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.
Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of ...the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.
Leisure time physical activity reduces the risk of premature mortality, but the years of life expectancy gained at different levels remains unclear. Our objective was to determine the years of life ...gained after age 40 associated with various levels of physical activity, both overall and according to body mass index (BMI) groups, in a large pooled analysis.
We examined the association of leisure time physical activity with mortality during follow-up in pooled data from six prospective cohort studies in the National Cancer Institute Cohort Consortium, comprising 654,827 individuals, 21-90 y of age. Physical activity was categorized by metabolic equivalent hours per week (MET-h/wk). Life expectancies and years of life gained/lost were calculated using direct adjusted survival curves (for participants 40+ years of age), with 95% confidence intervals (CIs) derived by bootstrap. The study includes a median 10 y of follow-up and 82,465 deaths. A physical activity level of 0.1-3.74 MET-h/wk, equivalent to brisk walking for up to 75 min/wk, was associated with a gain of 1.8 (95% CI: 1.6-2.0) y in life expectancy relative to no leisure time activity (0 MET-h/wk). Higher levels of physical activity were associated with greater gains in life expectancy, with a gain of 4.5 (95% CI: 4.3-4.7) y at the highest level (22.5+ MET-h/wk, equivalent to brisk walking for 450+ min/wk). Substantial gains were also observed in each BMI group. In joint analyses, being active (7.5+ MET-h/wk) and normal weight (BMI 18.5-24.9) was associated with a gain of 7.2 (95% CI: 6.5-7.9) y of life compared to being inactive (0 MET-h/wk) and obese (BMI 35.0+). A limitation was that physical activity and BMI were ascertained by self report.
More leisure time physical activity was associated with longer life expectancy across a range of activity levels and BMI groups. Please see later in the article for the Editors' Summary.
In Japan, cervical cancer incidence has increased since the late 1990s especially among young women, despite a decreasing trend in most developed countries. Here, we examined age, period and birth ...cohort trends in cervical cancer incidence rates from 1985 to 2012. Incidence rates were ascertained using three population‐based cancer registries and analyzed using Joinpoint regression and age‐period‐cohort models. We compared the findings in Japan to trends among Japanese‐Americans in the Surveillance, Epidemiology, and End Results Registries and among women in South Korea using the Korea Central Registry. Age‐standardized incidence rates in Japan decreased by 1.7% per year (95% confidence interval − 3.3%, 0.0%) until 1997 and thereafter increased by 2.6% per year (1.1%, 4.2%). Incidence rates increased among women under age 50, were stable among women aged 50–54, and decreased or remained stable among women aged 55 and over. The age‐standardized incidence rate ratio by birth cohort showed a U‐shaped pattern with the lowest rates in women born in the late 1930s and 1940s. In comparison, women born before 1920 and after 1970 had about double the incidence. Increasing risk in recent birth cohorts was not evident in Japanese‐American or South Korean women. The trends in Japan may be attributable to increasing prevalence of human papillomavirus (HPV) infection among young women. Screening and vaccination have been shown to be highly effective and would help reverse these trends.
What's new?
Why is cervical cancer on the rise in Japan, while it's decreasing in most other developed countries? These authors analyzed incidence rates in Japan and compared them with data from Japanese‐Americans and South Korean women. They found increasing incidence among recent birth cohorts in Japan, which were not seen among Japanese‐American or South Korean women. For one thing, cervical cancer screening uptake in Japan lags significantly behind that of South Korea and the US, reaching only 34% coverage in 2014. The strong birth cohort effect suggests an increasing prevalence of HPV, which can be counteracted by better screening and vaccination.
Summary Background Improvements in cancer survival have made the long-term risks from treatments more important, including the risk of developing a second cancer after radiotherapy. We aimed to ...estimate the proportion of second cancers attributable to radiotherapy in adults with data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries. Methods We used nine of the SEER registries to systematically analyse 15 cancer sites that are routinely treated with radiotherapy (oral and pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye and orbit, brain and CNS, and thyroid). The cohort we studied was composed of patients aged 20 years or older who were diagnosed with a first primary invasive solid cancer reported in the SEER registries between Jan 1, 1973, and Dec 31, 2002. Relative risks (RRs) for second cancer in patients treated with radiotherapy versus patients not treated with radiotherapy were estimated with Poisson regression adjusted for age, stage, and other potential confounders. Findings 647 672 cancer patients who were 5-year survivors were followed up for a mean 12 years (SD 4·5, range 5–34); 60 271 (9%) developed a second solid cancer. For each of the first cancer sites the RR of developing a second cancer associated with radiotherapy exceeded 1, and varied from 1·08 (95% CI 0·79–1·46) after cancers of the eye and orbit to 1·43 (1·13–1·84) after cancer of the testes. In general, the RR was highest for organs that typically received greater than 5 Gy, decreased with increasing age at diagnosis, and increased with time since diagnosis. We estimated a total of 3266 (2862–3670) excess second solid cancers that could be related to radiotherapy, that is 8% (7–9) of the total in all radiotherapy patients (≥1 year survivors) and five excess cancers per 1000 patients treated with radiotherapy by 15 years after diagnosis. Interpretation A relatively small proportion of second cancers are related to radiotherapy in adults, suggesting that most are due to other factors, such as lifestyle or genetics. Funding US National Cancer Institute.
Summary Background Reduction of premature mortality is a UN Sustainable Development Goal. Unlike other high-income countries, age-adjusted mortality in the USA plateaued in 2010 and increased ...slightly in 2015, possibly because of rising premature mortality. We aimed to analyse trends in mortality in the USA between 1999 and 2014 in people aged 25–64 years by age group, sex, and race and ethnicity, and to identify specific causes of death underlying the temporal trends. Methods For this analysis, we used cause-of-death and demographic data from death certificates from the US National Center for Health Statistics, and population estimates from the US Census Bureau. We estimated annual percentage changes in mortality using age-period-cohort models. Age-standardised excess deaths were estimated for 2000 to 2014 as observed deaths minus expected deaths (estimated from 1999 mortality rates). Findings Between 1999 and 2014, premature mortality increased in white individuals and in American Indians and Alaska Natives. Increases were highest in women and those aged 25–30 years. Among 30-year-olds, annual mortality increases were 2·3% (95% CI 2·1–2·4) for white women, 0·6% (0·5–0·7) for white men, and 4·3% (3·5–5·0) and 1·9% (1·3–2·5), respectively, for American Indian and Alaska Native women and men. These increases were mainly attributable to accidental deaths (primarily drug poisonings), chronic liver disease and cirrhosis, and suicide. Among individuals aged 25–49 years, an estimated 111 000 excess premature deaths occurred in white individuals and 6600 in American Indians and Alaska Natives during 2000–14. By contrast, premature mortality decreased substantially across all age groups in Hispanic individuals (up to 3·2% per year), black individuals (up to 3·9% per year), and Asians and Pacific Islanders (up to 2·6% per year), mainly because of declines in HIV, cancer, and heart disease deaths, resulting in an estimated 112 000 fewer deaths in Hispanic individuals, 311 000 fewer deaths in black individuals, and 34 000 fewer deaths in Asians and Pacific Islanders aged 25–64 years. During 2011–14, American Indians and Alaska Natives had the highest premature mortality, followed by black individuals. Interpretation Important public health successes, including HIV treatment and smoking cessation, have contributed to declining premature mortality in Hispanic individuals, black individuals, and Asians and Pacific Islanders. However, this progress has largely been negated in young and middle-aged (25–49 years) white individuals, and American Indians and Alaska Natives, primarily because of potentially avoidable causes such as drug poisonings, suicide, and chronic liver disease and cirrhosis. The magnitude of annual mortality increases in the USA is extremely unusual in high-income countries, and a rapid public health response is needed to avert further premature deaths. Funding US National Cancer Institute Intramural Research Program.
20 years ago, 3 manuscripts describing doses and potential cancer risks from CT scans in children raised awareness of a growing public health problem. We reviewed the epidemiological studies that ...were initiated in response to these concerns that assessed cancer risks from CT scans using medical record linkage. We evaluated the study methodology and findings and provide recommendations for optimal study design for new efforts. We identified 17 eligible studies; 13 with published risk estimates, and 4 in progress. There was wide variability in the study methodology, however, which made comparison of findings challenging. Key differences included whether the study focused on childhood or adulthood exposure, radiosensitive outcomes (
leukemia, brain tumors) or all cancers, the exposure metrics (
organ doses, effective dose or number of CTs) and control for biases (
latency and exclusion periods and confounding by indication). We were able to compare results for the subset of studies that evaluated leukemia or brain tumors. There were eight studies of leukemia risk in relation to red bone marrow (RBM) dose, effective dose or number of CTs; seven reported a positive dose-response, which was statistically significant (
< 0.05) in four studies. Six of the seven studies of brain tumors also found a positive dose-response and in five, this was statistically significant. Mean RBM dose ranged from 6 to 12 mGy and mean brain dose from 18 to 43 mGy. In a meta-analysis of the studies of childhood exposure the summary ERR/100 mGy was 1.78 (95%CI: 0.01-3.53) for leukemia/myelodisplastic syndrome (
= 5 studies) and 0.80 (95%CI: 0.48-1.12) for brain tumors (
= 4 studies) (p-heterogeneity >0.4). Confounding by cancer pre-disposing conditions was unlikely in these five studies of leukemia. The summary risk estimate for brain tumors could be over estimated, however, due to reverse causation. In conclusion, there is growing evidence from epidemiological data that CT scans can cause cancer. The absolute risks to individual patients are, however, likely to be small. Ongoing large multicenter cohorts and future pooling efforts will provide more precise risk quantification.
Purpose
Heart disease is a significant concern among breast cancer survivors, in part due to cardiotoxic treatments including chemotherapy and radiotherapy. Long-term trends in heart disease ...mortality have not been well characterized. We examined heart disease mortality trends among US breast cancer survivors by treatment type.
Methods
We included first primary invasive breast cancer survivors diagnosed between 1975 and 2016 (aged 18–84; survived 12 + months; received initial chemotherapy, radiotherapy, or surgery) in the SEER-9 Database. Standardized mortality ratios (SMRs) and 10-year cumulative heart disease mortality estimates accounting for competing events were calculated by calendar year of diagnosis and initial treatment regimen.
P
trends
were assessed using Poisson regression. All statistical tests were 2-sided.
Results
Of 516,916 breast cancer survivors, 40,812 died of heart disease through 2017. Heart disease SMRs declined overall from 1975–1979 to 2010–2016 (SMR 1.01 95%CI: 0.98, 1.03 to 0.74 0.69, 0.79,
p
trend
< 0.001). This decline was also observed for survivors treated with radiotherapy alone and chemotherapy plus radiotherapy. A sharper decline in heart disease SMRs was observed from 1975 to 1989 for left-sided radiotherapy, compared to right-sided. In contrast, there was a non-significant increasing trend in SMRs for chemotherapy alone, and significant by regional stage (
p
trend
= 0.036). Largest declines in 10-year cumulative mortality were observed from 1975–1984 to 2005–2016 among surgery only: 7.02% (95%CI: 6.80%, 7.23%) to 4.68% (95%CI: 4.39%, 4.99%) and radiotherapy alone: 6.35% (95%CI: 5.95%, 6.77%) to 2.94% (95%CI: 2.73%, 3.16%).
Conclusions
We observed declining heart disease mortality trends by most treatment types yet increasing for regional stage patients treated with chemotherapy alone, highlighting a need for additional studies with detailed treatment data and cardiovascular management throughout cancer survivorship.
The importance of reproductive history in breast tissue development and etiology of sporadic breast cancer in females is well established. However, there is limited evidence of factors, other than ...age, that modify risk of radiation-related breast cancer. In this study, we evaluated breast cancer incidence in the Life Span Study cohort of atomic bomb survivors, adding 11 years of follow-up and incorporating reproductive history data. We used Poisson regression models to describe radiation risks and modifying effects of age and reproductive factors. Among 62,534 females, we identified 1,470 breast cancers between 1958 and 2009. Of 397 new cases diagnosed since 1998, 75% were exposed before age 20. We found a strong linear dose response with excess relative risk (ERR) of 1.12 per Gy 95% confidence interval (CI): 0.73 to 1.59 for females at age 70 after exposure at age 30. The ERR decreased with increasing attained age ( P = 0.007) while excess absolute rate (EAR) increased with attained age up to age 70 ( P < 0.001). Age at menarche was a strong modifier of the radiation effect: for a given dose, both the ERR and EAR decreased with increasing age at menarche ( P = 0.007 and P < 0.001). Also, independently, age-at-exposure effects on ERR and EAR differed before and after menarche ( P = 0.043 and P = 0.015, respectively, relative to log-linear trends), with highest risks for exposures around menarche. Despite the small number of male breast cancers (n = 10), the data continue to suggest a dose response (ERR per Gy = 5.7; 95% CI: 0.3 to 30.8; P = 0.018). Persistently increased risk of female breast cancer after radiation exposure and its modification pattern suggests heightened breast sensitivity during puberty.
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