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

Institut für Biometrie, Epidemiologie und Medizinische Informatik

2RICC Study

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?


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Introduction

Source: German Federal Office for Radiation Protection


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Background

Source: German Federal Office for Radiation Protection, Yearly Report 2005


Typical doses in paediatric radiology

Examination

Entrance surface dose (µGy)

Age

0 1 5 15

Abdomen AP

Chest PA/AP

Pelvis AP

Skull AP

Skull LAT

110

60

170

/

/

340

80

350

600

340

590

110

510

1250

580

2010

110

1300

/

/

Source: NRPB-W14, 2000


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

Cohort/underlying condition Cancer site investigated

Breast Leukaemia All sites

Tuberculosis, USA

Tuberculosis, Canada

Scoliosis, USA

Diagnostic x-ray of broken bones, Canada

Diagnostic x-rays, China

Diagnostic x-rays, USA

Cardiac catheterisation, Israel

Cardiac catheterisation, Canada

X

X

X

X

X

X

X

X


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


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


RICC: Radiation induced Cancer in Children:

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

Objectives:To estimate precise radiation doseTo estimate cancer risk (in children)


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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


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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


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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


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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)


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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


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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!)


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CategoriesGroup Disease ICD-10-Codes„elevated mortality risk“

Acute pericarditis I30Acute rheumatic fever I00-I02Aneurysms I71-I72, Q25.4Appendicitis K35-K36Bronchopulmonary dysplasia P27Chronic rheumatic heart diseases I05-I09Other coagulation defects D68Diverticular disease of intestine K57 K60 K62Endocarditis I38Inflammatory diseases of the central nervous system (Meningitis, Encephalitis)

G00-G09

Epiglottitis J05.1 J37Cardiac defect (complex defects, not isolated ASD or VSD) Q20-Q24HIV-disease B20-B24

„elevated cancer risk“

Agranulocytosis and neutropenia D70Chromosome anomalies, not classified elsewhere Q90-Q99Colitis ulcerosa K50-K51Immunodeficiencies D80-83Crohn’s disease K50


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Methods: Dosimetry

Source: Michael Seidenbusch


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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


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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)


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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


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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


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Power calculation for RICC

Cancer endpoint Expected Numbers

All cancers 104

Leukaemia 36

Lymphocytic 30

Acute myeloid 5

CNS-tumours 22

Lymphoma 15

All others 31


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RICC: Year of first examination

0

1000

2000

3000

4000

5000

6000

1976 1981 1986 1991 1996 2001

Year of first X-ray examination

# S

ub

ject

s

UnknownGirlsBoys


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Results: Cohort

n %All Patients 92957 100 Boys 50005 54 Girls 41432 45 unknown gender 1520 1Patients with elevated mortality risk 14174 15Syndromes with elevated cancer risk 398 0,4

Premature children 279 0,3

Highly exposed 3428 5


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Results: Cohort

All % CasesAll Patients 92957 100 87 Boys 50005 54 52 Girls 41432 45 35 unknown gender 1520 1 0Patients with elevated mortality risk 14174 15 21Syndromes with elevated cancer risk 398 0,4 0

Premature children 279 0,3 0

Highly exposed 3428 5 4


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Results – Cohort

Age at inclusion n %

0 20546 22

1 9096 10

2 6945 7

3 6202 7

4 6387 7

5-9 24891 27

10-14 18890 20


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Results – Cohort

Number of examinations (per patient) All % 1 54605 59 2 17818 19 3 7515 8 4 4042 4 5 2341 3 6 1611 2 7 1128 1 8 737 1 9 561 1 10+ 2599 3


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Results: incident cases

Gender

ICCC-3

Diagnosis Boys Girls

I-XII All cancers 52 35

ILeukaemias, myeloproliferative diseases and myelodysplastic diseases

19 14

Ia Lymphocytic leukaemia 15 9Ib Acute myeloid leukaemia 2 3Ic-Ie Other leukaemias 2 2II Lymphoma 11 2III CNS-tumours 7 3IV-XII Other tumours 15 16


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38

Results: Cumulative exposure by status

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0- 100- 200- 300- 400- 500- 600- 700- 800- 900- 1000+

Cumulative effective Dose (µSv)

% S

ub

ject

s

0%

10%

20%

30%

40%

50%

60%

0- 10- 20- 30- 40- 50- 60- 70- 80- 90-


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Results – Exposure per examination, by age

(whiskers show 10% and 90% percentiles)


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Results – Exposure per examination, by year

(whiskers show 10% and 90% percentiles)


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Results: Cumulative exposure (µSv) ATTENTION: µSv

n / N Median

All patients 92957 7.0

Highly exposed 3428 24.0

RIS only 21319 3.0

MUNDUS 71638 10.0

elevated mortality risk 14174 84.0

elevated cancer risk 398 58.0

premature children 279 51.0


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External Comparison

O E SIR 95%-CI

Gender

Boys 52 52.8 0.99 0.74-1.29

Girls 35 35.2 1.00 0.69-1.38

All cancers 87 88.0 0.99 0.79-1.22

Leukaemia 33 30.5 1.08 0.74-1.52

Lymphocytic leukaemia 24 24.5 0.98 0.63-1.45

Acute myeloid leukaemia 5 4.3 1.16 0.38-2.70

Lymphoma 13 13.4 0.97 0.52-1.66

CNS-tumours 10 19.3 0.52 0.25-0.95

Other tumours 31 24.8 1.25 0.85-1.77


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Sensitivity Analysis

O E SIR 95%-CI

Elevated mortality risk

No 58 56.1 1.03 0.79-1.34

yes 21 16.4 1.28 0.79-1.96

Highly exposed

No 83 84.4 0.98 0.78-1.22

Yes 4 3.7 1.09 0.30-2.78


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SIR-Analysis: Effective dose

Trend test: p = 0,320,1

1

10

<1(16)

1-(10)

5-(14)

10-(12)

25-(11)

50-(6)

100-(8)

250-(5)

500+(5)

Cumulative effective dose (µSv)(# cases; p(trend) = 0.32)

SIR


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RR-Analysis

Eff. Dosis (µSv)

All cancersRR* 95%-KI

Total 0- 1.0010- 1.02 0.60-1.7450+ 1.01 0.60-1.71

elevated mortality risk excluded

0- 1.0010- 1.08 0.61-1.8950+ 1.04 0.55-1.96


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RR-Analysis

Eff. Dosis (µSv)

Leukaemia + Lymphoma

RR* 95%-KI

Total 0- 1.0010- 1.00 0.48-2.0750+ 1.04 0.51-2.12


0- 1.0010- 1.13 0.53-2.4450+ 1.24 0.54-2.83


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RR-Analysis

Eff. Dosis (µSv)

Solid Tumours

RR* 95%-CI

Total 0- 1.0010- 1.05 0.49-2.27

50+ 0.98 0.46-2.12


0- 1.00

10- 1.01 0.44-2.34

50+ 0.84 0.31-2.25


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Summary

Cohort of 92957 children Observed 1980-2006; 7,8 years

726200 person years 87 cancer cases

No increased incidence No dose-effect relationship


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Strengths

+ Unique patient collective

+ Large cohort

+ Prospective data acquisition

+ Good documentation

+ Excellent dosimetry

+ Cancer register with complete coverage,


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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


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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


Estimation Risk of CT Exposure


Estimated number of CT scans performed annually in the US

Source: Brenner et al. 2007


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


Estimated Organ Doses from Typical Single CT Scans of the Head

Source: Brenner et al. 2007


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


Age-related effect of a single pediatric head CT scan on tumor occurrence and fatality

Age at exposure

years

Lifetime risk of radiation induced cancer per 10 000

exposed children

tumour fatality

1 220 70

2 150 60

5 120 50

10 80 33

15 50 20

20 40 15Adjustment of table 4: Stein et al. 2008


65

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!!


66Nov. 2009 RICC Study 66IMBEI 12.08.2008

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


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Publications Hammer GP, Seidenbusch MC, Schneider K, Regulla DF, Zeeb H, Spix C,

Blettner M. A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposure. Radiat Res 2009; 171(4):504-512.

Seidenbusch MC, Regulla D, Schneider K., Zur Strahlenexposition von Kindern in der pädiatrischen Radiologie. Teile 1-6. Fortschr Röntgenstr 2008/2009 ; 180(5):410-422 ; 180(6):522-539 ; 180(12):1061-1081 ; 180(12):1082-1103 ; 181(5):454-471 ; 181(10):945-961.

Hammer GP, Seidenbusch MC, Schneider K, Regulla DF, Zeeb H, Spix C, Blettner M. Inzidenz von Kinderkrebs nach Röntgendiagnositik im Patientenkollektiv der Jahre 1976-2003 einer Universitätsklinik. Fortschr Röntgenstr 2010, 182: 404-414

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

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