Brain cancer after radiation exposure from CT examinations of children and young adults: results from the EPI-CT cohort study.

BACKGROUND: The European EPI-CT study aims to quantify cancer risks from CT examinations of children and young adults. Here, we assess the risk of brain cancer. METHODS: We pooled data from nine European countries for this cohort study. Eligible participants had at least one CT examination before age 22 years documented between 1977 and 2014, had no previous diagnosis of cancer or benign brain tumour, and were alive and cancer-free at least 5 years after the first CT. Participants were identified through the Radiology Information System in 276 hospitals. Participants were linked with national or regional registries of cancer and vital status, and eligible cases were patients with brain cancers according to WHO International Classification of Diseases for Oncology. Gliomas were analysed separately to all brain cancers. Organ doses were reconstructed using historical machine settings and a large sample of CT images. Excess relative risks (ERRs) of brain cancer per 100 mGy of cumulative brain dose were calculated with linear dose-response modelling. The outcome was the first reported diagnosis of brain cancer after an exclusion period of 5 years after the first electronically recorded CT examination. FINDINGS: We identified 948 174 individuals, of whom 658 752 (69%) were eligible for our study. 368 721 (56%) of 658 752 participants were male and 290 031 (44%) were female. During a median follow-up of 5·6 years (IQR 2·4-10·1), 165 brain cancers occurred, including 121 (73%) gliomas. Mean cumulative brain dose, lagged by 5 years, was 47·4 mGy (SD 60·9) among all individuals and 76·0 mGy (100·1) among people with brain cancer. A significant linear dose-response relationship was observed for all brain cancers (ERR per 100 mGy 1·27 [95% CI 0·51-2·69]) and for gliomas separately (ERR per 100 mGy 1·11 [0·36-2·59]). Results were robust when the start of follow-up was delayed beyond 5 years and when participants with possibly previously unreported cancers were excluded. INTERPRETATION: The observed significant dose-response relationship between CT-related radiation exposure and brain cancer in this large, multicentre study with individual dose evaluation emphasises careful justification of paediatric CTs and use of doses as low as reasonably possible. FUNDING: EU FP7; Belgian Cancer Registry; La Ligue contre le Cancer, L'Institut National du Cancer, France; Ministry of Health, Labour and Welfare of Japan; German Federal Ministry of Education and Research; Worldwide Cancer Research; Dutch Cancer Society; Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat de Catalunya, Spain; US National Cancer Institute; UK National Institute for Health Research; Public Health England.

Editor's Choice - Estimated Radiation Dose to the Operator During Endovascular Aneurysm Repair.

OBJECTIVE: To estimate operator organ doses from fluoroscopically guided infrarenal endovascular aneurysm repair (EVAR) procedures, using the detailed exposure information contained in radiation dose structured reports. METHODS: Conversion factors relating kerma area product (PKA) to primary operator organ doses were calculated using Monte Carlo methods for 91 beam angles and seven x-ray spectra typical of clinical practice. A computer program was written, which selects the appropriate conversion factor for each exposure listed in a structured report and multiplies it by the respective PKA. This system was used to estimate operator doses for 81 EVAR procedures for which structured reports were available. The impact of different shielding scenarios and variations in operator position was also investigated. RESULTS: Without any shielding, the median estimated effective dose was 113 µSv (interquartile range [IQR] 71, 252 µSv). The highest median organ doses were for the colon (154 µSv, IQR 81, 343) and stomach (133 µSv, IQR 76, 307). These dose estimates represent all exposures, including fluoroscopy and non-fluoroscopic digital acquisitions. With minimal shielding provided by 0.25 mm of Pb covering the torso and upper legs, the effective dose was reduced by a factor of around 6. With additional shielding from ceiling and table shields, a 25 to 50 fold reduction in dose is achievable. Estimated doses were highest where the primary beam was pointed directly away from the operator. CONCLUSION: The models suggest that with optimal use of shielding, operator doses can be reduced to levels equivalent to one to two days of natural background exposure and well below statutory dose limits.

Ionising radiation as a risk factor for lymphoma: a review.

The ability of ionising radiation to induce lymphoma is unclear. Here, we present a narrative review of epidemiological evidence of the risk of lymphoma, including chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM), among various exposed populations including atomic bombing survivors, industrial and medical radiation workers, and individuals exposed for medical purposes. Overall, there is a suggestion of a positive dose-dependent association between radiation exposure and lymphoma. The magnitude of this association is highly imprecise, however, with wide confidence intervals frequently including zero risk. External comparisons tend to show similar incidence and mortality rates to the general population. Currently, there is insufficient information on the impact of age at exposure, high versus low linear energy transfer radiation, external versus internal or acute versus chronic exposures. Associations are stronger for males than females, and stronger for non-Hodgkin lymphoma and MM than for Hodgkin lymphoma, while the risk of radiation-induced CLL may be non-existent. This broad grouping of diverse diseases could potentially obscure stronger associations for certain subtypes, each with a different cell of origin. Additionally, the classification of malignancies as leukaemia or lymphoma may result in similar diseases being analysed separately, while distinct diseases are analysed in the same category. Uncertainty in cell of origin means the appropriate organ for dose response analysis is unclear. Further uncertainties arise from potential confounding or bias due to infectious causes and immunosuppression. The potential interaction between radiation and other risk factors is unknown. Combined, these uncertainties make lymphoma perhaps the most challenging malignancy to study in radiation epidemiology.

Patient radiation dose from x-ray guided endovascular aneurysm repair: a Monte Carlo approach using voxel phantoms and detailed exposure information.

Endovascular aneurysm repair (EVAR) is a well-established minimally invasive technique that relies on x-ray guidance to introduce a stent through the femoral artery and manipulate it into place. The aim of this study was to estimate patient organ and effective doses from EVAR procedures using anatomically realistic computational phantoms and detailed exposure information from radiation dose structured reports (RDSR). Methods: Lookup tables of conversion factors relating kerma area product (PKA) to organ doses for 49 different beam angles were produced using Monte Carlo simulations (MCNPX2.7) with International Commission on Radiological Protection (ICRP) adult male and female voxel phantoms for EVAR procedures of varying complexity (infra-renal, fenestrated/branched and thoracic EVAR). Beam angle specific correction factors were calculated to adjust doses according to x-ray energy. A MATLAB function was written to find the appropriate conversion factor in the lookup table for each exposure described in the RDSR, perform energy corrections and multiply by the respective exposure PKA. Using this approach, organ doses were estimated for 183 EVAR procedures in which RDSRs were available. A number of simplified dose estimation methodologies were also investigated for situations in which RDSR data are not available. Results: Mean estimated bone marrow doses were 57 (range: 2-247), 86 (2-328) and 54 (8-250) mGy for infra-renal, fenestrated/branched and thoracic EVAR, respectively. Respective effective doses were 27 (1-208), 54 (1-180) and 37 (5-167) mSv. Dose estimates using non-individualised, average conversion factors, along with those produced using the alternative Monte Carlo code PCXMC, yielded reasonably similar results overall, though variation for individual procedures could exceed 100% for some organs. In conclusion, radiation doses from x-ray guided endovascular aneurysm repairs are potentially high, though this must be placed in the context of the life sparing nature and high success rate for this procedure.

The HARMONIC project: study design for the assessment of radiation doses and associated cancer risks following cardiac fluoroscopy in childhood.

The HARMONIC project (Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy in Paediatrics) is a European study aiming to improve our understanding of the long-term health risks from radiation exposures in childhood and early adulthood. Here, we present the study design for the cardiac fluoroscopy component of HARMONIC. A pooled cohort of approximately 100 000 patients who underwent cardiac fluoroscopy procedures in Belgium, France, Germany, Italy, Norway, Spain or the UK, while aged under 22 years, will be established from hospital records and/or insurance claims data. Doses to individual organs will be estimated from dose indicators recorded at the time of examination, using a lookup-table-based dosimetry system produced using Monte Carlo radiation transport simulations and anatomically realistic computational phantom models. Information on beam geometry and x-ray energy spectra will be obtained from a representative sample of radiation dose structured reports. Uncertainties in dose estimates will be modelled using 2D Monte Carlo methods. The cohort will be followed up using national registries and insurance records to determine vital status and cancer incidence. Information on organ transplantation (a major risk factor for cancer development in this patient group) and/or other conditions predisposing to cancer will be obtained from national or local registries and health insurance data, depending on country. The relationship between estimated radiation dose and cancer risk will be investigated using regression modelling. Results will improve information for patients and parents and aid clinicians in managing and implementing changes to reduce radiation risks without compromising medical benefits.

Cancer incidence among children and young adults who have undergone x-ray guided cardiac catheterization procedures.

Children and young adults with heart disease appear to be at increased risk of developing cancer, although the reasons for this are unclear. A cohort of 11,270 individuals, who underwent cardiac catheterizations while aged ≤ 22 years in the UK, was established from hospital records. Radiation doses from cardiac catheterizations and CT scans were estimated. The cohort was matched with the NHS Central Register and NHS Transplant Registry to determine cancer incidence and transplantation status. Standardized incidence ratios (SIR) with associated confidence intervals (CI) were calculated. The excess relative risk (ERR) of lymphohaematopoietic  neoplasia was also calculated using Poisson regression. The SIR was raised for all malignancies (2.32, 95% CI 1.65, 3.17), lymphoma (8.34, 95% CI 5.22, 12.61) and leukaemia (2.11, 95% CI 0.82, 4.42). After censoring transplant recipients, post-transplant, the SIR was reduced to 0.90 (95% CI 0.49, 1.49) for all malignancies. All lymphomas developed post-transplant. The SIR for all malignancies developing 5 years from the first cardiac catheterization (2 years for leukaemia/lymphoma) remained raised (3.01, 95% CI 2.09, 4.19) but was again reduced after censoring transplant recipients (0.98, 95% CI 0.48, 1.77). The ERR per mGy bone marrow dose for lymphohaematopoietic neoplasia was reduced from 0.541 (95% CI 0.104, 1.807) to 0.018 (95% CI - 0.002, 0.096) where transplantation status was accounted for as a time-dependent background risk factor. In conclusion, transplantation appears to be a large contributor to elevated cancer rates in this patient group. This is likely to be mainly due to associated immunosuppression, however, radiation exposure may also be a contributing factor.

Projected cancer risks potentially related to past, current, and future practices in paediatric CT in the United Kingdom, 1990-2020.

BACKGROUND: To project risks of developing cancer and the number of cases potentially induced by past, current, and future computed tomography (CT) scans performed in the United Kingdom in individuals aged <20 years. METHODS: Organ doses were estimated from surveys of individual scan parameters and CT protocols used in the United Kingdom. Frequencies of scans were estimated from the NHS Diagnostic Imaging Dataset. Excess lifetime risks (ELRs) of radiation-related cancer were calculated as cumulative lifetime risks, accounting for survival probabilities, using the RadRAT risk assessment tool. RESULTS: In 2000-2008, ELRs ranged from 0.3 to 1 per 1000 head scans and 1 to 5 per 1000 non-head scans. ELRs per scan were reduced by 50-70% in 2000-2008 compared with 1990-1995, subsequent to dose reduction over time. The 130 750 scans performed in 2015 in the United Kingdom were projected to induce 64 (90% uncertainty interval (UI): 38-113) future cancers. Current practices would lead to about 300 (90% UI: 230-680) future cancers induced by scans performed in 2016-2020. CONCLUSIONS: Absolute excess risks from single exposures would be low compared with background risks, but even small increases in annual CT rates over the next years would substantially increase the number of potential subsequent cancers.

Relationship between paediatric CT scans and subsequent risk of leukaemia and brain tumours: assessment of the impact of underlying conditions.

BACKGROUND: We previously reported evidence of a dose-response relationship between ionising-radiation exposure from paediatric computed tomography (CT) scans and the risk of leukaemia and brain tumours in a large UK cohort. Underlying unreported conditions could have introduced bias into these findings. METHODS: We collected and reviewed additional clinical information from radiology information systems (RIS) databases, underlying cause of death and pathology reports. We conducted sensitivity analyses excluding participants with cancer-predisposing conditions or previous unreported cancers and compared the dose-response analyses with our original results. RESULTS: We obtained information from the RIS and death certificates for about 40% of the cohort (n∼180 000) and found cancer-predisposing conditions in 4 out of 74 leukaemia/myelodysplastic syndrome (MDS) cases and 13 out of 135 brain tumour cases. As these conditions were unrelated to CT exposure, exclusion of these participants did not alter the dose-response relationships. We found evidence of previous unreported cancers in 2 leukaemia/MDS cases, 7 brain tumour cases and 232 in non-cases. These previous cancers were related to increased number of CTs. Exclusion of these cancers reduced the excess relative risk per mGy by 15% from 0.036 to 0.033 for leukaemia/MDS (P-trend=0.02) and by 30% from 0.023 to 0.016 (P-trend<0.0001) for brain tumours. When we included pathology reports we had additional clinical information for 90% of the cases. Additional exclusions from these reports further reduced the risk estimates, but this sensitivity analysis may have underestimated risks as reports were only available for cases. CONCLUSIONS: Although there was evidence of some bias in our original risk estimates, re-analysis of the cohort with additional clinical data still showed an increased cancer risk after low-dose radiation exposure from CT scans in young patients.

Secondary malignant neoplasms following radiotherapy for primary cancer in children and young adults.

A study was conducted to investigate secondary malignant neoplasm (SMN) occurrence following radiotherapy (RT) for cancer in children and young adults, to examine the spatial distribution of SMNs in relation to the irradiated field, and to evaluate a possible role of bystander effects in SMN distribution. Forty-two SMNs were identified among 7257 subjects diagnosed with cancer while living in Yorkshire, UK. Thirty-two of these occurred in patients receiving RT. Distances between SMN locations and RT field edge were estimated along with dose at SMN site. Expected radiation-induced SMN frequency in remote tissues receiving less than 0.1 Gy was predicted using risk estimates based on atomic bombing data. After a median follow-up period of 7.58 years, patients treated with RT were at a nearly five-fold increased risk of developing a subsequent primary neoplasm than the general population in the 0-29 years age range. The most common type of secondary malignancy associated with RT was of the central nervous system (28%), followed by sarcoma (25%) and leukemia (19%). Considering only solid SMNs developing 5 years or more from treatment, the spatial distribution showed a strong pattern of proximity to the irradiated field, with 68% occurring in-field or within 8 cm of the field edge. The SMN frequency in distant tissues receiving doses of less than 0.1 Gy was low but compatible with local absorbed dose.

The impact of the COVID-19 pandemic on the use of diagnostic imaging examinations in the Brazilian unified healthcare system (SUS).

Objectives: To assess the impact of the COVID-19 pandemic on the volumes of use of diagnostic imaging examinations in the Brazilian Unified Health System (SUS), the only healthcare provider for approximately 160 million people. Methods: We collected the monthly numbers of diagnostic imaging examinations in the years 2019, 2020, and 2021 from a database provided by SUS. Data were collected by specific type of examination across different imaging modalities, both for the outpatient (elective and emergency) and inpatient settings. Results: There was a large reduction in the annual volume of almost all types of diagnostic imaging examinations in SUS in 2020, compared to 2019. Decreases were generally greater among outpatients than in the hospital setting, in which the annual volume of use of most modalities was similar or even higher in 2021 than in the pre-pandemic period. Computed tomography (CT) was the only modality for which use increased in 2020 compared to 2019. In contrast to other types of examinations, the use of chest CT was much higher in both 2020 and 2021 than in the preceding years. The relative changes in diagnostic imaging use in SUS started around March-April 2020, when the pandemic began to get worse in Brazil, and tended to correlate to COVID-19 incidence in Brazil over the following months. Conclusions: The COVID-19 pandemic had a large impact on the use of diagnostic imaging examinations in the SUS. Policies and actions are needed to alleviate the resulting potential adverse health effects and to optimize the use of diagnostic tests in the future.

Radiological characterisation for the clearance of burnable waste produced at CERN.

Burnable waste produced at CERN during upgrading, maintenance and dismantling campaigns may be contaminated with radioactive nuclides produced through activation of accelerator components. Here, we present a methodology for the radiological characterisation of burnable waste, which takes into account the wide range of potential activation conditions (beam energy, material composition, location, irradiation and waiting time). Waste packages are measured using a total gamma counter, with the sum of clearance limit fractions estimated using the fingerprint method. Gamma spectroscopy was found to be unsuitable for classifying this waste due to the long counting times required to identify many expected nuclides, but was retained for quality control purposes. Using this methodology, a pilot campaign was performed in which we were able to clear 13 m3 of burnable waste as conventional non-radioactive waste.

Risk of hematological malignancies from CT radiation exposure in children, adolescents and young adults.

Over one million European children undergo computed tomography (CT) scans annually. Although moderate- to high-dose ionizing radiation exposure is an established risk factor for hematological malignancies, risks at CT examination dose levels remain uncertain. Here we followed up a multinational cohort (EPI-CT) of 948,174 individuals who underwent CT examinations before age 22 years in nine European countries. Radiation doses to the active bone marrow were estimated on the basis of body part scanned, patient characteristics, time period and inferred CT technical parameters. We found an association between cumulative dose and risk of all hematological malignancies, with an excess relative risk of 1.96 (95% confidence interval 1.10 to 3.12) per 100 mGy (790 cases). Similar estimates were obtained for lymphoid and myeloid malignancies. Results suggest that for every 10,000 children examined today (mean dose 8 mGy), 1-2 persons are expected to develop a hematological malignancy attributable to radiation exposure in the subsequent 12 years. Our results strengthen the body of evidence of increased cancer risk at low radiation doses and highlight the need for continued justification of pediatric CT examinations and optimization of doses.

Cancer Effects of Low to Moderate Doses of Ionizing Radiation in Young People with Cancer-Predisposing Conditions: A Systematic Review.

Moderate to high doses of ionizing radiation (IR) are known to increase the risk of cancer, particularly following childhood exposure. Concerns remain regarding risks from lower doses and the role of cancer-predisposing factors (CPF; genetic disorders, immunodeficiency, mutations/variants in DNA damage detection or repair genes) on radiation-induced cancer (RIC) risk. We conducted a systematic review of evidence that CPFs modify RIC risk in young people. Searches were performed in PubMed, Scopus, Web of Science, and EMBASE for epidemiologic studies of cancer risk in humans (<25 years) with a CPF, exposed to low-moderate IR. Risk of bias was considered. Fifteen articles focusing on leukemia, lymphoma, breast, brain, and thyroid cancers were included. We found inadequate evidence that CPFs modify the risk of radiation-induced leukemia, lymphoma, brain/central nervous system, and thyroid cancers and limited evidence that BRCA mutations modify radiation-induced breast cancer risk. Heterogeneity was observed across studies regarding exposure measures, and the numbers of subjects with CPFs other than BRCA mutations were very small. Further studies with more appropriate study designs are needed to elucidate the impact of CPFs on RIC. They should focus either on populations of carriers of specific gene mutations or on common susceptible variants using polygenic risk scores.

Dose Estimation for the European Epidemiological Study on Pediatric Computed Tomography (EPI-CT).

Within the European Epidemiological Study to Quantify Risks for Paediatric Computerized Tomography (EPI-CT study), a cohort was assembled comprising nearly one million children, adolescents and young adults who received over 1.4 million computed tomography (CT) examinations before 22 years of age in nine European countries from the late 1970s to 2014. Here we describe the methods used for, and the results of, organ dose estimations from CT scanning for the EPI-CT cohort members. Data on CT machine settings were obtained from national surveys, questionnaire data, and the Digital Imaging and Communications in Medicine (DICOM) headers of 437,249 individual CT scans. Exposure characteristics were reconstructed for patients within specific age groups who received scans of the same body region, based on categories of machines with common technology used over the time period in each of the 276 participating hospitals. A carefully designed method for assessing uncertainty combined with the National Cancer Institute Dosimetry System for CT (NCICT, a CT organ dose calculator), was employed to estimate absorbed dose to individual organs for each CT scan received. The two-dimensional Monte Carlo sampling method, which maintains a separation of shared and unshared error, allowed us to characterize uncertainty both on individual doses as well as for the entire cohort dose distribution. Provided here are summaries of estimated doses from CT imaging per scan and per examination, as well as the overall distribution of estimated doses in the cohort. Doses are provided for five selected tissues (active bone marrow, brain, eye lens, thyroid and female breasts), by body region (i.e., head, chest, abdomen/pelvis), patient age, and time period (1977-1990, 1991-2000, 2001-2014). Relatively high doses were received by the brain from head CTs in the early 1990s, with individual mean doses (mean of 200 simulated values) of up to 66 mGy per scan. Optimization strategies implemented since the late 1990s have resulted in an overall decrease in doses over time, especially at young ages. In chest CTs, active bone marrow doses dropped from over 15 mGy prior to 1991 to approximately 5 mGy per scan after 2001. Our findings illustrate patterns of age-specific doses and their temporal changes, and provide suitable dose estimates for radiation-induced risk estimation in epidemiological studies.

ORGAN DOSE ESTIMATION ACCOUNTING FOR UNCERTAINTY FOR PEDIATRIC AND YOUNG ADULT CT SCANS IN THE UNITED KINGDOM.

Since our previous publication of organ dose for the pediatric CT cohort in the UK, there have been questions about the magnitude of uncertainty in our dose estimates. We therefore quantified shared and unshared uncertainties in empirical CT parameters extracted from 1073 CT films (1978-2008) from 36 hospitals in the study and propagated these uncertainties into organ doses using Monte Carlo random sampling and NCICT organ dose calculator. The average of 500 median brain and marrow doses for the full cohort was 35 (95% confidence interval: 30-40) mGy and 6 (5-7) mGy, respectively. We estimated that shared uncertainty contributed ~99% of coefficient of variation of median brain doses in brain scans compared to unshared uncertainty (1% contribution). We found that the previous brain doses were slightly underestimated for <1990 and overestimated for >1990 compared to the results in the current study due to the revised CTDI models based on CT films.

The impact of iodinated contrast media on intravascular and extravascular absorbed doses in X-ray imaging: A microdosimetric analysis.

Studies suggest iodinated contrast media (ICM) may increase organ dose and blood cell DNA damage for a given X-ray exposure. The impact of ICM on dose/damage to extravascular cells and cancer risks is unclear. METHODS: We used Monte Carlo modelling to investigate the microscopic distribution of absorbed dose outside the lumen of arteries, capillaries and interstitial fluids containing blood and various concentrations of iodine. Models were irradiated with four X-ray spectra representing clinical procedures. RESULTS: For the artery model, The average dose enhancement factors (DEF) to blood were 1.70, 2.38, 7.38, and 12.34 for mass concentrations of iodine in blood (ρiI) of 5, 10, 50 and 100 mg/ml, respectively, compared to 0 mg/ml. Average DEFs were reduced to 1.26, 1.51, 3.48 and 5.56, respectively, in the first micrometre of the vessel wall, falling to 1.01, 1.02, 1.06 and 1.09 at 40-50 µm from the lumen edge. For the capillary models, DEF for extravascular tissues was on average 48% lower than DEF for the whole model, including capillaries. A similar situation was observed for the interstitial model, with DEF to the cell nucleus being 35% lower than DEF for the whole model. CONCLUSIONS: While ICM may modify the absorbed doses from diagnostic X-ray examinations, the effect is smaller than suggested by assays of circulating blood cells or blood dose enhancement. Conversely, the potentially large increase in dose to the endothelium of blood vessels means that macroscopic organ doses may underestimate the risk of radiation induced cardiovascular disease for ICM-enhanced exposures.

Enhanced radiation dose and DNA damage associated with iodinated contrast media in diagnostic X-ray imaging.

A review was undertaken of studies reporting increased DNA damage in circulating blood cells and increased organ doses, for X-ray exposures enhanced by iodinated contrast media (ICM), compared to unenhanced imaging. This effect may be due to ICM molecules acting as a source of secondary radiation (Auger/photoelectrons, fluorescence X-rays) following absorption of primary X-ray photons. It is unclear if the reported increase in DNA damage to blood cells necessarily implies an increased risk of developing cancer. Upon ICM-enhancement, the attenuation properties of blood differ substantially from surrounding tissues. Increased energy deposition is likely to occur within very close proximity to ICM molecules (within a few tens of micrometres). Consequently, in many situations, damage and dose enhancement may be restricted to the blood and vessel wall only. Increased cancer risks may be possible, in cases where ICM molecules are given sufficient time to reach the capillary network and interstitial fluid at the time of exposure. In all situations, the extrapolation of blood cell damage to other tissues requires caution where contrast media are involved. Future research is needed to determine the impact of ICM on dose to cells outside the blood itself and vessel walls, and to determine the concentration of ICM in blood vessels and interstitial fluid at the time of exposure.