Transcript A cohort study of childhood cancer incidence after

A cohort study of childhood cancer incidence
after postnatal diagnostic X-ray exposure
IMBEI, DKKR
Dr von Hauner‘sche Kinderhospital
Helmholz-München
Introduction
Institut für Biometrie, Epidemiologie
und Medizinische Informatik
 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
RICC Study
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Background
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Source: German Federal Office for Radiation Protection,
Yearly Report 2005
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Typical doses in paediatric radiology
Institut für Biometrie, Epidemiologie
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Entrance surface dose (µGy)
Age
Examination
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
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und Medizinische Informatik
Cohort/underlying condition
Cancer site investigated
Breast
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
Leukaemia
All sites
X
X
X
X
X
X
X
X
ERR of brain cancer by age at exposure among
selected cohorts treated with radiotherapy
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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)
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Institut für Biometrie, Epidemiologie
und Medizinische Informatik
RICC:
Radiation induced Cancer in Children:
A cohort study of childhood cancer incidence
after postnatal diagnostic X-ray exposure
Objectives:
To estimate precise radiation dose
To estimate cancer risk (in children)
Material
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Institut für Biometrie, Epidemiologie
und Medizinische Informatik
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
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und Medizinische Informatik
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
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und Medizinische Informatik
 Examination databases
 MINDIUS I-III
 Paper only
 RIS / discharge letters
1976 – 1991
1992 - 1997
1998 - 2003
 Additional databases
 X-ray machine details
 Dosimeter details
 Exposure modeling
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Cohort
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und Medizinische Informatik
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
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 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
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und Medizinische Informatik
 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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Categories
Group
„elevated
mortality risk“
„elevated
cancer risk“
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Disease
Acute pericarditis
Acute rheumatic fever
Aneurysms
Appendicitis
Bronchopulmonary dysplasia
Chronic rheumatic heart diseases
Other coagulation defects
Diverticular disease of intestine
Endocarditis
Inflammatory diseases of the central nervous system (Meningitis,
Encephalitis)
Epiglottitis
Cardiac defect (complex defects, not isolated ASD or VSD)
HIV-disease
Agranulocytosis and neutropenia
Chromosome anomalies, not classified elsewhere
Colitis ulcerosa
Immunodeficiencies
Crohn’s disease
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ICD-10-Codes
I30
I00-I02
I71-I72, Q25.4
K35-K36
P27
I05-I09
D68
K57 K60 K62
I38
G00-G09
J05.1 J37
Q20-Q24
B20-B24
D70
Q90-Q99
K50-K51
D80-83
K50
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Methods: Dosimetry
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Source: Michael Seidenbusch
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Radiation Exposure
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 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)
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 „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)
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 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:
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 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
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All cancers
Expected
Numbers
104
Leukaemia
36
Lymphocytic
30
Acute myeloid
5
CNS-tumours
22
Lymphoma
15
All others
31
RICC Study
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RICC: Year of first examination
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6000
Unknown
Girls
Boys
5000
# Subjects
4000
3000
2000
1000
0
1976
1981
1986
1991
1996
2001
Year of first X-ray examination
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Results: Cohort
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All Patients
Boys
Girls
unknown gender
Patients with elevated mortality risk
Syndromes with elevated cancer risk
Premature children
Highly exposed
RICC Study
n
92957
50005
41432
1520
14174
398
%
100
54
45
1
15
0,4
279
0,3
3428
5
31
Results: Cohort
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All Patients
Boys
Girls
unknown gender
Patients with elevated mortality risk
Syndromes with elevated cancer risk
Premature children
Highly exposed
RICC Study
All
92957
50005
41432
1520
14174
398
% Cases
100
87
54
52
45
35
1
0
15
21
0,4
0
279
0,3
0
3428
5
4
32
Results – Cohort
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Age at inclusion
0
1
2
3
4
n
20546
9096
6945
6202
6387
%
22
10
7
7
7
5-9
10-14
24891
18890
27
20
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Results – Cohort
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und Medizinische Informatik
Number of examinations (per patient)
1
2
3
4
5
6
7
8
9
10+
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All %
54605 59
17818 19
7515 8
4042 4
2341 3
1611 2
1128 1
737 1
561 1
2599 3
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Results: incident cases
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Gender
ICCCDiagnosis
3
I-XII
All cancers
I
Boys Girls
Leukaemias,
myeloproliferative diseases
and myelodysplastic diseases
Ia
Lymphocytic leukaemia
Ib
Acute myeloid leukaemia
Ic-Ie
Other leukaemias
II
Lymphoma
III
CNS-tumours
IV-XII Other tumours
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35
19
14
15
2
2
11
7
15
9
3
2
2
3
16
36
Results: Cumulative exposure
by status
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100%
60%
90%
50%
80%
40%
% Subjects
70%
60%
30%
50%
20%
40%
10%
30%
0%
0-
20%
10-
20-
30-
40-
50-
60-
70-
80-
90-
10%
0%
0-
100-
200-
300-
400-
500-
600-
700-
Cumulative effective Dose (µSv)
RICC Study
800-
900-
1000+
38
38
Results – Exposure per
examination, by age
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und Medizinische Informatik
(whiskers show 10% and 90% percentiles)
RICC Study
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Results – Exposure per
examination, by year
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(whiskers show 10% and 90% percentiles)
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Results: Cumulative exposure
(µSv) ATTENTION: µSv
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n/N
Median
92957
7.0
3428
24.0
RIS only
21319
3.0
MUNDUS
71638
10.0
14174
84.0
elevated cancer risk
398
58.0
premature children
279
51.0
All patients
Highly exposed
elevated mortality risk
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External Comparison
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O
E
SIR
95%-CI
Boys
52
52.8
0.74-1.29
Girls
35
35.2
0.99
1.00
87
88.0
0.79-1.22
33
30.5
Lymphocytic leukaemia
24
24.5
Acute myeloid leukaemia
5
4.3
Lymphoma
13
13.4
CNS-tumours
10
19.3
Other tumours
31
24.8
0.99
1.08
0.98
1.16
0.97
0.52
1.25
Gender
All cancers
Leukaemia
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0.69-1.38
0.74-1.52
0.63-1.45
0.38-2.70
0.52-1.66
0.25-0.95
0.85-1.77
44
Sensitivity Analysis
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und Medizinische Informatik
O
E
SIR
95%-CI
No
58
56.1
1.03
0.79-1.34
yes
21
16.4
1.28
0.79-1.96
No
83
84.4
0.98
0.78-1.22
Yes
4
3.7
1.09
0.30-2.78
Elevated mortality risk
Highly exposed
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SIR-Analysis: Effective dose
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SIR
10
1
0,1
Trend test: p = 0,32
<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)
Nov. 2009
RICC Study
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RR-Analysis
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Total
elevated mortality
risk excluded
Nov. 2009
RICC Study
Eff.
Dosis
(µSv)
01050+
01050+
All cancers
RR*
1.00
1.02
1.01
1.00
1.08
1.04
95%-KI
0.60-1.74
0.60-1.71
0.61-1.89
0.55-1.96
49
RR-Analysis
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und Medizinische Informatik
Eff.
Leukaemia +
Dosis
Lymphoma
(µSv) RR* 95%-KI
Total
elevated mortality
risk excluded
0-
1.00
10-
1.00 0.48-2.07
50+
1.04 0.51-2.12
0-
1.00
10-
1.13 0.53-2.44
50+
1.24 0.54-2.83
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RR-Analysis
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und Medizinische Informatik
Eff.
Solid Tumours
Dosis
(µSv) RR*
95%-CI
Total
0-
1.00
10-
1.05
0.49-2.27
50+
0.98
0.46-2.12
elevated mortality risk 0excluded
10-
1.00
1.01
0.44-2.34
50+
0.84
0.31-2.25
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Summary
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 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
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+ 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
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und Medizinische Informatik
- 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
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 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
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Estimation Risk of CT Exposure
Estimated number of CT scans performed annually
in the US
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und Medizinische Informatik
Source: Brenner et al. 2007
Special focus: CT scans in children
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 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
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Source: Brenner et al. 2007
Estimated lifetime risk from a single dose of radiation as a
function of age at exposure (BEIR 2006)
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und Medizinische Informatik
Age-related effect of a single pediatric head CT
scan on tumor occurrence and fatality
Institut für Biometrie, Epidemiologie
und Medizinische Informatik
Age at
exposure
years
Lifetime risk of radiation
induced cancer per 10 000
exposed children
1
2
tumour
220
150
fatality
70
60
5
10
120
80
50
33
15
50
20
20
40
15
Adjustment of table 4: Stein et al. 2008
CT-Cohort Study
Institut für Biometrie, Epidemiologie
und Medizinische Informatik
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!!
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Acknowledgements
Institut für Biometrie, Epidemiologie
und Medizinische Informatik
 Mainz:
 IMBEI:




 München:
 Michael Seidenbuch
 Karl Schneider
 Dieter Regulla
Gael Hammer
Hajo Zeeb
Doris Bardehle (!!)
Susanne Seuchter
 Data protection officer






 Irene Reinisch
 GCCR




Nov. 2009
IMBEI
12.08.2008
Claudia Bremensdorfer
Irene Jung
Claudia Spix
Thomas Ziegler
RICC Study
Monika-Maria Deml
Sieglinde Eberle
Toni Galitzendorfer
Sabine Heyn
Renate Ritzer
Ina Schneider
66
Publications
Institut für Biometrie, Epidemiologie
und Medizinische Informatik

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
RICC Study
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