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CA CANCER J CLIN 2012;62:75–100
Cancer Risks Associated With External Radiation From
Diagnostic Imaging Procedures
Martha S. Linet, MD, MPH1; Thomas L. Slovis, MD2; Donald L. Miller, MD, FSIR3; Ruth Kleinerman, MPH4;
Choonsik Lee, PhD5; Preetha Rajaraman, PhD6; Amy Berrington de Gonzalez, DPhil7
The 600% increase in medical radiation exposure to the US population since 1980 has provided immense benefit, but increased potential future cancer risks to patients. Most of the increase is from diagnostic radiologic procedures. The objectives of this review are to
summarize epidemiologic data on cancer risks associated with diagnostic procedures, describe how exposures from recent diagnostic
procedures relate to radiation levels linked with cancer occurrence, and propose a framework of strategies to reduce radiation from
diagnostic imaging in patients. We briefly review radiation dose definitions, mechanisms of radiation carcinogenesis, key epidemiologic
studies of medical and other radiation sources and cancer risks, and dose trends from diagnostic procedures. We describe cancer risks
from experimental studies, future projected risks from current imaging procedures, and the potential for higher risks in genetically susceptible populations. To reduce future projected cancers from diagnostic procedures, we advocate the widespread use of evidencebased appropriateness criteria for decisions about imaging procedures; oversight of equipment to deliver reliably the minimum radiation
required to attain clinical objectives; development of electronic lifetime records of imaging procedures for patients and their physicians;
and commitment by medical training programs, professional societies, and radiation protection organizations to educate all stakeholders
in reducing radiation from diagnostic procedures. CA Cancer J Clin 2012;62:75-100. Published 2012 American Cancer Society.†
Introduction
Since the discoveries of x-rays, radium, and radioactivity from uranium salts during the late 19th century, remarkable experimental, clinical, and technological developments in radiologic imaging have continued to transform medicine, as summarized in Table 1.1,2 A few years after x-rays were first used for radiologic imaging, physicians and other medical radiation
workers developed skin carcinomas, leukemia, dermatitis, cataracts, and other adverse health effects.7-10 Despite early recommendations to decrease stray radiation to the patient and restrict the x-ray beam,8,11 25 years passed before these recommendations were implemented1 and radiation protection committees were established.12 With the development and evolution of
measures of radiation dose, film badge monitoring, and personal (eg, lead aprons) and general (eg, lead shields) radiation protection equipment,2 occupational doses declined dramatically3,13,14 and the excesses of leukemia, skin cancer, and female breast
cancer in medical radiation workers employed before 1950 were no longer apparent in subsequent medical radiation workers.3
From 1956 to the present, epidemiologic studies have also linked diagnostic x-rays with cancer increases in patients,
including modest excesses of pediatric leukemia in the offspring of mothers undergoing diagnostic x-rays during pregnancy,15-19 and increased breast cancer risks in women with tuberculosis who were monitored using fluoroscopy20-23 and in
women with scoliosis who were evaluated with repeated x-rays.24 During the past 30 years, newer imaging modalities (such
as computed tomography [CT], myocardial perfusion scans, positron emission tomography [PET], and other radiologic
procedures) dramatically increased. These procedures have provided immense clinical benefit but also higher ionizing radiation exposures to patients. Medical radiation now comprises almost 50% of the per capita radiation dose, compared with
15% in the early 1980s (Fig. 1).25 Although the individual risk of developing radiation-related cancer from any single medical imaging procedure is extremely small, the substantial increase in the per capita effective dose between 1980 and 2006, as
well as reports of a substantial fraction of patients undergoing repeated higher dose examinations, motivate this review.25,26
1
Chief and Senior Investigator, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD;
Chief, Pediatric Radiology, Department of Radiology, Children’s Hospital of Michigan, Detroit, MI; 3Acting Chief, Diagnostic Devices Branch, Division of
Mammography Quality and Radiation Program Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD; 4Epidemiologist,
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; 5Investigator, Radiation Epidemiology
Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; 6Investigator, Radiation Epidemiology Branch, Division of
Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; 7Senior Investigator, Radiation Epidemiology Branch, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
2
Corresponding author: Martha S. Linet, MD, MPH, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute,
6120 Executive Blvd, EPS 7048, Bethesda, MD 20892-7238; [email protected]
We are grateful to Annelie Landgren, MPH, and Stephanie Glagola, BA, for technical support.
DISCLOSURES: This review was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute.
Published 2012 American Cancer Society, Inc. †This article is a US Government work and, as such, is in the public domain in the United States of America.
doi:10.3322/caac.21132. Available online at http://cacancerjournal.com
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Cancer Risks and Diagnostic Imaging
TABLE 1. Key Discoveries and Technological Developments in Diagnostic Radiography
YEAR
DISCOVERIES AND TECHNOLOGICAL DEVELOPMENTS
1895
Roentgen: x-rays
1896
Edison: calcium tungstate
1904
Self-regulated gas tubes
1908
Snook: generator provides selectable kV and mA
1913
Coolidge: first successful roentgen-ray tube
1914-1916
Patterson: fluoroscopic screen
1917
Potter-Bucky diaphragm: reduce scatter by secondary radiation
1917
Kodak: double emulsion acetate film
1924
Film changer for serial x-rays
1928
Siemens: 3-phase generators
1929
Hans Bouwers (at Philips research laboratories): rotating anode x-ray tube, shielding provided by tube housing integrated in tube assembly
1934
Ziedes des Plantes: optical subtraction of radiographic film to aid in visualization of small blood vessels
1941
First automatic film processor
1942
X-ray phototimers
1947
Xeroradiography
1948
Coltman: image intensifier tube for fluoroscopy
1960
DuPont: polyester film base replaces acetate
1964
Kodak: 90-s Xomat processor
1964-1968
Cormack and Hounsfield: CT scanner
1969
Dedicated mammographic unit with molybdenum target tube and compression cone
1971
Xeroradiography system for mammography
1972
Screen film system for mammography
1973
Buchanan: rare earth screen phosphors
1979
Fuji Photo Film Co.: digital subtraction angiography
1982
Ultrafast CT scanner
1984
Computed radiography systems
1985
American College of Radiology–National Electrical Manufacturers Association Digital Imaging and Communication Standard to develop
standards for medical picture archiving and communications (PACS)
1989
Heiken et al: slip-ring helical CT volume imaging
1993
Solid state digital x-ray detectors
1999
4-slice CT system
2000
Digital mammography system
2001
16-slice CT system with submillimeter collimation
2004
64-slice CT system
kV indicates kilovolts; mA, milliamperes; CT, computed tomography; PACS, picture archiving and communication system.
Modified from Linet MS, Kim KP, Miller DL, Kleinerman RA, Simon SL, de Gonzalez AB. Historical review of occupational exposures and cancer risks in medical
radiation workers. Radiat Res. 2010;174:793-808.3 Sources: Seibert JA. One hundred years of medical diagnostic imaging technology. Health Phys.
1995;69:695-7201; Hall E, Giaccia AJ. Milestones in the radiation sciences. In: Radiobiology for the Radiologist. 6th ed. Philadelphia: Lippincott Williams &
Wilkins; 2006:1-42; Haus AG. Historical technical developments in mammography. Technol Cancer Res Treat. 2002;1:119-1264; Wang Y, Best DE, Hoffman JG,
et al. ACR-NEMA digital imaging and communications standards: minimum requirements. Radiology. 1988;166:529-5325; and Flohr TG, Ohnesorge BM. Imaging
of the heart with computed tomography. Basic Res Cardiol. 2008;103:161-173.6
The objectives of this review are to summarize the key
epidemiologic and experimental data on cancer risks associated with diagnostic radiologic procedures, to relate radiation exposures from recent and current imaging procedures
76
CA: A Cancer Journal for Clinicians
to radiation levels statistically associated with cancer risks,
and to propose a framework of strategies for reducing
future cancer risks projected from current levels of diagnostic imaging procedures in patients.
CA CANCER J CLIN 2012;62:75-100
FIGURE 1. US Annual Per Capita Effective Radiation Dose in Millisieverts (mSv) From Various Sources for 1980 and 2006. The source for the estimated annual per capita
natural background exposure of 2.4 mSv in both time periods is the 1988 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) report.27 The
source for the estimated annual per capita total radiation exposure of 3.0 mSv for 1980 is National Council on Radiation Protection and Measurements (NCRP) Report No. 93,
published in 1987.28 The source for the estimated annual per capita total radiation exposure of 5.6 mSv for 2006 is NCRP Report No. 160, published in 2009.25 CT indicates
computed tomography; F&IF, fluoroscopy and interventional fluoroscopy. Reprinted with permission from Mettler FA Jr, Bhargavan M, Faulkner K, et al. Radiologic and nuclear
medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources–1950-2007. Radiology. 2009;253:520-531.29
Background
Radiation Dose Measures
The radiation dose is the amount of energy absorbed in the
body from radiation interactions. Early nonquantitative
measures of dose, based on skin erythema, were replaced by
measures of exposure (eg, the ability of x-rays to ionize air,
measured in roentgens [or R]) and measures of absorbed
dose (eg, energy absorption, measured initially in radiation
absorbed dose [or rad] and more recently in gray [Gy] or
milligray [mGy] [1 Gy ¼ 100 rad; 1 rad ¼ 10 mGy or
0.01 Gy]).2 Shown in Table 2 are definitions of the key
dose quantities and units. Different types of radiation may
produce different biological effects and the magnitude of
the effect can vary according to the rate at which radiation
is received (dose rate). The dose rate is a primary factor in
determining the biological effects of a given absorbed dose.
For example, as the dose rate is reduced and the exposure
time extended, the biologic effect of a given dose is generally reduced. Relative biological effectiveness, which
denotes the ability of a given type of radiation to produce a
specific biological outcome compared with x-rays or gamma
rays, is taken into account by the sievert (Sv), a metric for
biological equivalent dose that can be used to measure
mixed types of radiation exposure. The effective dose is the
sum of the equivalent doses to each tissue and organ
exposed multiplied by the appropriate tissue-weighting factor or, in other words, the whole-body dose of x-rays that
would have to be delivered to produce the same carcinogenic risk as the partial dose that was delivered. This quantity provides an easy assessment of overall risk and makes
the comparison of risks much simpler. Although effective
dose is emphasized in many surveys because this metric is
related to the risk of carcinogenic effects, effective dose
cannot be measured and cannot be used for individual risk
assessment. Only absorbed dose to a given tissue or organ
can be used for estimating cancer risks.30,31
Biological Mechanisms of Radiation
Carcinogenesis
Ionizing radiation is an established carcinogen, based on animal studies and studies of early radiologists, radium dial workers (who used radium-containing paint for glow-in-the-dark
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TABLE 2. Quantities and Units Used in Radiation Protectiona
UNIT
QUANTITY
ABSORBED DOSE
DEFINITION
NEW
OLD
b
RADb
ENERGY PER UNIT MASS
GRAY
Equivalent dose
(radiation weighted dose)
Average absorbed dose multiplied by the radiation weighting factor.
Svc
Rem
Effective dose
Sum of equivalent doses to organs and tissues exposed, each multiplied by the
appropriate tissue weighting factor.
Sv
Rem
Committed equivalent dose
Equivalent dose integrated over 50 y; takes into account absorbed dose from irradiation
from internally deposited radionuclides.
Sv
Rem
Committed effective dose
Effective dose integrated over 50 y; takes into account committed equivalent doses to
individual organs or tissues from irradiation from internally deposited radionuclides multiplied
by appropriate tissue weighting factors and then summed.
Sv
Rem
Collective equivalent dose
Product of the average equivalent dose to a population and the no. of persons exposed.
Person-Sv
Man-rem
Collective effective dose
Product of the average effective dose to a population and the no. of persons exposed.
Person-Sv
Man-rem
Collective committed effective dose
Effective dose over the entire population out to a period of 50 y; takes into account effective
doses from ingested or inhaled radionuclides that deposit dose over a prolonged period of time.
Person-Sv
Man-rem
FOR INDIVIDUALS
FOR POPULATIONS
Rad indicates radiation absorbed dose; Sv, sievert; Rem, roentgen equivalent man; Person-Sv, previously designated as Man-rem, is the sum of all individual
exposures or collective dose in a population (collective dose is the product of the average dose to a population and the number of persons exposed (if 100
persons receive an average equivalent dose of 0.1 Sv [10 Rem], the collective effective dose is 10 Person-Sv [1000 Man-rem])).
a
Caveat: effective doses allow for the comparison of doses from partial body exposures (eg, different anatomic sites), but are not appropriate estimates of
absorbed radiation doses to organs or tissues. Collective doses are useful for estimating average annual population doses, but caution must be exercised
when using collective dose estimates for calculating the probability of cancer in a population.
b
One gray (Gy) ¼ 100 rad; 1 rad ¼ 10 milligray or 0.01 Gy.
c
Sv is a metric for biological equivalent dose and mixed types of radiation exposures.
Source: Hall E, Giaccia AJ. Milestones in the radiation sciences. In: Radiobiology for the Radiologist. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.2
watch dials), uranium miners, the Japanese atomic bomb
survivors, patients treated with radiotherapy, and those
undergoing repeated fluoroscopic or radiographic diagnostic examinations.13,23,32-34 Two types of cellular damage,
deterministic and stochastic effects, are produced by radiation in the absence of adequate repair. Deterministic effects
occur above a threshold dose and are characterized by a
dose-related increasing risk and associated severity of outcome. A long-recognized adverse deterministic effect is
radiation-induced dermatitis,35 which was initially described
in 1902.7 After radiotherapy or fluoroscopically guided interventional procedures, generalized erythema may occur within
hours and then fade within hours to days, followed by a second phase of sustained erythema manifesting 10 to 14 days
after the exposure. The early erythema is considered to be
an acute inflammatory reaction with an increase in vascular permeability, while the more sustained erythema, without other epidermal changes, is thought to be mediated by
cytokines.36 Radiation cataractogenesis, particularly the
occurrence of posterior subcapsular opacities, has been
considered to be another classic example of a deterministic
late effect. Formerly, the threshold was reported to be
2 Gy for acute radiation exposure, 4 Gy for fractionated
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CA: A Cancer Journal for Clinicians
doses, and even higher levels for long-term exposure,31
but recent human and mechanistic studies suggest a lower
(eg, around 0.5 Gy) or no threshold.37
Stochastic effects, including cancer and hereditary
effects, are caused by a mutation or other permanent change
in which the cell remains viable. The probability of a stochastic effect increases with dose (probably with no threshold, an
assumption based on molecular knowledge of carcinogenesis:
a very small x-ray dose can cause a base change in DNA), but
the severity of the outcome is not related to the dose.2 For
many years, radiation dose-related cancer risks at low doses
were generally estimated from results of the follow-up studies
of the atomic bomb survivors and of patients treated
with moderate- to high-dose radiation. Major national and
international radiation expert committees concluded in comprehensive reviews published during 2005 to 2008 that the
available biological and biophysical data support a linear
no-threshold risk model for cancer (eg, dose response at low
levels occurs in a generally linear pattern without evidence of
a threshold31,38,39), and that this combined with an uncertain
dose and dose rate effectiveness factor for extrapolation from
high doses continues to be considered a conservative basis for
radiation protection at low doses and dose rates. Some recent
CA CANCER J CLIN 2012;62:75-100
reports, based mostly on findings from radiobiology, suggest
that there is substantially greater complexity regarding low
dose and low-dose rate effects from nontargeted effects of
low-dose radiation (eg, effects in nonirradiated cells near and
at distant sites from irradiated cells).40,41
Epidemiologic literature on low-dose and low-dose rate
effects is hampered by limited statistical power at cumulative
lifetime radiation levels of less than 100 millisieverts (mSv),
even for very large studies. Nevertheless, despite wide confidence limits, the results of individual large and pooled studies
of radiation workers reveal modest exposure-related increases
in the risk of solid tumors at low-dose levels.42,43 More
research is needed on radiobiologic effects along with continuing follow-up of existing and newer studies of radiation
workers to clarify the shape of the dose-response relationship
at low dose and low-dose rate radiation levels.41
Epidemiologic studies have shown minimum latency
periods of 2 to 5 years between radiation exposure and the
onset of leukemias, with many of the excess leukemias
occurring within the first 2 decades of exposure. There is
variation in the temporal pattern of radiation-related leukemia risks between exposures in childhood and adulthood
(with the decline in risk occurring sooner and in more pronounced manner for the former than the latter) and for different major subtypes of leukemia (with the excess risk of
chronic myeloid leukemia decreasing substantially about
10 years after exposure, the excess risk declining much
more slowly for acute myeloid leukemia, and the excess risk
of acute lymphocytic leukemia decreasing with attained age
based on data from follow-up of the atomic bomb survivors).13,44,45 Minimum latency periods are longer for solid
tumors, ranging from 10 years to many years after the initial radiation exposure. Risks of most solid tumors continue
to increase throughout the radiation-exposed person’s
lifetime.46 Radiation-related cancers generally occur at the
same ages as non-radiation-related cancers.
Cancer Risks Associated With External Radiation
From Sources Other Than Diagnostic Radiologic
Procedures: Highlights From Key
Epidemiological Studies
Much is known about cancer risks associated with a single
high-dose rate external radiation exposure from studies of
the Japanese atomic bomb survivors,44,46,47 fractionated
high-dose external radiation exposures in patients treated
with radiotherapy for benign or malignant disorders,13,22,23
and, to a lesser extent, chronic low-dose low dose rate exposures.42,43 The Life Span Study of more than 105,000
atomic bomb survivors (including 30,000 children), remains
one of the richest sources of information because of the
wide dose range (less than 0.005 Gy to 2-4 Gy [mean,
0.2 Gy]), wide range in age at exposure, and long-term
follow-up. This study has demonstrated evidence of a linear
dose response for all solid tumors combined, including a
statistically significant dose response for survivors with estimated doses under 0.15 Gy (Table 3).44-47 For the 17,448
incident first primary cancers diagnosed between 1958 and
1998 (including 850 cancers or 11% diagnosed in individuals with estimated doses greater than 0.005 Gy attributable
to the atomic bomb radiation exposure), significant
radiation-associated excess risks were observed for most,
but not all, specific types of solid tumors.46 Excess relative
risks (ERRs) per Gy (excess compared with baseline
population risks) and excess absolute rates (EARs) varied
according to organ or tissue and by age at exposure. ERRs
per Sv for acute lymphoid, acute myeloid, and chronic
myeloid leukemias were 9.1, 3.3, and 6.2, respectively,
while excess absolute rates per 10,000 person-year Sv were
0.6, 1.1, and 0.9, respectively.44 Minimum latency periods
of 2 to 5 years were apparent for the leukemias (excluding
chronic lymphocytic leukemia), but were longer for
solid tumors. Excess risk persisted throughout life for
most malignancies.
Among approximately 2500 atomic bomb survivors who
were in utero at the time of the bombings, there was no evidence of a radiation dose-related increase in cancer mortality among persons aged younger than 15 years at the time
of follow-up.49 In a follow-up of cancer incidence in this
population during 1958 through 199947 that compared
solid cancer incidence risks among in utero cohort members
(based on 94 incident cancers) with risks following postnatal exposures among survivors aged younger than 6 years
at the time of the bombings (based on 649 incident cancers), the investigators found that the ERRs per Sv at the
same attained age of 50 years were higher for the children
exposed postnatally (1.7 per Sv; 95% confidence interval
[95% CI], 1.1 Sv-2.5 Sv) than for those exposed in utero
(0.42 per Sv; 95% CI, 0.0 Sv to 2.0 Sv). The EARs per
10,000 person-years per Sv increased markedly with
attained age among those exposed in early childhood
(EAR, 56; 95% CI, 36-79), but showed a substantially
lower increase with attained age among those exposed in
utero (EAR, 6.8; 95% CI, 0.002-48). This landmark study
demonstrated that in utero radiation exposure from the
bombings was associated with an increased adult-onset solid
tumor risk,47 but could not provide detailed radiation-related
childhood cancer incidence risk estimates in the absence of
complete incidence between 1945 and 1957 (the period after
the bombings but before the establishment of populationbased cancer registries in Hiroshima and Nagasaki).
The dose response patterns for cancer risks associated
with high-dose fractionated radiotherapy are generally similar to those of the atomic bomb survivors, but the ERRs
per Gy are lower for patients treated with high-dose fractionated radiotherapy compared with those for atomic
bomb survivors, likely due to cell killing (Table 3). At high
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Cancer Risks and Diagnostic Imaging
TABLE 3. Summary of Findings From Key Epidemiological Studies Assessing Cancer Risks From Sources of External Radiation
(X-Rays or Gamma Rays) Other Than Studies of Diagnostic Radiologic Procedures
KEY STUDIES
WEIGHTED ORGAN DOSES
HIGHLIGHTS
Japanese atomic
bomb survivors
Preston 200746
Preston 199444
40% of population < 5 mGy; 3%
of population > 1 Gy
–Total solid cancer risk shows linear dose response.
–Dose-response for solid cancers is significantly increased at low doses
(eg, 0.15 Gy, similar doses to multiple CT scans).
–Significant radiation–associated excesses seen for most solid tumors.
–Risks higher for exposure at early ages (except lung, which rose with age).
–Data support a radiation–associated solid tumor increase throughout life.
–Approximately 11% of solid tumors due to the atomic radiation.
–Significantly elevated and high ERRs per Gy for AML, ALL, and CML.
–Dose-response excess persisted for several decades for ALL and CML, but
peaked at 10 y after the bombings for AML.
–High proportion of leukemia attributable to the atomic bomb–related radiation.
Radiotherapy for benign
conditions
Ron 200322
Organ doses to cancer sites
ranged from 1-15 Gy
–Benign conditions treated include ankylosing spondylitis, benign gynecologic
disorders, and peptic ulcer and, in children and adolescents, skin hemangiomas,
tinea capitis, tonsils, acne, and enlarged thymus.
–Partial body irradiation, fractionated doses.
–ERRs per Gy generally consistent with findings from atomic bomb
survivors; significant variation in risks for specific anatomic sites, gender,
age at exposure, and attained age.
–Some evidence, although not consistent, that fractionation reduced risk.
Radiotherapy for cancer
Boice 200623
Organ doses to second cancer sites
ranged from 2 to 200 Gy
–First cancers treated include uterine cervix and endometrial; Hodgkin lymphoma;
non–Hodgkin lymphoma; and breast, testicular, and pediatric cancers.
–Partial body irradiation, fractionated doses.
–Small absolute no. of second cancers.
–ERRs per Gy notably less than risks for atomic bomb survivors of
similar age at exposure, likely due to cell killing; risks by anatomic site
and age at exposure similar to atomic bomb survivors.
Nuclear workers
Cardis 200548
Cardis 200743
Muirhead 200942
Weighted organ doses ranged from
0 to 500 mSv; mean lifetime
dose ranged from 15-25 mSv
–Significantly increased ERR per Sv for all cancers combined other
than leukemias.42,43
–Significantly increased ERR per Sv for leukemias excluding chronic
lymphocytic leukemia.42
–Significantly increased ERR per Sv for lung cancer mortality.43
mGy indicates milligray; Gy, gray; CT, computed tomography; RR, relative risk; ERR, excess relative risk; AML, acute myeloid leukemia; ALL, acute lymphocytic
leukemia; CML, chronic myeloid leukemia; mSv, millisieverts; Sv, sievert.
doses, radiation kills cancer cells by irrevocably damaging
DNA so the cells are nonviable, whereas at lower doses cells
may undergo DNA damage, but a large proportion of irradiated cells remain viable. In radiotherapy, extensive efforts
are usually made to limit lower dose ‘‘radiation scatter’’ to
surrounding tissue, so that only a small proportion of cells
irradiated receive low doses.
Nuclear workers have experienced radiation dose-related
incidence and mortality risk increases for leukemias
(excluding chronic lymphocytic leukemia). In the United
Kingdom, incidence was slightly more elevated (ERR per
Gy, 1.712; 90% CI, 0.06-4.29) than the dose-associated
risks of the atomic bomb survivors (ERR per Gy, 1.4; 90%
CI, 0.1-3.4). These workers also had statistically significant
increases for all cancers combined other than leukemia.42,43
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CA: A Cancer Journal for Clinicians
Dose-associated increases were also apparent for lung
cancer in the 15-country study,42,43 although the associations with lung cancer may have been confounded by
smoking (Table 3).
Patterns and Trends in Diagnostic
Radiologic Procedures
Prior to 1980, exposures to the US general population from
environmental sources of ionizing radiation (eg, radon, natural background gamma radiation, and cosmic rays) were
estimated at about 2.8 mSv per capita versus 0.53 mSv
from medical sources (the latter comprising about 15% of
the estimated 3.6 mSv total).25 The estimated per capita
dose from medical radiation in the United States increased
approximately 600% from about 0.53 mSv in the early
CA CANCER J CLIN 2012;62:75-100
1980s to about 3.0 mSv in 2006 (the latter including about
1.5 mSv per capita from CT scans, 0.8 mSv from nuclear
medicine procedures, 0.4 mSv from interventional procedures, and 0.3 mSv from standard radiographic procedures)
(Fig. 1). Within the 25-year period, the proportion of per
capita individual radiation exposure from medical sources
increased from 15% to close to 50% (Fig. 1).25
Although US surveys for specific categories of radiologic
procedures have been conducted periodically since the early
1950s, comprehensive assessment across different radiologic procedures has been relatively infrequent. Comparison
of the estimated annual numbers and per capita doses
for categories of procedures performed during 1980 to
1982 with the annual numbers performed in 2006 showed
more than 2-fold increases in the total numbers of all
radiographic examinations excluding dental procedures, a
20-fold increase in CT scans, a 5-fold increase in dental
radiographic examinations, and a 1.5-fold increase in nuclear
medicine procedures, accompanied by a notable change in
the specific types of nuclear medicine procedures.25,29
Compared with an estimated 3.3 million CT scans performed between 1980 and 1982, there were an estimated
80 million CT scans performed in 2010.50 The nearly
6-fold increase in the annual estimated per capita effective
dose from all sources of medical radiation between 1980
through 1982 and 2006 was due mostly to the nearly
100-fold increase in per capita dose from CT scans and the
5-fold and 2.5-fold increases from nuclear medicine and interventional procedures, respectively.25,29 Although usage has also
increased in other countries, average annual per capita exposure
in the United States is 50% higher than in other high-income
countries (3 mSv vs 2 mSv per year, respectively).29 Recently,
however, there has been evidence of a decline in the percentage of annual increase in CT imaging among Medicare
fee-for-service beneficiaries from a compound annual
growth rate of 9.5% during 1998 to 2005 to 4.3% during
2005 to 2008.51 Among the Medicare beneficiaries, the
decline in the compound annual growth rate for all noninvasive procedures was greater for tests ordered by radiologists (from a 3.4% annual growth rate during 1998-2005
to 0.8% annually during 2005-2008) than for tests ordered
by all other physicians (from a 6.6% annual growth rate
during 1998-2005 to 1.8% annually during 2005-2008).
Survey data from the United Kingdom and the United
States demonstrate substantial variation in estimated effective
doses for different radiologic procedures (Table 4).13,52-55
For a given type of radiologic procedure, estimated effective doses differ by the anatomic site examined (Table 4),
by age at examination (particularly for children and adolescents) (Table 5), and by the facility where the examination was performed (Fig. 2). Variation among hospitals in
estimated effective doses associated with a specific radiologic procedure has been recognized for decades,60,61 despite
TABLE 4. Typical Effective Doses From Some Medical Imaging
Examinations
EFFECTIVE
DOSE (mSv)
TYPE OF EXAMINATION
NO. OF CHEST
X-RAYS RESULTING
IN SAME
EFFECTIVE DOSEa
Radiography
Skull AP or PA
0.015
1
Chest PA
0.013
1
L-spine AP
0.44
30
Abdomen AP
0.46
35
0.48
35
0.2
15
Pelvis AP
b
Mammography (4 views)
Screening
c
Dental radiography
Intraoral
0.013
1
Panoramic
0.012
1
Diagnostic fluoroscopy procedures
Barium swallowd
1
70
Barium enema
5
350
Angiography: cardiacc
7
500
Head
2
150
Chest
10
750
Abdomen
10
750
7
500
15
1100
C-spine
5
400
T-spine
8
550
L-spine
7
500
d
CT
e
Pelvis
Abdomen/pelvis
mSv indicates millisieverts; AP, anteroposterior; PA, posteroanterior; CT, computed tomography.
a
Number in the third column indicates the equivalent number of chest x-rays
for that procedure.
b
Effective dose was calculated using the mean glandular dose found in the
Mammography Quality Standards Act (MQSA) inspection in 2006 in the
United States.54
c
Average effective dose, health care level I countries, United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) report 2000.13
d
Effective dose was calculated using entrance surface dose, nationwide survey (2001-2006, United Kingdom), and effective dose conversion factor.52,53
e
Average effective doses for axial and helical scans from a nationwide survey
between 2000 and 2001 in the United States.55
early recommendations to restrict the x-ray beam to anatomic sites under study, reduce the numbers of x-ray projections, incorporate standardized protocols, and improve
physician training.61 Notable variation in estimated effective doses persists as was reported in 1999 for fetal doses
from radiologic examinations62 and more recently for CT
scans in adults (Fig. 2).63
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Cancer Risks and Diagnostic Imaging
TABLE 5. Radiation Dose to Children by Age at Diagnostic Examination
RADIATION DOSE TO CHILDREN (BY AGE AT EXPOSURE)
TYPE OF EXAMINATION
DOSE QUANTITY
a
0 YEARS
1 YEAR
5 YEARS
10 YEARS
15 YEARS
ADULTS
b
Radiography
Skull AP
ED (mSv)
-
0.037
0.058
-
-
0.084
Skull LAT
ED (mSv)
-
0.025
0.031
-
-
0.041
Chest PA
ED (mSv)
0.023
0.024
0.037
0.025
0.026
0.051
Abdomen AP
ED (mSv)
0.077
0.197
0.355
0.509
0.897
2.295
Pelvis AP
ED (mSv)
0.085
0.121
0.230
0.309
0.556
1.783
Dental radiographyc
Intraoral
Panoramic
ED (mSv)
0.008d
0.011
ED (mSv)
d
0.015
0.015
Diagnostic fluoroscopy procedures
MCUc
ED (mSv)
0.807
0.763
0.688
0.640
0.677
2.789
Barium swallowc
ED (mSv)
0.645
0.589
0.303
0.760
0.581
1.632
ED (mSv)
2.209
2.226
1.427
2.137
2.386
5.158
c
Barium meal
e
ED (mSv)
3.88
e
Cardiac-PDA occlusion
ED (mSv)
3.21d
Cardiac-VSD occlusione
ED (mSv)
Cardiac-ASD occlusion
d
12.1d
CTf
Brain
ED (mSv)
2.3
2.2
1.9
2.0
2.2
1.9
Facial bone/sinuses
ED (mSv)
1.4
0.5
0.5
0.5
0.6
0.9
Chest
ED (mSv)
1.9
2.2
2.5
3.0
3.3
5.9
Entire abdomen
ED (mSv)
3.6
4.8
5.4
5.8
6.7
10.4
Spine
ED (mSv)
4.4
11.4
8
7.6
6.9
10.1
AP, anteroposterior; ED, effective dose; mSv, millisieverts; LAT, lateral; PA, posteroanterior; MCU, micturating cystourethrography; ASD, atrial septal defect;
PDA, patent ductus arteriosus; VSD, ventricular septal defect; CT, computed tomography.
a
Dosimetric quantities are all shown as the ED.
b
Source: Hart D, Hillier MC. Dose to Patients From Medical X-Ray Examinations in the UK-2000 Review. Chilton, UK: National Radiological Protection Board; 200752;
and Hart D, Hillier MC. Dose to Patients From Medical X-Ray Examinations in the UK-2002 Review. Chilton, UK: National Radiological Protection Board; 2002.56
Source: Hart D, Hillier MC. Dose to Patients From Medical X-Ray Examinations in the UK-2000 Review. Chilton, UK: National Radiological Protection Board; 2007.52
c
d
Age is not specified.
e
Source: Onnasch DG, Schroder FK, Fischer G, Kramer HH. Diagnostic reference levels and effective dose in paediatric cardiac catheterization. Br J Radiol.
2007;80:177-185.57 The mean age of patients is 2.5 years.
f
Source: Galanski M, Nagel HD, Stamm G. Paediatric CT Exposure Practice in the Federal Republic of Germany–Results of a Nation-Wide Survey in 2005/
2006. Hannover, Germany: Hannover Medical School; 2006.58 Radiation doses to adults are based on a German nationwide survey on multislice CT.59 The
radiation dose in each age group category is the dose administered to pediatric patients who are newborn (the 0-y category), those ages >0-1 (the 1-y category), those ages 2 to 5 y (the 5-y category), those ages 6 to 10 y (the 10-y category), and those ages 11 to 15 y (the 15-y category).
Epidemiologic Studies of Cancer
Risks Associated With Diagnostic
Radiologic Procedures
The key studies examining the association between various
diagnostic radiological procedures and subsequent cancer
risk are reviewed below according to age at radiation exposure.
Methodologic issues related to the quality and importance of
the studies include the source of information about the radiologic procedures (self-reported vs those collected from medical
records), the study design (case-control vs cohort studies), the
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CA: A Cancer Journal for Clinicians
method for estimating doses (dose reconstruction for individual patients vs other approach), the timing of exposure in relation to the cancer, and adequacy of the sample size.
In Utero X-Rays and Pediatric Cancer Risks
Case-Control Studies
During the late 1940s through the 1960s, obstetricians frequently evaluated pregnancy-related medical problems with
whole-fetal imaging using abdominal radiographs and
gauged the likelihood of successful vaginal delivery with
CA CANCER J CLIN 2012;62:75-100
FIGURE 2. Variation in Estimated Effective Radiation Dose in Millisieverts (mSv) Associated With 11 Common Types of Diagnostic Computed Tomography Studies
Performed on 1119 Adult Patients in 4 San Francisco Bay Area Hospitals. Shown are the median values, interquartile ranges, and minimum and maximum values.
Reprinted with permission from Smith-Bindman R, Lipson J, Marcus R, et al. Radiation dose associated with common computed tomography examinations and the
C 2009 American Medical Association. All rights reserved.
associated lifetime attributable risk of cancer. Arch Intern Med. 2009;169:2078-2086.63 V
radiographic imaging of the maternal pelvis and fetal structures within the pelvis (pelvimetry). More than 50 years
ago, Stewart et al, in the large Oxford Survey of Childhood
Cancers (OSCC) case-control study,15 described a 2-fold
statistically significantly higher risk of total pediatric cancer
mortality in the offspring of women who underwent diagnostic x-ray procedures compared with risk in the offspring
of women who did not undergo radiographic procedures
during pregnancy. Radiation doses to maternal and fetal
gonads from pelvimetry based on nationwide UK surveys
in the 1950s ranged from 1.4 mGy to 22 mGy per
exposure, depending upon the projection and number of
exposures.61 There was also notable variation within and
among countries19 and over time64,65 in the proportion of
pregnant women undergoing pelvimetry or abdominal
x-rays. Although the interview-based 2-fold increase in risk
reported by Stewart et al15 was initially received with skepticism, more notice was taken when the significant risk
excess (RR, 1.39; 95% CI, 1.31-1.47) persisted after the
accrual of more than 15,000 pediatric cancer cases in the
OSCC between 1953 and 1981,66,67 maternal self-reports
correlated well with radiologic reports,67 and a similar
1.4-fold significantly increased risk of total pediatric cancer
based on medical records was reported in the offspring of
mothers undergoing prenatal radiographic examinations in
the northeast United States.17 Subsequently, other studies
from the United Kingdom, the United States, Finland, and
Sweden19,68 replicated the findings.
A 2008 meta-analysis of 32 case-control studies of pediatric
leukemia (excluding the hypothesis-generating OSCC
study)18 revealed a similar (RR, 1.32; 95% CI, 1.19-1.46),
albeit slightly lower, risk based on the 4052 pediatric leukemia
cases in the OSCC (RR, 1.49; 95% CI, 1.33-1.67).66 The risk
of pediatric leukemia from fetal diagnostic x-ray exposure in
case-control studies of twins69-71 was comparable to the risks
observed in singletons. In the OSCC, the estimated RR for
all solid tumors (1.47; 95% CI, 1.34-1.62) was similar to the
risk of leukemia (RR, 1.49; 95% CI, 1.33-1.67). A few early
studies reported modest 20% to 30% increased risks of pediatric central nervous system tumors in the offspring of mothers
undergoing diagnostic radiologic procedures with abdominal
radiation,17,66,72 but more recent studies generally found no
increase in risk.73,74 A limited number of case-control studies
with small numbers of cases have assessed the risks of other
pediatric tumors associated with in utero diagnostic x-rays.19
OSCC data showed a dramatically declining risk of total
pediatric cancer associated with fetal radiation exposure
over time, from a 5.4-fold excess among offspring born
between 1946 and 1947 to a 1.3-fold increase among children born between 1962 and 1963.64 Compared with the
1.5-fold to 2.2-fold increased risk of pediatric acute lymphoblastic leukemia in the offspring of mothers undergoing
abdominal or pelvic diagnostic x-ray procedures reported in
earlier studies,66,75,76 risks were substantially lower or not
increased in more recent studies,65,77-79 possibly due to
decreases in estimated radiation dose levels.
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Cancer Risks and Diagnostic Imaging
Cohort Studies
Cohort studies of pediatric cancer risks associated with in
utero diagnostic x-rays have included a few hundred to
39,166 exposed children, but the findings were based on
13 or fewer total pediatric cancer cases and 9 or fewer pediatric leukemia cases in each cohort. Summary RR were initially reported by Doll and Wakeford68 (RR, 1.2; 95% CI,
0.7-2.0) and subsequently by the International Commission
on Radiological Protection (ICRP) 2003 report80 for a
larger number of studies (RR, 1.08; 95% CI, 0.78-1.50).
The estimated RRs for the combined cohort studies were
not significantly increased, although the confidence intervals were compatible with both the 40% increase from the
case-control studies and with a decreased risk due to limited power and substantial uncertainty.68,80 A recent record
linkage study from Ontario that reported a nonsignificantly
reduced risk of total pediatric cancer (based on 4 childhood
cancer cases) in the offspring of 5590 mothers exposed to
major radiologic procedures in pregnancy compared with
cancer occurrence in the offspring of 1.83 million nonexposed mothers also had wide 95% CIs.81
Because the association between in utero diagnostic
x-ray exposure and pediatric cancer risk could be confounded by maternal or fetal medical conditions prompting
diagnostic x-ray examinations, epidemiologic studies of
twins were recommended to clarify whether confounding
could explain the association since a high proportion of
twins underwent pelvimetry in early years to determine fetal
positioning rather than for medical conditions.82 Cancer
risks have been investigated in twin cohorts ranging in size
from 13,000 to more than 125,000, with total pediatric
cancer cases ranging from 14 to 166 and pediatric leukemia
cases ranging from 3 to 55.83-89 RRs ranged from 0.70 to
0.96 for total cancer and from 0.7 to 1.14 for leukemia.
Cancer risks in twins have not changed over time as
pelvimetry has been replaced with ultrasonography,85 but
lower pediatric leukemia risks in twins compared with singletons may reflect biologic or clinical characteristics of
twins such as low birth weight, intrauterine growth restriction, 5-fold higher mortality in the first year of life, or
genetic factors, which may outweigh potentially carcinogenic risks associated with in utero radiation exposure.87,90
Confounding and Uncertainties
To address concerns that the observed associations between
fetal diagnostic x-ray exposure and elevated pediatric cancer
risk in offspring might be confounded by medical indications
for the x-rays, additional analyses were undertaken that demonstrated that the associations were still apparent when the
reasons for the diagnostic radiologic examinations were considered.67 In the medical record-based northeast US study, the
associations were specific for childhood cancer and not other
causes of death in children, and there was no evidence of
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CA: A Cancer Journal for Clinicians
confounding by many other factors.17 The studies of diagnostic x-rays in utero and the risk of pediatric leukemia and other
cancers are characterized by several uncertainties, the most
important being a lack of dose measurement data.18,68
Summary of Findings From Studies of In Utero
X-Rays and Cancer Risks in Offspring
In utero diagnostic x-rays in earlier decades have been consistently linked with a small excess of pediatric leukemia in
offspring. There continues to be debate about whether a
radiation dose estimated to be approximately 10 mGy could
give rise to cancer.91 Doll and Wakeford had previously
estimated that the lifetime excess risk of cancer for those
exposed in utero was 6%,68 which is 2-fold to 3-fold higher
than the ICRP lifetime excess risk estimate for exposure in
childhood,80 but data from the recent follow-up of the
atomic bomb survivors comparing ERRs and EARs of
those children exposed in utero and those exposed in early
childhood do not support a projection of a higher lifetime
risk for the former compared with the latter.47 Additional
follow-up is needed to quantify lifetime risks in the atomic
bomb survivors exposed early in life. Although ultrasound
replaced abdominal x-rays and pelvimetry several decades
ago, there recently have been reports of increasing levels of
radiologic imaging in pregnant women in the United
States. Investigators leading a large survey at one institution
reported that CT increased by 25% per year and nuclear
medicine by 12% per year during 1997 through 2006.92
Understanding the cancer risks from in utero exposures,
therefore, remains important.
Childhood and Adolescent X-Rays and Pediatric
and Lifetime Cancer Risks
Early Postnatal X-Rays and Pediatric Cancer Risks
The OSCC found no association between early life diagnostic exposure and risks of total pediatric cancer as
reported in interviews of mothers.16 Postnatal diagnostic
x-rays of children born between 1980 and 1983 in the
United Kingdom were associated with a nonsignificant
2-fold increase (95% CI, 0.32-12.51) of childhood cancer
risk based on interview data, but this association was largely
attenuated (RR, 1.11; 95% CI, 0.32-3.63) when risks were
recalculated for maternal reports of radiologic examinations
that were confirmed in medical records.93 More recently, a
nonsignificant modest increase in the risk of all pediatric
cancer (RR, 1.19; 95% CI, 0.82-1.74) was found in 2690
UK childhood cancer patients born between 1976 and 1996
based on evaluation of medical records.79 There was a slight
excess of cancer in 4891 Canadian children with congenital
heart disease who underwent cardiac catheterization during
1946 through 1968, and additional follow-up of a subset
revealed a nonsignificant 60% excess of leukemia (90% CI,
0.43-4.14 based on 3 cases among 5 total pediatric
CA CANCER J CLIN 2012;62:75-100
cancer cases).94 Among 675 Israeli children who underwent
cardiac catheterization for congenital anomalies during
1950 through 1970, there was a significant cancer excess
(observed vs expected, 2.3; 95% CI, 1.2-4.1) due to
increased risks of lymphomas and melanomas, based on
very small numbers of these malignancies.95
While 2 interview-based studies of early postnatal diagnostic x-rays found a significantly elevated risk of leukemia96,97 and a third observed a significant excess of acute
lymphoblastic leukemia (but not acute myeloid leukemia)98
with exposure to diagnostic radiation, other investigations,
including studies based on medical record assessment, have
not found significant increases.17,79 Few studies have
investigated whether early postnatal exposure to diagnostic
x-rays was linked with an increased risk of specific subtypes
of pediatric acute lymphocytic leukemia, but Shu et al65
found that the risk was significantly elevated for pre-B-cell
acute lymphoblastic leukemia, and Bartley et al98 reported
that the risk was significantly increased for B-cell acute
lymphocytic leukemia. Postnatal radiation exposure from
diagnostic radiographs has generally not been linked to an
increased risk of childhood brain tumors.19,99 There have
been relatively few studies of pediatric cancers following
postnatal radiation other than leukemia and brain tumors
and most have had small numbers of exposed cases, including 2 studies that found an increased risk of lymphoma.79,100
Childhood or Adolescent Diagnostic Radiologic and
Other Radiation Exposures and Lifetime Cancer Risks
Epidemiologic studies of atomic bomb survivors exposed as
young children47 and children treated with radiotherapy for
benign conditions22 or cancer101 found that children exposed
at young ages to ionizing radiation were at an increased risk
of developing radiation-related cancer later in life. Other evidence also indicates that exposure to diagnostic radiation in
childhood or adolescence may have implications for lifetime
cancer risk. Repeated diagnostic radiology examinations in
adolescents and young women monitored for scoliosis102 and
for tuberculosis20 have been associated with increased breast
cancer risks later in life. The ERR per Gy for breast cancer
incidence was 2.86 (P ¼ .058) in those monitored for scoliosis (mean dose to the breast was 120 mGy), and risks
remained elevated for at least 5 decades following exposure.
Risks of lung cancer and leukemia, however, were not elevated in either of these 2 groups of patients.103,104
Summary of Findings From Studies of Postnatal
X-Rays and Cancer Risks
Overall, studies of pediatric cancer risks in children undergoing radiographic examinations have produced ambivalent
results,18,19,105 perhaps due in part to methodologic limitations or differences (eg, insufficient age matching, recall
bias, incorporation of varying latency periods, differing
types of radiologic examinations evaluated, and reductions
in radiation doses over time for standard radiologic procedures). In addition, if diagnostic radiation exposures are truly
associated with very small risk increases, many epidemiologic
studies may be too small to detect these increases. Few epidemiologic studies of diagnostic radiation exposures in young
children have followed the population for sufficiently long
periods to assess risks in adulthood.20,47,102 There are major
initiatives currently underway around the world, however, to
assess the cancer risks from CT scans received in childhood.
These studies address many of the limitations described above.106
Adult X-Rays and Cancer Risks
Repeated Fluoroscopic Imaging Procedures
and Cancer Risks
There have been several large retrospective cohort studies
of patients with tuberculosis who were monitored frequently using fluoroscopy.20,21 There was a wide range in
the number of examinations. The mean dose to the most
highly exposed organs (the breast and the lung) was close
to 1 Gy. Significant dose-response relationships were found
for breast cancer (RR, 1.29; 95% CI, 1.1-1.5), but there
was no evidence of an increased risk of lung cancer. There
have been no other epidemiologic studies assessing cancer
risks in patients undergoing repeated fluoroscopic imaging
procedures. Epidemiologic studies of adults undergoing nonfluoroscopic imaging procedures have provided more limited
information due to the limited size of such studies, the lower
sensitivity of adults to the carcinogenic effects of ionizing
radiation compared with children, the lack of individual
patient dosimetry, and the potential for recall bias. Findings
from larger studies characterized by stronger methodology
and efforts to minimize biases are summarized below.
Adult Diagnostic X-Rays and Leukemia Risks
In a large case-control study conducted in a health maintenance organization in which over 25,000 x-ray procedures
were abstracted from medical records and each x-ray procedure was assigned a score based on estimated bone marrow
dose, there were small, nonsignificant elevations in risk of
leukemias other than chronic lymphocytic leukemia using
different lag periods (3-month lag: RR, 1.17 [95% CI,
0.8-1.8]; 2-year lag: RR, 1.42 [95% CI, 0.9-2.2]; and 5-year
lag: RR, 1.04 [95% CI, 0.6-1.8]), but no evidence of
dose-response relationships.109 Preston-Martin and Pogoda
found that risks rose with increasing estimated doses to bone
marrow to a 2.4-fold excess risk associated with an estimated
dose of 20 mGy in the 3 to 20 years prior to diagnosis in a
medical record-based case-control study of adult-onset acute
myeloid leukemia in Los Angeles that utilized a unique database of estimated doses and dose ranges based on review of
the dosimetry literature and consultation with radiology
experts.107 Radiographic procedures of the gastrointestinal
tract and multiple spinal x-rays were linked with an increased
risk of chronic myeloid leukemia in a case-control study in
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Cancer Risks and Diagnostic Imaging
Los Angeles.108 Three of 4 earlier studies of chronic myeloid
leukemia and diagnostic radiographic procedures (2 of which
examined medical records) found evidence of small risks and
one found a dose-response relationship with an increasing
number of x-ray films in the 20 years prior to diagnosis.108
Adult Diagnostic X-Rays and Cancers Other
Than Leukemia
From the large case-control study by Boice et al, small, nonsignificant increases were apparent for multiple myeloma for
all lag periods, and dose-response trends approached statistical
significance due to high RRs of patients in the highest exposure score category. There was no significant dose-response
relationship for non-Hodgkin lymphoma.109 In Sweden,
the cumulative number of x-ray examinations (derived from
medical record review) was not linked with thyroid cancer
risk.110 Meningiomas111,112 and parotid tumors in adults in
Los Angeles113 were associated with full-mouth and substantial numbers of dental x-rays prior to age 20 years or before
1945. Comparison of interview data with dental records
showed similar levels of agreement for cases and controls, suggesting that the findings were not due to recall bias.114
Summary of Findings From Studies of Adult
X-Rays and Cancer Risks
Overall, the most compelling results are the significant dose
response associations with breast cancer, but not lung cancer, in the cohort studies of patients undergoing repeated
fluoroscopic imaging examinations for tuberculosis. Inconsistent findings, limited numbers of epidemiologic studies,
and relatively small numbers of substantially exposed leukemia cases other than chronic lymphocytic leukemia make it
difficult to draw clear conclusions about diagnostic radiography and the risk of leukemia other than chronic lymphocytic leukemia. Limited data suggest a possible risk of chronic
myeloid leukemia. There are too few studies examining risks
of non-Hodgkin lymphoma, multiple myeloma, thyroid cancer, parotid tumors, or meningiomas to draw conclusions.
Recently, a statistical association was reported between chromosome translocation frequencies in cultures of peripheral
blood lymphocytes and increasing radiation dose score based
on numbers and types of diagnostic x-ray examinations in a
cohort of US radiologic technologists.115,116 Mechanistic
approaches in conjunction with epidemiologic and genetic
studies in selected populations may provide insights about the
role of low-dose radiation procedures and genetic susceptibility in breast, thyroid, and other radiogenic cancer risks.
Animal Studies
Results of Key Studies
Excess risks of liver, pituitary, and ovarian cancers have
been reported in the offspring of pregnant mice who were
irradiated with a single whole-body dose of 0.3 to 2.7 Gy
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CA: A Cancer Journal for Clinicians
in utero on days 16 to 18 postcoitus.117-119 In contrast, the
offspring of mice irradiated with 1.0 Gy on each day of
gestation experienced no significant increase in their
incidence of tumors as adults.120 The offspring of
1343 pregnant Beagle dogs irradiated with a single dose
of 0.16 or 0.81 Gy on days 8, 28, or 55 after breeding and
2, 70, and 365 days postpartum (120 dogs in each dose
and treatment day group) had a significant increase in
their incidence of benign and malignant neoplasms,
including fatal malignancies at young ages and during
their lifetime.121 Statistically significant increases in the
risk of lymphoma were seen in the beagles irradiated at
55 days postcoitus and significant increases of hemangiosarcomas occurred at 8 and 55 days postcoitus, respectively, but a significantly increasing trend with increasing
dose was seen only for hemangiosarcoma among dogs
irradiated on day 8 postcoitus.121
Studies examining the effects of radiation exposure of
0.5 to 3 Gy in mice during gestation have demonstrated
various effects consistent with radiation-related genomic
instability in fetal murine hematopoietic cells that are transferred though cell migration to postnatal bone marrow and
seen subsequently as chromosomal abnormalities in adult
bone marrow, but to date studies have not shown the
induction of leukemia from prenatal irradiation.122 Efforts
to track explicit chromosomal aberrations from fetus to
adult revealed that cells with these aberrations are eliminated during the early postnatal stage.123 Nakano et al124
showed that mean translocation frequencies in peripheral
blood T cells, spleen cells, and bone marrow cells evaluated
in mice at 20 weeks of age were very low when the mice
had been exposed to 1 or 2 Gy of x-rays during the fetal
or early postnatal stages, but translocation frequencies
increased with increasing age at irradiation and then plateaued for mice irradiated at 6 weeks of age or older. These
findings in mice were consistent with the absence of a radiation dose-related increase in the frequency of chromosome
translocations in atomic bomb survivors exposed in utero
(and studied at age 40 years), although the mothers of these
offspring were found to have a radiation dose-associated
increase in chromosomal translocations.125
Summary of Animal Studies and Future Directions
for Experimental Studies
Studies of laboratory animals have demonstrated the shape
of radiation-associated dose-response curves for cancer over a
broad range of doses; carcinogenic effects of acute, single-dose
versus fractionated or protracted doses; the radiation-related
dose response for cancer according to age at exposure, sex,
organ irradiated, genetic background, physiological condition, and environment of the animals; and cellular and
molecular mechanisms of carcinogenesis.39 Unfortunately, few
studies have exposed animals to radiation levels in the range
CA CANCER J CLIN 2012;62:75-100
of diagnostic radiologic procedures (less than 0.10 Gy).
In more recent years, investigators have developed experimental models to study the effects of radiation, cellular
interactions, and mechanisms at the cancer progenitor cell
level for studies of carcinogenic initiation. From these studies, accumulating data suggest that processes other than the
induction of specific locus mutations may be important.
Such processes may include increased transcription of specific genes, altered DNA methylation, delayed genomic
instability (eg, radiation-induced chromosomal alterations,
changes in ploidy, or mini- and microsatellite instabilities
or other changes occurring at delayed times after irradiation
and manifest in the progeny of exposed cells), and
bystander effects (eg, nontargeted cellular effects usually
associated with direct exposure to ionizing radiation but
occurring in nonirradiated cells).39
Risk Projection Studies
Rationale and Approach to Risk Projection
As described above, because the risks to individuals from
diagnostic radiation exposures are generally small, it is
often difficult to study them directly. However, because
of the large number of people exposed annually, even
small risks could translate into a considerable number of
future cancers. Risk projection models, which utilize the
wealth of existing information on the long-term cancer
risks after radiation exposure, can provide a more timely
assessment of the magnitude of the potential risks.
A number of expert committees have developed methodologies to estimate the future cancer risks from low-dose
radiation exposures. The National Academy of Science
BEIR VII committee was the most recent to develop
models for the US population,38 and the United Nations
Scientific Committee on the Effects of Atomic Radiation13 has also published models for a number of different populations. These reports were used in most of the
examples described below.
Based on the frequency of x-ray use in the United States
in the early 1990s, Berrington de Gonzalez and Darby126
estimated that about 1% of cancers in the United States
might be related to diagnostic x-rays and CT scans. At that
time, only very basic US survey data were available. Using
newly available detailed estimates of the frequency of diagnostic medical radiation exposures in the United States25
and state-of-the-art risk projection models for cancer risks
associated with low-dose radiation exposure to the US population,38 they recently published updated risk projections
for current levels of diagnostic radiation exposures in the
United States.127,128 The projected levels of risk and confidence limits assume a linear dose-response relationship for
solid tumors, although there is uncertainty about the magnitude of the risk at low doses.41
Diagnostic Radiologic Procedures
These recent estimates suggest that the 70 million CT
scans performed in the United States in 2007 could result
in approximately 29,000 future cancers (95% uncertainty
limits, 15,000-45,000).128 One-third of the projected cancers were from scans performed at ages 35 to 54 years, compared with 15% from scans performed before age 18 years;
abdomen/pelvis scans in adults contributed almost one-half
of the total risk. If CT scan use remains at the current level,
these results suggest that eventually about 2% (95% uncertainty limits, 1%-3%) of the 1.4 million cancers diagnosed
annually in the United States129 could be related to CT
scans.128 The most common projected cancers in decreasing
order were lung cancer, colon cancer, and leukemias.
Screening Procedures
Risk projection models have been used in a number of studies to estimate the potential radiation risks from repeated
screening. The results of those studies (eg, screening frequencies and age ranges) are shown in Table 6.130-134 The risks
range from about 40 radiation-related cancers per 100,000
screened for annual coronary artery calcification from ages
45 to 70 years131 to 1900 cancers per 100,000 for annual
whole-body CT screening from ages 45 to 70 years.133
The decision to expose large numbers of asymptomatic
individuals to radiation from screening tests such as CT
colonography needs careful assessment since most of the
persons screened will not develop the disease of interest. In
general, the benefits, where established, should outweigh
all risks, including the radiation risks from the radiologic
screening test. For example, the mortality reduction from
regular mammographic screening in women aged 50 years
or older is much greater than the estimated risk of radiation-related breast cancer.134 This may not be the case,
however, for some screening tests or for screening at ages
younger than the recommended ages because the radiation
risks are higher but the absolute benefits from screening are
typically lower.135 Whole-body CT screening is not currently recommended as a screening tool as no clear benefit
has been established.
Genetic Susceptibility and Radiation-Related
Cancer Risks
Patients With Chromosome Instability
Evidence for an association between radiation and cancer in
genetically susceptible populations with radiation sensitivity
comes primarily from studies of individuals with chromosome instability disorders, such as ataxia telangiectasia
(AT) and Nijmegen breakage syndrome (NBS).136-138
These rare, autosomal, recessive diseases predispose to
malignancies (leukemia and lymphoma for AT and B-cell
lymphoma prior to age 15 years for NBS) and in vitro
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TABLE 6. Estimated Risks of Radiation-Related Cancers From Repeated Screening
STUDY
SCREENING TEST
FREQUENCY
AGE, YEARS
RADIATION-RELATED CANCERS
(PER 100,000 SCREENED)
Brenner 2004130
Lung CT (smokers)
Annual
50-70
230 (males)
Kim 2009131
Coronary artery calcification CT
Annual
45-70 (males)
40 (males)
55-70 (females)
60 (females)
850 (females)
132
Berrington de Gonzalez 2011
CT colonography
Every 5 y
50-70
150
133
Whole-body CT
Annual
45-70
1900
134
Mammography
Annual at age < 55 y
45-74
90 (females)
Brenner & Elliston, 2004
Yaffe & Mainprize, 2011
Biannual at age 55 y
CT indicates computed tomography.
studies indicate that individuals with these disorders are
unusually sensitive to ionizing radiation.139,140 Clinical sensitivity to radiation has been observed following radiotherapy in these individuals,141 but it is not known whether
they are unusually sensitive to the lower radiation doses
typically received from diagnostic exposures. Defects in
DNA repair genes may predispose individuals to radiogenic
cancer or lower the threshold for the development of deterministic effects.34,142 Patients with serious and unanticipated
radiation injuries may be among the 1% of the population
that is heterozygous for the AT mutated (ATM) gene, an
autosomal recessive gene responsible for AT, or may harbor
some other ATM abnormality.34,142 Other clinical disorders
with a genetic component affecting DNA breakage or repair
also increase radiation sensitivity, including Fanconi anemia,
Bloom syndrome, and xeroderma pigmentosum34,142,143
Patients with familial polyposis, Gardner syndrome, hereditary malignant melanoma, and dysplastic nevus syndrome
may also be characterized by increased radiation sensitivity.142
cancers were observed in a cohort of 200 LFS family members, especially children, possibly related to radiotherapy.147
Children with NBCCS are very sensitive to radiation and
develop multiple basal cell cancers in irradiated areas.148 Due
to improved survival, patients with these syndromes are at
risk of second and third cancers, and they generally undergo
periodic imaging to detect new tumors. Although the association between diagnostic radiation and cancer risk has not
been evaluated in these populations, magnetic resonance
imaging (MRI) scans have been recommended in place of
imaging studies that produce ionizing radiation exposures to
follow up symptoms, evaluate abnormal physical findings, or
monitor the effects of cancer treatment, particularly in Rb
survivors149 and children with NBCCS, especially those who
have been diagnosed with medulloblastoma.150 In contrast,
[F-18]-fluorodeoxyglucose (18FDG )-PET scans have been
recommended for the detection of tumors in patients with
LFS151 and NF1.152
Low Penetrance Genetic Alleles, Radiation
Exposure, and Cancer Risk
Patients With Hereditary Syndromes
Increased cancer risks associated with radiotherapy have
been noted for individuals with hereditary cancer syndromes including retinoblastoma (Rb), neurofibromatosis
type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid
basal cell carcinoma syndrome (NBCCS).144 Genetic predisposition has a substantial impact on cancer risk in these
populations, which is further increased by radiotherapy. A
study of patients with hereditary Rb found a notably and
statistically significant radiation dose response for bone and
soft tissue sarcomas.145 Patients with NF1 who were irradiated for optic pathway gliomas are at increased risks of
developing other cancers including gliomas, soft tissue sarcomas, leukemia, and malignant peripheral nerve sheath
tumors.146 Elevated risks of developing second and third
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Despite much interest in the possibility that common
genetic variants confer an increased risk of radiationinduced cancer,142 there has been little empirical evidence
to date, particularly within the context of diagnostic radiation. One study of childhood leukemia reported a potential
modification of the relationship between diagnostic x-rays
and risk of leukemia by variants in the DNA mismatch
repair genes human mutS homolog 3 (hMSH3) (exon23
variant) and human MutL homolog 1 (hMLH1) (exon8
variant), but results from the study were sex-specific and
were not consistent between the first and second phases of
the study.96,153 A population-based study of breast cancer154 and a series of nested case-control studies in US
radiologic technologists have suggested that common
variants in genes involved in DNA damage repair,155,156
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apoptosis, and proliferation157 may alter the risk of
radiation-related breast cancer from diagnostic radiation
procedures, but these results need to be replicated.
Similarly, there is some indication that single nucleotide
polymorphisms in the O 6-methylguanine DNA methyltransferase (MGMT) and poly (ADP-ribose) polymerase 1
(PARP1) DNA repair genes could modify the relationship
between diagnostic radiation exposure and risk of
glioma,158 but this has not been reported in other studies.
Summary of Findings on Genetic Susceptibility
and Cancer Risk
A few rare genetic variants associated with human cancer
susceptibility syndromes appear to increase radiation susceptibility in individuals with chromosome instability disorders and certain hereditary cancer syndromes. Although
these syndromes affect only a small proportion of the general population, it is important to identify such individuals
and reduce their medical radiation exposure to the extent
possible. Genetic pathways including DNA damage repair,
radiation fibrogenesis, oxidative stress, and endothelial cell
damage have been implicated in cell, tissue, and gene studies of radiosensitivity,159 indicating that at least some part
of the genetic contribution defining radiation susceptibility
is likely to be polygenic, with elevated risk resulting from
the inheritance of several low-penetrance risk alleles (the
‘‘common-variant-common-disease’’ model). While common genetic variation underlying this susceptibility is
likely, identifying this variation is not straightforward. It is
essential that future studies addressing this question be
large in size and have sufficient power to adequately address
variation in demographic factors, and also include highquality radiation exposure information.
How Do Radiation Exposures From Imaging Procedures
Compare With Radiation Levels Associated
With Cancer Risks?
Radiation dose levels associated with significantly increased
cancer risks are shown in Table 7.18,20,42-44,46,66,102,160-162
These data are derived from epidemiologic studies assessing
low-dose radiation and cancer risks. Based on epidemiological data, an international, multidisciplinary group of radiation science experts concluded that the lowest dose of x- or
gamma radiation for which there is good evidence of
increased cancer risks in humans is approximately 10 to
50 mSv for an acute exposure and approximately 50 to
100 mSv for a protracted exposure, but they recognized
the uncertainties of these estimates and the difficulties of
increasing precision in estimating radiation dose response.91
Data from the most recent follow-up of solid cancer incidence in the atomic bomb survivors revealed a statistically
significant dose response in the range of 0 to 150 mGy, and
the pattern of the trend at low doses was consistent with the
trend for the full dose range.46 Although a linear extrapolation of cancer risks from intermediate to low radiation doses
appears to be the most reasonable hypothesis, it is acknowledged that there is uncertainty about the true relationship.41
From Table 4, the range of estimated effective doses from a
single CT scan is 2 to 15 mSv. Mettler et al have reported
that 30% of patients who undergo CT scans have at least 3
scans, 7% have at least 5 scans, and 4% have at least 9
scans.26 Patients who undergo multiple CT scans, as
described in studies assessing the use of CT among patients
with a wide range of medical disorders,163-166 may be
exposed to radiation doses associated with increased cancer
risks. A single CT examination may comprise multiple CT
scan sequences. Data from 2008 Medicare claims revealed
that some hospitals were performing 2-scan sequences for a
chest CT examination more than 80% of the time, even
though the national average is 5.4%. Overall, 2009 Medicare data showed little change from the 2008 data.167
Strategies For Reducing Radiation Exposure
From Diagnostic Imaging Procedures
Key Concepts
Justification
The referring medical practitioner is responsible for ensuring that a diagnostic procedure involving ionizing radiation
is necessary for a patient’s care and that the radiation dose
from the procedure is expected to do more good than harm,
a concept designated as justification by the ICRP.31
Optimization
The radiological medical practitioner (who is not always a
radiologist) is responsible for ensuring that the radiologic
procedure provides images adequate for diagnosis and treatment while keeping the radiation dose as low as reasonably
achievable (ALARA), a concept designated as optimization
by the ICRP.31 Optimization requires identifying imaging
parameters and using procedures and protocols to produce
the clinically required information while keeping radiation
doses as low as possible.
In addition, the imaging equipment must be properly set
up and maintained. To achieve optimization, radiological
medical practitioners and radiologic technologists, with
substantial input from manufacturers, must work closely
with medical physicists to ensure rigorous oversight of
radiation-producing imaging units. This includes accuracy
of settings, safeguards, calibration, and maintenance, as
highlighted in reports of excess radiation during CT brain
perfusion scans.168,169 In the United States, there are 2
more avenues for optimization of the CT unit. One is the
yearly state requirements for the evaluation of dose by a
physicist and by inspections. For CT, accreditation of technologists is rapidly becoming mandatory, while
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TABLE 7. Radiation Dose Levels Associated With Increased Cancer Risks in Epidemiologic Studies Assessing Low-Dose Radiation and
Cancer Risk
STUDY
46
Preston 2007
POPULATION SIZE
MEAN DOSE, mGy
CANCER OUTCOME
ERR/Gy (90% CI)
Atomic bomb survivors
30.8 weighted colon
All solid cancers, adult incidence
0.47 (0.40-0.54) for total
population
All ¼ 105,427
Cardis 200743
Statistically significant
dose response when
analyses limited to cohort
members with doses in
range of 0-150 mGy
15-country nuclear workers ¼ 407,391
20 weighted colon
All solid cancer, mortality
0.87 (0.03-1.9)
42
NRRW radiation workers ¼ 174,541
24.9 weighted colon
All solid cancers, mortality
0.275 (0.02-0.56)
160
Population radionuclide waste ¼ 29,873
30 stomach
All solid cancers, mortality
0.92 (0.2-1.7)
161
Krestinina 2007
Population radionuclide waste ¼ 17,433
40 stomach
All solid cancers, incidence
1.0 (0.3-1.9)
Preston 199444
Atomic bomb survivors
30.5 bone marrow
Non-CLL leukemia, mortality
(N ¼ 261)
1.4 (0.1-3.4)
Cardis 200743
15-country nuclear workers
15 mSv whole body
Non-CLL leukemia, mortality
(N ¼ 196)
1.93 (< 0-7.14)
Muirhead 200942
NRRW radiation workers ¼ 174,541
24.9 mSv whole body
Non-CLL leukemia, incidence
(N ¼ 177)
1.782 (0.17-4.36)
Krestinina 2005160
Population radionuclide waste ¼ 29,756
300 bone marrow
Non-CLL leukemia, incidence
(N ¼ 70)
4.9 (1.6-14.3)
Muirhead 2009
Krestinina 2005
Bithell & Stewart 197566 OSCC case-control study of diagnostic in
Approximately 10 bone All leukemias, mortality
utero radiation and risk of pediatric cancers marrow
(N ¼ 4052)
RR ¼ 1.49 (1.33-1.67)
Wakeford 200818
RR ¼ 1.32 (1.19-1.46)
Preston 200746
162
Ostroumova 2008
102
Ronckers 2008
Meta-analysis of epidemiologic studies of
diagnostic in utero radiation and pediatric
leukemias; 32 studies excluding OSCC
Unknown
All leukemias, mortality and
incidence
Atomic bomb survivors ¼ 105,427
30.8 breast
Breast cancer, incidence (N ¼ 527) 0.87 (0.55-1.3)
Population radionuclide waste ¼ 9908
40 stomach dose
Breast cancer, incidence (N ¼ 131) 13.5 (2.5-27.8)
Patients undergoing x-rays to
monitor scoliosis
121 breast
Breast cancer, incidence (N ¼ 78)
2.86 (0.07 to 8.62)
mGy indicates milligray; ERR, excess relative risk; Gy, gray; 95% CI, 95% confidence interval; NRRW, National Registry for Radiation Workers; non-CLL, leukemias other than chronic lymphocytic leukemia; mSv, millisieverts; OSCC, Oxford Survey of Childhood Cancers; RR, relative risk; TB, tuberculosis (patients
underwent repeated fluoroscopic examinations to monitor lung collapse treatment).
accreditation of the CT unit is now voluntary but will be
mandated for payment by Medicare in 2014.
Implementation of Justification and Optimization
Referring medical practitioners need guidance to determine
whether an imaging study is needed and, if an imaging study
is required, which type of imaging study will yield the necessary clinical information at the lowest achievable radiation
dose. Unfortunately, it has been well documented that many
physicians are often not conversant with the pros and cons of
various imaging modalities, with the types of imaging modalities producing ionizing radiation exposure, or with the levels
of radiation associated with specific imaging modalities.170172
Therefore, one of the most important roles of the radiological medical practitioner is to provide advice to the referring medical practitioner about the appropriate test for the
patient. The advice from the radiologic medical practitioner
can be provided in several ways. An efficient method would
be for the radiologic medical practitioner to screen requests
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for ‘‘high-dose’’ examinations such as CT and, if the appropriate indication is not given or if the patient has had the
same or similar radiologic procedures recently, to contact the
referring medical practitioner and discuss the case.
Reducing radiation exposure from diagnostic procedures
is a shared responsibility of the referring medical practitioner and the radiological medical practitioner.173 To
assist referring medical practitioners in decision-making
about imaging in the management of patients, the
American College of Radiology (ACR)174,175 and the
American College of Cardiology (ACC) in collaboration
with other professional societies176,177 in the United States
and the Royal College of Radiologists178 in the United
Kingdom have developed evidence- and/or consensus-based
guidelines. These guidelines, produced by a panel of experts,
generally take the form of identifying which modalities are
most appropriate. Below we summarize key elements of the
strategy to guide referring medical practitioners in selecting
the optimal imaging tests needed for clinical diagnosis and
CA CANCER J CLIN 2012;62:75-100
treatment while limiting associated radiation exposures to
levels as low as reasonably achievable. A few examples of the
relevant literature base are provided, but the scope of this
review precludes comprehensive assessment.
Evidence Justifying Selection of Imaging
Procedures: Data Are Limited
Justification: Evidence Basis
In general, only limited data provide strong evidence to
conclusively indicate who needs an imaging examination
involving ionizing radiation instead of an alternative that
does not expose the patient to ionizing radiation. Clearly, it
is inappropriate to utilize an imaging test in lieu of obtaining a detailed medical history and a carefully performed
physical examination (absent major trauma or a patient in
extremis). The concept of the benefit/risk ratio should
underlie justification decisions. If there is no difference in
the expected benefit, the least invasive imaging tests (or
those that do not require ionizing radiation) should be preferred over more invasive imaging tests (or those that do
expose patients to ionizing radiation). An effort should also
be made to avoid repeating the same examination for a
given constellation or bout of symptoms and to consider
the clinical urgency of the need for an imaging test
(eg, ordering a test that can be performed immediately [often
a CT]) versus another test, free of radiation-related risk, to
be undertaken when an appointment is available (eg, ultrasound) or scheduled within a few days (eg, MRI, which
does not involve ionizing radiation).
Because children and adolescents are at higher risk of
developing radiation-associated cancers than older persons,46 there has been substantial debate about the optimal
type of imaging tests for children and adolescents for certain indications (eg, CT scan vs ultrasound for suspected
appendicitis).179 The recognition that children are at higher
risk of developing cancer following exposure to radiation
than adults has led to increasing reliance on clinical history
and physical examination for children suspected of appendicitis and, only if necessary, the use of laboratory tests and
imaging to confirm the diagnosis.180-182
Examples of Important Aspects of Justification
Two examples illustrate important aspects of justification:
1) if higher dose imaging examinations are needed at all
(eg, certain pediatric head trauma patients) or 2) if 2 or
more higher dose imaging tests are needed at the same time
(eg, posttreatment response in pediatric cancer patients). A
third example, guidelines for breast cancer screening using
mammography, illustrates some complexities associated
with justification given knowledge gaps.
Head trauma is one of the most common reasons that a
CT scan is ordered. While there is little argument that
patients with a more severe head injury (eg, Glasgow coma
score less than 13) will experience a greater benefit from a
CT scan than any future radiation-related cancer risk, there
is a substantial debate concerning routine CT for a child
with a less severe injury (eg, Glasgow coma score greater
than 14). In a prospective cohort study of 42,412 children
presenting with Glasgow coma scale scores of 14 to 15,
trained investigators recorded patient history, injury mechanism, and symptoms and signs before imaging results were
known, and followed children to ascertain outcomes
(including death, neurosurgery, intubation for more than
24 hours, or hospital admission of 2 nights or more).183 CT
scans were obtained at the discretion of the emergency
department clinician (n ¼ 14,969 patients) and interpreted
onsite (780 patients had traumatic brain injuries on CT
scan). The investigators derived and validated age-specific
prediction rules for clinically important traumatic brain
injury. The prediction rules identified children at very low
risk for whom the investigators concluded that CT scans
were not required.183
Patients with pediatric cancer are frequently treated with
radiotherapy, depending upon the diagnosis and treatment
protocol implemented. Regardless of the specific treatments, patients with pediatric cancer also undergo extensive
imaging for diagnosis and clinical staging, treatment
response assessment, and follow-up monitoring after treatment has ended. This assessment entails significant cumulative radiation doses.184 Developing an evidence-based
approach to the diagnosis and ongoing monitoring of pediatric oncology patients is critical to limit cumulative radiation dose, but there is extensive debate.184 Although it is
clear that CT or PET/CT scans are valuable for diagnostic
purposes and during the early stages of treatment, it may
not be necessary to obtain diagnostic contrast-enhanced
CT at the same time as PET imaging.184 As noted earlier,
it is particularly important to consider alternative imaging
procedures for cancer patients who are at high risk of developing radiation-related second malignancies. The high
incidence of radiation-related second tumors in patients
with hereditary Rb has led pediatric ophthalmologists and
pediatric radiologists to propose guidelines that call for the
use of MRI rather than CT in such patients.149
Strong evidence from randomized trials has shown that
screening mammography from ages 40 to 69 years reduces
mortality from breast cancer.185 There are differing interpretations of the evidence and some differences among the
guidelines with regard to screening intervals and ages at
which to start and stop screening. Nevertheless, there is
good agreement about screening for women ages 50 to 74
years.186-188 Reasons for the differences are mostly due to
the absence of data from multiple large randomized trials to
address the following knowledge gaps: lack of accurate and
reproducible measures of the sensitivity of mammography
screening for the identification of breast cancer, particularly in
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those with dense breast tissue; and insufficient evidence about
the benefits versus harms of screening mammography in older
women (aged 75 years and older), annual versus biennial
screening, and overdiagnosis (eg, limited knowledge about
which ductal carcinomas in situ will go on to become invasive
and the rapidity of spread of invasive breast cancers). Given
these gaps, the screening guidelines that have been proposed
are based on expert consensus informed by critical assessment
of the literature186 or on statistical modeling.187,189 The estimated radiation dose associated with a single view in mammography is presently about 2 mGy.190 As indicated above,
the risk of radiation-induced breast cancer from routine
mammographic screening of women ages 50 to 74 years is
small compared with the expected mortality reduction from
screening in the general population,134,135 but the benefit
may not outweigh the risk of screening female BRCA mutation carriers younger than age 35 years.191
Optimization of Radiation Dose
Need for Protocols Tailored to Patient Characteristics
Once the decision has been made that a CT scan is appropriate, the radiological medical practitioner must tailor the
CT parameters (milliamperes, kilovoltage peak , automatic
exposure control, and others) and protocol (cover only the
anatomic region necessary) to the patient’s size and age.
There should be as few phases as possible (usually one) as
each run (without contrast, with contrast, delayed)
multiplies the dose. These considerations should be
applied to all patients, but young children, pregnant
women, and obese patients require further protocol
modifications to optimize dose.192 Technological improvements, including automatic tube current modulation
(which modifies the dose depending on the thickness of
the anatomic site to be examined) and noise reduction
filters,193-195 will reduce further the doses from CT while
continuing to improve images.
It is important to include the dose report on all CT and
other radiation-producing diagnostic procedures. As the
dose cannot be determined by the appearance of the
images, this is the only way to verify that the correct protocol was used. For CT, the current metric is the volumeweighted CT dose (CTDIvol). In the future, better metrics,
such as size-specific dose estimates CTDIvol as advocated
by the American Association of Physicists in Medicine,196
will hopefully become the norm.
Example of Successful Dose Reduction
A prospective, controlled, nonrandomized study enrolled
4995 sequential patients undergoing cardiac CT angiography
(CCTA) at 15 hospital imaging centers during a 2-month
control period, followed by an 8-month intervention period
using a best-practice CCTA scan model (including minimized
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scan range, heart rate reduction, electrocardiographic-gated
tube current modulation, and reduced tube voltage), and
then a 2-month follow-up period. Compared with the initial control period, patients’ estimated effective dose was
reduced from 21 mSv to 10 mSv, with the most notable
reduction in dose occurring at low-volume sites.197
Diagnostic Reference Levels
In 1990, the metric of normative values for patient radiation dose from a given procedure was introduced in the
United Kingdom and was subsequently recommended by
the ICRP.198 These normative measures, designated
‘‘diagnostic reference levels,’’ typically correspond to the
75th percentile of the distribution of measured dose values
for particular imaging procedures.199 Diagnostic reference
levels serve as benchmarks for comparing dose levels for
imaging tests at a given facility with the broad range of
dose levels from many other institutions. Such benchmarks
should be regularly evaluated and, if exceeded, addressed by
medical physicists and radiological medical practitioners, as
part of a facility’s quality assurance program in radiation
protection.200 These benchmarks should be periodically
reevaluated and reduced, as current practices will certainly
lower the 75th percentile dose.
Appropriateness Criteria and Evidence-Based
Radiology
History
The observation of striking regional (including small area)
variation in the use of medical procedures201 and debate
about overuse, underuse, and the ‘‘right’’ level of use202 led
to the concept of ‘‘appropriateness of medical procedures.’’
This concept was defined to mean that the expected health
benefits from procedures should exceed by a sufficiently
wide margin the expected negative consequences of performing the procedures.203 The RAND Corporation and
the University of California at Los Angeles operationalized
the concept of appropriateness of a specific medical procedure for specific indications by basing it on a quantitative
score provided by expert panels (drawn from multiple medical specialties and including physicians who did and those
who did not perform the procedure) that were guided by
formal literature review. Each specific procedure/indication
for use category was established for a homogeneous group
of patients meeting the criteria for appropriateness; there
could be many specific indications for a given procedure. A
rigorous, reproducible statistical technique was used to
obtain a consensus score on an ordinal scale. The approach
has demonstrated good reliability, validity, and predictive
power, and has confirmed the efficiency of the method for
estimating the appropriateness of a variety of specific procedures for medical care.204 Randomized trials comparing
general guidelines with specific appropriateness criteria in
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decisions about diagnostic testing have found that
appropriateness criteria were effective in achieving more
appropriate test ordering.205
Description of ACR Appropriateness Criteria
In 1993, the ACR developed the scientific-based ACR
Appropriateness Criteria to guide decisions about ordering
imaging procedures. These guidelines are comprehensive,
currently address more than 175 topics with over 850
variants, are produced through consensus of panels of recognized experts, are updated regularly, and incorporate
medical practice guidelines used by the Agency for Healthcare Research and Quality as designed by the Institute of
Medicine. The approach relies not only on evidence-based
assessment of the scientific evidence but also on expert consensus when data from scientific outcome and technology
assessment studies are insufficient.206
Limitations
The ACR Appropriateness Criteria have been criticized for
not utilizing the rigorous methodology of the evidencebased medicine approach for radiology.207 Although there is
support for the development of a systematic evidence-based
approach to evaluate each specific radiologic procedure/
indication, it is acknowledged that there is a lack of
even limited measures, such as sensitivity and specificity for
certain procedures, let alone more rigorous types of evaluation
such as randomized trials. These major limitations, in conjunction with the rapid adoption and use of new imaging
technologies, limit more comprehensive use of evidence-based
approaches.208,209 Similar limitations apply to the Appropriate
Use Criteria for Cardiac Computed Tomography developed
by the ACC and other collaborating organizations. Studies
have identified large proportions of clinical indications for
which matching clinical fields or variants cannot be identified
in the ACR or ACC Appropriateness Criteria.210,211 Another
major problem is the low utilization of the ACR and perhaps
the ACC appropriateness criteria, likely due to a lack of
awareness of these resources.212
Examples Illustrating Important Aspects of
Appropriateness Criteria
To evaluate a child with a first nonfebrile seizure (which
occurs in 1%-2% of children and is generally idiopathic),
unless a child is at high risk (eg, the presence of a predisposing condition), an emergent CT is not indicated and
well-appearing children who meet low-risk criteria can be
discharged if follow-up is assured.213 For low-risk children,
an evidence-based assessment demonstrates that MRI is a
sensitive neuroimaging modality that can detect neurodevelopmental lesions (eg, heterotopic gray matter, cortical dysplasia, and polymicrogyria, among others), some of which
may be difficult to detect on CT.214,215 Since many of the
causes of seizures are not seen as well or at all on CT,
the use of CT exposes children to risk without adequate
benefit. That is, CT in these children is not justified. Similarly, for a child with new onset of headaches, the Quality
Standards Subcommittee of the American Academy of
Neurology and the Practice Committee of the Child Neurology Society have concluded that routine neuroimaging is
not indicated for children with recurrent headaches and a
normal neurologic examination.216 Neuroimaging evaluation is justified in children with an abnormal neurologic examination or other physical findings or symptoms that may
suggest disease of the central nervous system. MRI in this
situation will provide more information without radiation
exposure compared with CT.
Studies Reporting Inappropriate Ordering
of CT Examinations
Evaluation of data from the National Hospital Ambulatory
Medical Care Survey (1998-2007) provides indirect evidence of inappropriate ordering of CT or MRI examinations in emergency department visits. These data revealed
that there was no change during the period in the prevalence of patients admitted to the hospital or intensive care
unit from emergency departments, whereas the prevalence
of CT or MRI use in the emergency departments increased
from 6% to 15%.217 Review of data to assess the use of
screening cervical CT examinations performed after trauma
revealed that close to 24% of the CT scans of patients that
were negative for an acute injury had no written documentation of any of the 5 criteria established by the National
Emergency X-Radiography Utilization Study to identify
patients with a low probability of cervical spine injury who
do not require cervical spine imaging.218 Retrospective
review of the medical records from 459 outpatient CT and
MRI examinations from primary care physicians in the
state of Washington using appropriateness criteria from a
radiology benefit management company similar to the
ACR Appropriateness Criteria revealed that 74% of the
imaging examinations were considered appropriate, while
26% were not considered appropriate (examples of the latter included brain CT for chronic headache, lumbar spine
MRI for acute back pain, knee or shoulder MRI in patients
with osteoarthritis, and CT for hematuria during a urinary
tract infection).219 The investigators followed up the results
of the examinations and found that 58% of the appropriate
studies but only 24% of the inappropriate studies had positive results and affected subsequent management.
Alternatives and Enhancements of the
Appropriateness Criteria
For some patients with chronic remitting and relapsing
disorders, such as Crohn disease, who may require
multiple imaging examinations, evaluation of appropriateness criteria may be less important than consideration of
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alternate imaging procedures that provide the data for clinical decision-making while reducing radiation-related
risks.220 Despite the ACR Appropriateness Criteria, the
continuing increase in imaging has led to consideration of
preauthorization programs based on Appropriateness Criteria. Utilization patterns of CT and MRI before and after
implementation of an Israeli managed care preauthorization
program, based on the ACR Appropriateness Criteria and
the UK Royal College of Radiology guidelines, demonstrated that annual performance rates of CT and MRI
decreased from 25.9 and 7 examinations, respectively, per
1000 in the year 2000 to 17.3 and 5.6 examinations, respectively, per 1000 in 2003, representing reductions of 33% for
CT and 9% for MRI.221 Decision support software that uses
the ACR Appropriateness Criteria has been built into a
computerized radiology examination ordering system, making it available at the time the imaging study is
requested.222,223 This method has been shown to be effective
in decreasing the rate of imaging utilization.223 It is also
essential for reports of all CT and other radiologic examinations to be incorporated into medical records immediately to
reduce the frequency of repetition of the same or similar
diagnostic radiologic procedures.
Other Strategies to Reduce Radiation Doses
From Diagnostic Examinations
Radiation Safety Alliances and Campaigns
by Professional Organizations
The Society for Pediatric Radiology sponsored the first
ALARA conference on CT dose reduction in 2001, bringing together physicists; radiation biologists; manufacturers;
and members of the US Food and Drug Administration
(FDA), the National Cancer Institute, and the National
Council on Radiation Protection and Measurements with
referring and radiologic practitioners. The Society has continued to sponsor biennial conferences focusing on various
topics to limit unnecessary procedures and decrease radiation doses from CT.224-227
A crucial offshoot of these efforts was the formation of
the Alliance for Radiation Safety in Pediatric Imaging in
2007. By 2008, this advocacy group was formalized with the
founding organizations including the Society for Pediatric
Radiology, the American Society of Radiologic Technologists, the ACR, and the American Association of Physicists
in Medicine. This coalition of professional health care
organizations joined with manufacturers of imaging equipment to work together for both appropriate imaging and for
reducing the radiation dose from imaging procedures. The
organization has continued to grow and now includes more
than 65 organizations committed to reducing radiation
dose.228,229 The Image Gently campaign is an initiative of
this organization (available at: www.imagegently.org).
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The Society for Pediatric Radiology has a program
to expose second- and third-year medical students to information about imaging and radiation-producing tests.
The Society is also working with the nationwide Children’s Oncology Group to devise dose-reducing protocols
for the diagnosis, treatment, and surveillance of patients
with pediatric cancers.
The ACR, the Radiological Society of North America,
the American Association of Physicists in Medicine, and
the American Society of Radiologic Technologists have
collaborated with the Image Gently campaign of the Alliance for Radiation Safety in Pediatric Imaging to create the
Image Wisely campaign, whose objectives are to apply the
same principles of appropriate and lower radiation doses to
diagnostic procedures undertaken in adults.
Summit of 60 Organizations to Discuss Causes
and Effects of Overutilization of Imaging
A 2009 summit cosponsored by the American Board of
Radiology Foundation, the National Institute of Biomedical Imaging and Bioengineering, and the American
Board of Radiology identified several contributors to
overutilization, including the payment system and
reimbursement of procedures on a procedure basis; little
control over the number of imaging devices available in
populations of patients; high reimbursement for imaging
procedures encouraging nonradiologists to add imaging
to services provided to patients; little legislative or
regulatory action to control inappropriate, financially
motivated self-referral practices that have led to higher
utilization230; defensive medicine practices (43% of 824
physicians completing a survey on defensive medicine
reported using imaging technology in clinically unnecessary circumstances231 and 28% of CT scans were ordered
primarily for defensive purposes in one state232); lack of
education of referring medical practitioners from medical
school through residency training, practice, and continuing medical education at meetings; failure to educate
referring medical practitioners when inappropriate tests
are ordered; failure of radiologists to review imaging
requests for appropriateness; failure to educate patients
who demand imaging tests about benefits and risks; and
inadvertent or deliberate duplication of imaging studies
(20% of all patients surveyed in 2007 had duplicate imaging examinations).233,234 Areas for improvement identified by summit participants included better education and
training of referring medical practitioners, a national collaborative effort to develop comprehensive evidence-based
appropriateness criteria for imaging, greater use of practice guidelines in requesting and conducting imaging
studies, decision support at the point of care, education of
patients and the public,235 accreditation of imaging facilities, management of self-referral and defensive medicine
CA CANCER J CLIN 2012;62:75-100
by the physician community acting in concert or by
legislative action to place restrictions on self-referral, and
payment reform.234
FDA Center for Devices and Radiological Health
Initiative to Reduce Unnecessary Radiation Exposure
From Medical Imaging
In February 2010 the FDA launched an Initiative to
Reduce Unnecessary Radiation Exposure. The overarching
goals are to promote the safe use of medical imaging devices, support informed clinical decision-making, and
increase patient awareness. To promote the safe use of
medical imaging devices, the FDA will establish requirements for manufacturers of CT and fluoroscopic devices to
incorporate additional safeguards into equipment design,
labeling, and user training; partner with the Centers for
Medicare and Medicaid Services to incorporate key quality assurance practices into accreditation and participation
criteria for imaging facilities and hospitals; and
recommend that the health care professional community,
in collaboration with the FDA, continue efforts to develop
diagnostic reference levels for CT, fluoroscopy, and nuclear
medicine procedures locally and also through a national
radiation dose registry. To support informed clinical
decision-making, the FDA will establish requirements for
manufacturers of CT and fluoroscopic devices to record
radiation dose information for use in patient medical records
or a radiation dose registry and will recommend that the
health care community continue to develop and adopt criteria for the appropriate use of CT, fluoroscopy, and nuclear
medicine procedures that use these techniques. To increase
patient awareness, the FDA will provide patients with tools
to track their personal medical imaging history.
Summary of Strategies for Reducing Radiation Exposure
from Diagnostic Imaging Procedures
Professionals and professional organizations that play a key
role in the appropriate utilization of medical imaging are
the referring medical practitioners who are responsible for
ensuring that a diagnostic procedure involving ionizing radiation is necessary for a patient’s care and should be expected
to do more good than harm (designated as justification) and
the radiological medical practitioners who, together with
qualified medical physicists and manufacturers of x-ray
equipment, provide images adequate for diagnosis and
treatment while keeping the radiation dose at levels as low
as reasonably achievable (designated as optimization). Only
limited data provide strong evidence about which categories
of patients should be evaluated with an imaging examination
involving ionizing radiation instead of an alternative.
Approaches for optimizing doses from imaging procedures
have undergone limited assessment. Diagnostic reference levels (corresponding to the 75th percentile of the distribution
of doses from all such examinations) provide normative
values and serve as benchmarks for comparing dose levels
and for investigating imaging practices if these levels are
exceeded. The history, methodology, and limitations of the
ACR Appropriateness Criteria program to guide decisions
about ordering imaging procedures are described. Growing
evidence provides documentation that a substantial proportion of imaging examinations are inappropriately ordered
and performed. Imaging examinations that do not require
ionizing radiation should be preferred, when appropriate,
for patients with chronic disorders who require repeated
imaging for diagnostic and treatment purposes. Strategies
that can reduce unnecessary imaging examinations include
preauthorization and the use of decision support software.
Finally, efforts to reduce radiation doses from diagnostic
procedures include those by radiation safety alliances of
radiologists, physicists, radiobiologists, clinicians, and
manufacturers; a summit of 60 organizations to discuss the
causes and effects of overutilization of imaging and to
identify areas for improvement; and the FDA Center for
Devices and Radiological Health Initiative to promote the
safe use of medical imaging devices, support informed
clinical decision-making, and increase patient awareness of
radiation exposures from medical imaging.
Recommendations for Clinicians
1. Become knowledgeable about the radiation doses for
the imaging studies.
2. Consider ultrasound and MRI when these are appropriate alternatives since these procedures do not subject
the patient to ionizing radiation.172,236
3. Do not order a higher radiation dose study if a lower
dose study (or an imaging study that does not use ionizing radiation) can provide the clinical information
needed.
4. All requests for imaging studies should be justified
(eg, when all benefits and risks are considered, the
study should be expected to do more good than harm).
5. Available aids for justification, such as the ACR’s Appropriateness Criteria and the ACC’s Appropriate Use
Criteria for Cardiac Computed Tomography, should be
utilized to provide guidance for choosing the most appropriate imaging examination.
6. Unnecessary imaging studies (duplicate studies and
those that are not medically necessary) should not be
performed.
7. In general, neither screening nor elective x-ray examinations should be performed on pregnant women.
8. Refer patients who require imaging studies to a facility
that strives to optimize radiation dose, so that imaging is
performed with the least amount of radiation necessary to
provide adequate image quality. n
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95
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