Venue Participants The National Board of Health Islands Brygge 67, København Denmark: Hans Storm, Jørgen H. Olsen, Marianne L. Gjerstorff Faroe Islands: Jóanis Erik Kötlum Finland: Timo Hakulinen, Risto Sankila Iceland: Laufey Tryggvadóttir Norway: Frøydis Langmark, Steinar Tretli, Freddie Bray Sweden: Åsa Klint, Jan Adolfsson 1. Opening (Marianne L. Gjerstorff) Marianne introduced Jakob Lynge Sandegaard (who unfortunately was not able to attend the meeting due to sickness) as her substitute during her maternity leave from April to November Adoption of the agenda One additional item was suggested to the agenda (Laufey Tryggvadóttir) regarding the laws on access to personal data in the different Nordic Countries, esp. in Norway since the new law on access to personal data in Iceland is inspired the Norwegian law. It was agreed the subject would be discussed with the status report from Norway. 3. Minutes of the ANCR Board Meeting on September 2 nd 2009 Minutes were accepted. 4. Short status reports from the Nordic Cancer Registries Denmark (Marianne L. Gjerstorff) - appended Faroe Islands (Jóanis Erik Kötlum) - appended Finland (Risto Sankila) - appended Iceland (Laufey Tryggvadóttir) - appended Norway (Frøydis Langmark) - appended In regard to legal basis for registration Norway has a problem with the storage of negative findings in their screening program. The legislation regulating this is the Health Registry Law, and it does not allow these normal findings to be stored for more than 6 months, unless there is informed consent according to the Data inspection team. Frøydis would very much like remarks from the other Nordic Cancer registries in regard to this demand for informed consent. In regards to Laufey s question Norway has a new Research Law (July 2009), which is a very good law, as the ethical committee together with this new law is easy to deal with. Sweden (Åsa Klint & Jan Adolfson) - appended 5. Brief NCU-related reports ANCR-NCU meeting spring 2010? (Marianne Gjerstorff) The NCU has its board meeting this very week, where they amongst other subjects will talk about a suggested revision of its epidemiological strategy and the Nordic Childhood Cancer Project. The ANCR board will await the outcome of the NCU board meeting before deciding on whether or not to initiate a joint board meeting. The ANCR is focused on the NCU keeping its epidemiological strategy and its funding of ANCR initiated projects such as NORDCAN, Summer School etc. Furthermore the NCU is relying on ANCR in producing predictions on Cancer prevalence. Hans Storm will contact Elizabeth Hjorth on the outcome of the NCU meeting. 1

2 Current status of NCU funds, NCU studies and Summer School (Hans Storm) See appendix International collaboration IACR (Freddie Bray) The IACR is currently planning the next IACR meeting in Yokohama, October 12 th -14 th, in collaboration with regional representatives. Chris Wild has been invited as keynote speaker. The IACR meeting in 2011 will be on Mauritius. And work is in progress on guidelines for the selection of the European host city of the 2012 meeting. A history of IACR by Sharon Whelan will probably be publicized as a special issue of Asian Pacific Journal of Cancer Prevention. Work is in progress on the questionnaire to IACR members on their thoughts of the association. IARC (Freddie Bray) Several new appointments have taken place at the IARC. David Forman has been appointed head the Cancer Information Section, Dr. Isabel Romey has been appointed head the Section of Nutrition and Metabolism. The biostatistics group has been moved to Paul Brennan s group (genetic epidemiology). The Globocan 2008 database will be presented soon. The scientific council will meet January 27 th -29 th. On a personal note Freddie Bray is moving to the agency to join David Forman s Section in April. He will still be holding an honorary position at the Norwegian Cancer Registry. He will resign from his position as general secretary. ENCR (Freddie Bray & Risto Sankila) The Steering Committee had a meeting in Turin, November ENCR is discussing its long term future which depend on funding. It may be possible to establish the ENCR as a legal entity, which would make it possible for the ENCR to apply for funds, alternatively it may be possible to establish a direct contract with the European Committee, a proposal has been sent and it will be answered in the second half of If the proposal is accepted, the future of the ENCR secretariat will be secured. The Haemacare proposal for a coding manual of haematological diseases has not been supported by the ENCR. Furthermore, an ENCR newsflash has been publicized last week (see EUROCOURSE (Hans Storm) Next meeting of the Steering Committee is on the 18 th march. WP 4 is working on a joint database with comparable data, much as the Nordcan database. Lyon may take the role of securing the database. WP 2 is working on a questionnaire, and is looking for experts to become engaged in the WP. David Forman has been engaged in the work. WP 3 & 4 has a meeting mid-february on data collection and coordination. Furthermore, a EUROCOURSE newsletter has been publicized (see ACCIS (Freddie Bray) The project is not very active. There is plans for an update of the database. EUROCARE (Timo Hakulinen) Data requests have been sent out along with a project protocol. The project has requested for identity codes in order to link the old datasets with the new. Timo expressed concerns as to whether this was a good idea, there will be revisions to old data in the new datasets, so there would be no benefit from linking the datasets. 2

3 Deadline is July 1st. Financing is still coming from the Bank of San Paolo. The data can now be delievered through a common platform. The analysis now includes multiple cancers and stage. Hans noted that the project protocol still is very unclear in regard to the academic purposes of the project. CONCORD (Timo Hakulinen) Michel Coleman s group is taking a break from the CONCORD project. The project has included more Cancer Registries. The work of Michel Coleman and his group is under evaluation by Cancer ResearchU.K. who is funding the group, further funding depends on the outcome of the evaluation. EUNICE (Freddie Bray) Selected cancer registries are part of a study, Finland and Norway are participating. A meeting is being planned in connection with the ANCR conference in Finland in HAEMACARE (Risto Sankila) A paper is being published on histology specific cancers leukaemia and lymphomas Haemacare s own grouping is being used. EUROCHIP-3 (Risto Sankila) Risto did not attend the last meeting, so there are not much news. The group is still funded by the Commission. NOCCA (Laufey Tryggvadóttir) Eero Pukkala is organising a NIVA course on NOCCA June 8 th -11 th Note that this, unfortumately, is the same dates as the ANCR conference. NOCCA has more in depth studies under way, looking at co-factors risks in combination with work. International Cancer Benchmarking Partnership (ICBP) (Marianne L. Gjerstorff & Hans Storm) The Benchmarking project has been launched, with Danish National Board of Health (Marianne), Norwegian Cancer Registry (Tom Børge Johannesen) and Swedish Association of Local Authorities and Regions (Jan Adolfsson), along with Canada (Ontario, Manitoba, Alberta, Br. Colombia), England, Northern Ireland, Wales and Australia (New South Wales and Victoria) participating. The project has been initiated by Mike Richards, who has a disbelief in the Eurocare results. The first module of the project entails a survival analysis including stage and treatment. Timo and Hans has both been asked to join the projects Academic Reference group, they are both considering whether or not to respond positively. 7. Other items Nordic Childhood Cancer Study (see appendix 3) (Jørgen H. Olsen) - Selection of three ANCR members for the Board The project has now got its funding from the Danish Council for Strategic Research. The study is setting up a board with 3 representatives from the epidemiological milieu and 3 representatives from clinicians working with childhood cancers. Jørgen, Risto and Frøydis were selected. 8. Next ANCR Board Meeting and Annual Meeting in Faroe Islands Next board meeting will be in connection with the ANCR conference on Faroe Islands June 9 th 2010 in the morning. Link to the conference homepage: List of appendix: 1. Country reports 2. Status of Nordic projects supported by NCU 3. Project description: Nordic Childhood Cancer Study 3

4 Appendix 1: Country reports Denmark Status In December 2009 the Danish Cancer registry was updated with data until Project on the validity of the Cancer Registry The joint project on the quality of the modernized Cancer Register between the National board of Health and the Danish Cancer Society is proceeding almost according to plan. There have been two setbacks in the project, firstly, and most importantly, the Cancer Registry will not be compared with the Danish Colorectal Cancer Registry, as the database now have enriched their data with data from the Patient Discharge Registry which is also the main data source for the Cancer Registry. Secondly the quality assessment of the lung cancers has not yet been finished as we have been delayed in getting patient records from the hospitals, which is the final step in scrutinizing the reasons for cases missing respectively in the Cancer Registry and the Danish Lung Cancer Registry. Breast tumours in the 2006 Cancer Registry have now been compared with the Danish Breast Cancer Register. Data has also been combined with the Pathological Registry and the Patient Discharge Registry with the purpose of scrutinizing the reasons for cases missing respectively in the Cancer Registry and in the DBCR. Report on the Modernized Cancer Registry, methods and quality In December 2009 the National Board of Health publicized a report, in Danish, documenting the modernized Cancer Register and the consequences of the modernization on the quality of the registry. No changes in staff in 2009 The staff still consists of: Ole B. Larsen, Medical adviser Milan Fajber, Data manager Margit Rasted, Gurli Larsen and Esther Knudsen, Medical coders Marianne L. Gjerstorff, Head of section (on maternity leave April November 2010, no substitute has yet been found). 4

5 Faroe Islands Status The Faroese Cancer Registry is working on Coding 2006 figures. The cancer forms from Doctor are collected and up to date for Mortality data We have data until 2007 Cancer Plan Was finished by October This plan has several recommendations among these an urgent improvement of the Cancer registration. Research The Faroese Cancer registry has been used for some genetic research project in hematology, Ovary and mammae. Staff Sæunn Óladóttir Hansen, chef secretary Landssjúkrahúsið Jóanis Erik Køtlum, Adviser Heilsumálaráðið Supervision and help from Kræftens bekæmpelse Danmark 5

6 Finland - A printed biannual report for was published in December The special theme of this report was predictions for 2020 on incidence, mortality and prevalence. Further, there are predicted survival rates for 2013 and future considerations on the screening programmes. - The incidence figures for 2008 will be published in the web in Feb On 16 Sept., the new board including members from the National Institute for Health and Welfare (THL) and the Cancer Society of Finland (CSF) agreed on the Contract and details on how the CSF will continue to run the registry as before. However, there are new requirements for electronic archiving, new electronic notification forms and some other aspects that would require increased funding from THL (e.g. mass screening registry activities). However, THL has to cut over 100 person-years and 30% of core funding in 2010, which means that there are no extra resources for cancer registration. - The Finland s Slot Machine Association will try NOT to continue financial support to the CSF for cancer registration activities after Their aim is to move the funding slowly into state budget. However, the gambling money for fiscal year 2011 should be secured and they have assured that they will continue the funding until the new source has been found. - The insulation of the old window sills of our newly rented office have rottened and actinomycosis appears in the office air. Therefore, we have to evacuate the whole office into another building in the same block for approx. 3 months. The new address -Erottajankatu/Skillnaden 5 - was the most expensive site in the Helsingfors version of the Monopoly game. Our mailing address will remain Pieni Roobertinkatu 9, Helsinki and the telephone numbers will not change either. - During 2009 we produced 84 scientific publications and 3 doctoral theses. - NIVA (Nordiska Institutionen för Vidareutbildning inom Arbetsmiljöområdet; Nordic Institute for Advanced Training in Occupational Health) organises a course on Nordic occupational cancer (NOCCA) studies on 8-11 June 2010, in Conference Hotel Sannäs Manor, Porvoo, Finland. The course organiser is Docent Eero Pukkala, University of Tampere, Finland. - The clinical and laboratory notification forms are being created on the national IT-platform that relates to the country-wide electronic hospital record archive that is under construction but severely delayed. 6

7 Iceland - The Icelandic Cancer Society (ICS) will have a new director in February 2010, when Ragnheiður Haraldsdóttir will replace Guðrún Agnarsdóttir. Her background is MSc in nursing and management from McGill University, Canada. She has longstanding management experience, both as one of the top managers at the University Hospital and at the Ministry of Health. - The first task of the new director will be to cut down on the expenses of the ICS, but it is currently not known how this will affect the Cancer Registry. - A new Director of Health, Dr. Geir Gunnlaugsson, was appointed January 1 st He is a paediatrician and has background in public health. - The Cancer Registry is one of several registries belonging to the Directorate of Health (DH) according to an act from The ICS signed a contract with the DH in October 2008 stating that the ICS will continue to run the Cancer Registry, and the Cancer Registry has made new working rules which were approved by the DH in October

8 Norway 1) Annual report Cancer in Norway 2008 published on our website; Special issue: The Janus Serum bank 2) Number of scientific publications: 102 Number of dissertations: 1 3) Four university hospitals in Oslo (The Radium Hospital, Rikshospitalet, Ullevål and Aker) are organized together in the large Oslo University Hospital under the largest Health Region South East RHF of Norway, (the other health regions are HR North, Mid-Norway and West). 4) We have had a lot of trouble the whole of 2009 with regard to questions of our legal basis for registration and storage of negative (normal) findings in our screening programs, with accompanying media noise. 8

9 Sweden Publications: Cancer Incidence in Sweden 2008 and Basal cell carcinoma in Sweden was published in Dec Reorganisation of Socialstyrelsen A complete reorganisation of Socialstyrelsen is in place since Jan 1, The cancer registry is under the department of Statistics and Evaluation, and under the unit Population statistics. The impact on the registry activities is still unclear. Simultaneously two large projects are going on at Socialstyrelsen o A new technical platform and structures for working with data (more efficient use of resources and less inventing the wheel for each new project). o Common in-data structure for all registries. Financing is unclear. A Swedish Government Official Report in December 2009 proposed a move of the health data registers to a separate institute. If this becomes reality it will likely be in place from early The number of cancer registry staff is probably unchanged due to reorganisation but still some changes. Head of Unit: Anders Åberg Managing director of CR: Åsa Klint (on leave Feb1-June1, 2010) Coding and statistics: Shiva Ayoubi Statistics: Staffan Khan Medical consultative staff: Jan Ericsson, Lars Holmberg, Barbro Lundh-Rozell The INCA-platform is doing well, currently 23 registers for different cancers and 2 benign registers more info during the scientific meeting. The national cancer strategy was published in February 2009 and the government aims towards establishing regional cancer centers throughout the country to provide better care across the country with as little regional variation as possible. Background in a large predicted increase in number of incident but mostly prevalent cases up to Kjell Asplund (former Head of Socialstyrelsen) has been appointed National Cancer Coordinator from Jan 1,

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15 Appendix 3 Revision 26 November 2009 Appendix D Project description Nordic Childhood Cancer Study: Late Effects and Their Prevention Jørgen H. Olsen 1, Henrik Hasle 2, Lene Mølgaard 2, Jeanette Falck Winther 1 and Nordic partners 3 1 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen 2 Department of Paediatrics, Aarhus University Hospital Skejby 3 Lars Hjorth (Lund), Harald Anderson (Lund), Åsa Klint (Stockholm), Frøydis Langmark (Oslo), Risto Sankila (Helsinki), Päivi M. Lähteenmäki (Turku), Kirsi Jahnukainen (Helsinki), Laufey Tryggvadóttír (Reykjavik) 1. Summary Cancer and its treatment during childhood and adolescence can result in a variety of long-term sequelae, such as impairment of growth and development, reproductive difficulties, chronic late morbidity, second cancers, increased mortality and psychosocial and familial problems. Survival rates after childhood cancer have improved substantially over the past four decades, and a rapidly increasing number of survivors pass reproductive age and adulthood to enter their 50s and early 60s, when the incidences of most chronic diseases in the general population begin to increase. Studies of late sequelae of childhood cancer require a large population of survivors if they are to yield reliable estimates of the relative and absolute risks. We propose to establish a large, retrospective, inter-nordic childhood cancer cohort (n = ) in order to compare their morbidityspecific incidence and cause-specific mortality with those of a sample of the general populations of the Nordic countries (n = ). The Nordic countries are ideal study areas for this type of clinical and epidemiological research, as a broad range of outcome data is available from high-quality, nationwide health and disease registers. We also propose to set up several case control studies nested in the childhood cancer cohort in order to investigate associations, including dose-response, between specific treatment regimens and selected outcomes. The ultimate goals are to allow better planning of treatment protocols for childhood cancer, with fewer late effects, to contribute to preventive intervention strategies and to improve the basis for patient counselling and optimal follow-up care. 2. Objective of the project The first objective is to establish a complete, population-based series of children and adolescents in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) in whom cancer was diagnosed during the period 1943 to 2008 and to follow them up individually to the present in various health-related national registers in order to investigate a range of treatment-related late complications in both the survivors themselves and their offspring. The surveillance for adverse late outcomes will be undertaken in a multinational retrospective cohort study. This will comprise the largest group of persons affected by cancer in childhood and a comparison population taken at random from the national populations. The second objective is to set up a number of clinical case control studies nested within the cohort of childhood cancer patients and their offspring, in which cases will be defined on the basis of selected serious outcomes. These studies are designed to investigate damaging late effects of specific treatment regimens in childhood. The overall purpose is to 15

16 contribute to the identification and characterization of high-risk populations, as this information is critical for making evidence-based recommendations for long-term follow-up of survivors of childhood cancer. 3. Main results of the project As a result of this international collaboration, an extraordinarily large cohort of childhood cancer cases (n = ) will be established, with a comparison cohort (n = ) taken at random from the general populations of the Nordic countries. Personal data on the patients and their diagnoses will be extracted from nationwide population-based cancer registries, forming an almost complete series of childhood cancer cases in this part of the world since the 1940s and 1950s (1). Accurate follow-up of patients and population controls will be achieved through the civil registration systems of the Nordic countries, and use of large-scale record linkage techniques with national outcome registers will provide a broad range of information on subsequent disease, independently of the person s status as a patient or a population control, including complete hospital histories since the 1960s and 1970s. The combined dataset will constitute a new, comprehensive, powerful surveillance instrument for estimating relative and absolute risks for medically verified, chronic health conditions in childhood cancer survivors. This is especially important for survivors aged 40 years, for whom there is little information on non-malignant outcomes. A large study in the USA indicated that childhood cancer survivors continue to face new-onset organ system morbidity as they age (2), possibly because several potentially life-threatening conditions remain subclinical until the survivor reaches late adulthood or middle age. A nested case control design will be applied to the childhood cancer survivor cohort as a hypothesis-testing instrument, in order to investigate relations between specific treatment regimens and serious late outcomes. Some outcomes have been selected a priori, but the screening phase in the first part of the study will identify any important new questions to be investigated. Detailed information on childhood cancer treatment will be obtained from the medical records of the patients and from other sources, following routine procedures previously established by our group (3,4). 4. Background and hypothesis of the project Since the start of cancer registration in Denmark (1943), Norway (1953), Finland (1953), Iceland (1955) and Sweden (1958), cancer has been diagnosed in more than children and adolescents aged 0 19 years (referred to as childhood cancer in this application) (1). In the 1940s and 1950s, few children survived their disease (5). At the beginning of the 1960s, however, therapies were developed which involved combinations of chemotherapeutic drugs and combinations of different treatment modalities (chemotherapy, radiation and surgery). These new approaches meant that increasing numbers of patients experienced sustained remission and cure; today, 80% of affected children can be expected to be long-term survivors. As a result of the continuous success of treatment, there is now a fast growing population of persons who have been cured of childhood cancer and have survived for decades since their first treatment. As the vast majority of these survivors received intensive exposure to radiation and highly toxic compounds as part of their treatment and during a period of life distinguished by organ growth and maturation, they now face significant, often uncharacterized sequelae, most of which become clinically apparent many years after the cancer has been cured (6). At the end of 2005, more than persons in the Nordic countries were survivors of childhood cancer, at that time constituting approximately 0.1% of the national populations (24 million around the century) (1). A ramified, accurate investigation of the late effects of treatment for childhood cancer requires large groups of survivors who have been followed for a substantial part of their life. Two comprehensive patient cohorts have previously been established to study survivors of childhood cancer: the Childhood Cancer Survivor Study cohort in North America, consisting of interviewed 5-year survivors treated at 26 institutions in Canada and the United States between 1970 and 1986 (7), and a similar cohort in the United Kingdom, consisting of year survivors of cancers diagnosed in (8). The risks for treatment-related second cancers have been investigated intensively in each cohort, with the cancer rates of the general population as reference. In addition, the North American cohort of survivors has been the basis for several studies on the occurrence of self-reported, disabling, non-malignant, chronic diseases, the results of which were recently summarized by Diller and co-workers (2). Overall, the analyses showed that the prevalence of at least one self-reported, severe or life-threatening, disabling chronic illness was 27.5% among survivors and 5.2% 16

17 among 3000 siblings of patients, and a number of associations were found between specific treatment regimens and adverse late outcomes (6). At the time of the analyses, the mean age of both the survivors and the siblings was 26.5 years, and the interval between primary diagnosis of cancer and interview was 17.5 years, with a range of 6 31 years. The study therefore had little statistical power for the age range 40 years. The self-reported outcomes among adult survivors were usually not validated against medical records because of restricted resources (2). In the British survivor study, information was collected from survivors by use of mailed questionnaires; the results for nonmalignant late effects are in preparation (8). In a retrospective cohort study in a childhood cancer treatment centre in The Netherlands, year survivors were invited to a clinic for medical assessment of late adverse events. The overall prevalence of late effects was substantial, but the analytical possibilities were limited by the relatively small size of the cohort and lack of a control population (9). The proposed Nordic survivor cohort could contribute importantly to detailed characterization of the main chronic health effects faced by childhood cancer survivors and make it possible to determine the risk factors for such conditions. The method to be used differs somewhat from that used in North America and the United Kingdom. Our cohort, which comprises year survivors and year survivors, is strictly population-based and consists of patients in whom cancer was diagnosed over a period of 60 years. It includes some , 6000, 2500 and 700 survivors actively followed-up beyond the ages of 30, 40, 50 and 60 years, respectively, in addition to a large control population, which will enhance the analytical possibilities even for the second half of life. The central population register in each country will keep track of all survivors and population controls, including their vital status, date of death (if deceased), date of emigration (if emigrated), current address and links to information on their offspring and other first-degree relatives (10). A unique advantage of conducting the study in the Nordic countries is that it is feasible to link patients and population controls to a number of high-quality national medical outcome registers, including hospital registers for detailed information on somatic and psychiatric diagnoses during follow-up, cancer registries for second cancers, registers of spontaneous and induced abortions, medical birth registers and registers of socioeconomic and demographic indicators (11). Deceased persons will be linked to national mortality files that contain information on the cause of death. In addition, the offspring of patients and population controls will be linked to these registers. With this cohort surveillance approach, we will assess the relative and absolute risks for all major diseases of adulthood and middle age, including endocrine, skeletal, pulmonary, cardiac and vascular diseases, as well as late relapses, reproductive effects and diseases in the offspring of survivors. As the treating hospital department is identified in the files of the cancer registries, we will be able to trace the medical records and other sources of treatment information (3,4). Specific, well-defined outcomes, such as myocardial infarction, cardiomyopathy, valvular abnormalities, cerebral haemorrhage, pulmonary insufficiency, osteonecrosis, diabetes, functional kidney disease, reproductive failure, perinatal mortality and serious diseases in the offspring, are considered to be investigated in case control studies nested in the childhood cancer survivor cohort. Dose response relations will be investigated. 5. Innovative value, impact and relevance of the project Because the risk and severity of many late effects of childhood cancer are modifiable, and some even preventable, leading paediatric oncologists recommend life-long health care for survivors (12). A systematic plan is needed for longitudinal screening, surveillance and prevention that incorporates risks assessed from data on the type of cancer, the type of therapy, genetic predisposition (if any), lifestyle behaviour and comorbid health conditions (13). Such evidence-based guidelines for surveillance are being initiated in countries like Canada, The Netherlands and the United States. Most childhood cancer survivors, however, are not followed up at a cancer centre or a late-effects clinic. Instead, over time, they generally drift back to their primary care physician, who is usually unaware of their risks and is likely to see fewer than five childhood cancer survivors, each with a different cancer treated with a different regimen. As most late effects become clinically apparent many years after the completion of cancer therapy, the transition of survivors to primary care physicians is an important barrier to the accumulation and evaluation of treatment-related adverse outcomes and thus a barrier to the development of evidencebased guidelines. In order to obtain new knowledge, large numbers of patients must be followed-up in a strictly systematic fashion. The Nordic childhood cancer survivor study, like the survivor studies in North America and the United Kingdom, is essential for collecting clinical and epidemiological data on the late effects of cancer treatment in childhood. Our proposal will strengthen the collection of data on late effects, not 17

18 least on those occurring in people aged 40 years. In addition, our study will yield risk estimates on late outcomes reflecting treatment traditions of the Nordic countries. 6. Project methods and results The first part of the study will be to establish a surveillance instrument, composed of a childhood cancer cohort and a control cohort, the latter reflecting morbidity in the background populations. Childhood cancer cohort - childhood cancer patients in each country as registered in the cancer registries (personal characteristics, diagnostic details and date of diagnosis); - aged 0 19 years at diagnosis; - recruitment period: Population comparison cohort - two controls for each childhood cancer patient (personal characteristics); - controls selected at random from the population registers of each Nordic country; - controls matched to patients on country, year of birth and gender; must be alive at the patient s date of diagnosis. Large-scale record linkage to population and outcome registers - linkage of patients and re-linkage of population controls to the central population register of each country for information on vital status and offspring (10); - linkage of patients and population controls to a set of outcome registers (listed below); and - allocation of a study number to each patient and control, with the link between the study number and the personal identification number kept in the respective cancer registry. Uploading of data Anonymous national data on patients and controls will be uploaded to a pooled Nordic dataset. Each variable will be reviewed and certified, and the data will be included in a strictly defined Nordic database situated in Copenhagen at the Institute of Cancer Epidemiology. Outcome registers for survivors and offspring Linkages with outcome registers will be performed by use of the personal identification numbers of the study subjects. These were introduced in Iceland in 1952, Norway in 1960, Sweden in 1961, Finland in 1967 and Denmark in For persons who died before that date, linkages will be performed by use of the full name and date of birth (14). - Cancer registers will be used to identify cases of second cancer among survivors (1,15). National cancer incidence rates will be used to calculate expected numbers of cases. - Death certificate files will be used to identify the cause of death of deceased childhood cancer patients. National mortality rates will be used to calculate expected numbers. Previous experience of our group (16) indicates that it may be necessary to review the death certificates to ensure correct coding. - In-patient registers are important, as they contain complete hospital histories of patients and population controls from the day they were established, including data on e.g. endocrine, skeletal, pulmonary, cardiac and vascular diseases as well as diseases in offspring. Hospital in-patient registers have been in operation in Sweden and Finland since the 1960s, in Denmark since the 1970s and in Norway and Iceland since the 1990s. After an initial running-in period, the in-patient registers covered practically all discharges from non-psychiatric hospitals in the five Nordic countries. For each discharge from hospital, the patient s identification number is registered, with the date of discharge and all main and supplementary diagnoses coded according to ICD-8, ICD-9 or ICD-10. Codes for surgical procedures are added when appropriate and coded according to Nordic classifications. All coding is performed by 18

19 medical staff at the treatment centres. In some of the countries, registration also covers outpatient visits to hospitals and psychiatric morbidity. In Denmark, Sweden and Finland, the inpatient registers have been used extensively in medical research, not least by our own group and our partners (17 20). In addition, the files of the inpatient registers will be used to study late relapses from childhood cancer. - Other national registers, including medical birth registers, registers of induced abortions and registers of congenital malformations, will be used to identify adverse events during pregnancy and adverse outcomes in offspring during the perinatal period. These include spontaneous and induced abortions, length of gestation, serious obstetric complications, fetal growth retardation, functional abnormalities in newborns and congenital malformations. Some of these outcomes have been studied previously by our group, but in the Danish subcohort only (21 24). Analysis of cohort data for surveillance Morbidity and mortality among cohort members will be analysed on the basis of person years at risk. The outcomes will be grouped according to the International Classification of Diseases (ICD), and in principle will include all chapters of the Classification and all major disease entities. Risks will be expressed as incidence or mortality rates, risk ratios, mortality ratios and excess absolute morbidity and mortality. Risks for fetal outcomes will be expressed as prevalences and prevalence proportions. Power and expected outcomes in cohort analyses The statistical power of the cohort study depends on the frequency of the outcome in the background population and the size of the relative risk among survivors. We have little information about the expected relative risks, but are able to estimate the person-years at risk. By applying the age-, gender- and calendar-specific first hospitalization rates for cardiovascular and autoimmune diseases of the population of Denmark to the Nordic survivor cohort (up to the end of 2005), we obtained the expected numbers of outcomes shown in the table below. These morbidity reference rates were generated as part of other studies, but the calculations indicate a substantial statistical power given the existence of moderate to high risk elevations for chronic diseases among survivors. First hospitalization for Expected number of outcomes (ICD-8; ICD-10) Both genders Men Women All cardiovascular diseases Ischaemic heart disease ( ; I20 I25) Chronic endocarditis or valvular disease (424; I34 I38) Chronic pericarditis (423; I31) Cardiomyopathy (425; I42) Conduction disorders or dysrhythmias ( ; I44 I49) Heart failure Other and not otherwise specified heart diseases (427.99, ; I51) Selected autoimmune diseases Rheumatoid arthritis ( ; M05, M06, M08) Sjögren disease, systemic lupus erythematosus, systemic sclerosis (734.90, , 734; M35, M32; M34) Sarcoidosis (135.99; D86) Limitations of the cohort analyses Unlike the interview-based childhood cancer survivor studies in North America and the United Kingdom, our study will not include information on lifestyle factors that might affect the risks for nonmalignant disease, mainly smoking habits. In order to define the profiles of the two cohorts in the Nordic study, we will link the study subjects in Denmark to a set of registers of socioeconomic and demographic indicators (11). In addition, we plan to study current and former smoking habits and other lifestyle factors in appropriate samples of long-term survivors and matched population controls. Most studies in Australia, Europe and the Unit- 19

20 ed States suggest, however, that survivors are less likely to have risky behaviour, such as cigarette smoking or drug use (25 27). Although most of the outcome registers have been in operation on a national scale in all five Nordic countries for decades, another limitation will be that some of the registers do not exist in one or more of the countries. Also, the date of start of the registers differs from country to country. This implies that analyses of some outcomes will be conducted on restricted study material. Moreover, cases of less severe outcomes will be missing as they do normally not result in a hospital contact. In general, the registers in the Nordic countries collect information on approximately the same set of variables, although the construction of the databases differs widely and will require national expertise to ensure compatibility. Depending on the type of outcome, it is expected that there will be some degree of non-differential misclassification. Any misclassification, however, will be evaluated by a review of a sample of medical records (28). This activity will be an obligatory part of the nested case control studies described below. Most importantly, the Nordic cancer registry files are limited for research on late effects by insufficient information on treatment variables, which may even be lacking for individual patients. This limitation will be overcome by two supplementary approaches: - a set of case control studies nested in the childhood cancer survivor cohort (see below) and - linkage of patients with leukaemia diagnosed in 1985 or later to the Childhood Leukaemia Registry of the Nordic Society for Paediatric Haematology and Oncology (see below). The second part of the study will be to establish and apply hypothesis-testing instruments to the research on late effects of childhood cancer treatments. Nested case control studies A set of case control studies nested in the survivor cohort will be established. Cases will be survivors who develop the disease chosen for study, and controls will be a random sample of survivors who are alive and free of the disease at that time. One to five controls will be selected, depending on the number of outcomes identified. The nested case control studies have two purposes: to verify the outcome under study according to standard criteria for the condition and to derive detailed information on the treatment given for the initial childhood cancer in cases and controls. The first will be taken from the medical record of the hospital department in which the outcome was diagnosed and the second from the department in which the childhood cancer was treated. On-going studies of childhood cancer survivors in Denmark indicate that medical records from paediatric oncology departments are obtained for 92% of cases ( ). A case-cohort design will be considered as an alternative approach. Outcomes considered a priori Nested case control studies are considered for hospitalizations due to myocardial infarction, valvular abnormalities, cardiomyopathy, cerebral haemorrhage, pulmonary insufficiency, osteonecrosis, diabetes, functional kidney diseases, selected reproductive failures, perinatal mortality and serious diseases in offspring, and dose response relations between treatment factors and risk for outcome will be assessed whenever possible. We also plan to investigate the personal and clinical characteristics of survivors who experience a late relapse and increased late mortality for other reasons. Other areas of research will be defined on the basis of the results of the first phase, i.e. the cohort analysis, and reports from other survivor studies, such as a recent report of the association between radiation for childhood cancer and diabetes (29). Analysis of nested case control studies Overall odds ratios and associated 95% confidence intervals will be assessed for each specific combination of treatment factor, e.g. chemotherapeutic agent or organ-specific dosimetry estimate, and outcome. Whenever possible, risks will be assessed as a function of cumulative dose of the treatment factor. Childhood Leukaemia Registry of the Nordic Society for Paediatric Haematology and Oncology The Nordic Society of Paediatric Haematology and Oncology has registered children on common Nordic leukaemia treatment protocols since the early 1980s (30). The individual treatment information in the clinical database is regarded as complete and of high quality since the mid-1980s. Data are available on the types and doses of chemotherapy and radiation. Of particular interest is the information for subcohorts who received cranial or total body irradiation. A study number system are used by the Childhood Leukaemia Registry, however a link between the study number and the personal identification number is kept nationally. By add- 20

21 ing these treatment data to our study, it becomes possible to analyse treatment of childhood leukaemia survivors on a controlled cohort basis (31). 7. Project plan The study comprises establishment of two inter-nordic cohorts (a childhood cancer cohort and a population control cohort), planning and executing a late-outcome surveillance system for the two cohorts, and establishing and conducting hypothesis-testing case control studies nested within the childhood cancer survivor cohort. Inter-Nordic cohorts (first milestone, to be reached by 1 April 2011) Establishment of a childhood cancer cohort and a population control cohort will be the first of six milestones in this 5-year project. This is expected to take 1.25 years and involve the following steps: - At a first joint Nordic meeting of partners, in January 2010, a detailed data collection plan will be completed, for: o final definition of the cohorts of childhood cancer patients and population controls; o methods for determining the vital or emigration status of cohort members; o details of registers and data on late outcomes available in each country; o a precise timetable for data extraction and data linkage; and o coordination of the wording of documents required to obtain study approval in each of the five countries. - Linkage will be performed nationally during the period March November The coordinating Principal Investigator (JHO) and a senior researcher (a post doc) hired for the study will act as permanent coordinators of this extensive work, in close contact with the five data collection centres. It is anticipated that at least one site visit to each centre will be arranged, preferably during September November In December 2010, data from the five countries will be formatted in accordance with the decisions taken at the beginning of the year, and the individually linked records will be made anonymous. - During January March 2011, anonymous data will be gathered into one, comprehensive dataset at the Institute of Cancer Epidemiology in Copenhagen. Each variable included will be reviewed and the data harmonized, ready for analysis. Outcome surveillance system and cohort analyses (second milestone, to be reached by 1 January 2014) A late outcome surveillance system will be established and the diseases of interest will be addressed one by one, starting with the four themes selected a priori followed by a screening activity: - cardiovascular and pulmonary diseases (July September 2011), - reproductive problems and diseases in offspring (October 2011 December 2011), - endocrine disorders (January March 2012) and - other late adverse outcomes (April 2012 December 2014). Nested case control studies on selected outcomes (third to sixth milestone, to be reached by December 2014) This activity includes: - selection of outcomes and generation of specific working hypotheses, - selection of controls, - review of medical records for confirmation and subgrouping of outcome and collection of data on childhood cancer treatment, including dosimetry estimations when appropriate, and - analysis. 21

22 22

23 1. Cardiovascular and pulmonary diseases (January 2011 December 2013), 2. Selected reproductive failures (July 2011 June 2014), 3. Selected endocrinologic disorders (January 2012 December 2014), and 4. Development of new protocols (January 2013 December 2014). Staffing A senior researcher (post doc) and a data manager will be hired for the entire 5-year period, January 2010 December Statistical support equivalent to 25% full-time work will be included for all five years. Three PhD students will be allocated to the four themes chosen a priori. Resource allocation from parties The applicants salaries will be covered by their respective institutions (the Danish Cancer Society and Skejby Hospital). Jørgen H. Olsen will allocate 25% of his working hours to the project throughout the 5-year period and Jeanette Falck Winther will allocate 50% of her time. Henrik Hasle and Lene Mølgaard will allocate 10% of their working hours to the project. The Institute of Cancer Epidemiology has powerful computer facilities. (Data processing expenses for the Institute in 2008 were DKK, which were covered by the Cancer Society). These will be available for the project without charge. Also, expenses for renting etc. will be covered on the core budget of the Institute. 8. International dimension of the project The study will be conducted as collaboration between paediatric oncologists, cancer epidemiologists and other health-care researchers in Denmark, Finland, Iceland, Norway and Sweden. Nordic collaboration in clinical and epidemiological research is of particular importance (and needed) for studies of relatively rare diseases, such as childhood cancer and the late consequences of treatment for childhood cancer. As the public health care systems of the Nordic countries are similar, it is relatively easy to increase the statistical power of a study by combining data across borders. This will greatly improve the possibility of deriving accurate information on childhood cancer and the late effects of treatment, which will contribute to the international fund of knowledge in this area. The applicants are known internationally for their work in childhood cancer research, as they have published more than 100 papers on various aspects of childhood cancer, many of which have appeared in high-impact journals with wide circulation. The planned Nordic study will be based on the largest collection of data ever established, based on a method that is somewhat different from that used in North America and the United Kingdom. The results will be received with interest by researchers and treating physicians worldwide. The project groups have collaborative links with leading researchers in the Childhood Cancer Survivor Study and the British equivalent. The three PhD positions and the position of senior researcher will be announced internationally. Finally, the Nordic Childhood Cancer Survivor study, if successful, may serve as a model for future collaboration between the Nordic countries in other areas of medical research that utilize register data on personal and medical data.

24 9. Legal, ethical and other aspects Widescale data linkage by use of personal identification numbers is possible in all the Nordic countries only with the permission of the respective data inspection agency (government institutions). In addition, studies on human populations require permission from the ethical committee system of each country. Neither permission is expected to be limited by reservations or restrictions, as no biological material is to be collected from study participants. A questionnaire study of samples of cohort participants may be conducted in order to obtain selfreported data on lifestyle factors from survivors and population controls. 10. Publication and promotional strategy Publications in scientific journals In order to guarantee appropriate documentation, all the results of this study will be published in international, peer-reviewed research journals. A minimum of 12 scientific publications are anticipated in the current plans. Reviews in Nordic journals Reviews of Nordic results and results of studies outside the Nordic area will be communicated in Nordic medical journals in Nordic languages to make them accessible to hospital doctors, doctors in the primary health-care system and other groups of health-care providers. Public information in the Nordic countries The information obtained will be communicated to the general public. The Nordic cancer societies, which are united under the Nordic Cancer Union, have decades of experience in the communication of scientific results to the public. For the current project, plans will be developed in collaboration with the cancer societies ( Training Three young researchers will be trained in the area of late effects of childhood cancer treatment. One post doc. will take the responsibility for the coordination and development of research plans in collaboration with the coordinating PI and the partners. This may importantly add to the formal education and training of paediatric oncologists and epidemiologists in the Nordic countries. Organizational links Dr Kirsi Jahnukainen at the University of Helsinki (partner) is Chairperson of the Late Effects Working Group of the Nordic Society for Paediatric Haematology and Oncology. The Society is a platform for collaboration among Nordic paediatric oncologists and is active in the coordination of Nordic clinical trials and in supplementary training of young paediatricians. Dr Lars J. Hjorth at the University of Lund (partner) is Chairperson of the Pan-European Network for Care of Survivors after Childhood and Adolescent Cancer (PanCare). 11. Exploitation of results The overall purpose of this study is to characterize the main chronic health conditions faced by childhood cancer survivors and to determine the risk factors for these conditions. This will involve either confirmation of observations made in previous studies (mainly the Childhood Cancer Survivor Study in North America) or the generation of new information. Such information is critical for establishing 2

25 evidence-based recommendations for long-term follow-up of survivors in the Nordic countries and elsewhere. With proactive and anticipatory risk-based care and healthy lifestyles, the frequency and severity of many late effects of cancer therapy can be significantly reduced (13). 12. Participating parties Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark The research institute was established in 1942 under the name the Danish Cancer Registry. In 1997, the cancer registration activity was moved to the Board of Health, while epidemiological research in cancer maintained its base at the Danish Cancer Society under a new name, Institute of Cancer Epidemiology. Since November 2000, Jørgen H. Olsen has been Director of the Institute. For more than a decade, late complications of treatment for childhood cancer have been an important research area, headed by Senior Researcher Jeanette Falck Winther. The Institute has longstanding collaborations with the cancer registries of the other Nordic countries, both directly and through the Association of the Nordic Cancer Registries. The Institute has a well-developed research infrastructure, with a range of professional expertise, which facilitates the collection of data on disease and health care, largescale data linkage and epidemiological analysis. Paediatric Department, Skejby Hospital, Aarhus, Denmark The Department serves as a centre for paediatric oncology in western Denmark, covering a population of 2.7 million inhabitants. The Department has a research unit for paediatric oncology, which runs a number of research programmes on Danish and other Nordic patients. Henrik Hasle is Professor and consultant in paediatric hematology and oncology, serves as Chairman for the Leukaemia-lymphoma Working Group of the Nordic Society for Paediatric Haematology and Oncology and is Principal Investigator of the NOPHO-AML2004 protocol. Dr Lene Mølgaard Hansen is a PhD student in the research unit and Principal Investigator of a Nordic study on treatment toxicity in childhood acute myeloid leukaemia in patients examined and diagnosed at 21 paediatric departments in the Nordic region. Swedish Cancer Registry, National Board of Health and Welfare, Stockholm, Sweden The Swedish Cancer Registry was founded in 1958 and covers the entire population of Sweden. Newly detected cancer cases must be reported compulsorily to the Registry by all health-care providers. Central registration builds on six regional registries, which are associated with the oncological centres in each medical region of Sweden. Registration, coding and quality control are performed in close collaboration with the reporting physician. The Swedish Cancer Registry, and other health data registers, are used for official statistics and serve as a basis for epidemiological studies. Petra Otterblad Olausson is Head of Department, Birgitta Stegmayr is Head of the Register Unit, and Åsa Klint is Managing Director of the Swedish Cancer Registry. The Swedish Cancer Registry is a member of the Association of the Nordic Cancer Registries and has participated in a number of Nordic collaborative projects. Division of Paediatric Oncology and Haematology, University Children s Hospital, Lund, Sweden The Division of Paediatric Oncology and Haematology is one of Sweden s tertiary childhood cancer centres, which receives new patients annually. Dr Lars Hjorth has been Head of Division since He is currently Chairperson of a national Swedish Working Group for Long-term Follow-up after Childhood Cancer. In addition, he is Chairperson of a Pan-European Network for Care of Survivors after Childhood and Adolescent Cancer (PanCare). Cancer Registry of Norway, Institute of Population-based Cancer Research, Oslo, Norway The Cancer Registry of Norway, Institute of Population-based Cancer Research, was established in It is one of the oldest cancer registries in the world. This, combined with the unique personal 3

26 identification number used in Norway, makes the Cancer Registry s data suitable for establishing new knowledge through research, and spreading information on cancer, also internationally. The information comes from several independent sources, thus securing a high rate of completeness. Dr Frøydis Langmark, a member of the Association of the Nordic Cancer Registries, has been the Director of the Cancer Registry since Finnish Cancer Registry, Cancer Society of Finland, Helsinki, Finland The Finnish Cancer Registry was founded in It has virtually complete coverage of childhood cancers as well as complete follow-up for death or emigration. The Registry has been involved in almost all cancer epidemiological studies in Finland and also in broad international collaborations. With over 1500 scientific publications, many based on complex linkages with different national register databases, the Registry is highly respected. Risto Sankila, Chief Medical Officer of the Finnish Cancer Registry, has been employed for over 20 years, including 2.5 years at the International Agency for Research on Cancer in Lyon, France. He has been in charge of most childhood cancer studies based on Registry data since the early 1990s. Unit of Paediatric Haematology and Oncology, Department of Paediatrics, University of Turku, Turku, Finland This Unit is one of five university paediatric departments in Finland. It has a comprehensive programme for the diagnosis and treatment of childhood cancer and stem-cell transplantation. The main focus of its research for years has been the late effects of childhood cancer and its treatment. Head of Unit Päivi M. Lähteenmäki has also been involved in national registry-based studies of late effects and has written several publications on the subject. Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland The Icelandic Cancer Registry was established in From the outset, it covered all cancers in the Icelandic population and has been active in epidemiological cancer research, including numerous Nordic cooperative studies and studies on childhood cancer. Dr Laufey Tryggvadóttir, a member of the board of the Association of the Nordic Cancer Registries since 1989, has been the Managing Director of the Icelandic Cancer Registry since Department of Paediatric Haematology and Oncology, Hospital for Children and Adolescents, Helsinki, Finland This is the largest of the five university pediatric haemato-oncologic units in Finland. It includes a comprehensive programme for the diagnosis and treatment of childhood cancer and stem-cell transplantation. A main focus of its research for years has been cardiac, metabolic and endocrine late complications of childhood cancer and its treatment, as well as risks of reproductive failure. Dr Kirsi Jahnukainen is reproduction physiologist of the unit, chairperson of the Late Effects Working Group of the Nordic Society of Pediatric Haematology and Oncology and member of the Nordic Network on Gonadal Preservation after Cancer Treatment in Children. Department of Cancer Epidemiology, Lund University, Lund, Sweden The Department is the university part of the Oncological Centre/Regional Tumour Registry of Lund University Hospital. It has expertise in cancer epidemiology, cancer registration, clinical studies and biostatistics, and it performs epidemiological and clinical studies on cancer in collaboration with national and international partners. Harald Anderson is Senior Statistician and has been the key person in the analysis of several Nordic studies of late effects of childhood cancer therapy. 13. Project management 4

27 The organization and management of the project are illustrated in the figure below. Coordinating Principal Investigator: Jørgen H. Olsen, DMSc, will be the study coordinator. Dr Olsen will also serve as Principal Investigator for Denmark. Senior Researcher (post doc): Day-to-day management will be the responsibility of a senior researcher experienced in cancer epidemiology, paediatric research and late effects of cancer treatment. This person will head the data management and analysis centre and will be allocated to the project on a full-time basis for 5 years. Data management and analysis centre: The centre will also have a full-time data manager and a statistician for a total of 4 months per year for 5 years. The centre will be hosted by the Institute of Cancer Epidemiology, which is headed by the coordinating Principal Investigator. Board of the Nordic Childhood Cancer Survivor Study: A board will be established to ensure that the project develops according to the present plan and to help develop this research project for the benefit of childhood cancer survivors in each of the five Nordic countries. The Board will comprise three representatives of the Board of the Association of the Nordic Cancer Registries and three representatives of the Board of the Nordic Society of Paediatric Haematology and Oncology. 5