Download genetic effects of radiotherapy for childhood cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 60, No. 2, pp. 542–552, 2004
Copyright © 2004 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/04/$–see front matter
doi:10.1016/j.ijrobp.2004.03.017
CLINICAL INVESTIGATION
Pediatrics
GENETIC EFFECTS OF RADIOTHERAPY FOR CHILDHOOD CANCER:
GONADAL DOSE RECONSTRUCTION
MARILYN STOVALL, PH.D.,* SARAH S. DONALDSON, M.D.,† RITA E. WEATHERS, B.S.,*
LESLIE L. ROBISON, PH.D.,‡ ANN C. MERTENS, PH.D.,‡ JEANETTE FALCK WINTHER, M.D.,§
JORGEN H. OLSEN, M.D.,§ AND JOHN D. BOICE, JR., SC.D.㛳
*Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; †Department of
Radiation Oncology, Stanford University Medical Center, Stanford, CA; ‡Department of Pediatrics, University of Minnesota,
Minneapolis, MN; §Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; and 㛳International
Epidemiology Institute, Rockville, MD, and Department of Medicine, Vanderbilt Medical Center and Vanderbilt-Ingram
Comprehensive Cancer Center, Nashville, TN
Purpose: To estimate the doses of radiation to organs of interest during treatment of childhood cancer for use
in an epidemiologic study of possible heritable diseases, including birth defects, chromosomal abnormalities,
cancer, stillbirth, and neonatal and premature death.
Methods and Materials: The study population was composed of more than 25,000 patients with cancer in
Denmark and the United States who were survivors of childhood cancer and subsequently had nearly 6,500
children of their own. Radiation therapy records were sought for the survivors who parented offspring who had
adverse pregnancy outcomes (>300 offspring), and for a sample of all survivors in a case-cohort design. The
records were imaged and centrally abstracted. Water phantom measurements were made to estimate doses for
a wide range of treatments. Mathematical phantoms were used to apply measured results to estimate doses to
ovaries, uterus, testes, and pituitary for patients ranging in age from newborn to 25 years. Gonadal shielding,
ovarian pinning (oophoropexy), and field blocking were taken into account.
Results: Testicular radiation doses ranged from <1 to 700 cGy (median, 7 cGy) and ovarian doses from <1 to
>2,500 cGy (median, 13 cGy). Ten percent of the records were incomplete, but sufficient data were available for
broad characterizations of gonadal dose. More than 49% of the gonadal doses were >10 cGy and 16% were >100
cGy.
Conclusions: Sufficient radiation therapy data exist as far back as 1943 to enable computation of gonadal doses
administered for curative therapy for childhood cancer. The range of gonadal doses is broad, and for many
cancer survivors, is high and just below the threshold for infertility. Accordingly, the epidemiologic study has
>90% power to detect a 1.3-fold risk of an adverse pregnancy outcome associated with radiation exposure to the
gonads. This study should provide important information on the genetic consequences of radiation exposure to
humans. © 2004 Elsevier Inc.
Childhood cancer, Genetic damage, Radiation, Dosimetry.
INTRODUCTION
outcomes of cancer survivors and their children are becoming increasingly important. However, there is limited
knowledge of the genetic consequences of treatments for
childhood cancer.
The objective of the ongoing Genetic Consequences of
Childhood Cancer Treatment (GCCCT) study is to determine the extent to which curative treatment, i.e., radiation therapy and chemotherapy that are mutagenic in test
The treatment of children with cancer has been a great
success. In the United States alone, more than 270,000
survivors of childhood cancers are presently alive. Nearly
77% of these children survive to adulthood (1), and many
are able to have children of their own. Consequently, the
possible adverse effects of curative treatments on the health
NO1-CP-40535).
Acknowledgments—The program of studies would not have been
possible without the efforts of the many participating survivors,
data abstractors, a large field staff, central clerical and data processing staff, and clinical collaborators.
Received Dec 3, 2003, and in revised form Mar 9, 2004.
Accepted for publication Mar 21, 2004.
Reprint requests to: Marilyn Stovall, Ph.D., Department of
Radiation Physics, The University of Texas M. D. Anderson
Cancer Center, Unit 544, 1515 Holcombe Blvd., Houston, TX
77030. Tel: (713) 745-8999; Fax (713) 794-1371; E-mail:
[email protected]
Supported in part by contracts and grants from Westlakes Research Institute (Agreement No. 01/12/99 DC), the Danish Cancer
Society, and the National Cancer Institute (U24 CA55727 and
542
Genetic effects of radiotherapy for childhood cancer
● M. STOVALL et al.
543
Table 1. Characteristics of Childhood Cancer Survivor Study (CCSS [US]) and Danish populations who received
radiation therapy (XRT)
Total with XRT
Male
Female
Age at end of XRT
0–4 yrs
5–9 yrs
10–14 yrs
15–19 yrs
20–25 yrs
Unknown
Total
Year of 1st XRT
44–49
50–59
60–69
70–79
80–89
90 or later
Unknown
Total
Primary diagnosis
Leukemia
Central nervous system tumor
Hodgkin disease
Non-Hodgkin lymphoma
Kidney (Wilms’)
Neuroblastoma
Soft tissue sarcoma
Bone tumors
Retinoblastoma
Other*
Total
CCSS
%
Danish
%
Total
%
609
236
373
100%
38.8%
61.2%
151
77
74
100%
51.0%
49.0%
760
313
447
100%
41.2%
58.8%
82
113
177
180
48
9
609
13.5%
18.6%
29.1%
29.6%
7.9%
1.5%
100%
21
22
29
64
11
4
151
13.9%
14.6%
19.2%
42.4%
7.2%
2.6%
100%
103
135
206
244
59
13
760
13.6%
17.8%
27.1%
32.1%
7.8%
1.7%
100%
0
0
0
390
209
1
9
609
0.0%
0.0%
0.0%
64.0%
34.3%
0.2%
1.5%
100%
19
33
39
31
23
2
4
151
12.6%
21.9%
25.8%
20.5%
15.2%
1.3%
2.6%
100%
19
33
39
421
232
3
13
760
2.5%
4.3%
5.1%
55.4%
30.5%
0.4%
1.7%
100%
170
44
194
65
35
18
52
31
0
0
609
27.9%
7.2%
31.9%
10.7%
5.7%
3.0%
8.5%
5.1%
0.0%
0.0%
100%
10
20
32
21
6
3
14
6
8
31
151
6.6%
13.2%
21.2%
13.9%
4.0%
2.0%
9.3%
4.0%
5.3%
20.5%
100%
180
64
226
86
41
21
66
37
8
31
760
23.7%
8.4%
29.7%
11.3%
5.4%
2.8%
8.7%
4.9%
1.1%
4.1%
100%
* Gonadal, thyroid, skin, and other carcinomas.
systems, contribute to adverse conditions for the offspring of childhood cancer patients, including cancer,
birth defects, chromosomal abnormalities, stillbirths, and
neonatal and other premature deaths (2). Medical records
are being reviewed to assess radiation doses and chemotherapy modalities used in childhood cancer treatment.
Essential to the epidemiologic interpretation of these data
is an accurate and reproducible assessment of radiation
dose to the gonads. The purpose of this article is to
describe the approach taken to reconstruct doses for
survivors of childhood cancer and to present preliminary
dosimetric data.
Ideally, human studies of the risks associated with
radiation provide estimates of absorbed dose to each
subject that are accurate and specific for the relevant
anatomic site. Patients undergoing radiation therapy are
especially suitable for such studies because irradiation is
performed under controlled conditions that are well documented. However, dosimetry estimation presents special
challenges. Treatments typically involve delivery of high
doses to the treatment site and a wide range of doses to
other organs. The dose outside treatment beams decreases
substantially with distance; for example, the dose to a site
10 cm from the edge of a treatment field may be less than
1% of the dose to the tumor. Even within a single organ,
the dose may vary considerably, and for paired organs,
such as the ovaries, the dose differential could be great.
Results from studies of pediatric patients add another
dimension to this problem because the age or size of the
child at the time of the treatment must be considered in
determining dose to sites of interest.
There has been little investigation of the dose received
by organs outside the primary treatment fields. In brief
summary, the sources of radiation absorbed dose outside
a treated volume are (1) leakage through the treatment
head of the machine, (2) scatter from the collimators and
beam modifiers, and (3) scatter within the patient from
the treatment beams. The relative contributions of these
three components to total dose have been reported by a
few investigators (3–9). Fraass and van de Geijn (4)
found that collimator scatter plus leakage is of the same
order of magnitude as patient scatter. Kase et al. (5) also
indicate that near the beam the collimator scatter contributes 20 – 40% of the total peripheral dose and that leakage
becomes the main contributor at greater distances from
the field edge. Greene et al. (7) found that collimator
544
I. J. Radiation Oncology
● Biology ● Physics
Volume 60, Number 2, 2004
scatter was the dominant component of the peripheral
dose near the treatment beam.
METHODS AND MATERIALS
Population studied
The details of the epidemiologic investigation can be
found elsewhere (2, 10). All childhood cancer survivors
who became parents were eligible for inclusion in the epidemiologic study. The GCCCT study utilizes a case-cohort
design (11, 12). To date, dosimetry has been completed for
a total of 760 patients treated with radiation. The characteristics of the cancer survivors who received radiation
along with the primary diagnoses, are shown in Table 1. A
unique aspect of the GCCCT study is the computation of
organ doses for individual patients based on information in
the radiation therapy records. For each patient, the doses to
the ovaries, uterus, testes and pituitary are estimated for all
radiation therapy delivered before the date of the relevant
conception, using the methods described in this article. The
epidemiologic results will be interpreted in light of dose–
response evaluations.
Dosimetry methods
The method described here estimates radiation dose outside a treatment beam where conventional treatment-planning programs cannot be suitably applied. The method uses
a dose measured in a water phantom to estimate organ doses
in a three-dimensional mathematical phantom that simulates
a patient of any size. This method has been used to estimate
organ doses for individual patients in several large studies
of the long-term effects of radiation therapy (13–15).
Out-of-beam measurements in a water phantom
The total radiation dose outside a treatment beam includes leakage through the head of the machine, scatter off
the collimators, and scatter within the patient from the
primary beam. It is essential that any estimate of dose
include all these components. For this reason, the method
described here is based on measurement of total radiation
dose.
The dose outside beams was measured on a three-dimensional grid in a large water phantom. Figure 1 shows a
beam’s-eye view and a lateral view of the measurement
setup. A typical set of data for one radiation energy consisted of measurements in four or more planes perpendicular
to the central axis at depths ranging from 2–15 cm from the
water surface. In each plane, dose was measured to a distance of 70 cm perpendicular to the central axis. Data were
measured for field sizes of 5 ⫻ 5, 10 ⫻ 10, 15 ⫻ 15, and 20
⫻ 20 cm2. The distance between measurement points was
smaller near the water surface and beam edge to provide
sufficient resolution in regions of rapid dose change. Outof-beam data were measured with the following beams:
60
Co (AECL Theratron-80, Mississauga, Ont., Canada), 4
MV (Varian Clinac 4, Palo Alto, CA), 6 and 10 MV (Varian
Clinac 2100C, Palo Alto, CA), and 25 MV (Allis-Chalmers
Fig. 1. Water phantom setup for out-of-beam measurements. (A)
Beam’s-eye view. (B) Lateral view.
Betatron, Milwaukee, WI). Additional data measured for
AAPM Task Group 36 (16, 17) are included in the library of
out-of-beam data; these are 18 MV (Varian Clinac 2100C,
Palo Alto, CA) and 25 MV (Philips SL25, Andover, MA).
Measurements were performed using thermoluminescent
dosimeters (TLDs) containing lithium fluoride powder. The
TLD measurements were verified by ionization chamber
measurements at selected points. Dosimeter response was
standardized in a 60Co beam with output measured by the
Accredited Dosimetry Calibration Laboratory at The M. D.
Anderson Cancer Center, which is sponsored by the National Institute of Standards and Technology.
The measured data were applied to individual patients
using one of three methods, depending on the distance from
the point of calculation to the treatment beam. “In-beam”
dose was calculated using depth-dose data in clinical use
(18). “Near-beam” dose was calculated using a log-linear
interpolation between points of measurement; this region
varies 7–15 cm from the beam edge, depending on radiation
energy. “Far-outside-beam” dose was calculated using a
curve derived from measured data. For field sizes and
depths other than those measured, a linear interpolation
between measured data was used.
Genetic effects of radiotherapy for childhood cancer
● M. STOVALL et al.
545
Fig. 2. Average height by sex and mathematical phantom height.
Mathematical phantom
The mathematical phantom simulates a person of any
age. The size of the phantom specific to each age group was
determined using measurements made for a study funded by
the National Safety Council (NSC) and reported by the
Society of Automotive Engineers (19). The NSC measurements were done in 1972 on more than 4,000 American
children between 3 months and 19 years of age. Dimensions
for newborns and children 1, 3, 5, 10, 15, and 19 (adult)
years of age were selected because sizes and proportions for
patients between these ages can be approximated by linear
interpolation. In children under age 15 there is very little
gender difference in average height, so no distinction is
made for height by sex in the mathematical phantom. In Fig.
2, the height for selected phantom age is plotted against
average height for age for males and females from CDC
standard growth charts (available at: www.cdc.gov/nchs/
about/major/nhanes/growthcharts/clinical_charts.htm
[2002]); the agreement is excellent at ages less than 15
years. Average height for age is used for all patients because
height and weight information for individuals is often not
available from radiotherapy records. Figure 3 shows the
frontal view of the external surface of the 1-, 3-, 5-, 10-, and
15 year-old phantoms and the adult phantom. Arms and legs
Fig. 3. Mathematical phantom, ages 1 through 15 years and adult.
546
I. J. Radiation Oncology
● Biology ● Physics
Volume 60, Number 2, 2004
Fig. 4. Total absorbed dose in a water phantom from 10 ⫻ 10 cm2 fields of 60Co gamma rays and 4-, 6-, 10-, 18-, and
25-MV photons at 10-cm depth, normalized to 100% on the central axis at depth of maximum dose (Dmax). From Stovall
et al. (16), with permission, of the American Association of Physicists in Medicine.
of the phantoms can be moved mathematically to simulate
their positions during treatment. The difference in proportions of body regions (trunk, leg, and arm length and head
size) is taken into account when calculating the size of a
patient at a specific age.
Organs were located in the phantoms using standard
anatomy references (20 –24). For the GCCCT study described here the organs of interest are ovaries, testes, uterus,
and pituitary. However, the phantom also contains additional organs for use in other studies: skeleton, brain, parotid glands, salivary glands, thyroid, breasts, lungs, adrenal
glands, kidneys, stomach, gallbladder, pancreas, liver, small
intestine, colon, rectum, bladder, and vagina. The phantom
includes the locations of active bone marrow, which is
divided into 40 partitions. The weight of each partition
depends on patient age (25, 26). Individual organs contain
between 1 and 400 points of calculation, depending on the
size of the organs and the degree of detail needed. Points
within organs are evenly spaced to allow calculation of
minimum, maximum, and average doses.
Calculation of dose to organs outside treatment beams
To calculate dose to an anatomic site outside a treatment
beam for an individual patient and a specific treatment, the
beam data measured in water are positioned on the appropriate size for age mathematical phantom. Additional input
specifies the size of the field on the surface of the patient,
beam energy, and treatment dose at maximum depth (Dmax).
Treatment dose at any other depth is corrected to dose at
Genetic effects of radiotherapy for childhood cancer
● M. STOVALL et al.
547
Fig. 5. Mathematical phantom for 3-year-old girl with central
nervous system tumor treated with 8 ⫻ 8 cm2 left and right lateral
fields to the posterior fossa, tumor dose of 4,000 cGy, from a 60Co
beam.
Dmax using standard central axis depth-dose data (18). Plane
geometry is used to calculate the lateral distance from the
nearest field edge and depth from the surface to each of the
points in the organs or anatomic regions of interest.
For patients whose gonads were inside or close to
treatment beams, special techniques were sometimes
used to reduce gonadal dose, including field blocking,
testicular shields (i.e., clam shells), or relocation of the
ovaries by means of oophoropexy. In general, these techniques reduce high gonadal doses to 10% or less of the
unshielded dose (27–36). Most special techniques are
documented in the patients’ medical records and doses
are reduced accordingly.
RESULTS
Figure 4 shows an example of out-of-beam data measured
in water, a 10 ⫻ 10 cm2 beam at 10-cm depth for six
energies (16, 17).
Fig. 7. Mathematical phantom for 16-year-old male patient with
osteosarcoma treated with 12 ⫻ 17 cm2 anterior and posterior
fields to the left midfemur, tumor dose of 5,500 cGy, from a 6-MV
photon beam.
Using the mathematical phantom, organ doses for three
typical treatments are illustrated as examples: dose to pituitary, thyroid, breasts, and ovaries in a 3-year-old patient
treated for brain cancer (Fig. 5); dose to pituitary, thyroid,
breasts, and ovaries in a 5-year-old patient with a Wilms’
tumor (Fig. 6); and dose to pituitary, thyroid, breasts, and
testes in a 16-year-old patient with osteosarcoma of the
femur (Fig. 7). Table 2 lists typical doses to the gonads and
uterus for radiation therapy of several common childhood
cancers. The data in Table 2 show the considerable variation
in dose among patients, depending on distance from the
treatment field, tumor dose, and radiation energy.
Figures 8 and 9 show that doses to the gonads in the
current study are higher and cover a wider range than any
previously conducted study of genetic effects. Testicular
doses ranged from ⬍1 to 700 cGy (median, 7 cGy) and
ovarian doses from ⬍1 to more than 2,500 cGy (median, 13
cGy). Figure 10 shows doses to the uterus for female
patients.
DISCUSSION
Fig. 6. Mathematical phantom for 5-year-old girl with Wilms’
tumor treated with 12 ⫻ 15 cm2 anterior and posterior fields to the
left abdomen, tumor dose of 2,500 cGy, from a 6-MV photon
beam.
Limitations of the mathematical phantom method
The calculation method described here is suitable for
estimating dose at any distance from square and rectangular
beams for patients of any age. Commercial treatment-planning computers should be used to calculate dose to points in
the field in either blocked or unblocked regions and to
points within 5 cm of the beam edge. For more distant
548
I. J. Radiation Oncology
● Biology ● Physics
Volume 60, Number 2, 2004
Table 2. Typical radiation doses (cGy) to gonads and uterus for common childhood cancers
Gonadal dose range
Tumor treated
Craniospinal tumors
Leukemia
Hodgkin’s disease
Age (yrs) at
radiotherapy
7
4
15
Wilms’ tumor
(kidney)
Neuroblastoma
4
2
Osteosarcoma
15
Regions treated
Tumor dose
range
Males
Females
Uterine
dose range
Brain
Brain only or brain ⫹ spine
Chest only
Chest and abdomen
Chest, abdomen, pelvis
4,500–5,500
1,800–2,500
3,500–4,500
3,500–4,500
3,500–4,500
2–7
1–84
3–13
13–54
250–500
3–13
2–2,000
6–23
73–175
300–4,500
3–13
2–2,400
5–22
56–142
300–4,500
Abdomen
Chest
Abdomen
Limb
1,500–2,500
1,200–2,500
1,200–2,500
5,500
18–67
2–21
7–54
115–200
139–330
4–35
28–125
16–55
85–230
4–34
22–120
20–55
points, where head leakage is the major contributor to total
dose, the method described here is suitable (37).
The method described here is designed for therapy machines without multileaf collimators (MLC) or universal
wedges (UW). Although the data presented could be used to
estimate out-of-beam doses for a given number of monitor
units from machines with MLCs and UWs, data measured
specifically for these machines is preferred (38).
Individual dose estimates are based on details of treatment documented in the patients’ records. Therefore, quality of dosimetry also depends on collection and management of data for individual patients. Diligence is required to
collect records of all radiation therapy before the date of the
outcome under investigation. Complete documentation includes details, such as daily log, diagram or photograph of
field placement, tumor dose, and special shielding or procedures to reduce gonadal dose. With sufficient effort, complete radiation therapy records can be obtained for approximately 85%–90% of patients, depending on the time
period, institution where therapy was delivered, and primary
disease site. Information about assisted pregnancies, sperm
banking, and other procedures performed to preserve or
enhance fertility is also of interest with doses reaching the
threshold dose for infertility.
Sources of uncertainty in the estimation of radiation dose
to gonads include misspecification of gonadal position with
respect to the treatment fields; missing information on the
use of gonadal shields or oophoropexy; and incorrect recording of treatment doses, field sizes and blocking position. Biologic uncertainties include issues of paternity for
male survivors and the use of technology-enhanced methods
to become pregnant. Because radiation-induced infertility
occurs at sufficiently high gonadal doses, there is an upper
limit to the gonadal dose for the cancer survivors who
became pregnant. Those who exceed this range are scrutinized as outliers and would be excluded if an explanation
for an impossibly high dose could not be found. Thus the
potential bias due to uncertainties in the radiotherapy procedures would be in the direction of an underestimation of
dose and perhaps overestimation of risk; however, because
cancer survivors who had children born with a genetic
condition will be compared with all survivors who had
children, it is unlikely that there will be any systematic bias
in the estimation of dose that could distort the estimation of
risk, other than the “normal” variation associated with any
exposure misclassification. Uncertainties in the biologic aspects such as paternity would work in the opposite direction
and tend to allow high doses inappropriately and result in an
Fig. 8. Absorbed radiation dose to testes of Childhood Cancer
Survivor Study (CCSS-US) and Danish patients.
Fig. 9. Absorbed radiation dose to ovaries of Childhood Cancer
Survivor Study (CCSS-US) and Danish patients.
Genetic effects of radiotherapy for childhood cancer
● M. STOVALL et al.
549
because of knowledge of the primary cancer, the age at
diagnosis, the calendar year of diagnosis and the treatment
center. For example, knowing that a child was treated for
retinoblastoma would be sufficient in itself to categorize
gonadal dose–-in this instance, in the dose category ⬍10
cGy. Children treated for glioblastoma and children treated
for leukemia without spinal fields, similarly could be accurately characterized with respect to gonadal dose. Imputation is anticipated for less than 5% of the patients.
Fig. 10. Absorbed radiation dose to uterus of Childhood Cancer
Survivor Study (CCSS-US) and Danish patients.
under-ascertainment of risk if cases differed appreciably
from the comparison cohort, which seems unlikely. Despite
these and other sources of uncertainty, deriving dose estimates consistently across a population of patients produces
doses that do not differ systematically between cases and the
comparison group and thus allow a meaningful estimate of
radiation risks. Because radiotherapy procedures are so well
characterized, radiation doses to the gonads will be reproducible and of the order of 1 Gy or less. This level of dose is higher
than currently experienced in occupational settings and is in the
range where cancer risks have been observed in human studies.
Thus the study will be able to provide important and meaningful data on the possible genetic consequences of relatively
high doses of ionizing radiation.
Because adverse pregnancy outcomes are so rare, every
effort is made to capture dosimetric information and estimate gonadal doses so that the statistical power of the
epidemiologic study is as strong as possible. In a few
instances where radiotherapy records were incomplete, we
were able to impute gonadal dose with little uncertainty
Comparison of dose estimates using the mathematical
phantom and anthropomorphic phantoms
To validate doses calculated using the method described
above, an extensive comparison of organ doses estimated
using the mathematical phantom and measurements in an
anthropomorphic phantom (Alderson Radiation Therapy
Phantom, available at: www.pi-medical.nl/rs-art.htm
[2002]) was done as part of a study of second tumors in
patients treated for cervical cancer (39). The anthropomorphic phantom irradiations utilized the same TLD dosimetry
system that was used for the water phantom measurements.
The comparison of organ doses calculated using the mathematical phantom and measured in an anthropomorphic
phantom is summarized in Table 3; results show agreement
to within 20% for most organs. This agreement is acceptable
from the perspective of the large range of doses outside a
beam. The two methods differ, however, in that the organs
may not be in exactly the same location, and for each organ
there are many more points of calculation in the mathematical phantom than points of measurement in the anthropomorphic phantom.
Comparison of results with the mathematical phantom
and published data
Van der Giessen et al. (37, 40) compared their out-of-beam
measurements with our data for high-energy photons and
found agreement within 15%. Van der Giessen and Bierhuizen
Table 3. Comparison of organ doses (cGy) estimated using a mathematical phantom and an
anthropomorphic phantom, AP/PA pelvic fields, 60Co gamma rays, 15 cm ⫻ 15 cm2 field size,
80-cm source-skin distance, and 3000 cGy dose to Dmax each field
Organ
Mathematical phantom
(average of many
points for each organ)
Anthropomorphic phantom
Alderson female
(average of TLD in
several phantom slices)
Brain
Breast
Kidney
Lung
Ovaries
Salivary glands
Stomach
Thyroid
Total active bone marrow
5
29
140
26
3,670
7
87
10
818
6
30
130
30
3,440
10
89
14
831
Abbreviations: AP/PA ⫽ Antero-posterior/postero-anterior; Dmax ⫽ maximum depth; TLD ⫽
thermoluminescent dosimetry.
550
I. J. Radiation Oncology
● Biology ● Physics
Table 4. Detectable relative risks (RR) and associated power for
total malformations among the offspring of survivors of
childhood cancer
RR
Radiation
(n ⫽ 1,960)
35%
Radiation
(n ⫽ 2,800)
50%
All survivors
(n ⫽ 5,600)
100%
1.20
1.25
1.30
1.35
1.40
54%
70%
82%
90%
95%
65%
80%
91%
96%
99%
84%
94%
99%
99%
99%
(40) also presented an extensive review of other published data
and found no large (⬎25%) systematic differences.
François et al. (41, 42) described a mathematical phantom similar to ours, based on measurements in a water
phantom. For individual organ doses, their data agree with
ours to ⫾ 30%, with no systematic differences. Differences
in organ doses could be explained to some extent by differences in organ locations.
Epidemiologic relevance
Radiation-induced heritable diseases have not been convincingly demonstrated in humans and estimates of genetic
risks for radiation protection purposes are based on mouse
experiments (43). The most comprehensive epidemiologic
study involved Japanese atomic bomb survivors and their
children; this study found little evidence for inherited defects attributable to parental exposure to radiation (44, 45).
Studies of workers exposed to occupational radiation or
populations exposed to environmental radiation appear to
involve sample sizes that are too small and exposures that
are too low to convincingly detect inherited genetic damage
(46 – 49). In contrast, studies of survivors of childhood
cancer offer a unique opportunity to provide quantitative
information on inherited genetic disease in offspring conceived after exposure. Large numbers of subjects are available, with a wide range of gonadal dose. In some instances
the doses are just below the threshold dose for infertility.
Previous studies of the offspring of survivors of childhood cancer have not linked radiation therapy or mutagenic
chemotherapy with increased rates of childhood cancer or
Volume 60, Number 2, 2004
leukemia (50 –52) or with congenital malformations (53–
58). Offspring of female but not male survivors of Wilms’
tumor have increased rates of low birth weight and possibly
birth defects attributable perhaps to radiation-induced damage to uterine musculature, abdominopelvic structures, and
blood flow and not germinal mutations (59, 60). Few studies, however, have attempted to quantify chemotherapy or
radiation dose to testes, ovaries, or uterus and none has been
of sufficient size to detect a moderate increase in heritable
risk in offspring (61, 62).
Study power
In Table 4, we present the relative risks and the associated
power to detect a difference in total malformations occurring among the offspring of childhood cancer survivors. The
power values are given for a one-sided 5% nominal significance level. The baseline malformation rate is calculated as
the number of offspring with malformations (n ⫽ 242)
reported in 4,225 offspring of siblings of Danish cancer
survivors in the initial analyses (2). The sample size in the
total sibling offspring group (comparison group) is estimated to be 11,500. Conservative assumptions are that
between 35% and 50% of all the parents received treatment
with radiation (60, 63). The power computations are based
on comparisons of (1) the offspring of all cancer survivors
and the offspring of the survivors’ siblings, and (2) the
offspring of all cancer survivors and the offspring of survivors who were treated with radiation. The total survivors’
exposure to some form of mutagenic therapy will fall between these ranges. As indicated in Table 4, the power of
the proposed study is sufficient to detect even modest increases in risk of total malformations among the offspring
of childhood cancer survivors.
In contrast, the study of atomic bomb survivors (44) considered doses of ⬍1 cGy to 300 cGy (mean, 27 cGy) and
occupational studies considered doses of ⬍1 cGy to 91 cGy
(mean, 3.0 cGy) (44, 47, 64). As shown in this article, the dose
distribution for childhood cancer survivors, reaching just below the level that would cause permanent sterility, coupled
with the increased survival and fertility of childhood cancer
patients, results in a powerful study to understand any genetic
consequences associated with radiation exposure to humans.
REFERENCES
1. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003.
CA Cancer J Clin 2003;53:5–26.
2. Boice JD Jr, Tawn EJ, Winther JF, et al. Genetic effects of
radiotherapy for childhood cancer. Health Phys 2003;85:
65–80.
3. Keller B, Mathewson C, Rubin P. Scattered radiation dosage
as a function of x-ray energy. Radiology 1974;111:447–449.
4. Fraass BA, van de Geijn J. Peripheral dose from megavolt
beams. Med Phys 1983;10:809–818.
5. Kase KR, Svensson GK, Wolbarst AB, et al. Measurements of
dose from secondary radiation outside a treatment field. Int J
Radiat Oncol Biol Phys 1983;9:1177–1183.
6. Greene D, Chu GL, Thomas DW. Dose levels outside radiotherapy beams. Br J Radiol 1983;56:543–550.
7. Greene D, Karup PG, Sims C, et al. Dose levels outside
radiotherapy beams. Br J Radiol 1985;58:453–456.
8. Sherazi S, Kase KR. Measurements of dose from secondary
radiation outside a treatment field: Effects of wedges and
blocks. Int J Radiat Oncol Biol Phys 1985;11:2171–2176.
9. McParland BJ. Peripheral doses of two linear accelerators
employing universal wedges. Br J Radiol 1990;63:295–
298.
10. Robison LL, Mertens AC, Boice JD, et al. Study design and
cohort characteristics of the Childhood Cancer Survivor
Genetic effects of radiotherapy for childhood cancer
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Study: A multi-institutional collaborative project. Med Pediatr
Oncol 2002;38:229–239.
Wacholder S. Practical considerations in choosing between
the case-cohort and nested case-control designs. Epidemiology
1991;2:155–158.
Barlow WE, Ichikawa L, Rosner D, et al. Analysis of casecohort designs. J Clin Epidemiol 1999;52:1165–1172.
Hawkins MM, Wilson LM, Burton HS, et al. Radiotherapy,
alkylating agents, and risk of bone cancer after childhood
cancer. J Natl Cancer Inst 1996;88:270–278.
Wong FL, Boice JD, Jr, Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk.
JAMA 1997;278:1262–1267.
Travis LB, Hill DA, Dores GM, et al. Breast cancer following
radiotherapy and chemotherapy among young women with
Hodgkin disease. JAMA 2003;290:465–475.
Stovall M, Blackwell CR, Cundiff J, et al. Fetal dose from
radiotherapy with photon beams: Report of AAPM Radiation
Therapy Committee Task Group No. 36. Med Phys 1995;22:
63–82.
Stovall M, Blackwell CR, Cundiff J, et al. Fetal dose from
radiotherapy with photon beams: Report of AAPM Radiation
Therapy Committee Task Group No. 36 [Med Phys 1995;22:
63– 82] (Erratum). Med Phys 1995;22:1353–1354.
Aird A, Burns JE, Day MJ, et al. Central axis depth dose data
for use in radiotherapy: 1996. A survey of depth doses and
related data measured in water or equivalent media. Vol 25.
London: Brit. Inst. Radiol; 1996.
Snyder RG, Schneider LW, Owings CL, et al. Anthropometry of
infants, children, and youths to age 18 for product safety design
SP450. Warrendale: Society of Automotive Engineers, 1977.
Eycleshymer AC, Schoemaker DM. A cross-section anatomy.
New York: Appleton-Century-Crofts; 1970.
Kieffer SA, Heitzman ER. An atlas of cross-sectional anatomy: Computed tomography, ultrasound, radiography, gross
anatomy. Hagerstown: Harper & Row; 1979.
Ferner H, Staubesand J. Sobotta atlas of human anatomy. Vol
1: Head, neck, upper extremities, 10th English ed. Baltimore:
Urban & Schwarzenberg; 1983.
Ferner H, Staubesand J. Sobotta atlas of human anatomy.
Vol 2: Thorax, abdomen, pelvis, lower extremities, skin.
10th English ed. Baltimore: Urban & Schwarzenberg; 1983.
Bo WJ. Basic atlas of sectional anatomy with correlated
imaging, 3rd ed. Philadelphia: Saunders; 1998.
Cristy M. Mathematical phantoms representing children of various ages for use in estimates of internal dose. Oak Ridge National Laboratory Report ORNL/NUREG/TM 367. Washington,
D.C.: U.S. Nuclear Regulatory Commission; 1980.
Cristy M. Active bone marrow distribution as a function of
age in humans. Phys Med Biol 1981;26:389–400.
Le Floch O, Donaldson SS, Kaplan HS. Pregnancy following
oophoropexy and total nodal irradiation in women with
Hodgkin’s disease. Cancer 1976;38:2263–2268.
Thomas PR, Winstanly D, Peckham MJ, et al. Reproductive
and endocrine function in patients with Hodgkin’s disease:
Effects of oophoropexy and irradiation. Br J Cancer 1976;33:
226–231.
Holmes GE, Holmes FF. Pregnancy outcome of patients
treated for Hodgkin’s disease: A controlled study. Cancer
1978;41:1317–1322.
Sharma SC, Williamson JF, Khan FM, et al. Measurement and
calculation of ovary and fetus dose in extended field radiotherapy for 10 MV x rays. Int J Radiat Oncol Biol Phys
1981;7:843–846.
Horning SJ, Hoppe RT, Kaplan HS, et al. Female reproductive
potential after treatment for Hodgkin’s disease. N Engl J Med
1981;304:1377–1382.
Kubo H, Shipley WU. Reduction of the scatter dose to the
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
● M. STOVALL et al.
551
testicle outside the radiation treatment fields. Int J Radiat
Oncol Biol Phys 1982;8:1741–1745.
Sprecht L, Hansen MM, Gieslen C. Ovarian function in
young women in long-term remission after treatment for
Hodgkin’s disease Stage I or II. Scand J Haematol 1984;
32:265–270.
Fraass BA, Kinsella TJ, Harrington FS, et al. Peripheral dose to
the testes: The design and clinical use of a practical and effective
gonadal shield. Int J Radiat Oncol Biol Phys 1985;11:609–615.
Gabriel DA, Bernard SA, Lambert J, et al. Oophoropexy
and the management of Hodgkin’s disease. A reevaluation
of the risks and benefits. Arch Surg 1986;121:1083–1085.
Niroomand-Rad A, Cumberlin R. Measured dose to ovaries
and testes from Hodgkin’s fields and determination of genetically significant dose. Int J Radiat Oncol Biol Phys 1993;25:
745–751.
Van der Giessen PH. A simple and generally applicable
method to estimate the peripheral dose in radiation teletherapy
with high energy x-rays or gamma radiation. Int J Radiat
Oncol Biol Phys 1996;35:1059–1068.
Mutic S, Esthappan J, Klein EE. Peripheral dose distributions
for a linear accelerator equipped with a secondary multileaf
collimator and universal wedge. J Appl Clin Med Phys 2002;
3:302–309.
Stovall M, Smith SA, Rosenstein M. Tissue doses from radiotherapy of cancer of the uterine cervix. Med Phys 1989;
16:726–733.
Van der Giessen PH, Bierhuizen HW. Comparison of measured and calculated peripheral doses in patients undergoing
radiation therapy. Radiother Oncol 1997;42:265–270.
François P, Beurtheret C, Dutreix A, et al. A mathematical
child phantom for the calculation of dose to the organs at risk.
Med Phys 1988;15:328–333.
François P, Beurtheret C, Dutreix A. Calculation of the dose
delivered to organs outside the radiation beams. Med Phys
1988;15:879–883.
United Nations Scientific Committee on the Effects of Atomic
Radiation. Report to the General Assembly, with scientific
annexes. Hereditary effects of radiation. New York: United
Nations; 2001.
Neel JV, Schull WJ. The children of atomic bomb survivors.
Washington: National Academy Press; 1991.
Neel JV. Genetic studies at the Atomic Bomb Casualty Commission-Radiation Effects Research Foundation: 1946-1997.
Proc Natl Acad Sci USA 1998;95:5432–5436.
Little MP. A comparison of the risk of stillbirth associated
with paternal pre-conception irradiation in the Sellafield workforce with that of stillbirth and untoward pregnancy outcome
among Japanese atomic bomb survivors. J Radiol Prot 1999;
19:361–373.
Boice JD, Jr, Robison LL, Mertens A, et al. Stillbirths and
male irradiation. J Radiol Prot 2000;20:321–322.
Doyle P, Maconochie N, Roman E, et al. Fetal death and
congenital malformation in babies born to nuclear industry
employees: Report from the nuclear industry family study.
Lancet 2000;356:1293–1299.
Wakeford R. Study of childhood cancer and paternal preconceptional irradiation at USA nuclear facilities. J Radiol Prot
2000;20:331–332.
Mulvihill JJ, Myers MH, Connelly RR, et al. Cancer in
offspring of long-term survivors of childhood and adolescent
cancer. Lancet 1987;2:813–817.
Hawkins MM, Draper GJ, Winter DL. Cancer in the offspring
of survivors of childhood leukaemia and non-Hodgkin lymphomas. Br J Cancer 1995;71:1335–1339.
Sankila R, Olsen JH, Anderson H, et al. Risk of cancer among
offspring of childhood-cancer survivors. Association of the
Nordic Cancer Registries and the Nordic Society of Paediatric
552
53.
54.
55.
56.
57.
58.
I. J. Radiation Oncology
● Biology ● Physics
Haematology and Oncology. N Engl J Med 1998;338:1339–
1344.
Hawkins MM, Smith RA. Pregnancy outcomes in childhood
cancer survivors: Probable effects of abdominal irradiation.
Int J Cancer 1989;43:399–402.
Green DM, Fiorello A, Zevon MA, et al. Birth defects and
childhood cancer in offspring of survivors of childhood
cancer. Arch Pediatr Adolesc Med 1997;151:379–383.
Byrne J, Rasmussen SA, Steinhorn SC, et al. Genetic
disease in offspring of long-term survivors of childhood
and adolescent cancer. Am J Hum Genet 1998;62:45–52.
Byrne J. Long-term genetic and reproductive effects of ionizing radiation and chemotherapeutic agents on cancer patients
and their offspring. Teratology 1999;59:210–215.
Chiarelli AM, Marrett LD, Darlington GA. Pregnancy outcomes in females after treatment for childhood cancer. Epidemiology 2000;11:161–166.
Mulvihill JJ, Strong LC, Robison LL. Investigators of the
Childhood Cancer Survivor Study: Genetic disease in offspring of survivors of childhood and adolescent cancer. Am J
Hum Genet 2001;69:A391.
Volume 60, Number 2, 2004
59. Critchley HO, Wallace WH, Shalet SM, et al. Abdominal
irradiation in childhood: The potential for pregnancy. Br J
Obstet Gynaecol 1992;99:392–394.
60. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome
of female survivors of childhood cancer: A report from the
Childhood Cancer Survivor Study. Am J Obstet Gynecol 2002;
187:1070–1080.
61. Averette HE, Boike GM, Jarrell MA. Effects of cancer chemotherapy on gonadal function and reproductive capacity. CA
Cancer J Clin 1990;40:199–209.
62. Blatt J. Pregnancy outcome in long-term survivors of childhood cancer. Med Pediatr Oncol 1999;33:29–33.
63. Green DM, Peabody EM, Nan B, Peterson S, Kalapurakal
JA, Breslow NE. Pregnancy outcome after treatment for
Wilms’ tumor: A report from the National Wilms’ Tumor
Study Group. J Clin Oncol 2002;20:2506–2513.
64. Parker L, Pearce MS, Dickinson HO, et al. Stillbirths
among offspring of male radiation workers at Sellafield nuclear reprocessing plant. Lancet 1999;354:1407–
1414.