Amy Berrington de Gonzalez

Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study

Summary Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. Methods In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. Findings During follow-up, 74 of 178 604 patients were diagnosed with leukaemia and 135 of 176 587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005–0·120; p=0·0097) and brain tumours (0·023, 0·010–0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46–6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose 60·42 mGy) was 2·82 (1·33–6·03). Interpretation Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain cancer. Because these cancers are relatively rare, the cumulative absolute risks are small: in the 10 years after the first scan for patients younger than 10 years, one excess case of leukaemia and one excess case of brain tumour per 10 000 head CT scans is estimated to occur. Nevertheless, although clinical benefits should outweigh the small absolute risks, radiation doses from CT scans ought to be kept as low as possible and alternative procedures, which do not involve ionising radiation, should be considered if appropriate. Funding US National Cancer Institute and UK Department of Health.

Radiation Dose Associated With Common Computed Tomography Examinations and the Associated Lifetime Attributable Risk of Cancer

BACKGROUND Use of computed tomography (CT) for diagnostic evaluation has increased dramatically over the past 2 decades. Even though CT is associated with substantially higher radiation exposure than conventional radiography, typical doses are not known. We sought to estimate the radiation dose associated with common CT studies in clinical practice and quantify the potential cancer risk associated with these examinations. METHODS We conducted a retrospective cross-sectional study describing radiation dose associated with the 11 most common types of diagnostic CT studies performed on 1119 consecutive adult patients at 4 San Francisco Bay Area institutions in California between January 1 and May 30, 2008. We estimated lifetime attributable risks of cancer by study type from these measured doses. RESULTS Radiation doses varied significantly between the different types of CT studies. The overall median effective doses ranged from 2 millisieverts (mSv) for a routine head CT scan to 31 mSv for a multiphase abdomen and pelvis CT scan. Within each type of CT study, effective dose varied significantly within and across institutions, with a mean 13-fold variation between the highest and lowest dose for each study type. The estimated number of CT scans that will lead to the development of a cancer varied widely depending on the specific type of CT examination and the patients age and sex. An estimated 1 in 270 women who underwent CT coronary angiography at age 40 years will develop cancer from that CT scan (1 in 600 men), compared with an estimated 1 in 8100 women who had a routine head CT scan at the same age (1 in 11 080 men). For 20-year-old patients, the risks were approximately doubled, and for 60-year-old patients, they were approximately 50% lower. CONCLUSION Radiation doses from commonly performed diagnostic CT examinations are higher and more variable than generally quoted, highlighting the need for greater standardization across institutions.

Body-mass index and mortality among 1.46 million white adults.

BACKGROUND A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries

BACKGROUND Diagnostic X-rays are the largest man-made source of radiation exposure to the general population, contributing about 14% of the total annual exposure worldwide from all sources. Although diagnostic X-rays provide great benefits, that their use involves some small risk of developing cancer is generally accepted. Our aim was to estimate the extent of this risk on the basis of the annual number of diagnostic X-rays undertaken in the UK and in 14 other developed countries. METHODS We combined data on the frequency of diagnostic X-ray use, estimated radiation doses from X-rays to individual body organs, and risk models, based mainly on the Japanese atomic bomb survivors, with population-based cancer incidence rates and mortality rates for all causes of death, using life table methods. FINDINGS Our results indicate that in the UK about 0.6% of the cumulative risk of cancer to age 75 years could be attributable to diagnostic X-rays. This percentage is equivalent to about 700 cases of cancer per year. In 13 other developed countries, estimates of the attributable risk ranged from 0.6% to 1.8%, whereas in Japan, which had the highest estimated annual exposure frequency in the world, it was more than 3%. INTERPRETATION We provide detailed estimates of the cancer risk from diagnostic X-rays. The calculations involved a number of assumptions and so are inevitably subject to considerable uncertainty. The possibility that we have overestimated the risks cannot be ruled out, but that we have underestimated them substantially seems unlikely.

Cervical cancer and use of hormonal contraceptives: a systematic review.

BACKGROUND Human papillomavirus (HPV) is believed to be the most important cause of cervical cancer. Recent studies suggest that long duration use of oral contraceptives increases the risk of cervical cancer in HPV positive women. METHODS Results from published studies were combined to examine the relationship between invasive and in situ cervical cancer and duration and recency of use of hormonal contraceptives, with particular attention to HPV infection. FINDINGS 28 eligible studies were identified, together including 12531 women with cervical cancer. Compared with never users of oral contraceptives, the relative risks of cervical cancer increased with increasing duration of use: for durations of approximately less than 5 years, 5-9 years, and 10 or more years, respectively, the summary relative risks were 1.1 (95% CI 1.1-1.2), 1.6 (1.4-1.7), and 2.2 (1.9-2.4) for all women; and 0.9 (0.7-1.2), 1.3 (1.0-1.9), and 2.5 (1.6-3.9) for HPV positive women. The results were broadly similar for invasive and in situ cervical cancers, for squamous cell and adenocarcinoma, and in studies that adjusted for HPV status, number of sexual partners, cervical screening, smoking, or use of barrier contraceptives. The limited available data suggest that the relative risk of cervical cancer may decrease after use of oral contraceptives ceases. However, study designs varied and there was some heterogeneity between study results. INTERPRETATION Although long duration use of hormonal contraceptives is associated with an increased risk of cervical cancer, the public health implications of these findings depend largely on the extent to which the observed associations remain long after use of hormonal contraceptives has ceased, and this cannot be evaluated properly from published data.

Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.

Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m2. Findings All-cause mortality was minimal at 20·0–25·0 kg/m2 (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m2; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m2), and increased significantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m2; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m2; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m2). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m2) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m2) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m2) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m2, mortality increased approximately log-linearly with BMI; the HR per 5 kg/m2 units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m2 units higher BMI (for BMI over 25 kg/m2) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

Leisure Time Physical Activity and Mortality: A Detailed Pooled Analysis of the Dose-Response Relationship

IMPORTANCE The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. OBJECTIVE To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. DESIGN, SETTING, AND PARTICIPANTS We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. EXPOSURES Leisure time moderate- to vigorous-intensity physical activity. MAIN OUTCOMES AND MEASURES The upper limit of mortality benefit from high levels of leisure time physical activity. RESULTS Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. CONCLUSIONS AND RELEVANCE Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis.

Analyzing data from over 650,000 individuals, Dr. Steven Moore and colleagues report that greater amounts of leisure-time physical activity were associated with higher life expectancy across a wide range of activity levels and body mass index groups.

Risks associated with low doses and low dose rates of ionizing radiation: why linearity may be (almost) the best we can do.

Deterministic and stochastic effects associated with high-dose ionizing radiation (x-ray) exposure have been known for almost as long as ionizing radiation itself (1–3). At lower doses, radiation risks are primarily stochastic effects, in particular, somatic effects (cancer) rather than the deterministic effects characteristic of higher-dose exposure (4–6). In contrast to deterministic effects, for stochastic effects, scientific committees generally assume that at sufficiently low doses there is a positive linear component to the dose response—that is, that there is no threshold (4–6). This does not preclude there being higher-order (eg, quadratic) powers of dose in the dose response that may be of importance at higher doses. It is on this basis that models linear (or linear-quadratic) in dose are often used to extrapolate the experience of the Japanese atomic bomb survivors (who were typically exposed at a high dose rate to moderate doses [average, 0.1 Sv]) to estimate risks from low doses and low dose rates (4–6). Most population-based cancer risk estimates are based primarily on the Japanese atomic bomb survivor Life Span Study (LSS) cohort data (4–6). However, evidence of excess risks comes from a large number of other studies as well. In the parallel editorial (7), evidence is presented for possible real (or at least “practical”) thresholds or “hormetic” (beneficial) effects of low doses of ionizing radiation. As we summarize here, and in contrast to the arguments of Tubiana et al (7), we judge that there is little epidemiologic or biologic evidence for these for cancer. The arguments are of three forms: (a) assessment of the degree of curvature in the cancer dose response within the Japanese atomic bomb survivors and other exposed groups (in particular, departure from linear or linear-quadratic curvature), (b) consistency of risks between the Japanese and other moderate- and low-dose cohorts, and (c) assessment of biologic data on mechanisms. Most of the information on radiation-induced cancer risk comes from (a) the Japanese atomic bomb survivors, (b) medically exposed populations, (c) occupationally exposed groups, and (d) environmentally exposed groups (6). In the higher-dose radiation therapy studies, where doses received are very much higher than in the LSS, sometimes in the range at which cell sterilization occurs, excess cancer risks per unit dose tend to be less than in comparable subsets of the LSS (8,9). However, as we show, risks in moderate- and low-dose medically and occupationally exposed groups are generally consistent with those in the LSS.

Coronary artery calcification screening: estimated radiation dose and cancer risk

BACKGROUND Multidetector computed tomography has been proposed as a tool for routine screening for coronary artery calcification in asymptomatic individuals. As proposed, such screening could involve tens of millions of individuals, but detailed estimates of radiation doses and potential risk of radiation-induced cancer are not currently available. We estimated organ-specific radiation doses and associated cancer risks from coronary artery calcification screening with multidetector computed tomography according to patient age, frequency of screening, and scan protocol. METHODS Radiation doses delivered to adult patients were calculated from a range of available protocols using Monte Carlo radiation transport. Radiation risk models, derived using data from Japanese atomic bomb survivors and medically exposed cohorts, were used to estimate the excess lifetime risk of radiation-induced cancer. RESULTS The radiation dose from a single coronary artery calcification computed tomographic scan varied more than 10-fold (effective dose range, 0.8-10.5 mSv) depending on the protocol. In general, higher radiation doses were associated with higher x-ray tube current, higher tube potential, spiral scanning with low pitch, and retrospective gating. The wide dose variation also resulted in wide variation in estimated radiation-induced cancer risk. Assuming screening every 5 years from the age of 45 to 75 years for men and 55 to 75 years for women, the estimated excess lifetime cancer risk using the median dose of 2.3 mSv was 42 cases per 100 000 men (range, 14-200 cases) and 62 cases per 100 000 women (range, 21-300 cases). CONCLUSIONS These radiation risk estimates can be compared with potential benefits from screening, when such estimates are available. Doses and therefore risks can be minimized by the use of optimized protocols.