Cumulative Radiation Exposure and Cancer Risk Estimation in Children With Heart DiseaseCLINICAL PERSPECTIVE
Background—Children with heart disease are frequently exposed to imaging examinations that use ionizing radiation. Although radiation exposure is potentially carcinogenic, there are limited data on cumulative exposure and the associated cancer risk. We evaluated the cumulative effective dose of radiation from all radiation examinations to estimate the lifetime attributable risk of cancer in children with heart disease.
Methods and Results—Children ≤6 years of age who had previously undergone 1 of 7 primary surgical procedures for heart disease at a single institution between 2005 and 2010 were eligible for the study. Exposure to radiation-producing examinations was tabulated, and cumulative effective dose was calculated in millisieverts. These data were used to estimate lifetime attributable risk of cancer above baseline using the approach of the Committee on Biological Effects of Ionizing Radiation VII. The cohort included 337 children exposed to 13 932 radiation examinations. Conventional radiographs represented 92% of examinations, whereas cardiac catheterization and computed tomography accounted for 81% of cumulative exposure. Overall median cumulative effective dose was 2.7 mSv (range, 0.1–76.9 mSv), and the associated lifetime attributable risk of cancer was 0.07% (range, 0.001%–6.5%). Median lifetime attributable risk of cancer ranged widely depending on surgical complexity (0.006%–1.6% for the 7 surgical cohorts) and was twice as high in females per unit exposure (0.04% versus 0.02% per 1-mSv effective dose for females versus males, respectively; P<0.001).
Conclusions—Overall radiation exposures in children with heart disease are relatively low; however, select cohorts receive significant exposure. Cancer risk estimation highlights the need to limit radiation dose, particularly for high-exposure modalities.
Children with congenital and acquired heart disease typically undergo imaging procedures that may expose them to large amounts of ionizing radiation.1–5 Radiation exposure in childhood is of particular concern because children have immature developing organ and tissue structures. These factors, as well as the potentially longer lifespan of these children, may significantly increase lifetime cancer risk.6–8
Editorial see p 135
Clinical Perspective on p 167
Previous studies of radiation exposure in children have largely focused on single exposure from various imaging modalities, including computed tomography (CT), fluoroscopy, nuclear medicine, and radiographs.9–15 Investigators have emphasized that the radiation risk from a single imaging modality can be high3,7,8,10,13,15; however, children with complex heart diseases are often exposed to repetitive imaging.16 According to current guidelines from the International Committee on Radiation Protection, stochastic exposure risks (ie, cancer) increase in a linear, dose-response fashion, and therefore, repetitive exposures are believed to incrementally increase risk.17 What is currently unknown in young children with heart disease is the amount of cumulative exposure, the relative contribution of various imaging modalities to cumulative exposure, and the associated lifetime attributable risk (LAR) of cancer.
In a cohort of young children undergoing 1 of 7 operations for congenital and acquired heart disease, we sought to estimate (1) the cumulative effective dose of radiation exposure across the spectrum of radiation-producing imaging modalities; (2) the relative contribution of various imaging modalities to cumulative effective dose; and (3) the estimated LAR of cancer from cumulative radiation exposure.
Children were eligible for inclusion if they were ≤6 years of age and had previously undergone 1 of 7 different primary surgical procedures for heart disease, including isolated atrial septal defect closure, isolated ventricular septal defect closure, atrioventricular canal defect repair (including complete, transitional, and partial atrioventricular canal defect), tetralogy of Fallot repair (excluding patients with tetralogy/atrioventricular canal defect, pulmonary atresia, or tetralogy with absent pulmonary valve), isolated arterial switch operation (excluding arterial switch with or without ventricular septal defect or coarctation repair), cardiac transplantation, and Norwood operation, at a single institution between July 1, 2005, and December 31, 2010. Surgical procedures used for study entry were chosen to represent more commonly performed surgical procedures and a spectrum of surgical complexity. Patients were grouped according to their initial surgical procedure unless their course ended in a cardiac transplantation, in which case they were analyzed in the transplant group. This study was approved by the Duke University Medical Center institutional review board with waiver of informed consent.
Patient demographics were collected from the electronic medical record and included sex, race, age at operation, and the presence of other congenital anomalies. Radiation exposure data were collected from birth, including all specific examinations with radiation-producing imaging modalities (radiographs, fluoroscopy, nuclear medicine, and CT) for each patient. Exposure data were collated by searching institutional databases and by searching specific current procedural terminology codes through the electronic medical record. A chart review was performed for 10% of the study population to confirm the accuracy of the search and demonstrated <5% missing data.
Effective Dose Calculation
Organ-specific radiation doses were measured with 2 ATOM family (CIRS, Norfolk, VA) anthropomorphic phantoms (representing 1 and 5 years of age). The phantoms include sectional slabs, each with a thickness of 25 mm, and are manufactured with tissue/organ-equivalent epoxy resins (including bone density formulated to represent a 1- and 5-year-old skeleton, respectively). The phantoms each incorporate dosimeters within cancer-susceptible tissue structures, including thyroid, lung, breast, thymus, bone marrow, kidney, adrenals, liver, esophagus, pancreas, spleen, stomach, intestine, ovaries, testes, prostate, and bladder. Doses were measured for all conventional angiographic projections. For fluoroscopy assessment, the pulsed frame rate was 15 frames per second, and for cineangiography, the frame rate was 30 frames per second, consistent with institutional protocols during the time of the study. Organ-specific data were used to develop a proprietary radiation dose calculator, which was then used to determine total catheterization effective dose by entering fluoroscopy and cineangiography times and camera angulation for catheterizations performed on the patient cohort. The 1-year-old calculator was used for exposures ≤2 years of age and the 5-year-old calculator for exposures between ages 3 and 6 years. The relative contribution of anteroposterior versus lateral fluoroscopy exposure was not known retrospectively for the time frame of study; therefore, it was assumed that two thirds and one third of the total fluoroscopy exposure came from the anteroposterior angle and lateral angle, respectively. These estimates were validated by review of 100 consecutive, more recent institutional cardiac catheterizations in which the mean contribution of fluoroscopy was 35±18% from the lateral camera angle. All phantom data acquisition was performed on a Philips Integris Allura 9 (Philips Healthcare, Amsterdam, The Netherlands) fluoroscopy system.
Other Imaging Modalities
Age-specific effective dose estimates for all other radiographic examinations were derived from a combination of previously published institutional data estimated with phantoms (upper gastrointestinal series with small bowel follow-through, chest CT, cardiac gated CT angiography, abdomen/pelvis multidetector array CT, chest CT) and data from the peer-reviewed radiology literature (Table I in the online-only Data Supplement). A central tendency value was used to define the effective dose of an examination in cases with several source estimates.
Cumulative effective dose estimates were calculated by summing effective doses over each patient’s imaging history. The average annual effective dose was defined as the average effective dose per year from birth to the time of last data collection. The postoperative effective dose was defined as the effective dose within the first 3 months after the initial surgical procedure.
LAR Cancer Estimation
Radiation dose was estimated by organ system and summed to estimate effective dose. Cumulative risk of cancer and age- and sex-specific LAR of cancer above baseline was estimated on the basis of the effective dose by use of the approach of the National Academy of Sciences Committee on Biological Effects of Ionizing Radiation (BEIR) VII.18 The lower- and upper-limit cancer risk estimations were calculated with the BEIR VII 5% and 95% risk estimates for exposure, respectively. These limits were calculated individually for each examination in each patient. The BEIR VII models assume a normal life expectancy, take into account the age at exposure and the sex of the population, and assume that cancer risk is proportional to the radiation dose, with no threshold. Therefore, every ionizing radiation-producing procedure performed on an individual produces a corresponding increase in cancer risk. To calculate cancer risk in our high-risk population with anticipated shorter life expectancy, excess relative cancer risk was calculated at 0.035 per 1-mSv exposure at mean follow-up of 10 years based on previous epidemiological data.19 For calculations, exposure was assumed to have occurred at age 5 years. Background cancer rates were based on reported US 5-year cancer incidence for adolescents (aged 15–19 years).20
The unit of observation for this analysis was a subject enrolled in the study. Summary statistics were used to describe the study variables, including means and standard deviations and frequency counts and percentages. Distributions of effective dose and LAR across procedure types were compared with a nonparametric Kruskal-Wallis test. All analyses were conducted with Stata 12.0 (College Station, TX), and a 2-tailed P value <0.05 was considered statistically significant.
Clinical characteristics are presented by surgical subgroup in Table 1. The study cohort consisted of 337 children undergoing 1 of 7 surgical procedures of interest. For the overall cohort, median age at surgery was 88 days (5th–95th percentile, 3–819 days), and median duration of follow-up from birth was 23.9 months (5th–95th percentile, 1.6–60.9 months).
The numbers of radiation-producing examinations and the average annual and cumulative effective dose per operative group are listed in Table 2. In total, 13 932 examinations were performed with a median of 17 examinations (5th–95th percentile, 4–158) per child and a median cumulative effective dose of 2.7 mSv (5th–95th percentile, 0.1–76.9 mSv) per child. Radiation exposure varied widely across surgical cohorts: Those with more complex heart disease (ie, cardiac transplantation and Norwood cohorts) received substantially greater cumulative exposure. In terms of timing of examinations, the majority were performed in the first 3 months after the entry surgical procedure (6992/13 932, 50%), but these immediate postoperative examinations accounted for only 26% of cumulative exposure (range, 23%–36% for the 7 surgical subgroups). The transplant patients represent a unique cohort in that they frequently have complex pretransplantation medical needs, particularly in those with a prior history of congenital heart disease (70% of the present study cohort). In these patients, posttransplantation radiation accounted for the majority of exposure (72%) with a median posttransplantation cumulative effective dose of 45.8 mSv (5th–95th percentile, 7.4–154.2 mSv).
Table 3 shows the relative contribution of radiation-producing examinations to the total cumulative effective dose. Conventional radiographic examinations represented 92% of total examinations but accounted for only 8% of the cumulative effective dose. Conversely, cardiac catheterization procedures represented 1.5% (n=303/13 932) of all examinations but contributed 60% of total radiation exposure (Figure 1). CT angiography of the chest, followed by interventional catheterization examinations, accounted for the highest effective dose per study (Table 3).
The estimated LAR of cancer above baseline per operative group and examination modality is listed in Table 4. Median LAR across surgical cohorts was 65 cases per 100 000 children exposed. Lower (43 cases per 100 000 exposed) and upper (112 cases per 100 000 exposed) limits of LAR represent the median cohort 5% and 95% LAR, respectively, based on the BEIR VII confidence intervals. LAR of cancer per unit exposure was substantially greater in females (41/100 000 versus 22/100 000 per 1 mSv effective dose for females versus males, respectively, P<0.001), which primarily reflects increased breast and thyroid cancer risk. The LAR per individual radiation-producing examination varied widely depending on examination, exceeding 350 cases per 100 000 children exposed to a CT angiography of the chest and interventional catheterization but only 0.2 cases per 100 000 children exposed to a portable chest radiograph (Figure 2).
Because the cardiac transplant and Norwood cohorts may not have a normal anticipated life expectancy, we also estimated relative cancer risk in the short term for these 2 cohorts. On the basis of cumulative exposure, the median 10-year sex-averaged relative risk of any cancer compared with an unexposed population was 3.2 (5th–95th percentile, 1.4–7.7) for the transplant cohort and 2.0 (5th–95th percentile, 1.0–5.0) for the Norwood cohort. On the basis of background cancer incidence among US adolescents, this translates to a median 5-year sex-averaged all-cancer incidence (between the ages of 15 and 19 years) of 69.4 and 43.4 per 100 000 for the 2 cohorts, respectively.
This is the largest study evaluating cumulative radiation exposure across the spectrum of imaging modalities to estimate the associated LAR of cancer in children with heart disease. Although commonly performed, radiographs contribute a relatively small proportion to total radiation exposure. Conversely, less commonly performed but higher-exposure imaging modalities such as catheterization and chest CT are the most important contributors to cumulative radiation exposure and therefore lifetime cancer risk.
In the United States and internationally, use of radiation-producing imaging examinations in children continues to rise.7 Although children benefit from advanced imaging procedures for more accurate diagnosis and less-invasive treatment, radiation has potential health risks. Several studies have shown that for a given dose of radiation, children are 3 to 4 times more likely than adults to develop malignancies.2,6,18
Risk associated with radiation exposure is particularly relevant for children with more complex heart diseases, who often receive repetitive imaging with high-exposure modalities. Even in the limited time frame studied, the estimated LAR of cancer above baseline was as high as 6.5%. Shortened anticipated lifespan in these high-risk cohorts does not mitigate cancer mortality and morbidity risks, because these children have a significantly increased relative risk of cancer even within the first 10 years after exposure. These data are consistent with epidemiological data demonstrating that the relative risk of cancer is highest in the early years after exposure.18 Conversely, for children with lower-complexity heart disease, and a presumably less complicated course, exposure was reassuringly low. For 5 of the 7 procedure cohorts, the median annual effective dose (0.09–0.29 mSv) from imaging procedures was substantially below the annual background exposure within the United States (3.0–3.5 mSv).21 Nonetheless, LAR of cancer exceeded 0.5% at the upper limits of exposure for 6 of 7 cohorts, with the notable exception of children after arterial switch operation.
These data provide actionable information that could be used to reduce exposure and suggest that the greatest risk reduction can be achieved with a targeted approach focused on minimizing radiation use during high-exposure examinations such as catheterization and CT. Although less frequently performed, these modalities are the main contributors to cumulative effective dose and can contribute up to 1800 times as much effective dose per examination as a standard radiograph. In our cohort, higher-risk patients were frequently exposed to these high-exposure imaging modalities repeatedly beyond the immediate postoperative period and consequently had much higher average annual effective doses. Conversely, conventional radiographic examinations were performed primarily during the immediate postoperative period and, although high in volume, contributed a relatively small amount of cumulative effective dose. This finding is consistent with prior publications.16 It is also important to recognize that risk of cancer was substantially higher in the female population because of the increased risk of breast and thyroid cancer.18
Strengths of the present analysis include the large sample size and our comprehensive approach to estimating effective dose. Our effective dose data are particularly robust, because many of the effective dose calculations (including the highest-exposure modalities, chest CT and catheterization) were obtained by use of data from dosimeters placed over vital tissue structures in anthropomorphic phantoms.15 In the case of the catheterization procedures, these data were then combined with actual patient data on fluoroscopic and cineangiographic times and camera angles. This allowed us to measure organ-specific exposures directly. The median effective dose from therapeutic and diagnostic cardiac catheterization procedures (13.77 and 9.10 mSv, respectively) was higher than in previous publications2–4; however, these previous publications all used simulation models to calculate an effective dose in millisieverts from the reported skin exposure represented in milligrays.2–4 Estimates of skin exposure calculated by the equipment from technical parameters may introduce error depending on the equipment used. External exposure data also fail to account for beam attenuation and other factors that alter absorbed radiation dose. Therefore, these data are generally less accurate. Although phantom data are more robust, there are also limits to them, because phantoms do not perfectly approximate the clinical setting, in which factors including body habitus, ergonomics, anatomy, and variation in imaging parameters all uniquely affect exposure.
The present study has several additional limitations. First, there are inherent limitations to a single-center observational study. In particular, the surgical cohorts were relatively small and heterogeneous, with the lifetime radiological history derived from hospital records over a 5-year period and a median per-patient follow-up of ≈2 years. The follow-up periods varied for the specific cohorts, and a meaningful number of patients died during follow-up. These factors lead unavoidably to an approximation that likely underestimates the total radiation exposure and may bias relative estimates in select cohorts. Second, there is variability in the dose of each radiation examination, and although phantom data provide the most accurate estimate of our institutional exposure, they may not be directly generalizable to institutions that use different imaging protocols or equipment.15,22 A third limitation is that cancer estimates made with BEIR VII tables are subject to sources of uncertainty caused by inherent limitations in epidemiological data and in the general understanding of how radiation exposure increases the risk of cancer. Moreover, we used effective dose to calculate LAR, whereas the BEIR VII data use summed cancer risks for individual organs after a total-body exposure. Although the use of effective dose in this context is not strictly correct, it has been shown that the 2 approaches yield similar values of LAR.23–26
The effective dose from radiation-producing imaging examinations varies greatly across the spectrum of imaging modalities. Overall, for the patient cohort in the present study, cumulative effective dose was relatively low, less than the annual background exposure in the United States; however, select children with complex heart disease can be exposed to large cumulative doses that increase the estimated LAR of cancer to up to 6.5% above baseline, even in the limited time frame studied. High-exposure imaging modalities such as catheterization and CT are the most important contributors to the cumulative effective dose. To reduce long-term cancer risk, providers should target reducing radiation exposure in the highest-risk cohorts, including those children who will require repetitive high-exposure imaging and females because of their increased cancer risk. Providers can consider our relative exposure estimates when choosing between various radiation-producing imaging modalities. Ultimately, novel technologies or therapies are needed to mitigate risk of radiation exposure. With a burgeoning population of children with heart disease surviving into adulthood, these advances will have a very meaningful public health impact.
Sources of Funding
Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001117 and the Mend a Heart Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Mend a Heart Foundation.
Dr Yoshizumi receives support from the US Nuclear Regulatory Commission and the US Department of Energy and from a Coulter research grant from Duke University for his work on radiation dosimetry. The other authors report no conflicts.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.113.005425/-/DC1.
- Received August 28, 2013.
- Accepted April 18, 2014.
- © 2014 American Heart Association, Inc.
- Andreassi MG
- Beels L,
- Bacher K,
- De Wolf D,
- Werbrouck J,
- Thierens H
- Bacher K,
- Bogaert E,
- Lapere R,
- De Wolf D,
- Thierens H
- Andreassi MG,
- Ait-Ali L,
- Botto N,
- Manfredi S,
- Mottola G,
- Picano E
- Strauss KJ,
- Kaste SC
- Fahey FH,
- Treves ST,
- Adelstein SJ
- Brody AS,
- Frush DP,
- Huda W,
- Brent RL
- Ait-Ali L,
- Andreassi MG,
- Foffa I,
- Spadoni I,
- Vano E,
- Picano E
- 17.↵The 2007 Recommendations of the International Commission on Radiological Protection: ICRP publication 103. Ann ICRP. 2007;37:1–332.
- 18.↵Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation; Nuclear and Radiation Studies Board, Division on Earth and Life Studies, National Research Council of the National Academies. Health Risks From Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: The National Academies Press; 2006.
- Mathews JD,
- Forsythe AV,
- Brady Z,
- Butler MW,
- Goergen SK,
- Byrnes GB,
- Giles GG,
- Wallace AB,
- Anderson PR,
- Guiver TA,
- McGale P,
- Cain TM,
- Dowty JG,
- Bickerstaffe AC,
- Darby SC
- 20.↵Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975–2000. http://seer.cancer.gov/archive/publications/aya/. Accessed October 28, 2013.
- 21.↵National Council on Radiation Protection and Measurements. Ionizing Radiation Exposure of the Population of the United States. National Council on Radiation Protection Report No. 160. Bethesda, MD: National Council on Radiation Protection and Measurements; 2009.
- Podberesky DJ,
- Angel E,
- Yoshizumi TT,
- Toncheva G,
- Salisbury SR,
- Alsip C,
- Barelli A,
- Egelhoff JC,
- Anderson-Evans C,
- Nguyen GB,
- Dow D,
- Frush DP
- Martin CJ
Children with heart disease are frequently exposed to ionizing radiation from medical imaging examinations, and there is an associated increase in lifetime cancer risk. We estimated radiation effective dose in millisieverts from various imaging examinations using dosimetry data from anthropomorphic phantoms and data compiled from the published literature. We used these data to calculate cumulative radiation dose in a cohort of 337 children undergoing various different heart surgeries. We then estimated the associated lifetime attributable risk of cancer using the methodology of the National Academy of Sciences Committee on the Biological Effects of Ionizing Radiation (BEIR VII). Over a median follow-up of 23.9 months, the cohort was exposed to a total of 13 932 medical imaging procedures that used ionizing radiation. Conventional radiographs represented the overwhelming majority (92%) of examinations, yet cardiac catheterization and computed tomography accounted for 81% of cumulative radiation dose. The cohort median cumulative radiation dose was relatively low (2.7 mSv), less than the average annual background exposure in the United States (3.0–3.5 mSv). However, there was wide variability, and children with more complex clinical courses often received substantial cumulative radiation doses. The associated cancer lifetime attributable risk exceeded 6% in select patients and notably was twice as high in females per 1 mSv of radiation dose compared with males. To reduce risk, quality improvement initiatives should target reductions in radiation exposure, especially in children who will require repetitive high-exposure imaging (catheterization and computed tomography) and in females because of their increased cancer susceptibility.