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A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposure

A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposure. IMBEI, DKKR Dr von Hauner‘sche Kinderhospital Helmholz-München. Introduction. Good epidemiologic knowledge on Adults and children exposed to high doses of radiation Atomic bomb victims

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A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposure

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  1. A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposure IMBEI, DKKR Dr von Hauner‘sche Kinderhospital Helmholz-München

  2. Introduction • Good epidemiologic knowledge on • Adults and children exposed to high doses of radiation • Atomic bomb victims • Patients following radiation radiotherapy • Adults exposed to low doses of radiation • NPW-workers, uranium mine workers, pilots… • Radon in homes • Adverse effects among children exposed to low level radiation? RICC Study

  3. Introduction Source: German Federal Office for Radiation Protection RICC Study 3

  4. Background Source: German Federal Office for Radiation Protection, Yearly Report2005 RICC Study 4

  5. Typical doses in paediatric radiology Source: NRPB-W14, 2000

  6. Major studies of cancer risk following diagnostic radiation exposure in childhood and adolescence

  7. ERR of brain cancer by age at exposure among selected cohorts treated with radiotherapy Dose ranges refer to doses to the brain. Source: Sadetzki & Mandelzweig, 2009

  8. Estimated lifetime risk from a single dose of radiation as a function of age at exposure (BEIR 2006)

  9. RICC: Radiation induced Cancer in Children:A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposureObjectives:To estimate precise radiation doseTo estimate cancer risk (in children)

  10. Material • Data collected at Dr. von Hauner Children’s Hospital - Munich • National X-ray ordinance 1973 • Protocol of all x-ray examinations since 1976 in databanks (as from 1998 RIS system) • 270.000 examinations until 2003 RICC Study 12

  11. Available data Patient history • Name, Gender, Date of birth, Date of examination, Height, Weight, Address Examination data • Projection radiography / Screening, Organ of interest, X-ray tube type, Radiation entry, Focus-skin distance (implicit), X-ray tube voltage, Total filtration (implicit), Exposure time / Duration of screening, mAs-Product / Dose area product Clinical data • Indication, Radiological diagnosis RICC Study 13

  12. Base data • Examination databases • MINDIUS I-III 1976 – 1991 • Paper only 1992 - 1997 • RIS / discharge letters 1998 - 2003 • Additional databases • X-ray machine details • Dosimeter details • Exposure modeling RICC Study 14

  13. Cohort Inclusion criteria • At least one diagnostic procedure performed at Dr. von Hauner’s Children’s Hospital • Age at “examination” ≤ 14.5 years • Main residence in Germany • Time period 1976-2003 • Cancer free at beginning (incl. first 6 months) RICC Study 16

  14. Follow-Up • Cancer: • Linkage of pseudonymised data with the German Childhood Cancer Registry • Observation period: 1980-2006 • Person Years: • No individual follow-up ! • Calculating PY with age-specific mortality rates • Excluding children with “high” mortality risk RICC Study 17

  15. Methods: Patient groups • On the basis of clinical indications / diagnosis • Patients with elevated mortality risk • Syndromes with elevated cancer risk • Pre-term babies • On the basis of exposure records • Highly exposed (CT, contrast media, single dose > 5 mSv, cardiac patients) • RIS only patients (no specific diagnosis available!) RICC Study 18

  16. Categories RICC Study 19

  17. Methods: Dosimetry Source: Michael Seidenbusch RICC Study 20

  18. Radiation Exposure • Organ dose was estimated • For risk analysis: • effective dose (=whole body dose) • Leukaemia: red bone marrow dose • Dose: continuous and categorical variable • Latency period: ½ year • Imputation for (some) missing values RICC Study 22

  19. Statistical Analyses Plan (SAP) • „External comparison“ • SIR (by sex): • All cancers, • Leukaemia,lymphocytic leukaemia, acute myeloid leukaemia, lymphoma, • CNS-tumours, other tumours) • Dose categories • Internal comparison: RR (multivariate) • Sensitivity analysis • Excluding specific subgroups • High exposed, elevated mortality risk • No. of examinations: 1, 2, 3+ • Cox Regression (time-dependent covariable) RICC Study

  20. Excurse: The German Childhood Cancer Registry (GCCR) • Begin of registration 1980 • Population base (children below 15) 13.0 million • Number of reported cases (1980-2008) 43.014 • Completeness of registration ca. 95 % • Number of cases annually 1,700-1,800 • Since 1991 inclusion of former GDR RICC Study

  21. GCCR: • Society for Paediatric Oncology and Haematology (GPOH) • 34 large treatment centres • treat 75% of all children • Each year nearly 70 hospitals report cases • since 1980 more than 130 reporting hospitals • 25 GPOH-clinical trials RICC Study

  22. Power calculation for RICC RICC Study 29

  23. RICC: Year of first examination RICC Study 30 30

  24. Results: Cohort RICC Study 31

  25. Results: Cohort RICC Study 32 32

  26. Results – Cohort RICC Study 33

  27. Results – Cohort RICC Study 34

  28. Results: incident cases RICC Study 36 36

  29. Results: Cumulative exposure by status detail 38 RICC Study

  30. Results – Exposure per examination, by age (whiskers show 10% and 90% percentiles) RICC Study 39

  31. Results – Exposure per examination, by year (whiskers show 10% and 90% percentiles) RICC Study

  32. Results: Cumulative exposure (µSv) ATTENTION: µSv RICC Study 43

  33. External Comparison RICC Study 44

  34. Sensitivity Analysis RICC Study 45

  35. SIR-Analysis: Effective dose Trend test: p = 0,32 RICC Study 47

  36. RR-Analysis Nov. 2009 RICC Study 49 49

  37. RR-Analysis RICC Study 50

  38. RR-Analysis RICC Study 51

  39. Summary • Cohort of 92957 children • Observed 1980-2006;  7,8 years • 726200 person years • 87 cancer cases • No increased incidence • No dose-effect relationship RICC Study 52

  40. Strengths Unique patient collective Large cohort Prospective data acquisition Good documentation Excellent dosimetry Cancer register with complete coverage, RICC Study

  41. Strengths and weaknesses Unique patient collective Large cohort Prospective data acquisition Good documentation Good dosimetry Cancer register with complete coverage, extensive inquiries Small numbers of cases Very low radiation doses Underestimation of exposure CT-exposures not yet quantified Confounding by indication No ascertainment of confounders No cancer after age 15 RICC Study

  42. Perspective • Current cohort • Further follow-up possible • Nested case-control study on biological markers ?? • Cohort of children with CT exposures • CT risks only roughly assessable up to now • Missing epidemiologic data • Pilot study is ongoing RICC Study 56

  43. Estimation Risk of CT Exposure

  44. Estimated number of CT scans performed annually in the US Source: Brenner et al. 2007

  45. Special focus: CT scans in children • Increase in CT use in children 1989: ~ 4% of all CT scans 1993: ~ 6% of all CT scans 2000: ~ 8-11 of all scans

  46. Estimated Organ Doses from Typical Single CT Scans of the Head Source: Brenner et al. 2007

  47. Estimated lifetime risk from a single dose of radiation as a function of age at exposure (BEIR 2006)

  48. Age-related effect of a single pediatric head CT scan on tumor occurrence and fatality Adjustment of table 4: Stein et al. 2008

  49. CT-Cohort Study Design: Similar to RICC Data sources: • Radiological and Neuro-radiology departments of several clinics (PACS and RIS) • Estimated size: 47 000 children exposed between 1990 and 2003 in Germany • Cohort planned: 5000 children • Feasibility study is ongoing • EU-consortium, BMBF funding Problems: • Data on indication, Confounding by indication • Dosimetry • Cancer after age 15!!

  50. Acknowledgements Mainz: IMBEI: Gael Hammer Hajo Zeeb Doris Bardehle (!!) Susanne Seuchter Data protection officer Irene Reinisch GCCR Claudia Bremensdorfer Irene Jung Claudia Spix Thomas Ziegler München: Michael Seidenbuch Karl Schneider Dieter Regulla Monika-Maria Deml Sieglinde Eberle Toni Galitzendorfer Sabine Heyn Renate Ritzer Ina Schneider IMBEI 12.08.2008 RICC Study 66

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