Swiss Childhood Cancer Registry Schweizer Kinderkrebsregister Registre Suisse du Cancer de l'enfant Registro Svizzero dei Tumori Infantili

Transcription

1 Swiss Childhood Cancer Registry Schweizer Kinderkrebsregister Registre Suisse du Cancer de l'enfant Registro Svizzero dei Tumori Infantili Jahresbericht Rapport annuel Relazione annuale Annual Report

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3 Swiss Childhood Cancer Registry Annual report 2004 Claudia Kuehni Gisela Michel Malcolm Sturdy Shelagh Redmond Bern, September 2005 Publisher: Swiss Childhood Cancer Registry (Management: Dr. med. Claudia Kuehni) Address: Dept. of Social and Preventive Medicine University of Bern Finkenhubelweg 11 CH-3012 Bern Switzerland Phone: Fax: kinderkrebsregister@ispm.unibe.ch Homepage: Logo: Elsbeth Kuehni Layout: Monica Röthlisberger Bern, Swiss Childhood Cancer Registry

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5 1 Introduction 3 2 Organisation of the Swiss Childhood Cancer Registry Brief history Staff Department of Social and Preventive Medicine (ISPM), University of Bern Swiss Paediatric Oncology Group (SPOG) General information about the childhood registry Inclusion criteria and data collection Current database Tumour coding Routine analyses Completeness of the data Summary tables for the whole data set National and international cooperation Membership of the IACR and ENCR Collaboration with VSKR Visits to DKKR and NRCT Current research projects at the SCCR Collaboration with SPOG studies (data-extraction) Research proposals Oncosuisse Wyeth Foundation Swiss Federal Statistical Office (SFSO) Berner Krebsliga (Cancer League of Bern) Review of activities Data protection Analysis of the data quality Missing information Data quality Concept for a new database Next steps in 2005/ Data managers report Survey on CNS-tumours

6 6.6 Webpage: Future activities New database concept Revision of the current database Sponsoring of the SCCR Research proposals Publications Peer reviewed papers MD theses References Abbreviations Appendices Appendix 1: Informed consent Appendix 2: Classification of childhood cancer used by the SCCR i) ICCC ii) ICD-O iii) ICD Appendix 3: Relationship models of the old and new database a) Old SCCR entity relationship model b) Working SCCR entity relationship model b) Old SCCR content description

7 1 Introduction The Swiss Childhood Cancer Registry is the national cancer registry for children in Switzerland. It is an epidemiological registry with integrated clinical data. In 2004, the SCCR became an associate member of the International Association of Cancer Registries (IACR) and the European Network of Cancer Registries (ENCR) (chapter 4). All Swiss hospitals treating paediatric cancer patients report newly diagnosed children to the registry. With the long-term follow up of these children, survival, late effects and secondary tumours are being studied. Data are collected by all clinicians caring for children with cancer in Switzerland, who are all members of the Swiss Paediatric Oncology Group (SPOG; clinics in Aarau, Basel, Bern, Genève, Lausanne, Luzern, St. Gallen, Locarno, Zürich). The SCCR collaborates with the Association of Swiss Cancer Registries (VSKR), the German Childhood Cancer Registry (GCCR), the National Registry of Childhood Tumours in the UK in Oxford (NRCT) and other national childhood cancer registries. This is the first annual report since the data centre of the Swiss Childhood Cancer Registry moved to the Dept of Social and Preventive Medicine at the University of Bern (ISPM Bern) in During the next three years, the Cancer Registry will be improved and reorganised, the database will be updated, validated and adapted to international standards: 1. Content, completeness and quality of the database will be analysed in detail and measures to improve data quality will be developed depending on the results. Inclusion of patients with CNS tumours will be optimised. 2. Content and structure of the database, diagnostic coding, data-flow and follow-up procedures will be revised in accordance with international standards. 3. Research projects will be developed in collaboration between ISPM, SPOG, VSKR and international partners. A description of the organisation at the ISPM and the staff is given in chapter 2 and a description of the data collected in the registry is shown in chapter 3. National and international collaborations are discussed in chapter 4, the current projects the SCCR is involved with in chapter 5, and details of the activities in 2004 are illustrated in chapter 6. To conclude, we will give a preview of the projects we intend to pursue in

8 2 Organisation of the Swiss Childhood Cancer Registry 2.1 Brief history In 1976, the Swiss Paediatric Oncology Group (SPOG) established a central archive of all patients participating in clinical trials. Since 1981 patients not participating in a trial were also included, and a yearly follow-up of the patients was introduced. In 1992 the registry was transferred into an electronic database and late effects in longterm survivors were assessed systematically. Until 2003 the database was run at the University Paediatric Hospital in Bern by PD Dr. Nicolas von der Weid. Since January 2004, the data centre of the SCCR is located at the Dept of Social and Preventive Medicine (ISPM), University of Bern. Since then a process involving the complete renewal, improvement and adaptation to international standards of the electronic database, data collection and all procedures is underway (Table 1). Table 1: Brief history of the SCCR Year 1976 Patients participating in clinical trials 1981 Patients not participating in clinical trials included Follow-up data for clinical state and treatment every 6 months 1992 Registration of late effects Electronic database 2004 Renewal, improvement and adaptation of database, data collection and all procedures 4

9 2.2 Staff The Swiss Childhood Cancer Registry (SCCR) is run jointly by the Swiss Paediatric Oncology Group (SPOG) and the Department of Social and Preventive Medicine (ISPM) Department of Social and Preventive Medicine (ISPM), University of Bern Finkenhubelweg 11, 3012 Bern, Tel: +41 (0) , Fax: +41 (0) , Management of the SCCR Claudia Kuehni Overall responsibility: Gisela Michel Project Management: Scientific Staff Elisabeth Kiraly Diagnostic Coding: Marie-Pierre Strippoli Statistics part-time: Administration and Computer Science Malcolm Sturdy Computer Science: Ursula Laubscher; Michel Bruhin and Inès Rajower were visiting workers who were at the ISPM for several months working for the SCCR Swiss Paediatric Oncology Group (SPOG) SIAK Koordinationszentrum, Effingerstrasse 40, 3008 Bern, Fax: +41 (0) SPOG Executive Nicolas von der Weid President Felix Niggli Vice President Heinz Hengartner Secretary Central Office in Bern Liselotte Lang central secretariat Friedgard Julmy clinical trials, ethic committee submissions Participating Clinics (Haemato-oncology Head of Division Local Data-Manager Aarau (Kinderklinik Aarau / Kantonsspital): P. Imbach R. Angst Basel (Universitätskinderspital beider Basel): T. Kühne V. Stahel Bern (Universitäts-Kinderklinik / Inselspital): A. Hirt B. Delaleu Genève (Hôpital des Enfants): P. Wacker M. Bernr Lausanne (Service de Pédiatrie CHUV): M. Beck-Popovic N. von der Weid R. M. Garcia Locarno (Ospedale Regionale di Locarno): L. Nobile L. Nobile Luzern (Kinderspital Luzern): U. Caflisch J. Bichsel St.Gallen (Ostschweiz. Kinderspital): J. Greiner R. Fussenegger Zürich (Kinderspital Zürich): F. Niggli H. Markievicz 5

10 2.3 General information about the childhood registry Inclusion criteria and data collection Included diagnoses: i) Acute and chronic leukaemias, including myelodysplastic syndrome, ii) All solid malignancies, iii) All CNS tumours, including benign tumours, iv)langerhans cell tumours and histiocytosis (type IIII). Every child below the age of 16 who is newly diagnosed with cancer at one of the nine Swiss centres for paediatric oncology and haematology is registered by the SCCR. Some older patients who are suffering from a paediatric cancer and treated at a childrens hospital are also registered but unsystematically, as are children who live outside Switzerland but are treated here. Follow-up data is extracted once or twice a year from the patients hospital records, as long as they are included in clinical trials and follow-up, usually for 5-10 years, thereafter they are obtained from the patients general practitioners or paediatricians. In each of the nine centres there is a data manager, who fills the data into the data forms. These are sent to the central office of the SPOG; from there they are forwarded to the SCCR at the ISPM where the data are entered into the database. Paper copies are stored by the SPOG. Figure 1 shows the dataflow diagram of the SCCR. Figure 1 Document- and dataflow of the SCCR Informed Consent GP / Paediatrician Patient & Parents Oncologist Follow-up Hospital chart Clinic Data manager First Notification / Follow-up First Notification / Follow-up First Notification / Follow-up Data entry SPOG Archive Archive SPOG Secretariat ISPM Data manager SCCR 6

11 2.3.2 Current database The electronic database of the SCCR which is currently in use has been developed by PD Dr. Nicolas von der Weid in Apart from minor adaptations to improve data entry no major changes have yet been made. At present, the database contains the following information on cancer patients (see Appendix 1 for details): Patients name, address, and phone number at the time of diagnosis. Name and address of the general practitioner or paediatrician and the paediatric cancer centre treating the child. Demographic information (date of birth, gender, postal code) Socio-economic information (parental profession, place of origin, country of residence) Tumour diagnosis, date of diagnosis, type of cancer, histology, stage, metastases Other diagnoses, pre-existing disease conditions which may be relevant. Clinical information and laboratory values Treatment (treatment protocols, medication and dosages, radiotherapy, surgical interventions, others) Follow-up data concerning survival/death and cause of death Late effects due to malignancy and therapy Tumour coding Until 2004, all tumours were coded according to the coding used by the American Paediatric Oncology Group (POG). In addition, the exact diagnosis including details on location and staging are recorded. In 2004 the SCCR started to code new tumours according to international classifications. Retrospective coding of the existing database is in progress. The SCCR has been using the following international classifications to enable international comparisons: i) The third revision of the International Classification of Childhood Cancer (ICCC-3) [1] ii) The third edition of the International Classification of Diseases for Oncology (ICD-O-3) [2] iii) The tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) [3] (see Appendix 2). To present data in the annual report the following classification for general diagnostic groups a summary from the ICCC-3 classification has been used: I. Leukaemias, II. Lymphomas, III. CNS tumours, IV. Sympathetic Nervous System (SNS) tumours, V. Retinoblastoma, VI. Renal tumours, VII. Hepatic tumours, VIII. Bone tumours, IX. Soft Tissue Sarcomas (STS) X. Germ cell tumours, XI. Other carcinomas, XII. Other neoplasms. In addition, mesoblastic nephroma and Langerhans cell histiocytoses are reported. 7

12 3 Routine analyses The database of the SCCR that is now hosted at the ISPM is a large and valuable dataset but before the important content can be used several changes have to be completed: Many variables (e.g. clinical trials, late effects, diagnosis), need recoding before reasonable analyses can be done, as they were entered in a free text format. The current diagnostic coding using the American Paediatric Oncology Group (POG) codes is being converted into the 12 ICCC-3 general coding categories (see Appendix 2). The completeness of the incidence and mortality data is currently being validated. Therefore we do not present detailed incidence and survival analyses. In this first annual report of the SCCR we will thus present a simple set of analyses including number of cases and diagnostic groups, separating for the nine SPOG clinics. In future reports numbers will probably change slightly because data validation may report additional cases (especially brain tumours), and diagnostic classification may change somewhat after the exact coding of ICD-O-3 has been completed. This chapter presents the relevant descriptive analyses of the SCCR as tables and figures from the total period of observation between 1976 and 2004 and the period for incidences. 3.1 Completeness of the data A first validation study comparing this database with independent information from cantonal cancer registries, mortality statistics and hospital archives showed that between , the database contained 83% of all paediatric leukaemia cases in Switzerland [4]. Following this study the number of annual registrations of new cases increased by 30% (Figure 1). Since 1990 the number of cases per year has remained relatively constant, suggesting that most cases are being registered. A validation study for other tumour types is planned. Nevertheless, the total incidence of childrens cancer is very similar in the SCCR and DKKR, suggesting that the registration is quite complete. It is estimated that the SCCR now includes 90-95% of all paediatric cancer cases in Switzerland. An exception is the registration of brain tumours. These tumours have also been underreported in the German Childhood Cancer Registry due to the fact that many of the cases have not been treated by chemotherapy and have not been seen in paediatric oncology clinics. The German registry was able to increase the proportion of the CNS tumours to 19.7% of all disease after they started to search systematically for the missing cases. In order to improve data completeness the SCCR has sent a questionnaire to all data managers to obtain more information on the missing CNS tumours. Results of this survey are reported in chapter Summary tables for the whole data set Up to 2004 a total of 5063 tumour cases have been registered (4358 being Swiss residents); of these 75 cases have been diagnosed in the period between 1964 and patients were reported to have died and 804 patients are lost to follow-up. For 1694 patients (33.5%) the latest follow-up information was reported after 2003 and for 419 patients the latest information comes from the time between 2000 and Systematic registration of all patients participating in clinical trials started in 1976 and the number of patients registered per year increased until After that annual registration remained quite stable with about 220 new cases each year (about 198 of them Swiss residents; Figure 1 and 8

13 Table 5). The age at first diagnosis is shown in Table 5 and Figure 2. Nearly half of the cases (45.5%) have been diagnosed aged 4 or less, 11 % under 1 year old and 34% between ages 1-4 years. In France 11% of cases are also under 1 year old, and in Germany 9.8% [5]. A peak can be observed at ages 1, 2 and 3 with more than 400 cases ( ) in each age group (Figure 3 and Figure 4). The frequency declines after age three and begins to increase again from 214 at age 9 up to 276 cases at age 13. This trend is also observed in the DKKR [6] One third of cancers diagnosed in childhood are leukaemias (32%), followed by tumours of the central nervous system (CNS-tumours, 16%) and lymphomas (14%). In tumours of the sympathetic nervous system (SNStumours) neuroblastomas contribute the major part (Figure 5 and Figure 6). Details of each diagnostic code (ICCC-3) for all patients diagnosed until 2004, and patients diagnosed in the last 10 years (between 1995 and 2004) are given in Table 6 and Table 7. As found in other childhood cancer registries, more boys than girls are registered in the SCCR (Fehler! Verweisquelle konnte nicht gefunden werden. and Figure 4). For all diagnostic codes apart from renal tumours and germ cell neoplasms there is a higher number of boys than girls. Hepatic tumours are more than twice as common in boys than in girls Table 6 and Table 7. The distribution of patients among the 9 SPOG clinics is shown in Table 8, Table 9, and Table 10. In 2004 most patients were treated in Zürich, followed by Lausanne and Bern. Incidence rates for cancer in childhood are very similar to rates reported by the DKKR. The average incidence of any childhood cancer in the past 10 years was 14.5 cases per person/years in Switzerland compared to 13.4 cases per in Germany [6] and 13.8 in France [5]. The incidence is slightly less than that in Scandinavia and the USA (15 16/100,000), and slightly more than in the rest of Europe (12-14/100,000) [7]. Age adjusted incidence is highest among less than 1 year olds with 29.9 cases per person/years and lowest in 8 to 9 year olds with 9.3 cases per person/years (Figure 7 and Figure 8). The incidence rate for the under 1 year olds compared to 1 year olds is much higher in Switzerland than in Germany, especially for girls. This may be a result of the lower numbers in the Swiss registry (4-5 times less cases per year), or reflect more frequent visits to the doctor in the first year of life so that cases of cancer are diagnosed earlier in Switzerland. Known Swiss residents account for 86.6 % of all patients, and foreign residents treated in Switzerland for 8.8 %. When cases of retinoblastoma are excluded, the number of Swiss residents rises to 88.7% and that of foreign residents drops to 6.7%, (ranging from 2.6% for histiocytosis to 14% for bone tumours). For retinoblastoma 51.3% of cases are foreign residents. There is a specialised retinoblastoma clinic in Lausanne which accounts for this, and has treated 159 of the total 240 cases of retinoblastoma. Of these 240 cases 122 are foreign residents, most notably 58 from Italy,16 from Portugal, 11 from Greece, 8 from Tunisia and 7 from Libya. These numbers may reflect collaborations with individual cancer treatment centres or oncologists in countries outside Switzerland. For bone tumours 37/265 cases are foreign residents, of these Libya is over-represented with 11 cases (4.4% of cases, or 30% of all foreign residents) compared to only 59 cases (1.23%) in the database as a whole. Table 2 Number of patients in the SCCR database 9

14 Number of patients % Total until December 31st, Died Last follow-up Last follow-up after Lost to follow-up

15 Table 3 Composition of the database according to country of residence Country Number of cases % of total cases % of non-swiss residents Switzerland Not applicable Neighbouring countries Other European countries Total Europe Middle East North Africa Other African countries Other countries Total non-swiss residents Total Cases Not applicable Table 4 Number of new cases in 5-year intervals Year of Diagnosis All patients Swiss residents Missing year 8 5 Total Figure 1 Number of new patients registered each year 300 Total Swiss Residents Foreign residents 250 Number of patients

16 Table 5 Age at first diagnosis in the SCCR the German (DKKR) and the French (FCCR) childhood cancer registry Age in years Number of Patients % SKKR DKKR FCCR Number of Swiss residents % Number of patients % Number of patients % > N.D. N.D. All reported cases Figure 2 Patient characteristics at diagnosis(age and gender for all patients in the SCCR until 31th December 2004) >14yrs 6% <1yr 11% 10-14yrs 24% Female 42% 1-4yrs 34% Male 58% 5-9yrs 25% 12

17 Figure 3 Age at diagnosis for Swiss and foreign residents treated in Switzerland Total Swiss residents Foreign residents Number of patients (n) < age (yrs) Figure Age at first diagnosis separated for boys and girls (including only Swiss patients registered in the SCCR until Dec 31, 2004) Girls Boys Number of patients (n) < age (yrs) 13

18 Figure 5 Distribution of diagnoses according to ICCC-3 Soft Tissue Sarcomas 6% Germ Cell Neoplasms 4% Other malignant disease 2% Langerhans Cell Histiocytosis 3% Bone Tumours 5% Hepatic Tumours 1% Renal Tumours 5% Leukaemias 32% Retinoblastoma 5% Sympathetic Nervous System Tumours 7% CNS Neoplasms 16% Lymphomas 14% Figure 6 Distribution of diagnosis according to ICCC-3 (for Swiss patients only) Soft Tissue Sarcomas 6% Germ Cell Neoplasms 4% Other Neoplasms 2% Langerhans Cell Histicytosis 3% Bone Tumours 5% Hepatic Tumours 1% Leukaemia 34% Renal Tumours 5% Retinoblastoma 5% Sympathetic Nervous System Tumours 7% CNS Neoplasms 16% Lymphomas 15% 14

19 Table 6 Details on diagnostic group (all patients) Diagnosis Number Relative Frequency Sex ratio (Boys:Girls Mean Age Leukaemias, Lymphomas CNS neoplasms Neuroblastoma Retinoblastoma Renal tumours Hepatic tumours Malignant bone tumours Soft tissue sarcomas Germ cell tumours Other malignant disease Langerhans Cell Histiocytosis Mesoblastic Nephroma Total

20 Table 7 Diagnosis according to ICCC-3 in Swiss patients < 15yrs diagnosed between 1995 and 2004 Number Relative Frequency Sex Ratio (male: female) Mean age Leukaemias, myeloproliferative diseases, and myelodysplastic diseases Lymphoid leukaemias Acute myeloid leukaemias Chronic myeloproliferative diseases Unspecified and other specified leukaemias Lymphomas and reticuloendothelial neoplasms Hodgkin lymphomas Non-Hodgkin lymphomas (except Burkitt) Burkitt lymphoma Misc. lymphreticular neoplasms Unspecified lymphomas CNS and miscellaneous intracranial and intraspinal neoplasms Ependymomas and choroid plexus tumours Astrocytomas Intracranial and intraspinal embryonal tumours Other gliomas Unspecified intracranial and intraspinal tumours Neuroblastomas and ganglioneuroblastomas Retinoblastomas Nephroblastoma and other nonepithelial tumours Hepatic tumours Hepatoblastomas Hepatic carcinomas Unspecified malignant hepatic tumours Malignant bone tumours Osteosarcomas Ewing tumour and related sarcomas of bon Soft tissue and other extraosseous sarcomas Rhabdomyosracomas Other specified soft tissue sarcomas Unspecified soft tissue sarcomas Germ cell tumours, trophoblastic tumours, and neoplasms of gonads Malignant extracranial and extragonadal tumours Malignant gonadal germ cell tumours Other and unspecified malignant gonadal tumours Other unspecified malignant tumours Other malignant diseases Langerhans Cell Histiocytosis

21 Table 8 Diagnosed cases*, by participating paediatric oncology clinic (total database ) Diagnosis Total % Aarau % Basel % Bern % Geneva % Lausanne % Locarno % Lucerne % StGallen % Zurich % Other % Leukaemias Lymphomas CNS neoplasms Neuroblastoma Retinoblastoma Renal tumours Hepatic tumours Malignant bone tumours Soft tissue sarcomas Germ cell tumours Other malignant disease Langerhans Cell Histiocytosis Mesoblastic Nephromas Total * Diagnosis coded according to the ICCC-3 [1] 17

22 Table 9 Diagnosed cases*, by participating paediatric oncology clinic (patients diagnosed between 1995 and 2004) Diagnosis Total % Aarau % Basel % Bern % Geneva % Lausanne % Locarno % Lucerne % StGallen % Zurich % Other % Leukaemias Lymphomas CNS neoplasms Neuroblastoma Retinoblastoma Renal tumours Hepatic tumours Malignant bone tumours Soft tissue sarcomas Germ cell tumours Other malignant disease Langerhans Cell Histiocytosis Total * Diagnosis coded according to the ICCC-3 [1] 18

23 Table 10 Diagnosed cases*, by participating paediatric oncology clinic (new patients diagnosed in 2004) Diagnosis Total Aarau Basel Bern Geneva Lausanne Locarno Lucerne StGallen Zurich Other Leukaemias Lymphomas CNS neoplasms Neuroblastoma Retinoblastoma Renal tumours Hepatic tumours Malignant bone tumours Soft tissue sarcomas Germ cell tumours Other malignant disease Langerhans Cell Histiocytosis Total * Diagnosis coded according to the ICCC-3 [1] 19

24 Figure 7 Incidence rates between 1990 and 2003 for children aged 0-14 years Incidence rate per 100,000 (0-14 years old) Total Boys Girls Figure 8 Age- and sex-specific incidence rates (Switzerland ) Incidence rates per 100,000 Girls Boys < Age (yrs) 20

25 4 National and international cooperation One of the priorities in the first year of the SCCR at the ISPM Bern was to establish contacts with other national and international cancer registries in order to be more fully informed about standard datasets, database structures, data validation procedures, diagnostic coding, and to establish working relationships in view of future scientific collaborations. 4.1 Membership of the IACR and ENCR An important step was becoming a member of the International Association of Cancer Registries (IACR, and the European Network of Cancer Registries (ENCR, In October 2004 the SCCR applied for membership of the IACR. The IACR Executive officers have reviewed the application. It was observed that the SCCR is a well-established registry that has been used for clinical studies but, until recently, had little interest in population-based studies, epidemiology and public health. Thus the registry has not published, so far, incidence rates or population-based survival data. The review board acknowledged that the new Head Office is now implementing international standards of classification and coding. The IACR Executive officers suggested that a little more will probably need to be done to enhance data collection from nonpaediatric hospital services. In February 2005, the SCCR was awarded Associate membership (Voting membership is not yet awarded to childhood cancer registries). We also attended the conference and became a member of the ENCR in October Collaboration with VSKR At the national level, collaboration with the Association of Swiss Cancer Registries (VSKR, was established. The nine cantonal cancer registries cover 13 Swiss cantons or 4.2 million inhabitants (56% of the Swiss population), registering about new cancer cases each year. We attended the yearly meeting of the VSKR in Luzern in November Visits to DKKR and NRCT The SCCR has visited several other national childhood cancer registries in Europe to establish working collaborations: in April 2004 the German Childhood Cancer Registry (DKKR, in Mainz (Dr. Peter Kaatsch); in July 2004 the National Registry of Childhood Tumours (NRCT, in Oxford, UK (Dr. Charles Stiller). The Hungarian Childhood Cancer Registry was visited by Dr. E. Kiraly. We got detailed insights into the data validation, tumour coding, data protection issues and routine analyses performed by these centres. 21

26 5 Current research projects at the SCCR 5.1 Collaboration with SPOG studies (data-extraction) We extracted subsets of the database for nested studies conducted in single SPOG clinics. Two dissertations (in Bern and in Zürich) used data from the SCCR for their project: 1. Title: "Ist die Inzidenz von Episoden von Fieber in Neutropenie (FN) höher bei Knaben als bei Mädchen" (Is the incidence of fever episodes in neutropenia higher in boys than in girls?) 1. Supervisor Dr. Roland Ammann Student: André Keisker Population: Children under age 17, diagnosed in Bern after 1993 and treated with chemotherapy (N=341) Data extracted: sex, date of birth, date of diagnosis, age at diagnosis, general diagnosis, exact diagnosis, protocol, regimen, radiation, therapy start date, therapy end date. Publications: in preparation 2. Title: "Zytogenetische Aberrationen in Korrelation klinischen Parametern insbesondere der Prognose bei akuten lymphatischen Leukämien im Kindesalter" (Cytogenetic aberrations in the correlation of clinical parameters, especially prognosis, in acute lymphatic leukaemia in children) Supervisor PD Dr. med. F. Niggli Student: Sacha Rothschild Population: Children diagnosed with acute lymphatic leukaemia between September 1994 and December 2001, at one of the 9 Swiss Paediatric Oncology Centres (N=96) Data extracted: institution, sex, date of death, cause of death, last seen, prior disease, date of diagnosis, age at diagnosis, general diagnosis, exact diagnosis, POG code of diagnosis, tumour localisation, initial leukocyte count, relapse code, relapse description, relapse date Publications: in preparation 5.2 Research proposals In 2004, three research proposals were submitted to different foundations Oncosuisse Title: Long-term outcome of childhood cancer: incidence and spectrum of late effects Applicants: PD Dr. Nicolas von der Weid, Prof. Dr. Matthias Egger, Dr. Claudia Kuehni, PD Dr. Nicole Probst- Hensch Aims: The proposed research project aims to investigate the long-term outcome of former childhood cancer patients who were diagnosed with cancer before the age of 16 and who survived for more than 5 years. The project aims to assess incidence of various somatic outcomes (late mortality, secondary malignancies, endocrine disorders, infertility, cardiovascular events) and health related quality of life (HRQoL), and their association with a number of risk factors assessed prospectively at the time of diagnosis (tumour, treatment modalities, demographic characteristics). In addition, the current practice of health-care provision and health behaviour in long-term survivors will be investigated. 22

27 Collaborators: The research proposal is a collaborative project of the SPOG (PD Dr. Nicolas von der Weid, Main Investigator), the ISPM Bern (Prof. Dr. Matthias Egger, Dr. Claudia Kuehni, Co-applicants) and the cantonal registries (PD Dr. Nicole Probst-Hensch, Co-applicant). Duration: The study will begin on 1 st December 2005 and will be funded for 3 years. Funding: CHF Wyeth Foundation As an add-on project to the study funded by Oncosuisse, a grant proposal was submitted at the Wyeth foundation. Title: Health related quality of life and health behaviour in childhood cancer survivors Applicants: Dr. Claudia Kuehni, Dr. Gisela Michel, Prof. Dr. Matthias Egger, PD Dr. Nicolas von der Weid Aims: Within Oncosuisse funded very late effects study, the modular add-on project funded by the Wyeth Foundation aims to investigate the long-term health related quality of life (HRQoL), and health behaviour of these children. Specifically, the main aims are: 1. To determine in long-term survivors of childhood cancer in Switzerland: a) health related quality of life (HRQoL), and the prevalence of risk behaviours (smoking, alcohol),information about physical activity, diet and body weight, and b). to compare these findings to existing data from general population samples in Switzerland. 2. To study associations between current HRQoL and health behaviour in survivors with prospectively collected data on risk factors, including socio-demographic and clinical determinants at the time of diagnosis, treatment modalities and relapses. This will allow to define groups of children at increased risk for detrimental effects and behaviours, who might profit from specific interventions. Collaborators: The research proposal is a collaborative project of the ISPM Bern (Dr. Claudia Kuehni, Main Investigator, Dr. Gisela Michel, Prof. Dr. Matthias Egger, Co-applicants) and of the SPOG (PD Dr. Nicolas von der Weid, Co-applicant). Duration: The study will begin on 1 st February 2005 and will be funded for 1.5 years. Funding: CHF Swiss Federal Statistical Office (SFSO) Title: Validating date and cause of death information in the Swiss Childhood Cancer Registry against death certificate information from the Swiss Federal Office of Statistics Applicants: Dr. Claudia Kuehni, Dr. Marcel Zwahlen, Prof. Dr. Matthias Egger, PD Dr. Nicolas von der Weid Aims: This study will match the Swiss Childhood Cancer Registry (SCCR) patients to information from official death certificates recorded by the SFSO, in order to validate SFSO death certificate information and to update information on vital status in the SCCR using an independent information source. Collaborators: The research project was submitted by Dr. Claudia Kuehni (Main Investigator, ISPM), Dr. Marcel Zwahlen, Prof. Dr. Matthias Egger (Co-Applicants, ISPM), and PD Dr. med. Nicolas von der Weid (Co-Applicant, SPOG). Duration: 1 st February 2005 until 31 st December 2005 Funding: 32'568CHF 23

28 5.2.4 Berner Krebsliga (Cancer League of Bern) Title: Completeness of cancer registration and diagnostic accuracy in the Swiss Childhood Cancer Registry: validation against independent sources of data Applicants: Dr. Claudia Kuehni, Prof. Dr. Matthias Egger, Dr. Silvia Ess, PD Dr. Nicolas von der Weid Aims: The proposed research project aims to validate and complete records of the SCCR against independent sources of data, including the central database of the Association of Swiss Cancer Registries (VSKR) and the Swiss hospital statistics. A standardised protocol for regular future cross-validation between these databases will be developed. Collaborators: The research project was submitted by Dr. Claudia Kuehni (Main Investigator, ISPM), Prof. Dr. Matthias Egger (Co-Applicants, ISPM), Dr. Silvia Ess (Co-applicant VSKR) and PD Dr. med. Nicolas von der Weid (Co-Applicant, SPOG). Duration: 1 st January 2005 until 31 st December 2005 Funding: CHF 24

29 6 Review of activities Data protection When the SCCR was founded in 1976, the collection, analysis and transmission of data in medical research were not legally organised. Only after the data protection act (Art. 321 bis StGB) came into force on 1 st July 1993, was the legal basis established. Since then, personal data can only be disclosed with the informed consent of the affected person, or if an expert commission authorises the disclosure and the informed person does not explicitly veto against it. When the SCCR moved to the ISPM, an application for a special exemption of the data protection act for the SCCR was submitted to the expert commission for data protection in medical research. After some open questions were answered in April, they approved the request with some conditions (see below). This exemption has been given upon demonstration of a series of measures taken to assure data security, including the separation of personal identifiers from anonymised clinical data, very restricted access to non-anonymised data, and storage of the encrypted data on a password-protected stand-alone computer in a locked room. All data extraction and analysis is done on anonymised data. In addition, this special exemption approved the data transmission from the nine SPOG clinical centres to the central database in Bern in the years since 1993, and the database transfer from the SPOG to the ISPM Bern. The database may only be used by collaborators of the SCCR signing a declaration of secrecy. The responsibility for the database and data protection was assigned to PD Dr. Nicolas von der Weid (SPOG) and Dr. Claudia Kuehni (ISPM Bern). Conditions imposed by the expert commission for data protection in medical research : New patients (or their parents or legal guardians) have to give informed consent to the transmission of medical data to the central database, i.e. they have to sign an informed consent form. This also includes patients who are still attending clinical follow-up at one of the nine SPOG clinics. Patients reaching the age of 16 years have to renew their consent. Patients whose data have been transmitted after 1 st January 1996, but who are no longer in clinical followup have to be informed about the possibility of veto against their non-anonymised record by appropriate means of publication. They do not have to give explicit informed consent Patients whose data were transmitted before 1 st January 1996 do not have to be informed or give consent, in accordance with the usual practice of the expert commission. Obviously, patients who died cannot be informed anymore, and their data can be used without seeking further consent. Implementation: In collaboration with the SPOG, consent forms for patients and their parents were developed and will be implemented in all clinics from the beginning of The consent is available in German, French and Italian (see Appendix 1 for the consent form). Announcements in various newspapers will inform former patients about their possibility to veto the use of their non-anonymised data. 25

30 6.2 Analysis of the data quality The current electronic database was programmed in 1992 and the data collected previously on paper was entered retrospectively. Since then records were entered by PD Dr. Nicolas von der Weid and Dr. Beatrice Delaleu. In this chapter, we would like to give an overview of the data-content and quality. Currently, the database contains the records of 5063 patients, 5150 tumours and 6806 therapies (14 April 2005) Missing information Core database containing patient information Details on patient characteristics are generally very complete. Only 3 birthdates are missing and for one child the gender is unknown (total 5063 patients). Other demographic characteristics are less complete: the postcode of the patients address is missing in 1451 cases (28.6%), the fathers profession is missing in 2414 (47.7%), the mothers profession in 3986 (78.7%) of cases. However, these high numbers are mainly due to cases registered before After 1999, registration improved dramatically (e.g. for the postcodes only 6.5% are missing after 1999). For 439 patients (8.7%) there is no information about prior disease. After therapy patients are usually followed for 5 to 10 years depending on participation in a clinical trial, and on which participating centre is involved. For 439 patients diagnosed before 2004 there is no follow-up information after diagnosis (385 of them Swiss residents). It is thus not known what happened to these patients. Tumour database containing information on tumour and diagnosis The main information about the tumour is very complete with only 1 general diagnosis missing and 9 dates of diagnosis missing (0.2%; total 5150 tumours). Exact diagnoses are more frequently missing (471 cases; 9.2%), but mostly of patients diagnosed before Localisation is rarely missing (185 cases; 3.6%) nor is staging (212 cases; 4.1%). Initial leukocyte count is missing in 1054 cases of leukaemia (63.4%). Therapy database For only 118 therapies (1.7%) out of 6806 therapies the date when the therapy began is missing. But for 1341 (19.7%) there is no end date for the therapy. In a few cases there is no information about the protocol (74 cases; 1.1%). However, this information is rather diverse at the moment and has to be recoded before detailed analysis can be done. In 840 cases (12.3%) there is no information given about the general therapy used, i.e. if radiotherapy, surgery or chemotherapy was used Data quality Data quality was analysed using illogical data combinations, e.g. the date of cancer diagnosis precedes the date of birth, or similar. Cases diagnosed before the establishment of the electronic database had to be entered retrospectively and tend to have illogical data. These data will be checked with patient records in the clinics. We used the logic that a child is first born, then diagnosed, a therapy begins, ends and has a status reached. After this there is a last seen date, followed by lost and/or death date. Naturally, one illogical date has impact on the comparison with several other dates, and in the comparison it is not directly apparent which of the two dates is wrong. Most of the illogical data concerns the date of diagnosis being after the start of therapy. However, it has to be taken into account that most of these dates correspond to differences of only a few days, and thus may be correct. Confirmed diagnosis may indeed only be available some days after starting the therapy (e.g. if a brain 26

31 tumour is removed and cytogenetic tests are then performed on this tissue). Other frequent illogical dates concern mostly therapy dates and date last seen. 6.3 Concept for a new database As previously mentioned, the current SCCR database was implemented in 1992 using the Microsoft Access 2.0 relational database system running on a self-contained Windows desktop PC. New requirements on the SCCR database, mainly in the areas of data security / privacy and data model, provided the opportunity to analyse the new situation, develop a replacement SCCR database concept and implement the result. 2004/5 can be considered as a transitional period for the SCCR database at the ISPM. The main tasks during this period included: SCCR operation: secure the continued operation of the current SCCR database until replacement in 2005/6 SCCR database infrastructure: analyse the current database; identify requirements on a replacement; investigate replacement options; develop concept for modernised SCCR database infrastructure SCCR data model: analyse the current database; identify requirements on a replacement; investigate replacement options; develop concept for modernised SCCR data model The current configuration was investigated in order to identify any potentially critical problems which could hinder the continued operation of the SCCR database until replacement in 2005/6. No problems were identified although it was decided to increase database security / privacy (e.g. file encryption, backups, etc.). For the transitional period, some minor changes to the database structure were made using Microsoft Access 2.0 (e.g. new fields for international tumour classification codes, etc.). Investigation of the current SCCR database infrastructure, replacement requirements and replacement options showed that the main factors influencing the decision for a modernised infrastructure were: stricter data security / privacy requirements; cost / availability of resources; migration / upgrade issues; future issues; etc. Considering these factors, it is conceived that the modernised SCCR database infrastructure will consist of a Microsoft Access 2000 client front-end application with a Microsoft SQL server back-end database. This solution can take advantage of existing ISPM infrastructure such as network, server (hardware and software), security, backup and administration procedures. However, because there is no longer any upgrade path from Access 2.0, programming effort will be needed to implement the client application. Effort will also be required to migrate and restructure the server database. A good data model is the most important part of a database project because it is the data model which represents the structure and content of a database (i.e. the data entities, their relationships, their attributes, keys and domain information). A data model is largely influenced by the requirements on the database (e.g. which data should be collected, entered, stored, processed, reported, etc. and in what quantity, format, etc.) but, in our case, we also had to consider the existing SCCR database model as starting point and as an important contributing factor with respect to data migration. (See the Current SCCR Entity Relationship Model, and the corresponding database content descriptions in Appendix 3). The requirements for the replacement SCCR database were collected initially as ideas from various sources and then, together with the existing SCCR database model, iteratively analysed to develop a data model for the replacement. The new requirements mentioned above were derived from a wide range of sources including: 27

32 the future strategy and concept for the SCCR together with ideas (epidemiological / clinical) from within ISPM and SPOG information (e.g. documents, processes, procedures, databases and/or dataset descriptions, etc.) pertaining to the following registries / agencies: o DKKR (German Childhood Cancer Registry / Mainz, Germany) o NRCT (National Registry of Childhood Tumours / Oxford, United Kingdom) o HPTR (Hungarian Paediatric Tumour Registry / Budapest, Hungary) o ACCIS (Automated Childhood Cancer Information System / Lyon, France) o VSKR (Vereinigung Schweizerischer Krebsregister / Switzerland) o BDS-GPOH (Basisdatensatz der Gesellschaft für Pädiatrische Onkologie und Hämatologie / Frankfurt am Main, Germany) o NHSIA (National Health Service Information Authority / Winchester, United Kingdom) o IARC (International Agency for Research on Cancer / Lyon, France) o SHCS (Swiss HIV Cohort Study / Lausanne, Switzerland). requirements stemming from the BAG (Bundesamt für Gesundheit) Expertenkommission für das Berufsgeheimnis in der medizinischen Forschung Eröffnung Sonderbewilligung for the SCCR (e.g. privacy, consent, etc.) international classification standards for diseases (ICD-10), oncology diseases (ICD-O-3) and childhood cancer (ICCC-3) information from interviews with the data managers at the 9 participating clinics (i.e. Aarau, Basel, Bern, Genève, Lausanne, Luzern, St. Gallen, Locarno and Zürich) experience from working with the existing SCCR database and associated procedures, forms, reports, etc. An evolutionary development procedure (i.e. ISPM and ISPM/SPOG meetings with iterative review/analysis of requirements and adaptation of the working data model) was then used to identify the concrete requirements and to develop the prototype data model concept for the replacement SCCR database. (See the Working SCCR Entity Relationship Model in Appendix 3). This activity should be completed by the end of Next steps in 2005/06 Complete the design and then realise the replacement SCCR database as follows including: finalise the prototype data model concept for the replacement SCCR database using the prototype data model concept: o adapt/extend as necessary for the planned SCCR work-flows o develop the blueprint for the database structure and content o develop the SCCR data migration concept o design the SCCR database entry forms (NOTE: synchronised with the SCCR paper/electronic forms for participating clinics) and database output reports (e.g. periodic summary/full reports for participating clinics) implement the replacement SCCR database (i.e. tables, forms, edits, reports, etc.) and migrate the existing SCCR data to the new database In addition to the above, database validation and consistency check procedures will be developed and realised, such as: design and implement procedures for validation of incidence and mortality data against other data sources (e.g. VSKR, SFSO, participating clinics, etc.); adapt existing (eg. IARCs CHILD-CHECK program) and/or develop new procedures for checking the internal consistency of individual cancer records. 28

33 6.4 Data managers report In order to improve the quality of the data in the SCCR it is important that the local data managers in the nine SPOG clinics provide accurate and detailed information on all cancer patients. The current notification form was created in 1992 but includes no details on how to fill in each question. The SCCR visited all data managers to look at the local resources available and to discuss the practical aspects of data notification. The visits took place between June and November On the basis of a semi-standardized questionnaire, general and detailed questions about the background, employment, and work of the data managers were asked. A list of requests, suggestions and ideas was collected to improve data quality, data entry and the notification form itself. The data managers in the nine clinics have a very diverse educational background. Four of them are medical doctors (in Aarau assistant doctors are doing data manager work in three month rotations), three had qualified as a nurse or pharmacy assistant, and two had a secretarial apprenticeship. Their employment varies between 80% (includes other than data management work) to one or two days each month. Collaboration with the treating physicians of the clinic is often quite good, but in some cases data managers might profit from better support. Most of the data managers did not have a detailed explanation of the notification form, nor was there a comprehensive description of the form and the notification process available that would help new data managers with their job e.g. a reminder that annual follow-up information should be sent to the SCCR. Due to frequent personnel changes in data management in some clinics continuity can easily be lost. The information is generally gathered from the patients clinical charts and records. Most of the information is on paper and only rarely is it stored electronically. However, in various clinics the data manager or the leading physician keep their own database of local patients (usually in Word or Excel). The current notification form in English was designed in 1992, when the registry was transferred to an electronic database. Three data managers would prefer a German version of the form and four an electronic form. As most information needs to be written down on paper anyway for other reasons, most data managers are content with a paper version. Because only three clinics in Switzerland have been treating patients according to COG studies (Childrens Oncology Group, formerly POG-Paediatric Oncology Group) the POG coding is rarely used. Information about parents occupations is no longer available in some clinics, and for several variables data managers would like to have more detailed information on what should be written down. Aarau does not send regular follow-up information due to a lack of resources. In the other clinics follow-up information is sent once a year. Most of the data managers would appreciate a short extract of their data in the SCCR to check their own data and to be used for research done at the clinic (e.g. dissertations). The conclusions resulting from this were that a new notification form with a comprehensive description was made (the notification form and the description can be obtained from the SCCR on request). Facilities for local electronic data entry will be established as a second step for the database renewal in Survey on CNS-tumours The percentage of CNS tumours in the SCCR has increased from around 17% of all malignancies at the beginning of the 1990s to about 22% since 2000 (see Figure 9). Despite this increase there is probably still some extent of under-registration of CNS-tumours because they may not be treated at the paediatric oncology centre but in another clinic, such as neurosurgery or a neurological unit. To explore the reasons for this under- 29

34 registration a small qualitative questionnaire about the practices of referral and treatment of CNS malignancies was designed and sent to the heads of the paediatric oncology units in December When asked why patients with CNS-tumours might be missed, 7 out of 8 clinics replied that not all patients are admitted to a paediatric oncology unit where they would definitely be registered. It is however very unlikely that patients are treated in a private hospital or that their stay is too short to get noticed. A more plausible reason is that patients are sent for treatment to neurosurgeons who do not know about the SCCR and do not register these patients or send information back to the paediatric oncologists. In most cases the paediatrician or GP refers a patient with a suspected CNS-tumour to either the paediatric oncology, the paediatric neurology, or the paediatric emergency unit. Other units are rare but it can happen that the patient is referred to another regional hospital. All respondents agreed that the paediatric oncology units should be responsible for the treatment, registration and follow-up of patients. However, when the patient is treated with surgery alone, the paediatric neurology unit is responsible for therapy and follow-up. These doctors are not aware of the SCCR, and may forget to register the patients or inform the paediatric oncologists. Their patients may thus be missed by the SCCR. The survey showed that the SCCR could improve the completeness of CNS-tumour registration. Collaboration with the paediatric neurology and the neurosurgery units of the clinics may help to discover a few otherwise unnoticed cases. Nevertheless registration of CNS-tumours has improved in the last decade suggesting that only a few cases are now missed. Figure 9 Registration of CNS neoplasms in the SCCR (percentage of total registration) % Year of Diagnosis 30

35 6.6 Webpage: The SCCR has its own homepage since January 2005 ( It includes an overview of collaborators from the SPOG and the ISPM, a short history and summary of the SCCR, and will be a platform to provide access to reports of the SCCR. The webpage was programmed by Michel Bruhin and the layout was designed by Elsbeth Kuehni. Figure 10 Webpage of the SCCR 31