Finite-Sample Bias of the Linear Excess Relative Risk in Cohort Studies of Computed Tomography-Related Radiation Exposure and Cancer.

The linear excess relative risk (ERR) is the most commonly reported measure of association in radiation epidemiological studies, when individual dose estimates are available. While the asymptotic properties of the ERR estimator are well understood, there is evidence of small sample bias in case-control studies of treatment-related radiation exposure and second cancer risk. Cohort studies of cancer risk after exposure to low doses of radiation from diagnostic procedures, e.g., computed tomography (CT) examinations, typically have small numbers of cases and risks are small. Therefore, understanding the properties of the estimated ERR is essential for interpretation and analysis of such studies. We present results of a simulation study that evaluates the finite-sample bias of the ERR estimated by time-to-event analyses and its confidence interval using simulated data, resembling a retrospective cohort study of radiation-related leukemia risk after CT examinations in childhood and adolescence. Furthermore, we evaluate how the Firth-corrected estimator reduces the finite-sample bias of the classical estimator. We show that the ERR is overestimated by about 30% for a cohort of about 150,000 individuals, with 42 leukemia cases observed on average. The bias is reduced for higher baseline incidence rates and for higher values of the true ERR. As the number of cases increases, the ERR is approximately unbiased. The Firth correction reduces the bias for all cohort sizes to generally around or under 5%. Epidemiological studies showing an association between radiation exposure from pediatric CT and cancer risk, unless very large, may overestimate the magnitude of the relationship, while there is no evidence of an increased chance for false-positive results. Conducting large studies, perhaps by pooling individual studies to increase the number of cases, should be a priority. If this is not possible, Firth correction should be applied to reduce small-sample bias.

Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model.

In vitro experiments show that the cells possibly responsible for radiation-induced acute myeloid leukemia (rAML) exhibit low-dose hyper-radiosensitivity (HRS). In these cells, HRS is responsible for excess cell killing at low doses. Besides the endpoint of cell killing, HRS has also been shown to stimulate the low-dose formation of chromosomal aberrations such as deletions. Although HRS has been investigated extensively, little is known about the possible effect of HRS on low-dose cancer risk. In CBA mice, rAML can largely be explained in terms of a radiation-induced Sfpi1 deletion and a point mutation in the remaining Sfpi1 gene copy. The aim of this paper is to present and quantify possible mechanisms through which HRS may influence low-dose rAML incidence in CBA mice. To accomplish this, a mechanistic rAML CBA mouse model was developed to study HRS-dependent AML onset after low-dose photon irradiation. The rAML incidence was computed under the assumptions that target cells: (1) do not exhibit HRS; (2) HRS only stimulates cell killing; or (3) HRS stimulates cell killing and the formation of the Sfpi1 deletion. In absence of HRS (control), the rAML dose-response curve can be approximated with a linear-quadratic function of the absorbed dose. Compared to the control, the assumption that HRS stimulates cell killing lowered the rAML incidence, whereas increased incidence was observed at low doses if HRS additionally stimulates the induction of the Sfpi1 deletion. In conclusion, cellular HRS affects the number of surviving pre-leukemic cells with an Sfpi1 deletion which, depending on the HRS assumption, directly translates to a lower/higher probability of developing rAML. Low-dose HRS may affect cancer risk in general by altering the probability that certain mutations occur/persist.

Estimating the risk of developing secondary hematologic malignancies in patients with T1/T2 prostate cancer undergoing diverse treatment modalities: A large population-based study.

BACKGROUND: Patients with prostate cancer (PC) are at a high risk of developing secondary hematologic malignancies (SHMs) after radiation therapy (RT), while no study has assessed the relationship of different treatment modalities with the occurrence of SHMs after PC at early stage. This study aimed to investigate the risks of developing SHMs in patients with T1/T2 PC undergoing different treatment modalities. METHODS: Patients with T1/T2 PC were identified from the Surveillance, Epidemiology, and End Results database. Competing risk regression (CRR) model was performed to evaluate the hazard ratios (HRs) of developing SHMs. As SHMs scarcely occur, the relative risk (RR) analysis was employed to compare the risks of different treatment modalities associating with the development of SHMs. RESULTS: The CRR analysis showed that undergoing RT was associated with a higher risk of developing SHMs (external beam radiation therapy [EBRT]: HR = 1.21, 95% confidence interval [CI]: 1.10-1.34; radioactive implant [RI]: HR = 1.20, 95% CI: 1.06-1.36). As for different types of SHMs, EBRT, and RI were correlated with decreased risks of developing CLL (RR = 0.67, 0.72; 95% CI: 0.53-0.85, 0.54-0.96, respectively), but with the increased risks of developing NHL (RR = 1.18, 1.23; 95% CI: 1.02-1.35, 1.05-1.44, respectively); EBRT also showed increased risks of developing acute/ chronic myeloid leukemia (AML/CML, RR = 1.54, 1.56; 95% CI: 1.16-2.03,1.05-2.33, respectively); No increased risk of developing SHMs was detected in patients who only underwent prostatectomy. CONCLUSIONS: Although RT was found to be associated with the increased risks of developing SHMs in patients with T1/T2 PC, this finding cannot be extended to diverse types of SHMs. RT was correlated with the increased risks of the development of NHL, AML, and CML, but with the decreased risk of developing CLL. Prostatectomy did not increase the risk of developing SHMs.

Domestic radon exposure and risk of childhood leukemia: A meta-analysis.

PURPOSE: This meta-analysis evaluated the potential influence of environmental radon exposure on childhood leukemia. METHODS: We searched comprehensive electronic databases from PubMed, EMBASE, and Cochrane Library to identify studies evaluating the association between radon and leukemia. RESULTS: Ten eligible studies published from 1995 to 2014 were enrolled. Of these 10 studies, 8 were case-control studies (involving 10803 cases and 16202 controls) and 2 were cohort studies (involving 1,428 cases). Overall results as odds ratio (OR) with the corresponding 95% confidence intervals (95%CI) for case-control studies and fully adjusted hazard ratio (HR) with corresponding 95%CI for cohort studies were identified. A positive but weak association was found between radon exposure and childhood leukemia in case-control studies (summary OR 1.22, 95%CI 1.01-1.42) rather than cohort studies (summary HR 0.97, 95%CI 0.81-1.15). Heterogeneity or publication bias was not observed. Moreover, overall ORs were not changed by removing any single study, suggesting the stability and reliability of conclusions. CONCLUSIONS: Future prospective studies with well-controlled confounders are needed to verify the conclusion.

Predicting residential radon concentrations in Finland: Model development, validation, and application to childhood leukemia.

Objectives Inhaled radon gas is a known alpha-emitting carcinogen linked especially to lung cancer. Studies on higher concentrations of indoor radon and childhood leukemia have conflicting but largely negative results. In this study, we aimed to create a sophisticated statistical model to predict indoor radon concentrations and apply it to a Finnish childhood leukemia case-control dataset. Methods Prediction was based on ~80 000 indoor radon measurements, which were linked to national registries for potential indoor radon predictors based on the literature. In modelling, we used classical methods, random forests and deep neural networks. We had 1093 cases and 3279 controls from a nationwide case-control study. We estimated odds ratio (OR) for childhood leukemia using conditional logistic regression adjusted for potential confounders. Results The r 2of the final log-linear model was 0.21 for houses and 0.20 for apartments. Using random forest method, we were able to obtain slightly better fit for both houses (r 2= 0.28) and apartments (r 2= 0.23). In a risk analysis based on the case-control data with log-linear model, we observed a non-significant (P=0.54) increase with predicted radon concentrations [OR for the 2 ndquartile 1.08, 95% confidence interval (CI) 0.77-1.50, OR 1.10 with 95% CI 0.79-1.53 for the 3 rd, and 1.29 with 95% CI 0.93-1.77 for the highest quartile]. Conclusions Our modelling and the previously published models performed similarly but involves major uncertainties, and the results should be interpreted with caution. We observed a slight non-significant increase in risk of childhood leukemia related to higher average indoor radon concentrations.

Risk of Leukemia Associated with Protracted Low-Dose Radiation Exposure: Updated Results from the National Registry for Radiation Workers Study.

While the link between risk of leukemia and acute radiation exposure is well established for large doses received acutely, uncertainty remains around the translation of these risk estimates to occupational exposure scenarios where the doses are low and accumulated over time, possibly over many years. We present leukemia incidence and mortality radiation risk estimates derived from the National Registry for Radiation Workers, which is a large cohort of occupationally exposed workers from the United Kingdom (UK). The cohort comprised 173,081 workers from the UK who were monitored for occupational exposure to radiation. The cohort was followed for a total of 5.3 million person-years and the incidence and mortality due to leukemia was identified through to the end of follow-up in 2011. Poisson regression was used to investigate the relationship between cumulative radiation dose and leukemia mortality and incidence rates using excess relative risk (ERR) and excess additive risk (EAR) models. The results of this work showed a collective dose of 4,414 person-Sv accumulated by the cohort with an average cumulative dose of 25.5 mSv. Among male workers both the ERR and EAR models showed evidence of increased leukemia risk (excluding chronic lymphatic leukemia) associated with increasing cumulative dose. The ERR was 1.38 per Sv (90% CI: 0.04; 3.24) and EAR was 1.33 per 10,000 person-year-Sv (90% CI: 0.04; 2.89) when a linear model was used. These excess risks were driven by increased risks for chronic myeloid leukemia [ERR/Sv = 6.77 (90% CI: 2.14; 15.44)]. In conclusion, this study provides further evidence that leukemia risks may be increased by low-dose and protracted external radiation exposure. The risks are generally consistent with those observed in the atomic bomb survivor studies, as well as with risk coefficients on which international radiation safety standards, including the dose limits and constraints used to control exposures, are based.

Changes over time in the reported risk for childhood leukaemia and magnetic fields.

There have been many studies from 1979 to the present reporting raised risks for childhood leukaemia with exposure to power-frequency magnetic fields. There are also suggestions that the reported risk has been decreasing. We examine trends in the risk over time from all available studies. For 41 studies, we combine reported risks using inverse-variance weighting, drawing risk estimates from previous pooled analyses where possible for greater consistency. We examine the cumulative risk for studies published up to each successive calendar year for all studies and for various subsets, and test for a trend over the period. The cumulative relative risk has indeed declined, for our most rigorous analysis from a maximum 2.44 in 1997 to 1.58 in 2017, but not statistically significantly when tested as a linear trend. We find suggestions of higher risks in studies looking at higher exposures and in studies with better quality exposure assessment. We conclude that there is a decline in reported risk from the mid 1990s to now, which is unlikely to be solely explained by improving study quality but may be due to chance, and an elevated risk remains.

Dependence of the human leukemia risk on the dose and dose rate of continuous irradiation: Modeling study.

A biologically motivated dynamical model of the radiogenic leukemia risk assessment (Smirnova, 2015, 2017; Smirnova and Cucinotta, 2018) is applied to the study of the effects of dose rate N and dose D on the excess relative risk ERR for non-CLL leukemia among continuously irradiated humans. In the study, the dose rate N of continuous irradiation is varied from 3×10-6 to 0.576 Sv/day and the dose D is varied from zero to 2.2 Sv. In the considered range of doses D, the developed model reproduces the linear dependence of ERR on D for the low dose rates N. For higher N, the dependence of ERR on D remains linear for low doses D and becomes nonlinear for higher D, that agrees with empirical observations. In turn, for the considered values of D, the developed model reproduces the practical independence of the ratio ERR/D on N at low N, the inverse dependence of the ratio ERR/D on N at higher N, and the direct dependence of the ratio ERR/D on N at more high N, that also conforms to empirical observations. Additionally, the modeling values of ERR obtained for the scenarios of continuous irradiation corresponding to those for the nuclear industry workers, Chernobyl cleanup workers, and patients treated with radiotherapy, practically, coincide with the respective empirical data. All these modeling findings, along with those obtained in our previous works, demonstrate the predictive power of the developed model and its capability of estimating, on quantitative level, the excess relative risk for non-CLL leukemia among humans exposed to continuous irradiation in wide ranges of doses and dose rates.

Usefulness of cancer-free survival in estimating the lifetime attributable risk of cancer incidence from radiation exposure.

Risk projection models estimating the lifetime cancer risk from radiation exposure are generally based on exposure dose, age at exposure, attained age, gender and study-population-specific factors such as baseline cancer risks and survival rates. Because such models have mostly been based on the Life Span Study cohort of Japanese atomic bomb survivors, the baseline risks and survival rates in the target population should be considered when applying the cancer risk. The survival function used in the risk projection models that are commonly used in the radiological protection field to estimate the cancer risk from medical or occupational exposure is based on all-cause mortality. Thus, it may not be accurate for estimating the lifetime risk of high-incidence but not life-threatening cancer with a long-term survival rate. Herein, we present the lifetime attributable risk (LAR) estimates of all solid cancers except thyroid cancer, thyroid cancer, and leukemia except chronic lymphocytic leukemia in South Korea for lifetime exposure to 1 mGy per year using the cancer-free survival function, as recently applied in the Fukushima health risk assessment by the World Health Organization. Compared with the estimates of LARs using an overall survival function solely based on all-cause mortality, the LARs of all solid cancers except thyroid cancer, and thyroid cancer evaluated using the cancer-free survival function, decreased by approximately 13% and 1% for men and 9% and 5% for women, respectively. The LAR of leukemia except chronic lymphocytic leukemia barely changed for either gender owing to the small absolute difference between its incidence and mortality. Given that many cancers have a high curative rate and low mortality rate, using a survival function solely based on all-cause mortality may cause an overestimation of the lifetime risk of cancer incidence. The lifetime fractional risk was robust against the choice of survival function.

Secondary Acute Leukemia in Sarcoma Patients: A Population-Based Study.

PURPOSE: To compare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia. METHODS AND MATERIALS: Patients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population. RESULTS: A total of 72,945 patients were identified, with median follow-up of 131 months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02). CONCLUSIONS: Patients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small.

Childhood leukaemia near nuclear sites in Belgium, 2002-2008.

This paper describes an ecological study investigating whether there is an excess incidence of acute leukaemia among children aged 0-14 years living in the vicinity of the nuclear sites in Belgium. Poisson regression modelling was carried out for proximity areas of varying sizes. In addition, the hypothesis of a gradient in leukaemia incidence with increasing levels of surrogate exposures was explored by means of focused hypothesis tests and generalized additive models. For the surrogate exposures, three proxies were used, that is, residential proximity to the nuclear site, prevailing winds and simulated radioactive discharges, on the basis of mathematical dispersion modelling. No excess incidence of acute leukaemia was observed around the nuclear power plants of Doel or Tihange nor around the nuclear site of Fleurus, which is a major manufacturer of radioactive isotopes in Europe. Around the site of Mol-Dessel, however, two- to three-fold increased leukaemia incidence rates were found in children aged 0-14 years living in the 0-5, 0-10 and the 0-15 km proximity areas. For this site, there was evidence for a gradient in leukaemia incidence with increased proximity, prevailing winds and simulated radioactive discharges, suggesting a potential link with the site that needs further investigation. An increased incidence of acute leukaemia in children aged 0-14 years was observed around one nuclear site that hosted reprocessing activities in the past and where nuclear research activities and radioactive waste treatment are ongoing.

The Krümmel (Germany) Childhood Leukaemia Cluster: a review and update.

The debate surrounding possible adverse health effects from the civil use of nuclear power under normal operating conditions has been on-going since its introduction. It was particularly intensified by the detection of three leukaemia clusters near nuclear installations, i.e. near the reprocessing plants in Sellafield and Dounreay, UK, and near the Krümmel nuclear power plant, Germany, the last of which commenced between 1990 and 1991 and was first described in 1992; it continued until 2003, and an elevated risk up to 2005 has been reported in the literature. A number of expert commissions and working groups were set up by the governments of the German federal states of Lower Saxony and Schleswig-Holstein to investigate the possible causes of the cluster. An overview of the many risk factors that were investigated as a possible explanation of the Krümmel cluster is given here, focussing on radiation, but also including other risk factors. Further, results from related epidemiological and cytogenetic studies are described. In summary, the cause of the occurrence of the Krümmel cluster has to be considered as unknown. Further research on the causes of childhood leukaemia is needed, focussing on epigenetics and on gene-environment interaction. An update of the leukaemia incidence around the Krümmel site shows that the incidence rates are now comparable to the average rate in Germany.

Residential Exposure to Natural Background Radiation and Risk of Childhood Acute Leukemia in France, 1990-2009.

BACKGROUND: Exposures to high-dose ionizing radiation and high-dose rate ionizing radiation are established risk factors for childhood acute leukemia (AL). The risk of AL following exposure to lower doses due to natural background radiation (NBR) has yet to be conclusively determined. METHODS: AL cases diagnosed over 1990-2009 (9,056 cases) were identified and their municipality of residence at diagnosis collected by the National Registry of Childhood Cancers. The Geocap study, which included the 2,763 cases in 2002-2007 and 30,000 population controls, was used for complementary analyses. NBR exposures were modeled on a fine scale (36,326 municipalities) based on measurement campaigns and geological data. The power to detect an association between AL and dose to the red bone marrow (RBM) fitting UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) predictions was 92%, 45% and 99% for exposure to natural gamma radiation, radon and total radiation, respectively. RESULTS: AL risk, irrespective of subtype and age group, was not associated with the exposure of municipalities to radon or gamma radiation in terms of yearly exposure at age reached, cumulative exposure or RBM dose. There was no confounding effect of census-based socio-demographic indicators, or environmental factors (road traffic, high voltage power lines, vicinity of nuclear plants) related to AL in the Geocap study. CONCLUSIONS: Our findings do not support the hypothesis that residential exposure to NBR increases the risk of AL, despite the large size of the study, fine scale exposure estimates and wide range of exposures over France. However, our results at the time of diagnosis do not rule out a slight association with gamma radiation at the time of birth, which would be more in line with the recent findings in the UK and Switzerland.

Myelodysplastic Syndromes and Acute Myeloid Leukemia After Radiotherapy for Prostate Cancer: A Population-Based Study.

BACKGROUND: To understand the impact of radiotherapy on the development of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) among elderly prostate cancer patients. METHODS: We performed a retrospective cohort study of elderly prostate cancer patients diagnosed during 1999-2011 by using the National Cancer Institute's Surveillance, Epidemiology and End Results-Medicare linked database. Competing risk analyses adjusting for patient characteristics were conducted to assess the impact of radiotherapy on the development of subsequent MDS/AML, compared with surgery. RESULTS: Of 32,112 prostate cancer patients, 14,672 underwent radiotherapy, and 17,440 received surgery only. The median follow-up was 4.68 years. A total of 157 (0.47%) prostate cancer patients developed subsequent MDS or AML, and the median time to develop MDS/AML was 3.30 (range: 0.16-9.48) years. Compared with prostate cancer patients who received surgery only, patients who underwent radiotherapy had a significantly increased risk of developing MDS/AML (hazard ratio [HR] =1.51, 95% confidence interval [CI]: 1.07-2.13). When radiotherapy was further categorized by modalities (brachytherapy, conventional conformal radiotherapy, and intensity-modulated radiotherapy [IMRT]), increased risk of second MDS/AML was only observed in the IMRT group (HR = 1.66, 95% CI: 1.09-2.54). CONCLUSIONS: Our findings suggest that radiotherapy for prostate cancer increases the risk of MDS/AML, and the impact may differ by modality. Additional studies with longer follow-up are needed to further clarify the role of radiotherapy in the development of subsequent myeloid malignancies. A better understanding may help patients, physicians, and other stakeholders make more informed treatment decisions. Prostate 77:437-445, 2017. © 2016 Wiley Periodicals, Inc.

Epidemiological study of power lines and childhood cancer in the UK: further analyses.

We report further analyses from an epidemiological study of childhood cancer and residence at birth near high-voltage power lines in the UK. These results suggest that the elevated risks for childhood leukaemia that we previously found for overhead power lines may be higher for older age at diagnosis and for myeloid rather than lymphoid leukaemia. There are differences across regions of birth but not forming any obvious pattern. Our results suggest the decline in risk we previously reported from the 1960s to the 2000s is linked to calendar year of birth or of cancer occurrence rather than the age of the power lines concerned. Finally, we update our previous analysis of magnetic fields to include later subjects.

[Exposure to CT scans in childhood and long-term cancer risk: A review of epidemiological studies]. / Exposition à la scanographie dans l'enfance et risque de cancer à long terme. Une synthèse des études épidémiologiques récentes.

Amongst medical exams requiring ionizing radiation, computed tomography (CT) scans are used more frequently, including in children. These CT examinations are associated with absorbed doses that are much higher than those associated with conventional radiology. In comparison to adults, children have a greater sensitivity to radiation and a longer life span with more years at cancer risks. Five epidemiological studies on cancer risks after CT scan exposure during childhood were published between 2012 and 2015. The results of these studies are consistent and show an increase of cancer risks in children who have been exposed to several CT scans. However, methodological limits due to indication bias, retrospective assessment of radiation exposure from CT scans and lack of statistical power are to be taken into consideration. International projects such as EPI-CT (Epidemiological study to quantify risks for pediatric computerized tomography and to optimize dose), with a focus on dosimetric reconstruction and minimization of bias will provide more precise results. In the meantime, available results reinforce the necessity of justification and optimization of doses.