Professor Amy Berrington
Group Leader: Clinical Cancer Epidemiology
Biography
Professor Amy Berrington originally trained in mathematics and applied statistics and then received a DPhil in Cancer Epidemiology from the University of Oxford in 2001. After completing her postdoctoral research in Professor Valerie Beral’s department at the University of Oxford she moved to the US in 2005 to take up a position as an Assistant Professor in Epidemiology & Biostatistics at the Johns Hopkins Bloomberg School of Public Health.
She joined the Radiation Epidemiology Branch at the US National Cancer Institute in 2008, was awarded scientific tenure as a Senior Investigator in 2011 and promoted to Branch Chief in 2014. Professor Berrington joined the ICR in 2022 as Group Leader in Clinical Cancer Epidemiology.
Professor Berrington specialises in using real world data to quantify the late-effects from cancer treatments, medical radiation exposures and other medications. She has led several large-scale electronic record linkage studies including a cohort study of breast cancer survivors, the UK Pediatric CT scan cohort and the first multi-center study comparing proton therapy to photon therapy for childhood cancer treatment.
She has a particular interest in the epidemiological methods that underpin the use of real world data and is co-editor of a forthcoming book on these methods for bias assessment. Since joining ICR she has become the Principal Investigator for the Generations Study.
Professor Berrington is the Vice-Chair of the National Academy of Science Nuclear and Radiation Studies, the founding President of the International Society for Radiation Epidemiology and Dosimetry (ISORED) and has served on many national and international radiation and cancer epidemiology advisory boards and review committees. She previously served on the editorial board for the American Journal of Epidemiology.
Related pages
Types of Publications
Journal articles
<h4>Background</h4>Breast cancer survivors are at increased risk for developing second primary cancers compared with the general population. Little is known about whether body mass index (BMI) increases this risk. We examined the association between BMI and second cancers among women with incident invasive breast cancer.<h4>Methods</h4>This retrospective cohort included 6481 patients from Kaiser Permanente Colorado and Washington of whom 822 (12.7%) developed a second cancer (mean follow-up was 88.0 months). BMI at the first cancer was extracted from the medical record. Outcomes included: 1) all second cancers, 2) obesity-related second cancers, 3) any second breast cancer, and 4) estrogen receptor-positive second breast cancers. Multivariable Poisson regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for second cancers associated with BMI adjusted for site, diagnosis year, treatment, demographic, and tumor characteristics.<h4>Results</h4>The mean age at initial breast cancer diagnosis was 61.2 (SD = 11.8) years. Most cases were overweight (33.4%) or obese (33.8%) and diagnosed at stage I (62.0%). In multivariable models, for every 5 kg/m2 increase in BMI, the risk of any second cancer diagnosis increased by 7% (RR = 1.07, 95% CI = 1.01 to 1.14); 13% (RR = 1.13, 95% CI = 1.05 to 1.21) for obesity-related cancers, 11% (RR = 1.11, 95% CI = 1.02 to 1.21) for a second breast cancer, and 15% (RR = 1.15, 95% CI = 1.04 to 1.27) for a second estrogen receptor-positive breast cancer.<h4>Conclusions</h4>We observed a statistically significant increased risk of second cancers associated with increasing BMI. These findings have important public health implications given the prevalence of overweight and obesity in breast cancer survivors and underscore the need for effective prevention strategies.
<h4>Purpose</h4>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.<h4>Methods</h4>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<sub>trends</sub> were assessed using Poisson regression. All statistical tests were 2-sided.<h4>Results</h4>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<sub>trend</sub> < 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<sub>trend</sub> = 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%).<h4>Conclusions</h4>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.
<h4>Background</h4>Although racial/ethnic disparities in U.S. COVID-19 death rates are striking, focusing on COVID-19 deaths alone may underestimate the true effect of the pandemic on disparities. Excess death estimates capture deaths both directly and indirectly caused by COVID-19.<h4>Objective</h4>To estimate U.S. excess deaths by racial/ethnic group.<h4>Design</h4>Surveillance study.<h4>Setting</h4>United States.<h4>Participants</h4>All decedents.<h4>Measurements</h4>Excess deaths and excess deaths per 100 000 persons from March to December 2020 were estimated by race/ethnicity, sex, age group, and cause of death, using provisional death certificate data from the Centers for Disease Control and Prevention (CDC) and U.S. Census Bureau population estimates.<h4>Results</h4>An estimated 2.88 million deaths occurred between March and December 2020. Compared with the number of expected deaths based on 2019 data, 477 200 excess deaths occurred during this period, with 74% attributed to COVID-19. Age-standardized excess deaths per 100 000 persons among Black, American Indian/Alaska Native (AI/AN), and Latino males and females were more than double those in White and Asian males and females. Non-COVID-19 excess deaths also disproportionately affected Black, AI/AN, and Latino persons. Compared with White males and females, non-COVID-19 excess deaths per 100 000 persons were 2 to 4 times higher in Black, AI/AN, and Latino males and females, including deaths due to diabetes, heart disease, cerebrovascular disease, and Alzheimer disease. Excess deaths in 2020 resulted in substantial widening of racial/ethnic disparities in all-cause mortality from 2019 to 2020.<h4>Limitations</h4>Completeness and availability of provisional CDC data; no estimates of precision around results.<h4>Conclusion</h4>There were profound racial/ethnic disparities in excess deaths in the United States in 2020 during the COVID-19 pandemic, resulting in rapid increases in racial/ethnic disparities in all-cause mortality between 2019 and 2020.<h4>Primary funding source</h4>National Institutes of Health 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 (<i>e.g.</i> leukemia, brain tumors) or all cancers, the exposure metrics (<i>e.g.</i> organ doses, effective dose or number of CTs) and control for biases (<i>e.g.</i> 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 (<i>p</i> < 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 (<i>n</i> = 5 studies) and 0.80 (95%CI: 0.48-1.12) for brain tumors (<i>n</i> = 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.
<h4>Purpose</h4>Since the 1980s, both the incidence of differentiated thyroid cancer (DTC) and use of radioactive iodine (RAI) treatment increased markedly. RAI has been associated with an increased risk of leukemia, but risks of second solid malignancies remain unclear. We aimed to quantify risks of second malignancies associated with RAI treatment for DTC in children and young adults, who are more susceptible than older adults to the late effects of radiation.<h4>Methods</h4>Using nine US SEER cancer registries (1975-2017), we estimated relative risks (RRs) for solid and hematologic malignancies associated with RAI (yes <i>v</i> no or unknown) using Poisson regression among ≥ 5- and ≥ 2-year survivors of nonmetastatic DTC diagnosed before age 45 years, respectively.<h4>Results</h4>Among 27,050 ≥ 5-year survivors (median follow-up = 15 years), RAI treatment (45%) was associated with increased risk of solid malignancies (RR = 1.23; 95% CI, 1.11 to 1.37). Risks were increased for uterine cancer (RR = 1.55; 95% CI, 1.03 to 2.32) and nonsignificantly for cancers of the salivary gland (RR = 2.15; 95% CI, 0.91 to 5.08), stomach (RR = 1.61; 95% CI, 0.70 to 3.69), lung (RR = 1.42; 95% CI, 0.97 to 2.08), and female breast (RR = 1.18; 95% CI, 0.99 to 1.40). Risks of total solid and female breast cancer, the most common cancer type, were highest among ≥ 20-year DTC survivors (RR<sub>solid</sub> = 1.47; 95% CI, 1.24 to 1.74; RR<sub>breast</sub> = 1.46; 95% CI, 1.10 to 1.95). Among 32,171 ≥ 2-year survivors, RAI was associated with increased risk of hematologic malignancies (RR = 1.51; 95% CI, 1.08 to 2.01), including leukemia (RR = 1.92; 95% CI, 1.04 to 3.56). We estimated that 6% of solid and 14% of hematologic malignancies in pediatric and young adult DTC survivors may be attributable to RAI.<h4>Conclusion</h4>In addition to leukemia, RAI treatment for childhood and young-adulthood DTC was associated with increased risks of several solid cancers, particularly more than 20 years after exposure, supporting the need for long-term surveillance of these patients.
<h4>Background</h4>Tea is frequently consumed worldwide, but the association of tea drinking with mortality risk remains inconclusive in populations where black tea is the main type consumed.<h4>Objective</h4>To evaluate the associations of tea consumption with all-cause and cause-specific mortality and potential effect modification by genetic variation in caffeine metabolism.<h4>Design</h4>Prospective cohort study.<h4>Setting</h4>The UK Biobank.<h4>Participants</h4>498 043 men and women aged 40 to 69 years who completed the baseline touchscreen questionnaire from 2006 to 2010.<h4>Measurements</h4>Self-reported tea intake and mortality from all causes and leading causes of death, including cancer, all cardiovascular disease (CVD), ischemic heart disease, stroke, and respiratory disease.<h4>Results</h4>During a median follow-up of 11.2 years, higher tea intake was modestly associated with lower all-cause mortality risk among those who drank 2 or more cups per day. Relative to no tea drinking, the hazard ratios (95% CIs) for participants drinking 1 or fewer, 2 to 3, 4 to 5, 6 to 7, 8 to 9, and 10 or more cups per day were 0.95 (95% CI, 0.91 to 1.00), 0.87 (CI, 0.84 to 0.91), 0.88 (CI, 0.84 to 0.91), 0.88 (CI, 0.84 to 0.92), 0.91 (CI, 0.86 to 0.97), and 0.89 (CI, 0.84 to 0.95), respectively. Inverse associations were seen for mortality from all CVD, ischemic heart disease, and stroke. Findings were similar regardless of whether participants also drank coffee or not or of genetic score for caffeine metabolism.<h4>Limitation</h4>Potentially important aspects of tea intake (for example, portion size and tea strength) were not assessed.<h4>Conclusion</h4>Higher tea intake was associated with lower mortality risk among those drinking 2 or more cups per day, regardless of genetic variation in caffeine metabolism. These findings suggest that tea, even at higher levels of intake, can be part of a healthy diet.<h4>Primary funding source</h4>National Cancer Institute Intramural Research Program.
Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (<sup>131</sup>I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood <sup>131</sup>I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.
<h4>Background</h4>Mammographic breast density (MBD) decline post-tamoxifen initiation is a favorable prognostic factor in estrogen receptor (ER)-positive breast cancer (BC) and has potential utility as a biomarker of tamoxifen response. However, the prognostic value of MBD decline may vary by molecular characteristics among ER-positive patients.<h4>Methods</h4>We investigated associations between MBD decline (≥10% vs <10%) and breast cancer-specific mortality (BCSM) among ER-positive breast cancer patients aged 36-87 years at diagnosis treated with tamoxifen at Kaiser Permanente Northwest (1990-2008). Patients who died of BC (case patients; n = 62) were compared with those who did not (control patients; n = 215) overall and by tumor molecular characteristics (immunohistochemistry [IHC]-based subtype [luminal A-like: ER-positive/progesterone receptor [PR]-positive/HER2-negative/low Ki67; luminal B-like: ER-positive and 1 or more of PR-negative, HER2-positive, high Ki67] and modified IHC [mIHC]-based recurrence score of ER/PR/Ki67). Percent MBD was measured in the unaffected breast at baseline mammogram (mean = 6 months before tamoxifen initiation) and follow-up (mean = 12 months post-tamoxifen initiation). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models. All statistical tests were 2-sided.<h4>Results</h4>MBD decline was statistically significantly associated with reduced risk of BCSM overall (OR = 0.38, 95% CI = 0.15 to 0.92). This association was, however, stronger among women with aggressive tumor characteristics including luminal B-like (OR = 0.17, 95% CI = 0.04 to 0.73) vs A-like (OR = 0.74, 95% CI = 0.19 to 2.92); large (OR = 0.26, 95% CI = 0.08 to 0.78) vs small (OR = 0.41, 95% CI = 0.04 to 3.79) tumors; PR-negative (OR = 0.02, 95% CI = 0.001 to 0.37) vs PR-positive (OR = 0.50, 95% CI = 0.18 to 1.40) disease; and high (OR = 0.25, 95% CI = 0.07 to 0.93) vs low (OR = 0.44, 95% CI = 0.10 to 2.09) mIHC3 score.<h4>Conclusion</h4>The findings support MBD decline as a prognostic marker of tamoxifen response among patients with aggressive ER-positive BC phenotypes, for whom understanding treatment effectiveness is critical.
<h4>Purpose</h4>To assess risk of developing a second benign brain tumor in a nationwide population of cancer survivors.<h4>Methods</h4>We evaluated the risk of developing second benign brain tumors among 2,038,074 1-year minimum cancer survivors compared to expected risk in the general population between 1973 and 2007 in nine population-based cancer registries in the NCI's surveillance, epidemiology, and end results program. Excess risk was estimated using standardized incidence ratios (SIRs) for all second benign brain tumors and specifically for second meningiomas and acoustic neuromas diagnosed during 2004-2008.<h4>Results</h4>1,025 patients were diagnosed with a second primary benign brain tumor, of which second meningiomas composed the majority (n = 745). Statistically significant increases in risk of developing a second meningioma compared to the general population were observed following first cancers of the brain [SIR = 19.82; 95 % confidence interval (CI) 13.88-27.44], other central nervous system (CNS) (SIR = 9.54; CI 3.10-22.27), thyroid (SIR = 2.05; CI 1.47-2.79), prostate (SIR = 1.21; CI 1.02-1.43), and acute lymphocytic leukemia (ALL) (SIR = 42.4; CI 23.18-71.13). Statistically significant decreases in risk were observed following first cancers of the uterine corpus (SIR = 0.63; CI 0.42-0.91) and colon (SIR = 0.56; CI 0.37-0.82). Differences in risk between patients initially treated with radiotherapy versus non-irradiated patients were statistically significant for second meningioma after primary cancers of the brain (p Het < 0.001) and ALL (p Het = 0.02). No statistically significant increased risks were detected for second acoustic neuromas (n = 114) following any first primary tumor.<h4>Conclusions</h4>Risk of second benign brain tumors, particularly meningioma, is increased following first primary cancers of the brain/CNS, thyroid, prostate, and ALL. Radiation exposure likely contributes to these excess risks.
This commentary summarizes the presentations and discussions from the 2016 Gilbert W. Beebe symposium "30 years after the Chernobyl accident: Current and future studies on radiation health effects." The symposium was hosted by the National Academies of Sciences, Engineering, and Medicine (the National Academies). The symposium focused on the health consequences of the Chernobyl accident, looking retrospectively at what has been learned and prospectively at potential future discoveries using emerging 21st Century research methodologies.
<h4>Purpose</h4>Radiation therapy (RT) techniques for prostate cancer are evolving rapidly, but the impact of these changes on risk of second cancers, which are an uncommon but serious consequence of RT, are uncertain. We conducted a comprehensive assessment of risks of second cancer according to RT technique (>10 MV vs ≤10 MV and 3-dimensional [3D] vs 2D RT) and modality (external beam RT, brachytherapy, and combined modes) in a large cohort of prostate cancer patients.<h4>Methods and materials</h4>The cohort was constructed using the Surveillance Epidemiology and End Results-Medicare database. We included cases of prostate cancer diagnosed in patients 66 to 84 years of age from 1992 to 2004 and followed through 2009. We used Poisson regression analysis to compare rates of second cancer across RT groups with adjustment for age, follow-up, chemotherapy, hormone therapy, and comorbidities. Analyses of second solid cancers were based on the number of 5-year survivors (n=38,733), and analyses of leukemia were based on number of 2-year survivors (n=52,515) to account for the minimum latency period for radiation-related cancer.<h4>Results</h4>During an average of 4.4 years' follow-up among 5-year prostate cancer survivors (2DRT = 5.5 years; 3DRT = 3.9 years; and brachytherapy = 2.7 years), 2933 second solid cancers were diagnosed. There were no significant differences in second solid cancer rates overall between 3DRT and 2DRT patients (relative risk [RR] = 1.00, 95% confidence interval [CI]: 0.91-1.09), but second rectal cancer rates were significantly lower after 3DRT (RR = 0.59, 95% CI: 0.40-0.88). Rates of second solid cancers for higher- and lower-energy RT were similar overall (RR = 0.97, 95% CI: 0.89-1.06), as were rates for site-specific cancers. There were significant reductions in colon cancer and leukemia rates in the first decade after brachytherapy compared to those after external beam RT.<h4>Conclusions</h4>Advanced treatment planning may have reduced rectal cancer risks in prostate cancer survivors by approximately 3 cases per 1000 after 15 years. Despite concerns about the neutron doses, we did not find evidence that higher energy therapy was associated with increased second cancer risks.
<b>Background:</b> We examined the relationship between estimated radiation dose from CT scans and subsequent Hodgkin lymphoma in the UK pediatric CT scans cohort.<b>Methods:</b> A retrospective, record linkage cohort included patients ages 0 to 21 years who underwent CT scans between 1980 and 2002 and were followed up for cancer or death until 2008. Poisson regression analysis was used to evaluate the relationship between estimated radiation dose (lagged by 2 years) and incident Hodgkin lymphoma diagnosed at least 2 years after the first CT scan.<b>Results:</b> There were 65 incident cases of Hodgkin lymphoma in the cohort of 178,601 patients. Neither estimated red bone marrow dose nor mean lymphocyte dose from CT scans was clearly associated with an increased risk of Hodgkin lymphoma (RR for 20+ mGy vs. <5 mGy = 0.92 (0.38-2.22) <i>P</i><sub>trend</sub> > 0.5 and 1.44 (0.60-3.48) <i>P</i><sub>trend</sub> > 0.5), respectively.<b>Conclusions:</b> Radiation exposure from pediatric CT scans 2 or more years before diagnosis was not associated with Hodgkin lymphoma in this large UK cohort.<b>Impact:</b> These findings are consistent with the majority of previous studies, which do not support a link between ionizing radiation and Hodgkin lymphoma. The results contrast our previous positive findings in this cohort for brain tumors and leukemia, both of which are known to be strongly linked to radiation exposure during childhood. <i>Cancer Epidemiol Biomarkers Prev; 26(5); 804-6. ©2017 AACR</i>.
<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Conclusions</h4>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.
<h4>Background</h4>Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites.<h4>Methods</h4>We evaluated long-term second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields.<h4>Results</h4>By the end of 2005 (median follow-up=13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI)=1.33-1.58) for high-dose second cancer sites (1+ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04-1.15) for contralateral breast cancer ( approximately 1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5-0.99 Gy, RR=0.89 (0.74-1.06)) or low doses (<0.5 Gy, RR=1.01 (0.95-1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI=69-284) contralateral breast cancers or 5% (2-8%) of the total in all 1+year survivors, and 292 (222-362) other solid cancers or 6% (4-7%) of the total.<h4>Conclusions</h4>Most second solid cancers in breast cancer survivors are not related to radiotherapy.
Risk projection methods allow for timely assessment of the potential magnitude of radiation-related cancer risks following low-dose radiation exposures. The estimation of such risks directly through observational studies would generally require infeasibly large studies and long-term follow-up to achieve reasonable statistical power. We developed an online radiation risk assessment tool (RadRAT) which can be used to estimate the lifetime risk of radiation-related cancer with uncertainty intervals following a user-specified exposure history (https://irep.nci.nih.gov/radrat). The uncertainty intervals constitute a key component of the program because of the various assumptions that are involved in such calculations. The risk models used in RadRAT are broadly based on those developed by the BEIR VII committee for estimating lifetime risk following low-dose radiation exposure of the US population for eleven site-specific cancers. We developed new risk models for seven additional cancer sites, oral, oesophagus, gallbladder, pancreas, rectum, kidney and brain/central nervous system (CNS) cancers, using data from Japanese atomic bomb survivors. The lifetime risk estimates are slightly higher for RadRAT than for BEIR VII across all exposure ages mostly because the weighting of the excess relative risk and excess absolute risk models was conducted on an arithmetic rather than a logarithmic scale. The calculator can be used to estimate lifetime cancer risk from both uniform and non-uniform doses that are acute or chronic. It is most appropriate for low-LET radiation doses < 1 Gy, and for individuals with life-expectancy and cancer rates similar to the general population in the US.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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.<h4>Interpretation</h4>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.<h4>Funding</h4>US National Cancer Institute.
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.
<h4>Objectives</h4>To assess the independent effect of waist circumference on mortality across the entire body mass index (BMI) range and to estimate the loss in life expectancy related to a higher waist circumference.<h4>Patients and methods</h4>We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20 to 83 years and enrolled from January 1, 1986, through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for the association of waist circumference with mortality.<h4>Results</h4>During a median follow-up of 9 years (maximum, 21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR, 1.52 for waist circumferences of ≥110 vs <90 cm; 95% CI, 1.45-1.59; HR, 1.07 per 5-cm increment in waist circumference; 95% CI, 1.06-1.08) and women (HR, 1.80 for waist circumferences of ≥95 vs <70 cm; 95% CI, 1.70-1.89; HR, 1.09 per 5-cm increment in waist circumference; 95% CI, 1.08-1.09). The estimated decrease in life expectancy for highest vs lowest waist circumference was approximately 3 years for men and approximately 5 years for women. The HR per 5-cm increment in waist circumference was similar for both sexes at all BMI levels from 20 to 50 kg/m(2), but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer.<h4>Conclusions</h4>In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20 to 50 kg/m(2). Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality.
<h4>Background</h4>Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies.<h4>Methods</h4>We pooled data from 1,941,300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status.<h4>Results</h4>Greater waist circumference (per 5 cm: HR = 1.04, 95% CI 1.03-1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05-1.09, P-value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m(2): HR = 1.15, 95% CI 1.06-1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m(2): HR = 0.99, 95% CI 0.93-1.06, P-value for trend = 0.79) or current smokers (per 5 kg/m(2): HR = 0.76, 95% CI 0.71-0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5 cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers.<h4>Conclusions</h4>Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers.
<h4>Background</h4>The optimum screening policy for lung cancer is unknown.<h4>Objective</h4>To identify efficient computed tomography (CT) screening scenarios in which relatively more lung cancer deaths are averted for fewer CT screening examinations.<h4>Design</h4>Comparative modeling study using 5 independent models.<h4>Data sources</h4>The National Lung Screening Trial; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial; the Surveillance, Epidemiology, and End Results program; and the U.S. Smoking History Generator.<h4>Target population</h4>U.S. cohort born in 1950.<h4>Time horizon</h4>Cohort followed from ages 45 to 90 years.<h4>Perspective</h4>Societal.<h4>Intervention</h4>576 scenarios with varying eligibility criteria (age, pack-years of smoking, years since quitting) and screening intervals.<h4>Outcome measures</h4>Benefits included lung cancer deaths averted or life-years gained. Harms included CT examinations, false-positive results (including those obtained from biopsy/surgery), overdiagnosed cases, and radiation-related deaths.<h4>Results of best-case scenario</h4>The most advantageous strategy was annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. It would lead to 50% (model ranges, 45% to 54%) of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer [model ranges, 1.4% to 8.3%]).<h4>Results of sensitivity analysis</h4>The number of cancer deaths averted for the scenario varied across models between 177 and 862; the number of overdiagnosed cases of cancer varied between 72 and 426.<h4>Limitations</h4>Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to lifetime follow-up.<h4>Conclusion</h4>Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-years' exposure to smoking.<h4>Primary funding source</h4>National Cancer Institute.
<h4>Background</h4>The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.<h4>Methods and findings</h4>In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.<h4>Conclusions</h4>Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary.
Multiple myeloma (MM) is a rare but highly fatal malignancy. High body weight is associated with this cancer, but several questions remain regarding the aetiological relevance of timing and location of body weight. To address these questions, we conducted a pooled analysis of MM mortality using 1·5 million participants (including 1388 MM deaths) from 20 prospective cohorts in the National Cancer Institute Cohort Consortium. Proportional hazards regression was used to calculate pooled multivariate hazard ratios (HRs) and 95% confidence intervals (CIs). Associations with elevated MM mortality were observed for higher early-adult body mass index (BMI; HR = 1·22, 95% CI: 1·09-1·35 per 5 kg/m(2) ) and for higher cohort-entry BMI (HR 1·09, 95% CI: 1·03-1·16 per 5 kg/m(2) ) and waist circumference (HR = 1·06, 95% CI: 1·02-1·10 per 5 cm). Women who were the heaviest, both in early adulthood (BMI 25+) and at cohort entry (BMI 30+) were at greater risk compared to those with BMI 18·5 ≤ 25 at both time points (HR = 1·95, 95% CI: 1·33-2·86). Waist-to-hip ratio and height were not associated with MM mortality. These observations suggest that overall, and possibly also central, obesity influence myeloma mortality, and women have the highest risk of death from this cancer if they remain heavy throughout adulthood.
The higher incidence of thyroid cancer in women compared with men suggests an influence of sex steroid hormones in the etiology of this malignancy. We investigated a comprehensive set of potential indicators of lifetime sex steroid hormone exposure in relation to thyroid cancer risk. Using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, which enrolled 70,047 women, 50 to 78 years old, we prospectively examined associations of self-reported history of benign breast and gynecologic conditions, reproductive factors, and exogenous sex hormone use with thyroid cancer risk. Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated in models using age as the time metric. During follow-up (median, 11 years), 127 women were diagnosed with first primary thyroid cancer. Older age at natural menopause (≥55 vs. <50 years; HR, 2.24; 95% CI, 1.20-4.18), greater estimated lifetime number of ovulatory cycles (≥490 vs. <415 cycles; HR, 2.40; 95% CI, 1.33-4.30), greater number of live births (≥5 vs. 1-2; HR, 1.72; 95% CI, 1.05-2.82), and history of uterine fibroids (HR, 1.72; 95% CI, 1.18-2.50) were associated with an increased risk of thyroid cancer. Earlier age at menarche, greater number of reproductive years, history of a tubal ligation, and history of ovarian cysts were nonsignificantly associated with increased thyroid cancer risk. No associations were observed for oral contraceptive use, menopausal hormone therapy, or history of benign breast disease or endometriosis. In general, we found that factors reflecting a greater length of exposure to endogenous hormones, particularly during the reproductive years, were associated with risk of postmenopausal thyroid cancer.
<h4>Background</h4>Numerous studies have suggested that selenium deficiency may be associated with an increased risk for several types of cancer, but few have focused on thyroid cancer.<h4>Materials and methods</h4>We examined the association between post-diagnostic fingernail selenium levels and differentiated thyroid cancer risk in a French Polynesian matched case-control study. Conditional logistic regression models were used to estimate odds ratios and 95% confidence intervals.<h4>Results</h4>The median selenium concentration among controls was 0.76 μg/g. Significantly, we found no association between fingernail selenium levels and thyroid cancer risk after conditioning on year of birth and sex and additionally adjusting for date of birth (highest versus lowest quartile: odds-ratio=1.12, 95% confidence interval: 0.66-1.90; p-trend=0.30). After additional adjustment for other covariates, this association remained non-significant (p-trend=0.60). When restricting the analysis to thyroid cancer of 10 mm or more, selenium in nails was non-significantly positively linked to thyroid cancer risk (p-trend=0.09). Although no significant interaction was evidenced between iodine in nails and selenium in nails effect (p=0.70), a non-significant (p-trend =0.10) positive association between selenium and thyroid cancer risk was seen in patients with less than 3 ppm of iodine in nails. The highest fingernail selenium concentration in French Polynesia was in the Marquises Islands (M=0.87 μg/g) and in the Tuamotu-Gambier Archipelago (M=0.86 μg/g).<h4>Conclusions</h4>Our results do not support, among individuals with sufficient levels of selenium, that greater long-term exposure to selenium may reduce thyroid cancer risk. Because these findings are based on post-diagnostic measures, studies with prediagnostic selenium are needed for corroboration.
<h4>Background</h4>With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology.<h4>Methods</h4>We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements.<h4>Results</h4>Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers.<h4>Conclusions</h4>Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues-some of which are barriers to specific research questions-that require special attention.<h4>Impact</h4>Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information.
<h4>Purpose</h4>Data on smoking and second cancer risk among cancer survivors are limited. We assessed associations between smoking before first cancer diagnosis and risk of second primary smoking-associated cancers among survivors of lung (stage I), bladder, kidney, and head/neck cancers.<h4>Methods</h4>Data were pooled from 2,552 patients with stage I lung cancer, 6,386 with bladder cancer, 3,179 with kidney cancer, and 2,967 with head/neck cancer from five cohort studies. We assessed the association between prediagnostic smoking and second smoking-associated cancer risk with proportional hazards regression, and compared these estimates to those for first smoking-associated cancers in all cohort participants.<h4>Results</h4>Compared with never smoking, current smoking of ≥ 20 cigarettes per day was associated with increased second smoking-associated cancer risk among survivors of stage I lung (hazard ratio [HR] = 3.26; 95% CI, 0.92 to 11.6), bladder (HR = 3.67; 95% CI, 2.25 to 5.99), head/neck (HR = 4.45; 95% CI, 2.56 to 7.73), and kidney cancers (HR = 5.33; 95% CI, 2.55 to 11.1). These estimates were similar to those for first smoking-associated cancer among all cohort participants (HR = 5.41; 95% CI, 5.23 to 5.61). The 5-year cumulative incidence of second smoking-associated cancers ranged from 3% to 8% in this group of cancer survivors.<h4>Conclusion</h4>Understanding risk factors for second cancers among cancer survivors is crucial. Our data indicate that cigarette smoking before first cancer diagnosis increases second cancer risk among cancer survivors, and elevated cancer risk in these survivors is likely due to increased smoking prevalence. The high 5-year cumulative risks of smoking-associated cancers among current smoking survivors of stage I lung, bladder, kidney, and head/neck cancers highlight the importance of smoking cessation in patients with cancer.
<h4>Importance</h4>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.<h4>Objective</h4>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.<h4>Design, setting, and participants</h4>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.<h4>Exposures</h4>Leisure time moderate- to vigorous-intensity physical activity.<h4>Main outcomes and measures</h4>The upper limit of mortality benefit from high levels of leisure time physical activity.<h4>Results</h4>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.<h4>Conclusions and relevance</h4>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.
<h4>Background</h4>A prior analysis of postmenopausal breast cancer patients linked a decline in mammographic density (MD) following the initiation of tamoxifen treatment with improved survival, but excluded premenopausal women, for whom tamoxifen is the primary anti-endocrine therapy. Therefore, we evaluated change in MD after tamoxifen and breast cancer death among patients age 32 to 87 years.<h4>Methods</h4>This case-control study included 349 estrogen receptor (ER)-positive breast cancer patients who were treated with tamoxifen at Kaiser Permanente Northwest (1990-2008): 97 who died from breast cancer (case patients) and 252 who did not (control patients), matched on age and year at diagnosis and disease stage. Percent MD in the unaffected breast was measured at baseline (mean six months before tamoxifen initiation) and follow-up (mean 12 months after initiation). Associations between change in MD and breast cancer death were estimated using conditional logistic regression.<h4>Results</h4>Patients in the highest tertile of MD decline had a lower risk of breast cancer death when compared with women in the lowest tertile (odds ratio [OR] = 0.44, 95% confidence interval [CI] = 0.22 to 0.88); results were similar after adjustment for baseline MD (OR = 0.49, 95% CI = 0.23 to 1.02). Reductions in death were observed only among patients in the middle and upper tertiles of baseline MD. Associations did not differ by age, tamoxifen use duration, estrogen and/or progestin use, body mass index, or receipt of chemotherapy or radiotherapy.<h4>Conclusion</h4>These data suggest that younger and older ER-positive breast cancer patients who experience large reductions in MD following tamoxifen initiation have an improved prognosis.
<h4>Background</h4>Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk.<h4>Design</h4>We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood (ages 18-21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later (n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models.<h4>Results</h4>Higher waist-to-hip ratio (HR = 1.09, 95% CI 1.02-1.17 per 0.1 increment) and waist circumference (HR = 1.07, 95% CI 1.00-1.14 per 10 cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality (HR = 1.18, 95% CI 1.11-1.25 per 5 kg/m(2)), with increased risk observed in both overweight and obese individuals (compared with BMI of 21.0 to <23 kg/m(2), HR = 1.36, 95% CI 1.20-1.55 for BMI 25.0 < 27.5 kg/m(2), HR = 1.48, 95% CI 1.20-1.84 for BMI 27.5 to <30 kg/m(2), HR = 1.43, 95% CI 1.11-1.85 for BMI ≥30 kg/m(2)). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality (HR = 1.05, 95% CI 1.01-1.10 per 5 kg/m(2)).<h4>Conclusions</h4>Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life.
Pooled analyses among whites and East Asians have demonstrated positive associations between all-cause mortality and body mass index (BMI), but studies of African Americans have yielded less consistent results. We examined the association between BMI and all-cause mortality in a sample of African Americans pooled from seven prospective cohort studies: NIH-AARP, 1995-2009; Adventist Health Study 2, 2002-2008; Black Women's Health Study, 1995-2009; Cancer Prevention Study II, 1982-2008; Multiethnic Cohort Study, 1993-2007; Prostate, Lung, Colorectal and Ovarian Screening Trial, 1993-2009; Southern Community Cohort Study, 2002-2009. 239,526 African Americans (including 100,175 never smokers without baseline heart disease, stroke, or cancer), age 30-104 (mean 52) and 71% female, were followed up to 26.5 years (mean 11.7). Hazard ratios (HR) and 95% confidence intervals (CI) for mortality were derived from multivariate Cox proportional hazards models. Among healthy, never smokers (11,386 deaths), HRs (CI) for BMI 25-27.4, 27.5-29.9, 30-34.9, 35-39.9, 40-49.9, and 50-60 kg/m(2) were 1.02 (0.92-1.12), 1.06 (0.95-1.18), 1.32 (1.18-1.47), 1.54 (1.29-1.83), 1.93 (1.46-2.56), and 1.93 (0.80-4.69), respectively among men and 1.06 (0.99-1.15), 1.15 (1.06-1.25), 1.24 (1.15-1.34), 1.58 (1.43-1.74), 1.80 (1.60-2.02), and 2.31 (1.74-3.07) respectively among women (reference category 22.5-24.9). HRs were highest among those with the highest educational attainment, longest follow-up, and for cardiovascular disease mortality. Obesity was associated with a higher risk of mortality in African Americans, similar to that observed in pooled analyses of whites and East Asians. This study provides compelling evidence to support public health efforts to prevent excess weight gain and obesity in African Americans.
<h4>Objective</h4>Although CT scans provide great medical benefits, concerns have been raised about the magnitude of possible associated cancer risk, particularly in children who are more sensitive to radiation than adults. Unnecessary high doses during CT examinations can also be delivered to children, if the scan parameters are not adjusted for patient age and size. We conducted the first survey to directly assess the trends in CT scan parameters and doses for paediatric CT scans performed in Great Britain between 1978 and 2008.<h4>Methods</h4>We retrieved 1073 CT film sets from 36 hospitals. The patients were 0-19 years old, and CT scans were conducted between 1978 and 2008. We extracted scan parameters from each film including tube current-time product [milliampere seconds (mAs)], tube potential [peak kilovoltage (kVp)] and manufacturer and model of the CT scanner. We estimated the mean mAs for head and trunk (chest and abdomen/pelvis) scans, according to patient age (0-4, 5-9, 10-14 and 15-19 years) and scan year (<1990, 1990-1994, 1995-1999 and ≥2000), and then derived the volumetric CT dose index and estimated organ doses.<h4>Results</h4>For head CT scans, mean mAs decreased by about 47% on average from before 1990 to after 2000, with the decrease starting around 1990. The mean mAs for head CTs did not vary with age before 1990, whereas slightly lower mAs values were used for younger patients after 1990. Similar declines in mAs were observed for trunk CTs: a 46% decline on an average from before 1990 to after 2000. Although mean mAs for trunk CTs did not vary with age before 1990, the value varied markedly by age, from 63 mAs for age 0-4 years compared with 315 mAs for those aged >15 years after 2000. No material changes in kVp were found. Estimated brain-absorbed dose from head CT scans decreased from 62 mGy before 1990 to approximately 30 mGy after 2000. For chest CT scans, the lung dose to children aged 0-4 years decreased from 28 mGy before 1990 to 4 mGy after 2000.<h4>Conclusion</h4>We found that mAs for head and trunk CTs was approximately halved starting around 1990, and age-specific mAs was generally used for paediatric scans after this date. These changes will have substantially reduced the radiation exposure to children from CT scans in Great Britain.<h4>Advances in knowledge</h4>The study shows that mAs and major organ doses for paediatric CT scans in Great Britain began to decrease around 1990.
<h4>Purpose</h4>To determine whether prediagnostic body mass index (BMI) is associated with risk of second obesity-associated cancers in colorectal cancer (CRC) survivors, and whether CRC survivors have increased susceptibility to obesity-associated cancer compared with cancer-free individuals.<h4>Patients and methods</h4>Incident first primary CRC cases (N = 11,598) were identified from five prospective cohort studies. We used Cox proportional hazards regression models to examine associations between baseline (prediagnostic) BMI and risk of second obesity-associated cancers (postmenopausal breast, kidney, pancreas, esophageal adenocarcinoma, endometrium) in CRC survivors, and compared associations to those for first obesity-associated cancers in the full cohort.<h4>Results</h4>Compared with survivors with normal prediagnostic BMI (18.5-24.9 kg/m(2)), those who were overweight (25-29.9 kg/m(2)) or obese (30+ kg/m(2)) had greater risk of a second obesity-associated cancer (n = 224; overweight hazard ratio [HR], 1.39; 95% CI, 1.01 to 1.92; obese HR, 1.47; 95% CI, 1.02 to 2.12; per 5-unit change in BMI HR, 1.12; 95% CI, 0.98 to 1.29). The magnitude of risk for developing a first primary obesity-associated cancer was similar (overweight HR, 1.18; 95% CI, 1.14 to 1.21; obese HR, 1.61; 95% CI, 1.56 to 1.66; per 5-unit change in BMI HR, 1.23; 95% CI, 1.21 to 1.24). Before diagnosis CRC patients were somewhat more likely than the overall cohort to be overweight (44% v 41%) or obese (25% v 21%).<h4>Conclusion</h4>CRC survivors who were overweight or obese before diagnosis had increased risk of second obesity-associated cancers compared with survivors with normal weight. The risks were similar in magnitude to those observed for first cancers in this population, suggesting increased prevalence of overweight or obesity, rather than increased susceptibility, may contribute to elevated second cancer risks in colorectal cancer survivors compared with the general population. These results support emphasis of existing weight guidelines for this high-risk group.
<h4>Objective</h4>To describe the medical conditions associated with the use of CT in children or young adults with no previous cancer diagnosis.<h4>Methods</h4>Radiologist reports for scans performed in 1995-2008 in non-cancer patients less than 22 years of age were collected from the radiology information system in 44 hospitals of Great Britain. By semantic search, an automated procedure identified 185 medical conditions within the radiologist reports. Manual validation of a subsample by a paediatric radiologist showed a satisfactory performance of the automatic coding procedure.<h4>Results</h4>Medical information was extracted for 37,807 scans; 19.5% scans were performed in children less than 5 years old; 52.0% scans were performed in 2000 or after. Trauma, diseases of the nervous (mainly hydrocephalus) or the circulatory system were each mentioned in 25-30% of scans. Hydrocephalus was mentioned in 19% of all scans, 59% of scans repeated ≥5 times in a year, and was the most frequent condition in children less than 5 years of age. Congenital diseases/malformations, disorders of the musculoskeletal system/connective tissues and infectious or respiratory diseases were each mentioned in 5-10% of scans. Suspicionor diagnosis of benign or malignant tumour was identified in 5% of scans.<h4>Conclusion</h4>This study describes the medical conditions that likely underlie the use of CT in children in Great Britain. It shows that patients with hydrocephalus may receive high cumulative radiation exposures from CT in early life, i.e. at ages when they are most sensitive to radiation. Advances in knowledge: The majority of scans were unrelated to cancer suspicion. Repeated scans over time were mainly associated with the management of hydrocephalus.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
<h4>Background</h4>Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality.<h4>Methods</h4>This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information.<h4>Results</h4>During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5 cm) = 1.07 [1.04-1.10], BMI (per 5 kg/m2) = 1.06 [1.02-1.10], waist circumference (per 5 cm) = 1.03 [1.01-1.05], young-adult BMI (per 5 kg/m2) = 1.13 [1.02-1.25], and adulthood BMI gain (per 5 kg/m2) = 1.07 [1.00-1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women (p = 0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality.<h4>Conclusion</h4>The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies.
Tamoxifen-associated mammographic density (MD) reductions are linked to improved breast cancer survival. We evaluated MD at six time points to determine the timing of greatest reduction following tamoxifen initiation. We sampled 40 Kaiser Permanente Northwest estrogen receptor (ER)-positive breast cancer patients from a prior study of MD change, according to tamoxifen use duration and age at diagnosis: <4 years tamoxifen and ≤50 years (N = 6) or >50 years (N = 10) old; ≥4 years tamoxifen and ≤50 years (N = 13) or >50 years (N = 11) old. A single reader evaluated percent MD in the contralateral breast on baseline (pre-diagnosis) and five approximately yearly post-diagnostic (T1 to T5) mammograms. Mean MD change was calculated. Interactions with age (≤50 and >50 years), tamoxifen duration (<4 and ≥4 years), and baseline MD (tertiles) were tested in linear regression models. Overall, the largest MD decline occurred by T1 (mean 4.5%) with little additional decline by T5. Declines differed by tertile of baseline MD (Pinteraction < 0.01). In the highest tertile, the largest reduction occurred by T1 (mean 14.9%), with an additional reduction of 3.6% by T5. Changes were smaller in the middle and lowest baseline MD tertiles, with cumulative reductions of 3.0% and 0.4% from baseline to T5, respectively. There were no differences by age (Pinteraction = 0.36) or tamoxifen duration (Pinteraction = 0.42). Among ER-positive patients treated with tamoxifen and surviving ≥5 years, most of the MD reduction occurred within approximately 12 months of tamoxifen initiation, suggesting that MD measurement at a single time point following tamoxifen initiation can identify patients with substantial density declines.
The number of incident cancers and long-term cancer survivors is expected to increase substantially for at least a decade. Advanced technology radiotherapies, e.g., using beams of protons and photons, offer dosimetric advantages that theoretically yield better outcomes. In general, evidence from controlled clinical trials and epidemiology studies are lacking. To conduct these studies, new research methods and infrastructure will be needed. In the paper, we review several key research methods of relevance to late effects after advanced technology proton-beam and photon-beam radiotherapies. In particular, we focus on the determination of exposures to therapeutic and stray radiation and related uncertainties, with discussion of recent advances in exposure calculation methods, uncertainties, in silico studies, computing infrastructure, electronic medical records, and risk visualization. We identify six key areas of methodology and infrastructure that will be needed to conduct future outcome studies of radiation late effects.
<h4>Importance</h4>Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood.<h4>Objective</h4>To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking.<h4>Design, setting, and participants</h4>We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015.<h4>Exposures</h4>Leisure-time physical activity of a moderate to vigorous intensity.<h4>Main outcomes and measures</h4>Incident cancer during follow-up.<h4>Results</h4>A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers.<h4>Conclusions and relevance</h4>Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.
Radiation has long been associated with carcinogenesis. Nevertheless, it is an important part of multimodality therapy for many malignancies. It is critical to assess the risk of secondary malignant neoplasms (SMNs) after radiation treatment. The authors reviewed the literature with a focus on radiation and associated SMNs for primary hematologic, breast, gynecologic, and pediatric tumors. Radiation appeared to increase the risk of SMN in all of these; however, this risk was found to be associated with age, hormonal influences, chemotherapy use, environmental influences, genetic predisposition, infection, and immunosuppression. The risk also appears to be altered with modern radiotherapy techniques. Practitioners of all specialties who treat cancer survivors in follow-up should be aware of this potential risk. Cancer 2016;122:1809-21. © 2016 American Cancer Society.
<h4>Background</h4>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.<h4>Methods</h4>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/m(2).<h4>Findings</h4>All-cause mortality was minimal at 20·0-25·0 kg/m(2) (HR 1·00, 95% CI 0·98-1·02 for BMI 20·0-<22·5 kg/m(2); 1·00, 0·99-1·01 for BMI 22·5-<25·0 kg/m(2)), and increased significantly both just below this range (1·13, 1·09-1·17 for BMI 18·5-<20·0 kg/m(2); 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/m(2); 1·20, 1·18-1·22 for BMI 27·5-<30·0 kg/m(2)). The HR for obesity grade 1 (BMI 30·0-<35·0 kg/m(2)) was 1·45, 95% CI 1·41-1·48; the HR for obesity grade 2 (35·0-<40·0 kg/m(2)) was 1·94, 1·87-2·01; and the HR for obesity grade 3 (40·0-<60·0 kg/m(2)) was 2·76, 2·60-2·92. For BMI over 25·0 kg/m(2), mortality increased approximately log-linearly with BMI; the HR per 5 kg/m(2) 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/m(2) units higher BMI (for BMI over 25 kg/m(2)) 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.<h4>Interpretation</h4>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.<h4>Funding</h4>UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.
While most cancers of the uterine cervix are squamous cell carcinomas, the relative and absolute incidence of adenocarcinoma of the uterine cervix has risen in recent years. It is not clear to what extent risk factors identified for squamous cell carcinoma of the cervix are shared by cervical adenocarcinomas. We used data from six case-control studies to compare directly risk factors for cervical adenocarcinoma (910 cases) and squamous cell carcinoma (5649 cases) in a published data meta-analysis. The summary odds ratios and tests for differences between these summaries for the two histological types were estimated using empirically weighted least squares. A higher lifetime number of sexual partners, earlier age at first intercourse, higher parity and long duration of oral contraceptive use were risk factors for both histological types. Current smoking was associated with a significantly increased risk of squamous cell carcinoma, with a summary odds ratio of 1.47 (95% confidence interval: 1.15-1.88), but not of adenocarcinoma (summary odds ratio=0.82 (0.60-1.11); test for heterogeneity between squamous cell and adenocarcinoma for current smoking: P=0.001). The results of this meta-analysis of published data suggest that squamous cell and adenocarcinomas of the uterine cervix, while sharing many risk factors, may differ in relation to smoking. Further evidence is needed to confirm this in view of the limited data available.
Pancreatic cancer is the eighth major form of cancer-related death worldwide, causing 227 000 deaths annually. Type-II diabetes is widely considered to be associated with pancreatic cancer, but whether this represents a causal or consequential association is unclear. We conducted a meta-analysis to examine this association. A computer-based literature search from 1966 to 2005 yielded 17 case-control and 19 cohort or nested case-control studies with information on 9220 individuals with pancreatic cancer. The age and sex-adjusted odds ratio (OR) for pancreatic cancer associated with type-II diabetes was obtained from each study. The combined summary odds ratio was 1.82 (95% confidence interval (95% CI) 1.66-1.89), with evidence of heterogeneity across the studies (P=0.002 for case-control and P=0.05 for cohort studies) that was explained, in part, by higher risks being reported by smaller studies and studies that reported before 2000. Individuals in whom diabetes had only recently been diagnosed (< 4 years) had a 50% greater risk of the malignancy compared with individuals who had diabetes for > or =5 years (OR 2.1 vs 1.5; P=0.005). These results support a modest causal association between type-II diabetes and pancreatic cancer.
Simple tests are given for consistency of the data with additive and with multiplicative effects of two risk factors on a binary outcome. A combination of the procedures will show whether data are consistent with neither, one or both of the models of no additive or no multiplicative interaction. Implications for the size of the study needed to detect differences between the models are also addressed. Because of the simple form of the test statistics, combination of evidence from different studies or strata is straightforward. Illustration of how the method could be extended to data from a 2xRxC table is also given.
Mammographic screening before age 50 years is less effective than at older ages and the associated radiation risks are higher. We estimated how many breast cancer deaths could be caused and how many could be prevented by a decade of annual two-view mammographic screening starting at ages 20, 30 and 40 years, respectively, in the UK; for all women, and for women with first-degree relatives affected with breast cancer. We extrapolated from a radiation risk model to estimate the number of radiation-induced breast cancer deaths, and used results from randomised trials, which suggest a reduction in breast cancer mortality of 10-20% in women invited to screening before age 50 years, to estimate the number of deaths that could be prevented. The net change in breast cancer deaths was defined as the number of radiation-induced deaths minus the number of prevented deaths. For all women, assuming a reduction in mortality from screening of 20%, a decade of annual screening was estimated to induce more deaths than it prevents if started at age 20 years and at age 30 years (net increase = 0.86 and 0.37 breast cancer deaths, respectively, per 1000 women screened). The corresponding estimate for screening starting at age 40 years was a net decrease of 0.46 deaths/1000 women screened and a zero net change assuming a 10% mortality reduction. Results for women with first-degree relatives with breast cancer were generally in the same direction but, because their background incidence rates are higher, the net increases or decreases were greater. In conclusion, our estimates suggest that a decade of annual two-view mammographic screening before age 40 years would result in a net increase in breast cancer deaths, and that starting at age 40 years could result in a material net decrease only if breast cancer mortality is reduced by about 20% or more in women screened. Although these calculations were based on a number of uncertain parameters, in general, the conclusions were not altered when these parameters were varied within a feasible range.
The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of the vagina and anus are likewise caused by HPV, as are a fraction of cancers of the vulva, penis, and oropharynx. HPV-16 and -18 account for about 70% of cancers of the cervix, vagina, and anus and for about 30-40% of cancers of the vulva, penis, and oropharynx. Other cancers causally linked to HPV are non-melanoma skin cancer and cancer of the conjunctiva. Although HPV is a necessary cause of cervical cancer, it is not a sufficient cause. Thus, other cofactors are necessary for progression from cervical HPV infection to cancer. Long-term use of hormonal contraceptives, high parity, tobacco smoking, and co-infection with HIV have been identified as established cofactors; co-infection with Chlamydia trachomatis (CT) and herpes simplex virus type-2 (HSV-2), immunosuppression, and certain dietary deficiencies are other probable cofactors. Genetic and immunological host factors and viral factors other than type, such as variants of type, viral load and viral integration, are likely to be important but have not been clearly identified.
Tobacco smoking is the only established risk factor for pancreatic cancer. Results from several epidemiologic studies have suggested that increased body mass index and/or lack of physical activity may be associated with an increased risk of this disease. We examined the relationship between anthropometry and physical activity recorded at baseline and the risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (n = 438,405 males and females age 19-84 years and followed for a total of 2,826,070 person-years). Relative risks (RR) were calculated using Cox proportional hazards models stratified by age, sex, and country and adjusted for smoking and self-reported diabetes and, where appropriate, height. In total, there were 324 incident cases of pancreatic cancer diagnosed in the cohort over an average of 6 years of follow-up. There was evidence that the RR of pancreatic cancer was associated with increased height [RR, 1.74; 95% confidence interval (95% CI), 1.20-2.52] for highest quartile compared with lowest quartile (P(trend) = 0.001). However, this trend was primarily due to a low risk in the lowest quartile, as when this group was excluded, the trend was no longer statistically significant (P = 0.27). A larger waist-to-hip ratio and waist circumference were both associated with an increased risk of developing the disease (RR per 0.1, 1.24; 95% CI, 1.04-1.48; P(trend) = 0.02 and RR per 10 cm, 1.13; 95% CI, 1.01-1.26; P(trend) = 0.03, respectively). There was a nonsignificant increased risk of pancreatic cancer with increasing body mass index (RR, 1.09; 95% CI, 0.95-1.24 per 5 kg/m(2)), and a nonsignificant decreased risk with total physical activity (RR, 0.82; 95% CI, 0.50-1.35 for most active versus inactive). Future studies should consider including measurements of waist and hip circumference, to further investigate the relationship between central adiposity and the risk of pancreatic cancer.
The International Collaboration of Epidemiological Studies of Cervical Cancer has combined individual data on 11,161 women with invasive carcinoma, 5,402 women with cervical intraepithelial neoplasia (CIN)3/carcinoma in situ and 33,542 women without cervical carcinoma from 25 epidemiological studies. Relative risks (RRs) and 95% confidence intervals (CIs) of cervical carcinoma in relation to number of full-term pregnancies, and age at first full-term pregnancy, were calculated conditioning by study, age, lifetime number of sexual partners and age at first sexual intercourse. Number of full-term pregnancies was associated with a risk of invasive cervical carcinoma. After controlling for age at first full-term pregnancy, the RR for invasive cervical carcinoma among parous women was 1.76 (95% CI: 1.53-2.02) for > or => or =7 full-term pregnancies compared with 1-2. For CIN3/carcinoma in situ, no significant trend was found with increasing number of births after controlling for age at first full-term pregnancy among parous women. Early age at first full-term pregnancy was also associated with risk of both invasive cervical carcinoma and CIN3/carcinoma in situ. After controlling for number of full-term pregnancies, the RR for first full-term pregnancy at age <17 years compared with > or => or =25 years was 1.77 (95% CI: 1.42-2.23) for invasive cervical carcinoma, and 1.78 (95% CI: 1.26-2.51) for CIN3/carcinoma in situ. Results were similar in analyses restricted to high-risk human papilloma virus (HPV)-positive cases and controls. No relationship was found between cervical HPV positivity and number of full-term pregnancies, or age at first full-term pregnancy among controls. Differences in reproductive habits may have contributed to differences in cervical cancer incidence between developed and developing countries.
Squamous cell carcinomas account for about 80% of cancers of the uterine cervix, and the majority of the remainder are adenocarcinomas. There is limited evidence on the extent to which these histological types share a common etiology. The International Collaboration of Epidemiological Studies of Cervical Cancer has brought together and combined individual data on 8,097 women with invasive squamous cell carcinoma, 1,374 women with invasive adenocarcinoma and 26,445 women without cervical cancer (controls) from 12 epidemiological studies. Compared to controls, the relative risk of each histological type of invasive cervical cancer was increased with increasing number of sexual partners, younger age at first intercourse, increasing parity, younger age at first full-term pregnancy and increasing duration of oral contraceptive use. Current smoking was associated with a significantly increased risk of squamous cell carcinoma (RR = 1.50, 95% CI: 1.35-1.66) but not of adenocarcinoma (RR = 0.86 (0.70-1.05)), and the difference between the two histological types was statistically significant (case-case comparison p < 0.001). A history of screening (assessed as having had at least one previous nondiagnostic cervical smear) was associated with a reduced risk of both histological types, but the reduction was significantly greater for squamous cell carcinoma than for adenocarcinoma (RR = 0.46 (0.42-0.50) and 0.68 (0.56-0.82), respectively; case-case comparison, p = 0.002). A positive test for cervical high-risk HPV-DNA was a strong risk factor for each histological type, with 74% of squamous cell carcinomas and 78% of adenocarcinomas testing positive for HPV types 16 or 18. Squamous cell and adenocarcinoma of the cervix share most risk factors, with the exception of smoking.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
In a population-based study of 313 case-control pairs in Kuwait, we evaluated whether a family history of benign thyroid disease (BTD) and thyroid or other cancers was associated with an increased risk of thyroid cancer, the second most common neoplasm among women in this and several other Arab countries in the Gulf region. Family history of BTD was reported by 78 (24.9%) cases and 40 (12.8%) controls in 132 and 57 relatives, respectively. There was an approximately 2-fold increased risk of thyroid cancer in individuals who had a mother (Odds Ratio (OR)=2.3; 95% Confidence Intervals (95% CI): 1.1-5.1), sister(s) (OR=2.6; 95% CI: 1.3-5.3) or aunt(s) (OR=2.1; 95% CI: 0.9-5.3) with BTD; there was also a significant trend in increasing risk with an increasing number of affected female relatives (P<0.0001). Stratification by age at diagnosis of the case showed that individuals aged </= 35 years, who had an affected first- or second/third-degree relative(s), had an approximately 3-fold increased risk of the cancer. Family history of thyroid cancer was reported by 9 (2.9%) cases in 13 relatives (11 females, 2 males) and by 3 controls in 3 relatives (all females) (OR=3.0; 95% CI: 0.8-11.1). The OR for all hormone-related cancers combined was 1.5 (95% CI: 0.8-2.6). There was no clear association with family history of breast or any other common cancer. Our data suggest that a family history of BTD is associated with an increased risk of thyroid cancer, and point to the role of familial susceptibility to BTD and thyroid cancer in the Kuwaiti population.
<h4>Purpose</h4>Although ovarian cancer incidence rates have declined in the United States, less is known of ovarian cancer trends among survivors of breast cancer. Therefore, we examined second primary ovarian cancers after first primary breast cancer.<h4>Methods</h4>Data were obtained from the Surveillance, Epidemiology, and End Results program (1973 to 2008). Standardized incidence ratios (SIRs) were calculated as the observed numbers of ovarian cancers among survivors of breast cancer compared with the expected numbers in the general population. Absolute rates were measured as the incidence rates for second primary ovarian cancer by year of diagnosis of the first primary breast cancer adjusted for age of breast cancer diagnosis and years since diagnosis.<h4>Results</h4>SIRs for second primary ovarian cancer were elevated over the entire study period (SIR, 1.24; 95% CI, 1.2 to 1.3), whereas the absolute rates declined with an estimated annual percentage change near 1% (-1.34% to -0.09% per year). Secular trends for second ovarian cancers were similar after estrogen receptor (ER) -positive and ER-negative breast cancers, whereas the age-specific patterns varied significantly by ER expression (P for interaction < .001). The largest SIR was among women age less than 50 years with ER-negative breast cancer (SIR, 4.35; 95% CI, 3.5 to 5.4).<h4>Conclusion</h4>Persistently elevated SIRs along with decreasing absolute rates over the entire study period suggest that ovarian cancers in both the general population and survivors of breast cancer are declining in parallel, possibly because of common risk factor exposures. Analytic studies are needed to further assess the parallel overall trends and the age-specific interaction by ER expression.
Although diagnostic x-ray procedures provide important medical benefits, cancer risks associated with their exposure are also possible, but not well characterized. The US Radiologic Technologists Study (1983-2006) is a nationwide, prospective cohort study with extensive questionnaire data on history of personal diagnostic imaging procedures collected prior to cancer diagnosis. We used Cox proportional hazard regressions to estimate thyroid cancer risks related to the number and type of selected procedures. We assessed potential modifying effects of age and calendar year of the first x-ray procedure in each category of procedures. Incident thyroid cancers (n = 251) were diagnosed among 75,494 technologists (1.3 million person-years; mean follow-up = 17 years). Overall, there was no clear evidence of thyroid cancer risk associated with diagnostic x-rays except for dental x-rays. We observed a 13% increase in thyroid cancer risk for every 10 reported dental radiographs (hazard ratio = 1.13, 95% confidence interval: 1.01, 1.26), which was driven by dental x-rays first received before 1970, but we found no evidence that the relationship between dental x-rays and thyroid cancer was associated with childhood or adolescent exposures as would have been anticipated. The lack of association of thyroid cancer with x-ray procedures that expose the thyroid to higher radiation doses than do dental x-rays underscores the need to conduct a detailed radiation exposure assessment to enable quantitative evaluation of risk.
<h4>Objective</h4>In a large prospective cohort, we examined the relationship of body mass index (BMI) with mortality among blacks and compared the results to those among whites in this population.<h4>Design and methods</h4>The study population consisted of 7,446 non-Hispanic black and 130,598 white participants, ages 49-78 at enrollment, in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. BMI at baseline, BMI at age 20, and BMI change were calculated using self-reported and recalled height and weight. Relative risks were stratified by race and sex and adjusted for age, education, marital status, and smoking.<h4>Results</h4>During follow-up, 1,495 black and 18,236 white participants died (mean = 13 years). Clear J-shaped associations between BMI and mortality were observed among white men and women. Among black men and women, the bottoms of these curves were flatter, and increasing risks of death with greater BMI were observed only at higher BMI levels (≥35.0). Associations for BMI at age 20 and BMI change also appeared to be stronger in magnitude in whites versus blacks, and these racial differences appeared to be more pronounced among women.<h4>Conclusion</h4>Our results suggest that BMI may be more weakly associated with mortality in blacks, particularly black women, than in whites.
Abstract Ionizing radiation increases risk for acute leukemia, but less is known about radiation and risk of other hematologic malignancies such as non-Hodgkin lymphoma (NHL). We compared second primary NHL incidence among patients who did and did not receive initial radiotherapy for first primary solid malignancy during 1981-2007 reported in nine Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries. We identified 5590 second NHL cases among 1 450 962 1-year cancer survivors. NHL risk was increased after initial radiotherapy for all solid cancers combined (multivariate Poisson regression relative risk [RR]: 1.13, 95% confidence interval [CI]: 1.06-1.20), non-small cell lung cancer (RR: 1.53, 95% CI: 1.08-2.17) and prostate cancer (RR: 1.19, 95% CI: 1.09-1.32). NHL risk increased with longer latency after radiotherapy for non-small cell lung cancer (ptrend = 0.003) but decreased for prostate cancer (ptrend = 0.017). There was no clear NHL risk pattern by NHL subtype or age. Our study provides limited evidence that radiotherapy for solid malignancy is associated with increased risk of subsequent NHL.
<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Findings</h4>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.<h4>Interpretation</h4>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.<h4>Funding</h4>US National Cancer Institute Intramural Research Program.
Purpose To compare mortality rates from all causes, specific causes, total cancers, and specific cancers to assess whether differences between radiologists and psychiatrists are consistent with known risks of radiation exposure and the changes in radiation exposure to radiologists over time. Materials and Methods The authors used the American Medical Association Physician Masterfile to construct a cohort of 43 763 radiologists (20% women) and 64 990 psychiatrists (27% women) (comparison group) who graduated from medical school in 1916-2006. Vital status was obtained from record linkages with the Social Security Administration and commercial databases, and cause of death was obtained from the National Death Index. Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for all causes and specific causes of death. Results During the follow-up period (1979-2008), 4260 male radiologists and 7815 male psychiatrists died. The male radiologists had lower death rates (all causes) compared with the psychiatrists (RR = 0.94; 95% CI: 0.90, 0.97), similar cancer death rates overall (RR = 1.00; 95% CI: 0.93, 1.07), but increased acute myeloid leukemia and/or myelodysplastic syndrome death rates (RR = 1.62; 95% CI: 1.05, 2.50); these rates were driven by those who graduated before 1940 (RR = 4.68; 95% CI: 0.91, 24.18). In these earliest workers (before 1940) there were also increased death rates from melanoma (RR = 8.75; 95% CI: 1.89, 40.53), non-Hodgkin lymphoma (NHL) (RR = 2.69; 95% CI: 1.33, 5.45), and cerebrovascular disease (RR = 1.49; 95% CI: 1.11, 2.01). The 208 deaths in female radiologists precluded detailed investigation, and the number of female radiologists who graduated before 1940 was very small (n = 47). Conclusion The excess risk of acute myeloid leukemia and/or myelodysplastic syndrome mortality in radiologists who graduated before 1940 is likely due to occupational radiation exposure. The melanoma, NHL, and cerebrovascular disease mortality risks are possibly due to radiation. The authors found no evidence of excess mortality in radiologists who graduated more recently, possibly because of increased radiation protection and/or lifestyle changes. <sup>©</sup> RSNA, 2016 Online supplemental material is available for this article.
<h4>Importance</h4>Within 10 years after breast cancer diagnosis, roughly 5% of patients develop contralateral breast cancer (CBC). Randomized trials have found that therapy including tamoxifen citrate and aromatase inhibitors (AIs) reduces CBC risk. But little is known about the magnitude and duration of protective associations within the context of real-world clinical management settings, where varying durations of and gaps in treatment are common.<h4>Objective</h4>To determine the association between adjuvant tamoxifen and AI therapy and CBC risk within a general community setting.<h4>Design, setting, and participants</h4>A retrospective cohort study of CBC risk among 7541 patients diagnosed with a first primary unilateral invasive breast cancer at Kaiser Permanente Institute for Health Research (Colorado) or Kaiser Permanente Northwest Center for Health Research (Oregon) between January 1, 1990, and December 31, 2008. Data were analyzed from 1 year after diagnosis of the first breast cancer through the earliest of the following events: CBC diagnosis, other second cancer diagnosis, death, last tumor registry follow-up, exit from the Kaiser Permanente health care plan, or end of study follow-up (December 31, 2010, for Oregon and December 31, 2011, for Colorado).<h4>Exposures</h4>Adjuvant tamoxifen use and AI therapy were treated as time-dependent exposures, assessed using electronic prescription records.<h4>Main outcomes and measures</h4>Incident CBC based on long-term systematic follow-up.<h4>Results</h4>Among 7541 women with invasive breast cancer, median age at initial breast cancer diagnosis was 60.6 years (age range, 24.9-84.9 years). Women were predominantly (92.9% [7009 of 7541]) of white race. During a median of 6.3 years (range, 1-20.9 years) of follow-up, 248 women developed CBC (45 in situ and 203 invasive). Contralateral breast cancer risk decreased significantly with increasing tamoxifen therapy duration. In current users, the relative risk (RR) per year of tamoxifen use was 0.76 (95% CI, 0.64-0.89), with an estimated 66% (RR, 0.34; 95% CI, 0.29-0.40) RR reduction for 4 years of use compared with nonusers. Risk reductions were slightly smaller for past users but were still significant at least 5 years after stopping tamoxifen therapy (RR per year of use, 0.85; 95% CI, 0.71-0.995). In addition, AI use without tamoxifen therapy was associated with reduced CBC risk (RR for AI users compared with nonusers, 0.48; 95% CI, 0.22-0.97). Risk reductions were most apparent among women whose primary and CBCs were estrogen receptor positive.<h4>Conclusions and relevance</h4>Tamoxifen therapy was associated with reduced CBC risk during treatment and after its cessation, with risk progressively decreasing as tamoxifen therapy duration increased. Among those surviving at least 5 years, tamoxifen use for at least 4 years was estimated to prevent 3 CBCs per 100 women by 10 years after an estrogen receptor-positive first breast cancer, an absolute risk reduction that is consistent with findings from clinical trials. If adjuvant endocrine therapy is indicated for breast cancer treatment, these findings in concert with trial data suggest that women should be encouraged to complete the full course.
<b>Background:</b> There are few established risk factors for gallbladder cancer beyond gallstones. Recent studies suggest a higher risk with high body mass index (BMI), an indicator of general heaviness, but evidence from other body size measures is lacking.<b>Methods:</b> Associations of adult BMI, young adult BMI, height, adult weight gain, waist circumference (WC), waist-height ratio (WHtR), hip circumference (HC), and waist-hip ratio (WHR) with gallbladder cancer risk were evaluated. Individual-level data from 1,878,801 participants in 19 prospective cohort studies (14 studies had circumference measures) were harmonized and included in this analysis. Multivariable Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI).<b>Results:</b> After enrollment, 567 gallbladder cancer cases were identified during 20.1 million person-years of observation, including 361 cases with WC measures. Higher adult BMI (per 5 kg/m<sup>2</sup>, HR: 1.24; 95% CI, 1.13-1.35), young adult BMI (per 5 kg/m<sup>2</sup>, HR: 1.12; 95% CI, 1.00-1.26), adult weight gain (per 5 kg, HR: 1.07; 95% CI, 1.02-1.12), height (per 5 cm, HR: 1.10; 95% CI, 1.03-1.17), WC (per 5 cm, HR: 1.09; 95% CI, 1.02-1.17), WHtR (per 0.1 unit, HR: 1.24; 95% CI, 1.00-1.54), and HC (per 5 cm, HR: 1.13; 95% CI, 1.04-1.22), but not WHR (per 0.1 unit, HR: 1.03; 95% CI, 0.87-1.22), were associated with higher risks of gallbladder cancer, and results did not differ meaningfully by sex or other demographic/lifestyle factors.<b>Conclusions:</b> These findings indicate that measures of overall and central excess body weight are associated with higher gallbladder cancer risks.<b>Impact:</b> Excess body weight is an important, and potentially preventable, gallbladder cancer risk factor. <i>Cancer Epidemiol Biomarkers Prev; 26(4); 597-606. ©2017 AACR</i>.
<h4>Objectives</h4>To estimate the risk of developing cancer in relation to the typical radiation doses received from a range of X-ray guided cardiac catheterisations in children, taking variable survival into account.<h4>Methods</h4>Radiation doses were estimated for 2749 procedures undertaken at five UK hospitals using Monte Carlo simulations. The lifetime attributable risk (LAR) of cancer incidence was estimated using models developed by the Biological Effects of Ionising Radiation committee, based on both normal life expectancy, and as a function of attained age, from 20 to 80 years, to take reduced life expectancy into account.<h4>Results</h4>The radiation-related risks from these procedures are dominated by lung and breast cancer (for females). Assuming normal life expectancy, central LAR estimates for cancer incidence, based on median doses, ranged from <1 in 2000 for atrial septal defect occlusions to as high as 1 in 150 for valve replacements. For a reduced life expectancy of 50 years, estimated risks are lower by a factor of around 7. For conditions with especially poor survival (age 20 years), such as hypoplastic left heart syndrome, estimated cancer risks attributable to radiation were <1 in 20 000.<h4>Conclusions</h4>Based on recent UK radiation dose levels, the risk of cancer following cardiac catheterisations is relatively low and strongly modified by survival and the type of procedure. The risk of breast cancer, especially following pulmonary artery angioplasty and valve replacements, is the greatest concern.
Purpose To compare total and cause-specific mortality rates between physicians likely to have performed fluoroscopy-guided interventional (FGI) procedures (referred to as FGI MDs) and psychiatrists to determine if any differences are consistent with known radiation risks. Materials and Methods Mortality risks were compared in nationwide cohorts of 45 634 FGI MDs and 64 401 psychiatrists. Cause of death was ascertained from the National Death Index. Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for FGI MDs versus psychiatrists, with adjustment (via stratification) for year of birth and attained age. Results During follow-up (1979-2008), 3506 FGI MDs (86 women) and 7814 psychiatrists (507 women) died. Compared with psychiatrists, FGI MDs had lower total (men: RR, 0.80 [95% CI: 0.77, 0.83]; women: RR, 0.80 [95% CI: 0.63, 1.00]) and cancer (men: RR, 0.92 [95% CI: 0.85, 0.99]; women: RR, 0.83 [95% CI: 0.58, 1.18]) mortality. Mortality because of specific types of cancer, total and specific types of circulatory diseases, and other causes were not elevated in FGI MDs compared with psychiatrists. On the basis of small numbers, leukemia mortality was elevated among male FGI MDs who graduated from medical school before 1940 (RR, 3.86; 95% CI: 1.21, 12.3). Conclusion Overall, total deaths and deaths from specific causes were not elevated in FGI MDs compared with psychiatrists. These findings require confirmation in large cohort studies with individual doses, detailed work histories, and extended follow-up of the subjects to substantially older median age at exit. <sup>©</sup> RSNA, 2017 Online supplemental material is available for this article.
This commentary provides some historical context to the analysis of smoking and lung cancer risk by Lubin and colleagues in this issue of epidemiology. It also considers the potential utility of ongoing efforts to apply complex mathematical models to epidemiologic data on smoking and lung cancer risk. We conclude that the work of Lubin and colleagues adds to the models already developed and points to some potential complexities that models should incorporate.
<h4>Rationale</h4>Computed tomography (CT) is being considered as a tool for routine monitoring of lung damage in people with cystic fibrosis. Concern has been raised, however, about the associated risk of radiation-induced cancer.<h4>Objectives</h4>To estimate the risk of radiation-induced cancer from lung CT for patients with cystic fibrosis, assuming annual monitoring starting at age 2 years.<h4>Methods</h4>Radiation risk models (derived primarily from the study of Japanese atomic bomb survivors) were used to estimate the excess risk of radiation-induced cancer for the organs that receive measurable doses from lung CT. Two scenarios were considered: median survival to age 36 years (approximate current median survival) and median survival to age 50 years (projected median survival by 2030).<h4>Measurements and main results</h4>The estimated risk of radiation-induced cancer from annual lung CT was 0.02% for males and 0.07% for females assuming median survival to age 36 years. The estimated risks increased to 0.08% for males and 0.46% for females assuming median survival increases to age 50 years. The risks are higher for females because of the risk of radiation-induced breast cancer (50% of total risk) and higher risk of thyroid cancer.<h4>Conclusions</h4>The cumulative risk of radiation-induced cancer from repeated lung CT scans for patients with cystic fibrosis is relatively small (less than 0.5%). However, routine monitoring should not be recommended until there is a demonstrated benefit that will outweigh these risks.
<h4>Objectives</h4>To estimate the risk of radiation-induced lung cancer mortality from three annual low-dose lung computed tomography (CT) screens before age 55 years (starting at age 30, 40 or 50) and the mortality reduction from screening (i.e. the efficacy) needed to outweigh these risks for never and current-smokers. The risk of radiation-induced breast cancer was also estimated for women.<h4>Methods</h4>The Biological Effectiveness of Ionizing Radiation VII committee's risk models were used to estimate radiation risk. Lung cancer mortality rates (based on the Bach model for current and the Cancer Prevention Study for never-smokers) were used to estimate the mortality reduction needed to outweigh this risk.<h4>Results</h4>For never-smokers, the estimated excess lifetime risk of radiation-induced lung cancer mortality from annual screening aged 40-42 was 1/10,000 (90% credibility interval: 0.4-3) for men and 3/10,000 (2-6) for women. For current-smokers, the estimated risks were approximately two-fold higher, with wider credibility intervals. Risks from screening age 30-32 or 50-52 years were of similar magnitude. The mortality reduction required to outweigh these risks was, for female never-smokers: 125% (40-300%) age 30-32 years, 70% (30-190%) age 40-42 years and 25% (10-70%) age 50-52 years, and for male current-smokers: 70% (20-120%) age 30-32 years, 10% (3-20%) age 40-42 years and 2% (1-4%) age 50-52 years. These figures were two to three times higher for females because of the higher radiation risks. The risk of radiation-induced breast cancer was in the range of three to six cases/10,000 females screened.<h4>Conclusion</h4>Before age 50, the mortality reduction from lung CT screening that is required to outweigh the radiation risk may be substantial, and in some cases unattainable (i.e. >100%).
<h4>Background</h4>Oral contraceptives were introduced almost 50 years ago, and over 100 million women currently use them. Oral contraceptives can reduce the risk of ovarian cancer, but the eventual public-health effects of this reduction will depend on how long the protection lasts after use ceases. We aimed to assess these effects.<h4>Methods</h4>Individual data for 23,257 women with ovarian cancer (cases) and 87,303 without ovarian cancer (controls) from 45 epidemiological studies in 21 countries were checked and analysed centrally. The relative risk of ovarian cancer in relation to oral contraceptive use was estimated, stratifying by study, age, parity, and hysterectomy.<h4>Findings</h4>Overall 7308 (31%) cases and 32,717 (37%) controls had ever used oral contraceptives, for average durations among users of 4.4 and 5.0 years, respectively. The median year of cancer diagnosis was 1993, when cases were aged an average of 56 years. The longer that women had used oral contraceptives, the greater the reduction in ovarian cancer risk (p<0.0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased but became somewhat attenuated over time-the proportional risk reductions per 5 years of use were 29% (95% CI 23-34%) for use that had ceased less than 10 years previously, 19% (14-24%) for use that had ceased 10-19 years previously, and 15% (9-21%) for use that had ceased 20-29 years previously. Use during the 1960s, 1970s, and 1980s was associated with similar proportional risk reductions, although typical oestrogen doses in the 1960s were more than double those in the 1980s. The incidence of mucinous tumours (12% of the total) seemed little affected by oral contraceptives, but otherwise the proportional risk reduction did not vary much between different histological types. In high-income countries, 10 years use of oral contraceptives was estimated to reduce ovarian cancer incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100; for every 5000 woman-years of use, about two ovarian cancers and one death from the disease before age 75 are prevented.<h4>Interpretation</h4>Use of oral contraceptives confers long-term protection against ovarian cancer. These findings suggest that oral contraceptives have already prevented some 200,000 ovarian cancers and 100,000 deaths from the disease, and that over the next few decades the number of cancers prevented will rise to at least 30,000 per year.
There is increasing evidence that type 2 diabetes mellitus and glucose intolerance are a cause, not just a consequence, of pancreatic cancer. We examined whether other factors that characterize the insulin resistance syndrome are also risk factors for pancreatic cancer in a prospective cohort study of 631,172 men and women (ages 45+ years) who received health insurance from the Korean Medical Insurance Corporation. The biennial medical evaluations from 1992 to 1995 provided the baseline information for this study. Relative risks (RR) were estimated using proportional hazards models adjusted for age, sex, smoking, and fasting serum glucose (after excluding the first 2 years of follow-up). There were 2,194 incident cases of pancreatic cancer diagnosed in the cohort over a median follow-up of 12 years. There was no evidence that pancreatic cancer risk was associated with total cholesterol, systolic blood pressure, WBC count, or body mass index. Abnormal levels of aspartate aminotransferase and alanine aminotransferase were both associated with a moderately increased risk of developing the disease (40+ versus <20; RR, 1.33; 95% CI, 1.14-1.55; P(trend) = 0.05 and RR, 1.34; 95% CI, 1.16-1.56; P(trend) = 0.02, respectively). Excluding 6 years of follow-up reduced this RR (95% CI) for aspartate aminotransferase to 1.22 (1.01-1.49), but even after excluding 10 years follow-up the RR (95% CI) for alanine aminotransferase was unchanged [1.36 (1.01-1.83)]. Although fasting serum glucose has been found previously to be associated with pancreatic cancer risk in this cohort, most other factors that characterize insulin resistance syndrome were not associated with pancreatic cancer risk. The association with elevated liver enzyme levels is a novel finding that warrants further investigation.
<h4>Objective</h4>To examine the duration and magnitude of increased risk of venous thromboembolism after different types of surgery.<h4>Design</h4>Prospective cohort study (Million Women Study).<h4>Setting</h4>Questionnaire data from the Million Women Study linked with hospital admission and death records.<h4>Participants</h4>947 454 middle aged women in the United Kingdom recruited in 1996-2001 and followed by record linkage to routinely collected NHS data on hospital admissions and deaths. During follow-up 239 614 admissions were for surgery; 5419 women were admitted, and a further 270 died, from venous thromboembolism.<h4>Main outcome measures</h4>Adjusted relative risks and standardised incidence rates for hospital admission or death from venous thromboembolism (pulmonary embolism or deep vein thrombosis), by time since and type of surgery.<h4>Results</h4>Compared with not having surgery, women were 70 times more likely to be admitted with venous thromboembolism in the first six weeks after an inpatient operation (relative risk 69.1, 95% confidence interval 63.1 to 75.6) and 10 times more likely after a day case operation (9.6, 8.0 to 11.5). The risks were lower but still substantially increased 7-12 weeks after surgery (19.6, 16.6 to 23.1 and 5.5, 4.3 to 7.0, respectively). This pattern of risk was similar for pulmonary embolism (n=2487) and deep venous thrombosis (n=3529). The postoperative risks of venous thromboembolism varied considerably by surgery type, with highest relative risks after inpatient surgery for hip or knee replacement and for cancer-1-6 weeks after surgery the relative risks were, respectively, 220.6 (187.8 to 259.2) and 91.6 (73.9 to 113.4).<h4>Conclusion</h4>The risk of deep vein thrombosis and pulmonary embolism after surgery is substantially increased in the first 12 postoperative weeks, and varies considerably by type of surgery. An estimated 1 in 140 middle aged women undergoing inpatient surgery in the UK will be admitted with venous thromboembolism during the 12 weeks after surgery (1 in 45 after hip or knee replacement and 1 in 85 after surgery for cancer), compared with 1 in 815 after day case surgery and only 1 in 6200 women during a 12 week period without surgery.
BRCA mutation carriers are recommended to start mammographic screening for breast cancer as early as age 25-30 years. We used an excess relative risk model (based on a pooled analysis of three cohorts with 7600 subjects who received radiation exposure) to estimate the lifetime risk of radiation-induced breast cancer from five annual mammographic screenings in young (<40 years) BRCA mutation carriers. We then estimated the reduction in breast cancer mortality required to outweigh the radiation risk. Breast cancer rates for mutation carriers were based on a pooled analysis of 22 pedigree studies with 8139 subjects. For BRCA1 mutation carriers, the estimated lifetime risk of radiation-induced breast cancer mortality per 10,000 women resulting from annual mammography was 26 (95% confidence interval [CI] = 14 to 49) for screening at age 25-29 years, 20 (95% CI = 11 to 39) for screening at age 30-34 years, and 13 (95% CI = 7 to 23) for screening at age 35-39 years. To outweigh these risks, screening would have to reduce breast cancer mortality by 51% (95% CI = 27% to 96%) at age 25-29 years, by 12% (95% CI = 6% to 23%) at age 30-34 years, and by 4% (95% CI = 2% to 7%) at age 35-39 years; estimates were similar for BRCA2 mutation carriers. If we assume that the mortality reduction from mammography is 15%-25% or less for young women, these results suggest that there would be no net benefit from annual mammographic screening of BRCA mutation carriers at age 25-29 years; the net benefit would be zero or small at age 30-34 years, but there should be some net benefit at age 35 or older. These results depend on a number of assumptions due to the absence of empiric data. The impact of varying these assumptions was therefore examined.
High-risk human papillomavirus (HPV) types cause most cervical carcinomas and are sexually transmitted. Sexual behavior therefore affects HPV exposure and its cancer sequelae. The International Collaboration of Epidemiological Studies of Cervical Cancer has combined data on lifetime number of sexual partners and age at first sexual intercourse from 21 studies, or groups of studies, including 10,773 women with invasive cervical carcinoma, 4,688 women with cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ, and 29,164 women without cervical carcinoma. Relative risks for invasive cancer and CIN3 were estimated by conditional logistic regression. Risk of invasive cervical carcinoma increased with lifetime number of sexual partners (P for linear trend <0.001). The relative risk for > or =6 versus 1 partner, conditioned on age, study, and age at first intercourse, was 2.27 [95% confidence interval (95% CI), 1.98-2.61] and increased to 2.78 (95% CI, 2.22-3.47) after additional conditioning on reproductive factors. The risk of invasive cervical carcinoma increased with earlier age at first intercourse (P for linear trend <0.001). The relative risk for age at first intercourse < or =14 versus > or =25 years, conditioned on age, study, and lifetime number of sexual partners was 3.52 (95% CI, 3.04-4.08), which decreased to 2.05 (95% CI, 1.54-2.73) after additional conditioning on reproductive factors. CIN3/carcinoma in situ showed a similar association with lifetime number of sexual partners; however, the association with age at first intercourse was weaker than for invasive carcinoma. Results should be interpreted with caution given the strong correlation between sexual and reproductive factors and the limited information on HPV status.
<h4>Objectives</h4>A history of type 2 diabetes is one of few consistent risk factors for pancreatic cancer. Potentially modifiable factors related to fasting insulin and glucose concentrations may influence pancreatic cancer risk.<h4>Methods</h4>Multiple linear regression models were used to identify anthropometric, clinical, behavioral, and dietary factors associated with fasting insulin and glucose in a subcohort of non-diabetics in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 366). Hazards ratios (HRs) and 95% confidence intervals (CIs) were calculated among the larger cohort (n = 27,035).<h4>Results</h4>During follow-up (median 16.1 years), 305 participants developed pancreatic cancer. Fasting insulin and/or glucose were positively associated with body mass index (BMI), height, and dietary total and saturated fat and inversely associated with serum high-density lipoprotein cholesterol (HDL) and dietary available carbohydrates, sucrose, and alcohol. Comparing highest to lowest quintiles, total fat (HR = 1.54, 95% CI 1.05-2.25, p-trend = 0.01) and saturated fat (HR = 1.38, 95% CI 0.97-1.98, p-trend = 0.06) were positively associated and available carbohydrates (HR = 0.63, 95% CI 0.44-0.90, p-trend = 0.01), particularly sucrose (HR = 0.62, 95% CI 0.43-0.89, p-trend = 0.09), were inversely associated with risk of pancreatic cancer. BMI, HDL, height, and alcohol were not associated with pancreatic cancer risk.<h4>Conclusion</h4>Dietary fat is associated with higher fasting insulin concentrations and may increase pancreatic cancer risk in smokers.
<h4>Background</h4>Certain studies suggest that alcohol may reduce the risk of thyroid cancer in women, but the effect in men remains unclear.<h4>Methods</h4>We analysed the association between alcohol and thyroid cancer in a large (n=490 159) prospective NIH-AARP Diet and Health Study with self-reported beer, wine, and liquor intakes.<h4>Results</h4>Over 7.5 years of follow-up (median), 170 men and 200 women developed thyroid cancer. Overall, the thyroid cancer risk decreased with greater alcohol consumption (> or =2 drinks per day vs none, relative risk=0.57, 95% CI 0.36-0.89, P-trend=0.01).<h4>Conclusions</h4>These results suggest a potential protective role for alcohol consumption in thyroid cancer.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 patient's 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.<h4>Conclusion</h4>Radiation doses from commonly performed diagnostic CT examinations are higher and more variable than generally quoted, highlighting the need for greater standardization across institutions.
The incidence of thyroid cancer has been rapidly increasing in the United States, but few risk factors have been established. The authors prospectively examined the associations of self-reported medical history, anthropometric factors, and behavioral factors with thyroid cancer risk among 90,713 US radiologic technologists (69,506 women and 21,207 men) followed from 1983 through 2006. Incident thyroid cancers in 242 women and 40 men were reported. Elevated risks were observed for women with benign thyroid conditions (hazard ratio (HR) = 2.35, 95% confidence interval (CI): 1.73, 3.20), benign breast disease (HR = 1.56, 95% CI: 1.08, 2.26), asthma (HR = 1.68, 95% CI: 1.00, 2.83), and body mass index > or =35.0 versus 18.5-24.9 kg/m(2) (HR = 1.74, 95% CI: 1.03, 2.94; P-trend = 0.04). Current smoking was inversely associated with thyroid cancer risk (HR = 0.54). No clear associations emerged for reproductive factors, other medical conditions, alcohol intake, or physical activity. Despite few thyroid cancers in men, men with benign thyroid conditions had a significantly increased risk of thyroid cancer (HR = 4.65, 95% CI: 1.62, 13.34), and results for other risk factors were similar to those for women. Consistent with prior studies, obesity and benign thyroid conditions increased and current smoking decreased the risk of thyroid cancer. The novel findings for benign breast disease and asthma warrant further investigation.
<h4>Background</h4>The use of computed tomographic (CT) scans in the United States (US) has increased more than 3-fold since 1993 to approximately 70 million scans annually. Despite the great medical benefits, there is concern about the potential radiation-related cancer risk. We conducted detailed estimates of the future cancer risks from current CT scan use in the US according to age, sex, and scan type.<h4>Methods</h4>Risk models based on the National Research Council's "Biological Effects of Ionizing Radiation" report and organ-specific radiation doses derived from a national survey were used to estimate age-specific cancer risks for each scan type. These models were combined with age- and sex-specific scan frequencies for the US in 2007 obtained from survey and insurance claims data. We estimated the mean number of radiation-related incident cancers with 95% uncertainty limits (UL) using Monte Carlo simulations.<h4>Results</h4>Overall, we estimated that approximately 29 000 (95% UL, 15 000-45 000) future cancers could be related to CT scans performed in the US in 2007. The largest contributions were from scans of the abdomen and pelvis (n = 14 000) (95% UL, 6900-25 000), chest (n = 4100) (95% UL, 1900-8100), and head (n = 4000) (95% UL, 1100-8700), as well as from chest CT angiography (n = 2700) (95% UL, 1300-5000). One-third of the projected cancers were due to scans performed at the ages of 35 to 54 years compared with 15% due to scans performed at ages younger than 18 years, and 66% were in females.<h4>Conclusions</h4>These detailed estimates highlight several areas of CT scan use that make large contributions to the total cancer risk, including several scan types and age groups with a high frequency of use or scans involving relatively high doses, in which risk-reduction efforts may be warranted.
<h4>Objective</h4>To investigate whether the positive association of body mass index (BMI, kg/m(2)) with risk of pancreatic cancer is modified by age, sex, smoking status, physical activity, and history of diabetes.<h4>Methods</h4>In a pooled analysis of primary data of seven prospective cohorts including 458,070 men and 485,689 women, we identified 2,454 patients with incident pancreatic cancer during an average 6.9 years of follow-up. Cox proportional hazard regression models were used in data analysis.<h4>Results</h4>In a random-effects meta-analysis, for every 5 kg/m(2) increment in BMI, the summary relative risk (RR) was 1.06 (95% confidence interval (CI) 0.99-1.13) for men and 1.12 (95% CI 1.05-1.19) for women. The aggregate analysis showed that compared with normal weight (BMI: 18.5 to <25), the adjusted RR was 1.13 (95% CI 1.03-1.23) for overweight (BMI: 25 to <30) and 1.19 (95% CI 1.05-1.35) for obesity class I (BMI: 30 to <35). Tests of interactions of BMI effects by other risk factors were not statistically significant. Every 5 kg/m(2) increment in BMI was associated with an increased risk of pancreatic cancer among never and former smokers, but not among current smokers (P-interaction = 0.08).<h4>Conclusion</h4>The present evidence suggests that a high BMI is an independent risk factor of pancreatic cancer.
Epidemiological studies of medical radiation workers have found excess risks of leukemia, skin and female breast cancer in those employed before 1950 but little consistent evidence of cancer risk increases subsequently. Occupational radiation-related dose-response data and recent and lifetime cancer risk data are limited for radiologists and radiologic technologists and lacking for physicians and technologists performing fluoroscopically guided procedures. Survey data demonstrate that occupational doses to radiologists and radiologic technologists have declined over time. Eighty mostly small studies of cardiologists and fewer studies of other physicians reveal that effective doses to physicians per interventional procedure vary by more than an order of magnitude. For medical radiation workers, there is an urgent need to expand the limited information on average annual, time-trend and organ doses from occupational radiation exposures and to assess lifetime cancer risks of these workers. For physicians and technologists performing interventional procedures, more information about occupational doses should be collected and long-term follow-up studies of cancer and other serious disease risks should be initiated. Such studies will help optimize standardized protocols for radiologic procedures, determine whether current radiation protection measures for medical radiation workers are adequate, provide guidance on cancer screening needs, and yield valuable insights on cancer risks associated with chronic radiation exposure.
<h4>Objective</h4>To examine childhood cancer risks associated with exposure to diagnostic radiation and ultrasound scans in utero and in early infancy (age 0-100 days).<h4>Design</h4>Case-control study.<h4>Setting</h4>England and Wales.<h4>Participants</h4>2690 childhood cancer cases and 4858 age, sex, and region matched controls from the United Kingdom Childhood Cancer Study (UKCCS), born 1976-96.<h4>Main outcome measures</h4>Risk of all childhood cancer, leukaemia, lymphoma, and central nervous system tumours, measured by odds ratios.<h4>Results</h4>Logistic regression models conditioned on matching factors, with adjustment for maternal age and child's birth weight, showed no evidence of increased risk of childhood cancer with in utero exposure to ultrasound scans. Some indication existed of a slight increase in risk after in utero exposure to x rays for all cancers (odds ratio 1.l4, 95% confidence interval 0.90 to 1.45) and leukaemia (1.36, 0.91 to 2.02), but this was not statistically significant. Exposure to diagnostic x rays in early infancy (0-100 days) was associated with small, non-significant excess risks for all cancers and leukaemia, as well as increased risk of lymphoma (odds ratio 5.14, 1.27 to 20.78) on the basis of small numbers.<h4>Conclusions</h4>Although the results for lymphoma need to be replicated, all of the findings indicate possible risks of cancer from radiation at doses lower than those associated with commonly used procedures such as computed tomography scans, suggesting the need for cautious use of diagnostic radiation imaging procedures to the abdomen/pelvis of the mother during pregnancy and in children at very young ages.
In 2008, the worldwide estimated age-standardised incidence rates for thyroid cancer incidence were 4.7 and 1.5 per 100,000 women and men, respectively. Thyroid cancer's overall contribution to the worldwide cancer burden is relatively small, but incidence rates have increased over the last three decades throughout the world. This trend has been hypothesised to reflect a combination of technological advances enabling increased detection, but also changes in environmental factors, including population exposure to ionising radiation from fallout, diagnostic tests and treatment for benign and malignant conditions. Studies of the atomic bomb survivors and populations treated with radiotherapy have established radiation as a risk factor for thyroid cancer, particularly from early life exposure. About 0.62 mSv (20%) of the global annual per caput effective radiation dose comes from diagnostic medical and dental radiation for the period of 1997-2007, increased from 0.4 mSv for the years 1991-1996. This international trend of increasing population exposure to medical diagnostic sources of radiation, attributed in large part to the growing use of computed tomography scans, but also interventional radiology procedures, has raised concerns about exposure to radiosensitive organs such as the thyroid. Worldwide, medical and dental X-rays constitute the most common type of diagnostic medical exposures, but their contribution to the cumulative effective dose is relatively low, whereas computed tomography scans account for 7.9% of diagnostic radiology examinations but 47% of the collective effective dose from diagnostic radiation procedures in parts of the world. Although the radiation exposure from computed tomography scans is substantially lower than that from radiotherapy, multiple computed tomography scans could result in non-trivial cumulative doses to the thyroid. Studies are currently underway to assess the incidence of cancer in large cohorts of children who received computed tomography scans. National and international efforts have been developed to raise awareness and to standardise procedures for use of computed tomography and interventional radiology procedures in paediatric and general populations.
<h4>Background</h4>Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain.<h4>Methods</h4>We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex.<h4>Results</h4>Over follow-up (mean=10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m2: HR in women, 1.16 (95% CI, 1.08-1.24); HR in men, 1.21 (95% CI, 0.97-1.49)]. There was no significant heterogeneity between studies (both P>0.05). For women and men combined, the HRs for overweight (25.0-29.9 kg/m2) and obesity (≥30 kg/m2) compared with normal-weight (18.5-24.9 kg/m2) were 1.20 (95% CI, 1.04-1.38) and 1.53 (95% CI, 1.31-1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18-20) with thyroid cancer risk was also observed [per 5-kg/m2 increase: HR, 1.18 (95% CI, 1.03-1.35)].<h4>Conclusion</h4>BMI was positively associated with thyroid cancer risk in both men and women.<h4>Impact</h4>Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer.
Although exposure to estrogen may directly influence or modify the association between cigarette smoking and lung cancer risk, results from epidemiologic studies examining the association between reproductive and hormonal factors and risk of lung cancer among women have been inconsistent. Between 1998 and 2008, 430 women diagnosed with nonsmall cell lung cancer, 316 hospital controls and 295 population controls were recruited into the multi-center Maryland Lung Cancer Study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) according to reproductive and hormonal exposures adjusting for age, smoking, passive smoking, education and household income. Results were similar for hospital and population based controls, so the control groups were combined. Reduced risks of lung cancer were observed among women with greater parity (≥ 5 vs. 1-2 births: OR = 0.50, 95% CI = 0.32, 0.78, p-trend = 0.002) and later ages at last birth (≥ 30 vs. <25 years old: OR = 0.68, 95% CI = 0.48, 0.98, p-trend = 0.04). After mutual adjustment parity, but not age at last birth, remained significantly inversely associated with risk (p-trend = 0.01). No associations were found for nonsmall cell lung cancer risk with age at menarche, age at first birth, menopausal status, oral contraceptive use or menopausal hormone use, including use of oral estrogens. Compatible with findings from recent epidemiologic studies, we observed a reduction in the risk of nonsmall cell lung cancer with increasing number of births. Other reproductive and hormonal exposures, including menopausal hormone therapy use, were not associated with risk.
Nulliparity is an established breast cancer risk factor, particularly when compared with parity at young ages. The authors aggregated data from 4 US prospective studies (1979-2006) including 32,641 nulliparous (1,612 breast cancers) and 204,270 parous (8,180 breast cancers) women to examine the hypothesis that nulliparity may increase susceptibility to established postmenopausal breast cancer risk factors. The aggregated hazard ratio for nulliparous versus all parous women = 1.27 (95% confidence interval: 1.21, 1.34), and that for nulliparous versus women <25 years of age at first birth = 1.38 (95% confidence interval: 1.30, 1.46). Among nulliparous women, the hazard ratios for current menopausal hormone therapy use (vs. never use), body mass index ≥30 kg/m(2) (vs. <25 kg/m(2)), and weekly consumption of ≥7 alcoholic drinks (vs. none) ranged from 1.3 to 1.6. The hazard ratios did not differ by parity. In a model including all women, the joint association for each of these factors and nulliparity combined compared with first birth before age 25 years was an approximately 2-fold increased breast cancer risk. Although the baseline risk is higher for nulliparous women compared with parous women, these results suggest that the associations between hormone-related factors and breast cancer do not differ by parity.
<h4>Purpose</h4>Contralateral breast cancer (CBC) is the most frequent new malignancy among women diagnosed with a first breast cancer. Although temporal trends for first breast cancers have been well studied, trends for CBC are not so well established.<h4>Patients and methods</h4>We examined temporal trends in CBC incidence using US Surveillance, Epidemiology, and End Results database (1975 to 2006). Data were stratified by estrogen receptor (ER) status of the first breast cancer for the available time period (1990+). We estimated the annual percent change (EAPC) in CBC rates using Poisson regression models adjusted for the age at and time since first breast cancer diagnosis.<h4>Results</h4>Before 1985, CBC incidence rates were stable (EAPC, 0.27% per year; 95% CI, -0.4 to 0.9), after which they declined with an EAPC of -3.07% per year (95% CI, -3.5 to -2.7). From 1990 forward, the declines were restricted to CBC after an ER-positive cancer (EAPC, -3.18%; 95% CI, -4.2 to -2.2) with no clear decreases after an ER-negative cancer. Estimated current age-specific CBC rates (per 100/year) after an ER-positive first cancer were: 0.45 for first cancers diagnosed before age 30 years and 0.25 to 0.37 for age 30 years or older. Rates after an ER-negative cancer were higher: 1.26 before age 30 years, 0.85 for age 30 to 35 years, and 0.45 to 0.65 for age 40 or older.<h4>Conclusion</h4>Results show a favorable decrease of 3% per year for CBC incidence in the United States since 1985. This overall trend was driven by declining CBC rates after an ER-positive cancer, possibly because of the widespread usage of adjuvant hormone therapies, after the results of the Nolvadex Adjuvant Trial Organisation were published in 1983, and/or other adjuvant treatments.
<h4>Objective</h4>The purpose of this study was to estimate the ratio of cancers prevented to induced (benefit-risk ratio) for CT colonography (CTC) screening every 5 years from the age of 50 to 80 years.<h4>Materials and methods</h4>Radiation-related cancer risk was estimated using risk projection models based on the National Research Council's Biological Effects of Ionizing Radiation (BEIR) VII Committee's report and screening protocols from the American College of Radiology Imaging Network's National CT Colonography Trial. Uncertainty intervals were estimated using Monte Carlo simulation methods. Comparative modeling with three colorectal cancer microsimulation models was used to estimate the potential reduction in colorectal cancer cases and deaths.<h4>Results</h4>The estimated mean effective dose per CTC screening study was 8 mSv for women and 7 mSv for men. The estimated number of radiation-related cancers resulting from CTC screening every 5 years from the age of 50 to 80 years was 150 cases/100,000 individuals screened (95% uncertainty interval, 80-280) for men and women. The estimated number of colorectal cancers prevented by CTC every 5 years from age 50 to 80 ranged across the three microsimulation models from 3580 to 5190 cases/100,000 individuals screened, yielding a benefit-risk ratio that varied from 24:1 (95% uncertainty interval, 13:1-45:1) to 35:1 (19:1-65:1). The benefit-risk ratio for cancer deaths was even higher than the ratio for cancer cases. Inclusion of radiation-related cancer risks from CT examinations performed to follow up extracolonic findings did not materially alter the results.<h4>Conclusion</h4>Concerns have been raised about recommending CTC as a routine screening tool because of potential harms including the radiation risks. Based on these models, the benefits from CTC screening every 5 years from the age of 50 to 80 years clearly outweigh the radiation risks.
<h4>Purpose</h4>To further clarify the relationship between total cholesterol and cancer, which remains unclear.<h4>Methods</h4>We prospectively examined the association between total cholesterol and site-specific and all-cancer incidence among 1,189,719 Korean adults enrolled in the National Health Insurance Corporation who underwent a standardized biennial medical examination in 1992 to 1995 and were observed for 14 years until cancer diagnosis or death.<h4>Results</h4>Over follow-up, 53,944 men and 24,475 women were diagnosed with a primary cancer. Compared with levels less than 160 mg/dL, high total cholesterol (≥ 240 mg/dL) was positively associated with prostate cancer (hazard ratio [HR], 1.24; 95% CI, 1.07 to 1.44; P trend = .001) and colon cancer (HR, 1.12; 95% CI, 1.00 to 1.25; P trend = .05) in men and breast cancer in women (HR, 1.17; 95% CI, 1.03 to 1.33; P trend = .03). Higher total cholesterol was associated with a lower incidence of liver cancer (men: HR, 0.42; 95% CI, 0.38 to 0.45; P trend < .001; women: HR, 0.32; 95% CI, 0.27 to 0.39; P trend < .001), stomach cancer (men: HR, 0.87; 95% CI, 0.82 to 0.93; P trend ≤ .001; women: HR, 0.86; 95% CI, 0.77 to 0.97; P trend = .06), and, in men, lung cancer (HR, 0.89; 95% CI, 0.82 to 0.96; P trend < .001). Results for liver cancer were slightly attenuated after additional adjustment for liver enzyme levels and hepatitis B surface antigen status (men: HR, 0.60; P trend < .001; women: HR, 0.46; P trend = .003) and exclusion of the first 10 years of follow-up (men: HR, 0.59; P trend < .001; women: HR, 0.44; P trend < .001). Total cholesterol was inversely associated with all-cancer incidence in both men (HR, 0.84; 95% CI, 0.81 to 0.86; P trend < .001) and women (HR, 0.91; 95% CI, 0.87 to 0.95; P trend < .001), but these associations were attenuated after excluding incident liver cancers (men: HR, 0.95; P trend < .001; women: HR, 0.98; P trend = .32).<h4>Conclusion</h4>In this large prospective study, we found that total cholesterol was associated with the risk of several different cancers, although these relationships differed markedly by cancer site.
<h4>Background</h4>Increases in thyroid papillary carcinoma incidence rates have largely been attributed to heightened medical surveillance and improved diagnostics. We examined papillary carcinoma incidence in an equal-access health care system by demographics that are related to incidence.<h4>Methods</h4>Incidence rates during 1990-2004 among white and black individuals aged 20 to 49 years in the military, and the general U.S. population were compared using data from the Department of Defense's Automated Central Tumor Registry and the National Cancer Institute's Surveillance Epidemiology and End Results (SEER-9) program.<h4>Results</h4>Incidence was significantly higher in the military than in the general population among white women [incidence rate ratio (IRR) = 1.42; 95% confidence interval (CI), 1.25-1.61], black women (IRR = 2.31; 95% CI, 1.70-2.99), and black men (IRR = 1.69, 95% CI, 1.10-2.50). Among whites, differences between the two populations were confined to rates of localized tumors (women: IRR = 1.73, 95% CI, 1.47-2.00; men: IRR = 1.51, 95% CI, 1.30-1.75), which may partially be due to variation in staging classification. Among white women, rates were significantly higher in the military regardless of tumor size and rates rose significantly over time both for tumors ≤ 2 cm (military: IRR = 1.64, 95% CI, 1.18-2.28; general population: IRR = 1.55, 95% CI, 1.45-1.66) and > 2 cm (military: IRR = 1.74, 95% CI, 1.07-2.81; general population: IRR = 1.48, 95% CI, 1.27-1.72). Among white men, rates increased significantly only in the general population. Incidence also varied by military service branch.<h4>Conclusions</h4>Heightened medical surveillance does not appear to fully explain the differences between the two populations or the temporal increases in either population.<h4>Impact</h4>These findings suggest the importance of future research into thyroid cancer etiology.
Body mass index (BMI) has been positively associated with thyroid cancer risk in several studies, but the underlying mechanisms remain unclear. We examined the associations for waist and hip circumference and weight change during adulthood with thyroid cancer risk among 125,347 men and 72,363 women in the NIH-AARP Diet and Health Study who completed a second mailed questionnaire in 1996-1997. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated separately by sex and adjusted for race/ethnicity, education and smoking status. During follow-up (median = 10.1 years), 106 men and 105 women were diagnosed with a first primary thyroid cancer, as identified through linkage to state cancer registries. Having a large waist circumference (above the clinical cutpoint for normal: > 102 cm in men and > 88 cm in women) was associated with increased risk in both men (HR = 1.79, 95% CI: 1.21-2.63) and women (HR = 1.54, 95% CI: 1.05-2.26). Having both a large waist and BMI in the obese range (≥ 30 kg/m2) approximately doubled the risk of thyroid cancer (HR in men = 2.13, 95% CI: 1.18-3.85; HR in women = 1.91, 95% CI: 1.31-3.25) compared to having a normal waist circumference/normal BMI (18.5-24.9 kg/m2). We also observed positive association for weight gain between ages 18-35 in men (gained ≥ 10.0 kg vs. lost/gained < 5 kg, HR = 1.49, 95% CI: 0.93-2.39, p-trend = 0.03), but the association was less pronounced in women. No clear association for weight gain in later life was observed. These results support a potential role for hormonal and metabolic parameters common to central adiposity in thyroid carcinogenesis.
<h4>Background</h4>Worldwide, thyroid cancer incidence rates are higher among women than men. While this suggests a possible etiologic role of female sex hormones, clear associations between hormonal and reproductive factors and thyroid cancer have not been observed. However, few large prospective studies have been conducted.<h4>Methods</h4>Hazard ratios (HRs) and 95% confidence intervals (CIs) for hormonal and reproductive factors and incident thyroid cancer were estimated using Cox regression methods in the prospective US NIH-AARP Diet and Health Study. Between 1995 and 2006, 312 first primary incident thyroid cancers were diagnosed among 187,865 postmenopausal women ages 50-71 at baseline.<h4>Results</h4>Thyroid cancer was not associated with ages at menarche or menopause, menopause type, or parity. Oral contraceptive use for ≥10 years (vs. never use) was inversely associated with thyroid cancer risk (HR, 0.48; 95%CI, 0.28-0.84; P(trend)=0.01). Women who reported current menopausal hormone therapy at baseline had an increased thyroid cancer risk vs. never users (HR 1.38; 95% CI: 1.07-1.79) but there was no trend with increasing duration of use. Women with benign breast disease (BBD) had a significantly higher thyroid cancer risk vs. women without BBD (HR, 1.47; 95% CI, 1.09-1.99).<h4>Conclusions</h4>Our results do not support a strong role for female hormonal and reproductive factors including ages at menarche and menopause, type of menopause or parity, in thyroid cancer etiology among postmenopausal women. Compared with previous studies, no clear patterns emerge for exogenous hormone use but further analysis in large, prospective populations may be informative. The HR for BBD is consistent with the one previous prospective analysis that examined this association.
PURPOSE: Although many studies have linked obesity with increased risk of thyroid cancer, few have investigated the role of obesity-related lifestyle characteristics and medical conditions in the etiology of this disease. We examined the associations of self-reported physical activity and diabetes history with thyroid cancer risk in a large pooled analysis of prospective cohort studies. METHODS: Data from five prospective studies in the U.S. (n = 362,342 men, 312,149 women) were coded using standardized exposure, covariate, and outcome definitions. Hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer were estimated using age as the time metric and adjusting for sex, education, race, marital status, cigarette smoking, body mass index, alcohol intake, and cohort. Effect modification by other risk factors (e.g., age, sex, and body mass index) and differences by cancer subtype (e.g., papillary, follicular) were also examined. RESULTS: Over follow-up (median = 10.5 years), 308 men and 510 women were diagnosed with a first primary thyroid cancer. Overall, subjects reporting the greatest amount of physical activity had an increased risk of the disease (HR = 1.18, 95% CI:1.00-1.39); however, this association was restricted to participants who were overweight/obese (≥25 kg/m(2); HR = 1.34, 95% CI:1.09-1.64) as opposed to normal-weight (<25 kg/m(2); HR = 0.92, 95% CI:0.69-1.22; P-interaction = 0.03). We found no overall association between self-reported history of diabetes and thyroid cancer risk (HR = 1.08, 95% CI:0.83-1.40). CONCLUSION: Neither physical inactivity nor diabetes history was associated with increased risk of thyroid cancer. While it may have been a chance finding, the possible increased risk associated with greater physical activity warrants further investigation.
<h4>Background</h4>Combined oral contraceptives are classified by the International Agency for Research on Cancer as a cause of cervical cancer. As the incidence of cervical cancer increases with age, the public-health implications of this association depend largely on the persistence of effects long after use of oral contraceptives has ceased. Information from 24 studies worldwide is pooled here to investigate the association between cervical carcinoma and pattern of oral contraceptive use.<h4>Methods</h4>Individual data for 16,573 women with cervical cancer and 35,509 without cervical cancer were reanalysed centrally. Relative risks of cervical cancer were estimated by conditional logistic regression, stratifying by study, age, number of sexual partners, age at first intercourse, parity, smoking, and screening.<h4>Findings</h4>Among current users of oral contraceptives the risk of invasive cervical cancer increased with increasing duration of use (relative risk for 5 or more years' use versus never use, 1.90 [95% CI 1.69-2.13]). The risk declined after use ceased, and by 10 or more years had returned to that of never users. A similar pattern of risk was seen both for invasive and in-situ cancer, and in women who tested positive for high-risk human papillomavirus. Relative risk did not vary substantially between women with different characteristics.<h4>Interpretation</h4>The relative risk of cervical cancer is increased in current users of oral contraceptives and declines after use ceases. 10 years' use of oral contraceptives from around age 20 to 30 years is estimated to increase the cumulative incidence of invasive cervical cancer by age 50 from 7.3 to 8.3 per 1000 in less developed countries and from 3.8 to 4.5 per 1000 in more developed countries.
<h4>Background</h4>Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships.<h4>Methods and findings</h4>Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index. Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05-1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m(2) increase in body mass index was 1.10 (95% CI, 1.07-1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92-0.99; p=0.02) in ever-users of hormone therapy.<h4>Conclusions</h4>Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade. Please see later in the article for the Editors' Summary.
There are nearly 12 million cancer survivors living in the United States, and the number continues to rise with ongoing improvements in treatment and screening. Assuring the long-term health of these patients poses both clinical and public health concerns. Survivorship research covers multiple aspects of life after a cancer diagnosis, including quality of life, acute and late effects of cancer treatment and mortality. Answering these questions requires a wide array of data, including information on the outcomes of interest, treatment history, and lifestyle. One potentially efficient approach to studying late effects and survivorship is to convert or extend existing epidemiologic studies of cancer etiology. In this article, we evaluate the different potential approaches for doing this and the challenges this entails. Our evaluation highlights the combinations of research topic and design most likely to succeed. We show that any question that relates to the existing information including prediagnosis lifestyle factors or genetics (if samples are available) could be efficiently studied, with an appropriate design. On the other hand, most, though not all converted studies would be ill-suited to the evaluation of the effect of treatment and postdiagnosis lifestyle changes. In terms of endpoints, hard outcomes including mortality and second cancers are more likely to be available within the existing study framework than other morbidities or quality of life. In light of the costs and time required to build new cohorts, appropriately leveraging the existing studies offers an important opportunity to gain new insights into cancer survivorship for both clinicians and patients.
The 600% increase in medical radiation exposure to the US population since 1980 has provided immense benefit, but increased potential future cancer risks to patients. Most of the increase is from diagnostic radiologic procedures. The objectives of this review are to summarize epidemiologic data on cancer risks associated with diagnostic procedures, describe how exposures from recent diagnostic procedures relate to radiation levels linked with cancer occurrence, and propose a framework of strategies to reduce radiation from diagnostic imaging in patients. We briefly review radiation dose definitions, mechanisms of radiation carcinogenesis, key epidemiologic studies of medical and other radiation sources and cancer risks, and dose trends from diagnostic procedures. We describe cancer risks from experimental studies, future projected risks from current imaging procedures, and the potential for higher risks in genetically susceptible populations. To reduce future projected cancers from diagnostic procedures, we advocate the widespread use of evidence-based appropriateness criteria for decisions about imaging procedures; oversight of equipment to deliver reliably the minimum radiation required to attain clinical objectives; development of electronic lifetime records of imaging procedures for patients and their physicians; and commitment by medical training programs, professional societies, and radiation protection organizations to educate all stakeholders in reducing radiation from diagnostic procedures.
<h4>Objective</h4>We examined the associations between cigarette smoking, alcohol intake, and thyroid cancer risk in a pooled analysis of five prospective studies.<h4>Methods</h4>Data from five prospective U.S. studies were standardized and then combined into one aggregate dataset (384,433 men and 361,664 women). Pooled hazard ratios (HR) and 95 % confidence intervals (CI) for thyroid cancer were estimated from mutually adjusted models of cigarette smoking and alcohol intake, which were additionally adjusted for age, sex, education, race, marital status, body mass index, and cohort.<h4>Results</h4>Over follow-up, 1,003 incident thyroid cancer cases (335 men and 668 women) were identified. Compared to never smokers, current smoking was associated with reduced risk of thyroid cancer (HR = 0.68, 95 % CI 0.55-0.85); this association was slightly stronger among non-drinkers (HR = 0.46, 95 % CI 0.29-0.74). No reduction in risk was observed for former, compared to never, smokers. Greater smoking intensity, duration, and pack-years were associated with further reductions in risk among former and current smokers. Alcohol intake was also inversely associated with thyroid cancer risk (≥7 drinks/week versus 0, HR = 0.72, 95 % CI 0.58-0.90, p trend = 0.002). Inverse associations with smoking and alcohol were more pronounced for papillary versus follicular tumors.<h4>Conclusion</h4>The results of this pooled analysis suggest that both cigarette smoking and alcohol consumption are associated with reduced risks of papillary thyroid cancer and, possibly, follicular thyroid cancer.
Despite great potential benefits, there are concerns about the possible harm from medical imaging including the risk of radiation-related cancer. There are particular concerns about computed tomography (CT) scans in children because both radiation dose and sensitivity to radiation for children are typically higher than for adults undergoing equivalent procedures. As direct empirical data on the cancer risks from CT scans are lacking, the authors are conducting a retrospective cohort study of over 240,000 children in the UK who underwent CT scans. The main objective of the study is to quantify the magnitude of the cancer risk in relation to the radiation dose from CT scans. In this paper, the methods used to estimate typical organ-specific doses delivered by CT scans to children are described. An organ dose database from Monte Carlo radiation transport-based computer simulations using a series of computational human phantoms from newborn to adults for both male and female was established. Organ doses vary with patient size and sex, examination types and CT technical settings. Therefore, information on patient age, sex and examination type from electronic radiology information systems and technical settings obtained from two national surveys in the UK were used to estimate radiation dose. Absorbed doses to the brain, thyroid, breast and red bone marrow were calculated for reference male and female individuals with the ages of newborns, 1, 5, 10, 15 and 20 y for a total of 17 different scan types in the pre- and post-2001 time periods. In general, estimated organ doses were slightly higher for females than males which might be attributed to the smaller body size of the females. The younger children received higher doses in pre-2001 period when adult CT settings were typically used for children. Paediatric-specific adjustments were assumed to be used more frequently after 2001, since then radiation doses to children have often been smaller than those to adults. The database here is the first detailed organ-specific paediatric CT scan database for the UK. As well as forming the basis for the UK study, the results and description of the methods will also serve as a key resource for paediatric CT scan studies currently underway in other countries.
<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.
<h4>Purpose</h4>Lung cancers account for 5 % of second primary cancers after breast cancer. The low overall 5-year relative survival rate of lung cancer makes it a particularly concerning new malignancy for breast cancer survivors. It is unknown whether second lung cancer risk varies by estrogen receptor (ER) expression of the first breast cancer.<h4>Methods</h4>We evaluated second primary lung cancer risks using standardized incidence ratios (SIRs) (95 % confidence intervals (CIs)) among 222,148 one-year breast cancer survivors in the NCI-SEER Program registry database (1992-2008). Relative risks (RRs) and 95 % CIs for lung cancer following ER(-) compared with ER(+) breast cancer were estimated using Poisson regression, adjusted for age, year, and stage of breast cancer diagnosis, attained age, latency, and radiotherapy. We also examined the reciprocal association of second ER(-) and ER(+) breast cancers among 28,107 1-year lung cancer survivors.<h4>Results</h4>There were 418 and 1,444 second lung cancers diagnosed following 50,781 ER(-) and 171,367 ER(+) breast cancers. Second lung cancer rates were significantly elevated after ER(-) (SIR = 1.20 (1.09-1.33)), but not ER(+) (SIR = 0.96 (0.91-1.01)) breast cancer. The adjusted RR for a second lung cancer following ER(-) compared with ER(+) breast cancer was 1.22 (1.10-1.37). The reciprocal adjusted RR for a second ER(-) compared with ER(+) breast cancer following lung cancer was 1.29 (0.98-1.70).<h4>Conclusion</h4>The parallel increase for a second lung cancer following an ER(-) first breast cancer and for a second ER(-) breast cancer after a first lung cancer suggests that there may be shared etiologic factors for these cancers. Further evaluation of lung cancer risk after ER(-) breast cancer may identify women at high risk for this fatal malignancy.
Although exposure to moderate-to-high doses of ionizing radiation is the only established environmental risk factor for brain and CNS tumors, it is not clear whether this relationship differs across tumor subtypes, by sex or age at exposure, or at the low-to-moderate range of exposure. This systematic review summarizes the epidemiologic evidence on the association between ionizing radiation exposure and risk of brain/CNS tumors. Articles included in this review estimated radiation exposure doses to the brain and reported excess relative risk (ERR) estimates for brain/CNS tumors. Eight cohorts were eligible for inclusion in the analysis. Average age at exposure ranged from 8 months to 26 years. Mean dose to the brain ranged from 0.07 to 10 Gy. Elevated risks for brain/CNS tumors were consistently observed in relation to ionizing radiation exposure, but the strength of this association varied across cohorts. Generally, ionizing radiation was more strongly associated with risk for meningioma compared with glioma. The positive association between ionizing radiation exposure and risk for glioma was stronger for younger vs older ages at exposure. We did not observe an effect modification on the risk for meningioma by sex, age at exposure, time since exposure, or attained age. The etiologic role of ionizing radiation in the development of brain/CNS tumors needs to be clarified further through additional studies that quantify the association between ionizing radiation and risk for brain/CNS tumors at low-to-moderate doses, examine risks across tumor subtypes, and account for potential effect modifiers.
<h4>Background</h4>Although the prevalence of obesity (body mass index, kg/m(2), BMI ≥30) is higher in non-Hispanic blacks than in non-Hispanic whites, the relation of BMI to total mortality in non-Hispanic blacks is not well defined.<h4>Purpose</h4>We investigated the association between BMI and total mortality in 16,471 non-Hispanic blacks in the NIH-AARP Diet and Health Study, a prospective cohort of adults aged 50-71 years.<h4>Methods</h4>During an average of 13 years of follow-up, 2,609 deaths were identified using the Social Security Administration Death Master File and the National Death Index. Cox proportional hazard models were used to estimate relative risks and two-sided 95% confidence intervals (CI), adjusting for potential confounders.<h4>Results</h4>Among individuals with no history of cancer or heart disease at baseline and had a BMI of 20 or greater, the relative risk for total death was 1.12 (95% CI:1.05, 1.19, for a 5-unit increase in BMI) in men and 1.09 (95% CI:1.03, 1.15) in women. Among never smokers with no history of cancer or heart disease at baseline, relative risks for total death for BMI 25-<30, 30-<35, 35-<40, and 40-50, compared with BMI 20-<25, were 1.27 (95% CI: 0.91, 1.78), 1.56 (95% CI: 1.07, 2.28), 2.48 (95% CI: 1.53, 4.05), and 2.80 (95% CI: 1.46, 5.39), respectively, in men and 0.78 (95% CI: 0.59, 1.04), 1.17 (95% CI: 0.88, 1.57), 1.35 (95% CI: 0.96, 1.90), and 1.93 (95% CI: 1.33, 2.81), respectively, in women.<h4>Conclusions</h4>Our findings suggest that overweight is related to an increased risk of death in black men, but not in black women, while obesity is related to an increased risk of death in both black men and women. A large pooled analysis of existing studies is needed to systematically evaluate the association between a wide range of BMIs and total mortality in blacks.
<h4>Background</h4>We evaluated the association of central versus overall adiposity on levels of thyroid stimulating hormone (TSH), free triiodothyronine (fT(3)), and free thyroxine (fT(4)) among euthyroid subjects taken from a cross-sectional, representative sample of the adult non-institutionalized U.S. population.<h4>Methods</h4>The National Health and Nutrition Examination Survey 2007-2008 included 1,623 men and 1,491 women who were 20 years and older, with no history of thyroid or liver disease, kidney failure, diabetes, or thyroid function-altering prescription medication use (based on self-report), and having TSH, fT(3), and fT(4) levels between 0.5-4.49 mIU/L, 2.5-3.9 pg/mL, and 0.6-1.6 ng/dL, respectively. Associations between body mass index (BMI) and waist circumference (measures of overall and central adiposity, respectively) and TSH, fT(3), and fT(4) levels were estimated using multivariable linear regression models stratified by sex and adjusted for age, race, smoking status, and alcohol intake.<h4>Results</h4>An increase in serum TSH levels was observed for every 1-quartile increase in BMI in euthyroid men (3.8% [95% CI 0.8%, 6.8%]) and euthyroid women (4.0% [95% CI 1.6%, 6.5%]). Similar, albeit slightly weaker, associations were observed with waist circumference. We also found increases in fT(3) levels with every 1-quartile increase in BMI (1.0% in men and 1.3% in women) and waist circumference (1.2% in men and 1.2% in women). No associations were observed with fT(4.)<h4>Conclusions</h4>Our results provide support that BMI and waist circumference are positively associated with levels of serum TSH and f T(3) but not fT(4) among euthyroid adults. Longitudinal studies are needed to define the temporality of these associations and their potential health implications.
In the past 30 y, the numbers and types of fluoroscopically-guided (FG) procedures have increased dramatically. The objective of the present study is to provide estimated radiation doses to physician specialists, other than cardiologists, who perform FG procedures. The authors searched Medline to identify English-language journal articles reporting radiation exposures to these physicians. They then identified several primarily therapeutic FG procedures that met specific criteria: well-defined procedures for which there were at least five published reports of estimated radiation doses to the operator, procedures performed frequently in current medical practice, and inclusion of physicians from multiple medical specialties. These procedures were percutaneous nephrolithotomy (PCNL), vertebroplasty, orthopedic extremity nailing for treatment of fractures, biliary tract procedures, transjugular intrahepatic portosystemic shunt creation (TIPS), head/neck endovascular therapeutic procedures, and endoscopic retrograde cholangiopancreatography (ERCP). Radiation doses and other associated data were abstracted, and effective dose to operators was estimated. Operators received estimated doses per patient procedure equivalent to doses received by interventional cardiologists. The estimated effective dose per case ranged from 1.7-56 μSv for PCNL, 0.1-101 μSv for vertebroplasty, 2.5-88 μSv for orthopedic extremity nailing, 2.0-46 μSv for biliary tract procedures, 2.5-74 μSv for TIPS, 1.8-53 μSv for head/neck endovascular therapeutic procedures, and 0.2-49 μSv for ERCP. Overall, mean operator radiation dose per case measured over personal protective devices at different anatomic sites on the head and body ranged from 19-800 (median = 113) μSv at eye level, 6-1,180 (median = 75) μSv at the neck, and 2-1,600 (median = 302) μSv at the trunk. Operators' hands often received greater doses than the eyes, neck, or trunk. Large variations in operator doses suggest that optimizing procedure protocols and proper use of protective devices and shields might reduce occupational radiation dose substantially.
<h4>Background</h4>Radiotherapy decreases cancer mortality, but is associated with an increased incidence of second primary cancers, including osteosarcomas, especially after exposure in childhood. It remains uncertain whether radiation is related to other histologic types of bone sarcomas such as chondrosarcomas that are more common in adulthood.<h4>Methods</h4>Using data from 1973 to 2008 Surveillance Epidemiology and End Results registries, we evaluated long-term risk of bone cancer in 1,284,537 adult 5-year cancer survivors. We used standardized incidence ratios (SIR) to compare second bone sarcoma rates to the general population for each histologic type. We also used multivariate Poisson regression to estimate the relative risk (RR) associated with radiotherapy for the most common subtypes, osteosarcoma and chondrosarcoma.<h4>Results</h4>By the end of 2008, 159 second bone sarcomas were reported. Compared with the general population, the risk of developing any bone sarcoma was increased by 25% in patients with no history of radiotherapy [Observed (O) = 89, SIR = 1.25 (1.00-1.54)] and by 257% in patients with a history of radiotherapy [O = 70, SIR = 3.57 (2.78-4.50)]. For each histologic subtype, SIRs were higher among patients who had previously received radiotherapy than among those who had not. The RR for radiotherapy for osteosarcoma (n = 63) was 5.08 (3.05-8.59) and for chondrosarcoma (n = 69) was 1.54 (0.88-2.59), and these risks were even greater for second sarcomas that arose in the radiotherapy field used to treat the first cancer [osteosarcoma, RR = 10.35 (4.96-23.66); chondrosarcoma RR = 8.21 (2.09-39.89)].<h4>Conclusions</h4>Our findings provide the first evidence of a likely association between radiation exposure and chondrosarcoma.<h4>Impact</h4>These results further our understanding of radiotherapy-related cancer risks and will potentially direct practices in long-term surveillance of cancer survivors.
<h4>Background</h4>Although cigarette smoking and alcohol drinking increase the risk of several cancers and certain components of cigarette smoke and alcohol can penetrate the blood-brain barrier, it remains unclear whether these exposures influence the risk of glioma.<h4>Methods</h4>We examined the associations between cigarette smoking, alcohol intake, and risk of glioma in the National Institutes of Health-AARP Diet and Health Study, a prospective study of 477,095 US men and women ages 50-71 years at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using models with age as the time metric and adjusted for sex, race/ethnicity, education, and marital status.<h4>Results</h4>During a median 10.5 person-years of follow-up, 492 men and 212 women were diagnosed with first primary glioma. Among men, current, heavier smoking was associated with a reduced risk of glioma compared with never smoking, but this was based on only nine cases. No associations were observed between smoking behaviours and glioma risk in women. Greater alcohol consumption was associated with a decreased risk of glioma, particularly among men (>2 drinks per day vs <1 drink per week: HR=0.67, 95% CI=0.51-0.90).<h4>Conclusion</h4>Smoking and alcohol drinking do not appear to increase the risk of glioma.
<h4>Purpose</h4>Obesity has consistently been linked to an increased risk of colorectal cancer, particularly among men. Whether body mass index (BMI) differentially influences the risk across the stages of colorectal cancer development remains unclear. We evaluated the associations of BMI with colorectal adenoma incidence, adenoma recurrence, and cancer in the context of a large screening trial, in which cases and controls had an equal chance for disease detection.<h4>Methods</h4>We prospectively evaluated the association between baseline BMI and the risk of incident distal adenoma (1,213 cases), recurrent adenoma (752 cases), and incident colorectal cancer (966 cases) among men and women, ages 55 to 74 years, randomly assigned to receive flexible sigmoidoscopy screening as part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We calculated odds ratios (ORs) and 95% CIs for adenoma incidence and recurrence, and hazard ratios (HRs) and 95% CIs for colorectal cancer incidence, using multivariable-adjusted models.<h4>Results</h4>Compared with normal-weight men (18.5 to 24.9 kg/m(2)), obese men (≥ 30 kg/m(2)) had significantly higher risk of incident adenoma (OR, 1.32; 95% CI, 1.06 to 1.65) and colorectal cancer (HR, 1.48; 95% CI, 1.16 to 1.89) and a borderline increased risk of recurrent adenoma (OR, 1.50; 95% CI, 0.98 to 2.30). No associations were observed for either adenoma or cancer in women.<h4>Conclusion</h4>Data from this large prospective study suggest that obesity is important throughout the natural history of colorectal cancer, at least in men, and colorectal cancer prevention efforts should encourage the achievement and maintenance of a healthy body weight in addition to regular screenings.
<h4>Objectives</h4>We investigated the association between body mass index (BMI) and mortality among Asian Americans.<h4>Methods</h4>We pooled data from prospective cohort studies with 20 672 Asian American adults with no baseline cancer or heart disease history. We estimated hazard ratios and 95% confidence intervals (CIs) with Cox proportional hazards models.<h4>Results</h4>A high, but not low, BMI was associated with increased risk of total mortality among individuals aged 35 to 69 years. The BMI was not related to total mortality among individuals aged 70 years and older. With a BMI 22.5 to < 25 as the reference category among never-smokers aged 35 to 69 years, the hazard ratios for total mortality were 0.83 (95% CI = 0.47, 1.47) for BMI 15 to < 18.5; 0.91 (95% CI = 0.62, 1.32) for BMI 18.5 to < 20; 1.08 (95% CI = 0.86, 1.36) for BMI 20 to < 22.5; 1.14 (95% CI = 0.90, 1.44) for BMI 25 to < 27.5; 1.13 (95% CI = 0.79, 1.62) for BMI 27.5 to < 30; 1.82 (95% CI = 1.25, 2.64) for BMI 30 to < 35; and 2.09 (95% CI = 1.06, 4.11) for BMI 35 to 50. Higher BMI was also related to increased cardiovascular disease and cancer mortality.<h4>Conclusions</h4>High BMI is associated with increased mortality risk among Asian Americans.
Taller stature and obesity in adulthood have been consistently associated with an increased risk of thyroid cancer, but few studies have investigated the role of childhood body size. Using data from a large prospective cohort, we examined associations for height and body mass index (BMI) at ages 7 to 13 years with risk of thyroid cancer in later life. The study population included 321,085 children from the Copenhagen School Health Records Register, born between 1930 and 1989 in Copenhagen, Denmark, with measurements of height and weight from 7 to 13 years of age. These data were linked with the Danish Cancer Registry to identify incident thyroid cancer cases (1968-2010). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for age- and sex-specific height and BMI SD scores (SDS) using proportional hazards models stratified by birth cohort and sex. During follow-up (median = 38.6 years), 171 women and 64 men were diagnosed with thyroid cancer. Both height and BMI were positively associated with thyroid cancer risk, and these associations were similar by age at measurement. Using age 10 as an example, HRs per 1 unit increase in SDS for height (~6-7 cm) and BMI (~1.5-2 kg/m(2)) were 1.22 (95% CI, 1.07-1.40) and 1.15 (95% CI, 1.00-1.34), respectively. These results, together with the relatively young ages at which thyroid cancers are diagnosed compared with other malignancies, suggest a potential link between early-life factors related to growth and body weight and thyroid carcinogenesis.
<h4>Purpose</h4>Radiotherapy for ductal carcinoma (DCIS) is increasing, but the risks and benefits of the treatment remain uncertain. We aimed to investigate the relationship between radiotherapy for DCIS and risk of second non-breast cancers in a large US cohort.<h4>Methods</h4>We conducted a retrospective cohort study of 52,556 women in 12 U.S. population-based cancer registries diagnosed with first primary DCIS during 1992-2008 at age 25-79 years. We estimated relative risks (RRs), attributable risks (AR), and excess absolute risks (EAR) of second non-breast cancers associated with radiotherapy using Poisson regression adjusted for age at year of diagnosis, grade, hormonal therapy (yes/no or unknown), and time since diagnosis.<h4>Results</h4>Approximately half of the women (46.3%) received radiotherapy. Radiotherapy was associated with an increased risk of all second non-breast cancers combined [RR 1.17, 95% confidence interval (CI) 1.08-1.28] and all in-field, radiation-related second cancers combined (RR 1.37, 95% CI 1.15-1.63), driven by second lung cancers (RR 1.33, 95% CI 1.10-1.60) and non-CLL leukemia (RR 1.71, 95% CI 1.02-2.86). The estimated cumulative excess risk of all second non-breast cancers was 0.8% by 15 years after DCIS diagnosis.<h4>Conclusions</h4>Radiotherapy was associated with an increased risk of second non-breast cancers. The specific excess of cancers at sites likely in/near the radiotherapy field suggests the findings are unlikely due exclusively to confounding, but further research into factors related to receipt of radiotherapy is needed. Our risk estimates can be used to help assess the balance of the risks and benefits of radiotherapy for DCIS and to inform clinical practice.
Despite decades of epidemiological research, it remains uncertain whether ionizing radiation can cause lymphomas. Most epidemiological studies of lymphoma risk following non-uniform exposure used dose to red bone marrow (RBM), constituting a small fraction of the lymphocytes, as a surrogate of dose to the lymphocytes. We developed a method to estimate dose to the lymphocytes using the reference distribution of lymphocytes throughout the body and Monte Carlo simulations of computational human phantoms. We applied our method to estimating lymphocyte doses for a pediatric CT patient cohort in the United Kingdom. Estimated dose to the RBM was greater than lymphocyte dose for most scan types (up to 2.6-fold higher, a 5-year-old brain scan) except abdomen scan (RBM dose was about half the lymphocyte dose, a 5-year-old abdomen scan). The lymphocyte dose in the UK cohort showed that T-spine and whole body scans delivered the highest lymphocyte doses (up to 22.4 mGy).
The role of lifestyle risk factors in prostate cancer risk remains elusive despite a large number of epidemiologic studies. In a pooled analysis of data from South and East Asian countries published in this issue, Fowke et al. (Am J Epidemiol. 2015;182(5):381-389) found no evidence for an association between prostate cancer mortality and obesity, alcohol, or smoking. Prostate cancer screening is very uncommon in these countries, and previous evidence for associations with lifestyle factors comes primarily from studies carried out in North America, where screening is very common. Fowke et al. concluded that screening biases are likely to explain the differences in study results. In this commentary, we discuss the potential influence of population-based cancer screening programs in estimates of association from epidemiologic studies. This highlights the importance of carefully considering the impact of screening in the analysis and interpretation of results, in order to advance our understanding of the etiology of cancers that can be detected by screening.
Smoking and diabetes are the only established risk factors for pancreatic cancer. Findings from recent studies suggest that obesity may also be associated with an increased risk of pancreatic cancer, but several earlier studies were less conclusive. We examined this relationship in a meta-analysis of published data. Six case-control and eight cohort studies involving 6391 cases of pancreatic cancer were identified from a computer-based literature search from 1966 to 2003. The relative risk per unit increase in body mass index was estimated for each of the studies from the published data. In a random effects model, the summary relative risk per unit increase in body mass index was 1.02 (95% CI: 1.01-1.03). There was some evidence of heterogeneity between the studies' results (P=0.1). The summary relative risk estimates were slightly higher for studies that had adjusted for smoking and for case-control studies that had not used proxy respondents. The estimated per unit increase in body mass index would translate into a relative risk of 1.19 (95% CI: 1.10-1.29) for obese people (30 kg m(-2)) compared to people with a normal body weight (22 kg m(-2)). These results provide evidence that the risk of pancreatic cancer may be weakly associated with obesity. However, the small magnitude of the summary risk means the possibility of confounding cannot be excluded.
Most information concerning possible cancer risks attributable to lifetime exposure to diagnostic x-rays comes from studies in which x-ray history was ascertained by interview or questionnaire, but little is known about the accuracy of such information. The authors assessed agreement between medical x-ray histories obtained through interview and by review of medical records from thyroid cancer case-control studies conducted in Sweden (1985-1992; 123 cases and 123 controls) and from members of a prepaid health plan in the United States (1986-1991; 50 cases and 50 controls). In both studies, substantial disagreement was found between the numbers of x-ray examinations reported in the interview and in the medical records. There was an indication of relatively poorer reporting among controls, particularly for certain types of x-ray examinations and for large numbers of such examinations. Estimates of the risk associated with exposure to diagnostic x-rays were similar, regardless of whether interview or medical record data were used, even though ordinal dose classifications based on the two sources differed considerably. In populations with a high frequency of exposure, spurious associations with numbers of x-ray examinations or estimated thyroid dose might arise because of differences in recall. However, in the present data, reporting errors by cases and controls seemed to be largely nondifferential.
Human papillomavirus (HPV) infection is thought to be a necessary but not sufficient cause of most cases of cervical cancer. Since oral contraceptive use for long durations is associated with an increased risk of cervical cancer, it is important to know whether HPV infection is more common in oral contraceptive users. We present a systematic review of 19 epidemiological studies of the risk of genital HPV infection and oral contraceptive use. There was no evidence for a strong positive or negative association between HPV positivity and ever use or long duration use of oral contraceptives. The limited data available, the presence of heterogeneity between studies and the possibility of bias and confounding mean, however, that these results must be interpreted cautiously. Further studies are needed to confirm these findings and to investigate possible relations between oral contraceptive use and the persistence and detectability of cervical HPV infection.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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%.<h4>Interpretation</h4>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.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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.<h4>Interpretation</h4>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.
We report results on risk factors for invasive squamous cell and adenocarcinomas of the cervix in women aged 20-44 years from the UK National Case-Control Study of Cervical Cancer, including 180 women with adenocarcinoma, 391 women with squamous cell carcinoma and 923 population controls. The risk of both squamous cell and adenocarcinoma was strongly related to the lifetime number of sexual partners, and, independently, to age at first intercourse. The risk of both types of cervical cancer increased with increasing duration of use of oral contraceptives, and this effect was most marked in current and recent users of oral contraceptives. The risk of squamous cell carcinoma was associated with high parity and the risk of both squamous cell and adenocarcinoma increased with early age at first birth. Long duration smoking (20 or more years) was associated with a two-fold increase in the risk of squamous cell carcinoma, but smoking was not associated with the risk of adenocarcinoma. Further studies are needed to confirm the suggestion from this and other studies of differences in risk related to smoking between squamous cell and adenocarcinomas of the cervix.
Young age at first sexual intercourse (AFI) is an important risk factor for cervical cancer, but no simple statistical model of its influence has been established. We investigated the relationship between risk of cervical carcinoma and time since first intercourse using data on monogamous women (5,074 cases and 16,137 controls) from the International Collaboration of Epidemiological Studies of Cervical Cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from pooled data on 20 studies using conditional logistic regression. The OR for invasive cervical carcinoma is approximately proportional to the square of time since first intercourse (exponent 1.95, 95% CI: 1.76-2.15) up to age 45. First cervical infection with human papillomavirus (HPV) often occurs soon after first sexual intercourse, so early AFI is a reasonable proxy for early age at first exposure to HPV. In addition, age-specific incidence rates of cervical cancer in unscreened populations remain fairly constant above age 45. Cervical cancer thus resembles other cancers caused by strong early-stage carcinogens, with incidence rates proportional to a power of time since first exposure and also resembles cancers of the breast and other hormone-dependent epithelia, where a similar flattening of age-specific incidence rates is seen at the time menopausal changes start. Taken together, these observations suggest that HPV vaccination may prevent the majority of cervical cancers by delaying HPV infection without necessarily providing lifetime protection against HPV.
Tobacco smoking has been classified as a cause of cervical cancer, but the effect of different patterns of smoking on risk is unclear. The International Collaboration of Epidemiological Studies of Cervical Cancer has brought together and combined individual data on 13,541 women with and 23,017 women without cervical carcinoma, from 23 epidemiological studies. Relative risks (RRs) and 95% confidence intervals (CIs) of carcinoma of the cervix in relation to tobacco smoking were calculated with stratification by study, age, sexual partners, age at first intercourse, oral contraceptive use and parity. Current smokers had a significantly increased risk of squamous cell carcinoma of the cervix compared to never smokers (RR = 1.60 (95% CI: 1.48-1.73), p<0.001). There was increased risk for past smokers also, though to a lesser extent (RR = 1.12 (1.01-1.25)), and there was no clear trend with time since stopping smoking (p-trend = 0.6). There was no association between smoking and adenocarcinoma of the cervix (RR = 0.89 (0.74-1.06) and 0.89 (0.72-1.10) for current and past smokers respectively), and the differences between the RRs for smoking and squamous cell and adenocarcinoma were statistically significant (current smoking p<0.001 and past smoking p = 0.01). In current smokers, the RR of squamous cell carcinoma increased with increasing number of cigarettes smoked per day and also with younger age at starting smoking (p<0.001 for each trend), but not with duration of smoking (p-trend = 0.3). Eight of the studies had tested women for cervical HPV-DNA, and in analyses restricted to women who tested positive, there was a significantly increased risk in current compared to never smokers for squamous cell carcinoma (RR = 1.95 (1.43-2.65)), but not for adenocarcinoma (RR = 1.06 (0.14-7.96)). In summary, smokers are at an increased risk of squamous cell but not of adenocarcinoma of the cervix. The risk of squamous cell carcinoma increases in current smokers with the number of cigarettes smoked per day and with younger age at starting smoking.
The NHS Breast Screening Programme (NHSBSP) began in 1988. It aims to invite all women aged 50-70 years for mammographic screening once every three years. The programme now screens 1.3 million women each year, about 75% of those invited, and diagnoses about 10,000 breast cancers annually. Although some have questioned the value of screening for breast cancer, the scientific evidence demonstrates clearly that regular mammographic screening between the ages of 50 and 70 years reduces mortality from the malignancy. Screened women are slightly more likely than unscreened women to be diagnosed with breast cancer. The cancers in screened women are smaller and are less likely to be treated with mastectomy than they would have been if diagnosed without screening. For every 400 women screened regularly by the NHSBSP over a 10-year period, one woman fewer will die from breast cancer than would have died without screening. The current NHSBSP saves an estimated 1400 lives each year in England. The screening programme spends about pound sterling 3000 for every year of life saved.
This paper deals with the synthesis of information from different studies when there is lack of independence in some of the contrasts to be combined. This problem can arise in several different situations in both case-control studies and clinical trials. For efficient estimation we appeal to the method of generalized least squares to estimate the summary effect and its standard error. This method requires estimates of the covariances between those contrasts that are not independent. Although it is not possible to estimate the covariance between effects that have been adjusted for confounding factors we present a method for finding upper and lower bounds for this covariance. In the simplest discussion homogeneity of the relative risks is assumed but the method is then extended to allow for heterogeneity in an overall estimate. We then illustrate the method with several examples from an analysis in which case-control studies of cervical cancer and oral contraceptive use are synthesized.
<h4>Objectives</h4>To summarise the available epidemiological evidence regarding the relationship between the use of progestogen-only contraceptives and bone mineral density.<h4>Design and methods</h4>Overview of the published epidemiological literature.<h4>Results</h4>Overall, 17 studies of the use of progestogen-only contraceptives and bone mineral density were identified, involving 1529 women exposed to progestogen-only contraceptives and 2086 controls. Sixty-eight percent of the data relate to the effects of use of depot medroxyprogesterone acetate. Average bone mineral density was reduced in current users of depot medroxyprogesterone acetate compared with non-users, although density in users was within one standard deviation of the mean in non-users. There was significant heterogeneity between the results of different studies (P < 0.0001). The reduction in bone mineral density appeared to be greater at the lumbar spine, femoral neck and ultradistal forearm than at the midshaft of the ulna. Studies involving women with a longer average duration of use of depot medroxyprogesterone acetate displayed greater reductions in bone mineral density compared with studies of women with shorter durations of use. Based on limited data, no difference in bone mineral density was observed between former and never users of depot medroxyprogesterone acetate. Results regarding the effect of levonorgestrel implants were conflicting. Studies of progestogen-only oral contraceptives and the progesterone vaginal ring were small and restricted to lactating women.<h4>Conclusions</h4>Women currently using depot medroxyprogesterone acetate have a lower average bone mineral density than non-users. The magnitude of this effect is uncertain but appears to be greater with longer durations of use.
Radiologists and radiotherapists were one of the earliest occupational groups to be exposed to ionizing radiation. Their patterns of mortality provide information on the long-term effects of fractionated external radiation exposure. British radiologists who registered with a radiological society between 1897 and 1979 have now been followed-up until 1 January 1997, and the mortality experience examined among those who registered with a society after 1920, when the first radiological protection recommendations were published. The observed number of cancer deaths in those who registered after 1920 was similar to that expected from death rates for all medical practitioners combined (SMR=1.04; 95% CI 0.89-1.21). However, there was evidence of an increasing trend in risk of cancer mortality with time since first registration with a radiological society (p=0.002), such that in those registered for more than 40 years there was a 41% excess risk of cancer mortality (SMR=1.41; 95% CI 1.03-1.90). This is probably a long-term effect of radiation exposure in those who first registered during 1921-1935 and 1936-1954. There was no evidence of an increase in cancer mortality among radiologists who first registered after 1954, in whom radiation exposures are likely to have been lower. Non-cancer causes of death were also examined in more detail than has been reported previously. There was no evidence of an effect of radiation on diseases other than cancer even in the earliest radiologists, despite the fact that doses of the size received by them have been associated with more than a doubling in the death rate among the survivors of the Japanese atomic bombings.
Genetic polymorphism of the carcinogen metabolizing enzyme N-acetyl transferase 2 (NAT2) may influence susceptibility to bladder cancers related to smoking or to occupational exposure to arylamine carcinogens. This article reviews the results of 21 published case-control studies of NAT2 polymorphism and bladder-cancer risk, with a total of 2700 cases and 3426 controls. The published evidence suggests that NAT2 slow acetylator phenotype or genotype may be associated with a small increase in bladder cancer risk. However, given the possibility of selective publication of results from studies that found an excess risk, the current evidence is not sufficient to conclude that there is a real increase in risk. Only five of the 21 studies reported results separately for the effect of NAT2 on bladder cancer risk in smokers and non-smokers. Although the results suggest that the effect may be greater in smokers than in non-smokers, the possibility of publication bias makes these results difficult to interpret. There was insufficient evidence to assess the joint effect of NAT2 and occupational exposure to arylamines on bladder cancer risk. Even if estimates of the effect of NAT2 from published data are correct, studies with around 3000-5000 cases will be needed to confirm them.
Marimastat is a specific inhibitor of matrix metalloproteinases that has been shown to be effective in cancer models. A pilot, escalating-dose study of oral marimastat was performed in patients with recurrent colorectal cancer, in whom evaluation of serological response was made by measurement of carcinoembryonic antigen (CEA) levels. The study assessed the safety and tolerability of 4 weeks administration of marimastat, and determined a dose range producing detectable serological effects. Patients were recruited with a serum CEA level greater than 5 ng ml(-1), and rising by more than 25% over a 4-week screening period. Patients were treated for 28 days and entered into a continuation protocol if a serological response or clinical benefit was observed. Pharmacokinetic and safety data determined that groups of patients were recruited sequentially at 25 mg and 50 mg twice daily, and, thereafter, 10 mg twice daily, 10 mg once daily, 5 mg once daily and 20 mg once daily. A biological effect (BE) was defined as a CEA value on day 28 no greater than on day 0; a partial biological effect (PBE) was defined as a rise in CEA over the 28-day treatment period of less than 25%. Of 70 patients recruited, 63 completed the 28-day treatment period, and 55 were eligible for cancer antigen analysis. Examination of the dose-effect relationships provides evidence for a causal relationship between marimastat and biological effects: the proportion of patients with BE or PBE was higher with twice daily dosing (16 out of 25, 64%) than with once daily dosing (11 out of 30, 37%) (P = 0.043, chi2 test). Furthermore, the median rates of rise of CEA fell markedly during treatment compared with the screening period for patients receiving twice daily marimastat (P<0.0001), but not for patients receiving marimastat once daily (P = 0.25). Musculoskeletal adverse events emerged as the principal drug-related toxicity of marimastat, occurring in a dose- and time-dependent fashion. It was concluded that marimastat was associated with dose-dependent biological effects in cancer patients. The occurrence of musculoskeletal side-effects define 25 mg twice daily as the upper limit of the dose range for continuous use in further studies. Therefore, a dose range of 20 mg once daily to 25 mg twice daily seems appropriate for further studies, which should aim to demonstrate the efficacy of the drug in terms of conventional clinical end points and describe the long-term tolerability of this novel agent.
This combined analysis investigated the effect of marimastat, a specific inhibitor of matrix metalloproteinases, on markers of tumor progression measured in patients with advanced cancer. By defining the tolerability and biological activity of the drug, it aimed to establish an appropriate dose range for use in Phase III trials. Patients with advanced, serologically progressive ovarian, prostatic, pancreatic, and colorectal cancer were recruited into six nonrandomized, dose ranging, multicenter clinical trials in North America and Europe. The biological activity of marimastat was assessed by serial measurements of the serum tumor markers carcinoembryonic antigen, CA125, CA19-9, and prostate-specific antigen. Patients were recruited with tumor markers rising by more than 25% averaged over a 4-week screening period. A biological effect was defined as a level of tumor marker at the end of treatment no greater than at study entry; a partial biological effect was defined as a rise in the level of tumor marker over the treatment period of 0-25% per 4 weeks. Pharmacokinetic and safety data were collected and assessed as the studies progressed. All patients were followed up for survival.
Mammographic breast density (MD) reflects breast fibroglandular content. Its decline following adjuvant tamoxifen treated, estrogen receptor (ER)-positive breast cancer has been associated with improved outcomes. Breast cancers arise from structures termed lobules, and lower MD is associated with increased age-related lobule involution. We assessed whether pre-treatment involution influenced associations between MD decline and risk of breast cancer-specific death. ER-positive tamoxifen treated patients diagnosed at Kaiser Permanente Northwest (1990-2008) were defined as cases who died of breast cancer (<i>n</i> = 54) and matched controls (remained alive over similar follow-up; <i>n</i> = 180). Lobule involution was assessed by examining terminal duct lobular units (TDLUs) in benign tissues surrounding cancers as TDLU count/mm<sup>2</sup>, median span and acini count/TDLU. MD (%) was measured in the unaffected breast at baseline (median 6-months before) and follow-up (median 12-months after tamoxifen initiation). TDLU measures and baseline MD were positively associated among controls (<i>p</i> < 0.05). In multivariable regression models, MD decline (≥10%) was associated with reduced risk of breast cancer-specific death before (odds ratio (OR): 0.41, 95% CI: 0.18-0.92) and after (OR: 0.41, 95% CI: 0.18-0.94) adjustment for TDLU count/mm<sup>2</sup>, TDLU span (OR: 0.34, 95% CI: 0.14-0.84), and acini count/TDLU (OR: 0.33, 95% CI: 0.13-0.81). MD decline following adjuvant tamoxifen is associated with reduced risk of breast cancer-specific death, irrespective of pre-treatment lobule involution.
Sarcomas were one of the first solid cancers to be linked to ionizing radiation exposure. We reviewed the current evidence on this relationship, focusing particularly on the studies that had individual estimates of radiation doses. There is clear evidence of an increased risk of both bone and soft tissue sarcomas after high-dose fractionated radiation exposure (10 + Gy) in childhood, and the risk increases approximately linearly in dose, at least up to 40 Gy. There are few studies available of sarcoma after radiotherapy in adulthood for cancer, but data from cancer registries and studies of treatment for benign conditions confirm that the risk of sarcoma is also increased in this age-group after fractionated high-dose exposure. New findings from the long-term follow-up of the Japanese atomic bomb survivors suggest, for the first time, that sarcomas can be induced by acute lower-doses of radiation (<5 Gy) at any age, and the magnitude of the risk is similar to that observed for other solid cancers. While there is evidence that individuals with certain rare familial genetic syndromes predisposing to sarcoma, particularly Nijmegen Breakage Syndrome, are particularly sensitive to the effects of high dose radiation, it is unclear whether this is also true in very low-dose settings (<0.1 Gy). The effects of common low-penetrance alleles on radiosensitivity in the general population have not been well-characterized. Some evidence suggests that it may be possible to identify radiation-induced sarcomas by a distinct molecular signature, but this work needs to be replicated in several dose settings, and the potential role of chemotherapy and tumor heterogeneity needs to be examined in more detail. In summary, radiation exposure remains one of the few established risk factors for both bone and soft tissue sarcomas. Similar to many other cancers children have the highest risks of developing a radiation-related sarcoma. Efforts to limit unnecessary high-dose radiation exposure, particularly in children, therefore remain important given the high fatality rates associated with this disease.
Computed tomographic colonography (CTC) has emerged as an alternative screening tool for colorectal cancer due to the potential to provide good efficacy combined with greater acceptability than optical colonoscopy or fecal occult blood testing. However, some organizations have raised concerns about the potential harms, including perforation rates and radiation-related cancer risks, and have not recommended that it currently be used as a screening tool in the general population in the US. In this article the authors review the current evidence for these potential harms from CTC and compare them to the potential harms from the alternatives including colonoscopy and double-contrast barium enema.
<h4>Background</h4>Myocardial perfusion scans contribute up to 20% of the estimated annual collective radiation dose to the US population. We estimated potential future cancer risk from these scans by age at exposure and current frequency of use in the United States.<h4>Methods and results</h4>Usage patterns were determined from national survey data, and radionuclide dosage was based on current guidelines. Cancer risk projection models were generated on the basis of the National Research Council Biological Effects of Ionizing Radiation VII report, under the assumption that risk has a linear relationship with radiation exposure even at low doses. The mean projected number of radiation-related incident cancers and 95% uncertainty intervals were estimated with the use of Monte Carlo simulations. Estimated risks for a scan performed at age 50 years ranged from 2 cancers per 10,000 scans (95% uncertainty interval, 1 to 5) for a positron emission tomography ammonia-13 test to 25 cancers per 10,000 scans (95% uncertainty interval, 9 to 58) for a dual-isotope (thallium-201 plus technetium-99m) scan. Risks were 50% lower at age 70 years but were similar for men and women. The combination of cancer risk estimates and data on frequency of use suggests that the 9.1 million myocardial perfusion scans performed annually in the United States could result in 7400 (95% uncertainty interval, 3300 to 13,700) additional future cancers.<h4>Conclusions</h4>The lifetime cancer risk from a single myocardial perfusion scan is small and should be balanced against likely benefit and appropriateness of the test. The estimates depend on a number of assumptions, including life expectancy. They apply directly to asymptomatic individuals with life expectancies similar to those of the general population. For individuals with a symptomatic clinical profile, on whom such scans are typically performed, the risks will be lower because of shorter life expectancy.
<h4>Importance</h4>Cancer is the second leading cause of mortality in the US. Despite national decreases in cancer mortality, Black individuals continue to have the highest cancer death rates.<h4>Objective</h4>To examine national trends in cancer mortality from 1999 to 2019 among Black individuals by demographic characteristics and to compare cancer death rates in 2019 among Black individuals with rates in other racial and ethnic groups.<h4>Design, setting, and participants</h4>This serial cross-sectional study used US national death certificate data obtained from the National Center for Health Statistics and included all cancer deaths among individuals aged 20 years or older from January 1999 to December 2019. Data were analyzed from June 2021 to January 2022.<h4>Exposures</h4>Age, sex, and race and ethnicity.<h4>Main outcomes and measures</h4>Trends in age-standardized mortality rates and average annual percent change (AAPC) in rates were estimated by cancer type, age, sex, and race and ethnicity.<h4>Results</h4>From 1999 to 2019, 1 361 663 million deaths from cancer occurred among Black individuals. The overall cancer death rate significantly decreased among Black men (AAPC, -2.6%; 95% CI, -2.6% to -2.6%) and women (AAPC, -1.5%; 95% CI, -1.7% to -1.3%). Death rates decreased for most cancer types, with the greatest decreases observed for lung cancer among men (AAPC, -3.8%; 95% CI, -4.0% to -3.6%) and stomach cancer among women (AAPC, -3.4%; 95% CI, -3.6% to -3.2%). Lung cancer mortality also had the largest absolute decreases among men (-78.5 per 100 000 population) and women (-19.5 per 100 000 population). We observed a significant increase in deaths from liver cancer among men (AAPC, 3.8%; 95% CI, 3.0%-4.6%) and women (AAPC, 1.8%; 95% CI, 1.2%-2.3%) aged 65 to 79 years. There was also an increasing trend in uterus cancer mortality among women aged 35 to 49 years (2.9%; 95% CI, 2.3% to 2.6%), 50 to 64 years (2.3%; 95% CI, 2.0% to 2.6%), and 65 to 79 years (1.6%; 95% CI, 1.2% to 2.0%). In 2019, Black men and women had the highest cancer mortality rates compared with non-Hispanic American Indian/Alaska Native, Asian or Pacific Islander, and White individuals and Hispanic/Latino individuals.<h4>Conclusions and relevance</h4>In this cross-sectional study, there were substantial decreases in cancer death rates among Black individuals from 1999 to 2019, but higher cancer death rates among Black men and women compared with other racial and ethnic groups persisted in 2019. Targeted interventions appear to be needed to eliminate social inequalities that contribute to Black individuals having higher cancer mortality.
<h4>Purpose</h4>Estrogen receptor (ER) + /progesterone receptor (PR) - or ER-/PR + breast cancer prognosis has not been well-described outside of clinical trials. We evaluated the relationship between ER/PR (ER + /PR-, ER-/PR + , ER + /PR + , ER-/PR-) subgroups and breast cancer-specific mortality within a general community setting in the US.<h4>Methods</h4>A Retrospective cohort of 11,737 women diagnosed with breast cancer between 1990 and 2016 within US integrated healthcare systems (median follow-up = 7 years; 1,104 breast cancer-specific deaths) were included in this analysis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusting for site, demographic and clinicopathological characteristics, and treatment (surgery/radiotherapy, chemotherapy, endocrine therapy).<h4>Results</h4>Breast cancer-specific mortality was higher for those with ER + /PR- (n = 1,233) compared with ER + /PR + tumors (n = 8,439) before (HR = 1.43; 95% CI = 1.17-1.75) and after treatment adjustment (HR = 1.58; 95% CI = 1.27-1.97). ER + /PR- breast cancer-specific mortality remained higher than ER + /PR + tumors when stratified by treatment received. Breast cancer-specific mortality was similar in ER-/PR + (n = 161) compared with ER + /PR + tumors.<h4>Conclusion</h4>Our findings suggest that ER + /PR- tumors may have worse breast cancer-specific mortality than ER + /PR + tumors in a community setting.
<h4>Purpose</h4>This retrospective cohort study examined patterns of endocrine therapy initiation over time and by demographic, tumor, and treatment characteristics.<h4>Methods</h4>We included 7777 women from three U.S. integrated healthcare systems diagnosed with incident stage I-III hormone receptor-positive breast cancer between 2001 and 2016. We extracted endocrine therapy from pharmacy dispensings, defining initiation as dispensings within 12 months of diagnosis. Demographic, tumor, and treatment characteristics were collected from electronic health records. Using generalized linear models with a log link and Poisson distribution, we estimated initiation of any endocrine therapy, tamoxifen, and aromatase inhibitors (AI) over time with relative risks (RR) and 95% confidence intervals (CI) adjusted for age, tumor characteristics, diagnosis year, other treatment, and study site.<h4>Results</h4>Among women aged 20+ (mean 62 years), 6329 (81.4%) initiated any endocrine therapy, and 1448 (18.6%) did not initiate endocrine therapy. Tamoxifen initiation declined from 67 to 15% between 2001 and 2016. AI initiation increased from 6 to 69% between 2001 and 2016 in women aged ≥ 55 years. The proportion of women who did not initiate endocrine therapy decreased from 19 to 12% between 2002 and 2014 then increased to 17% by 2016. After adjustment, women least likely to initiate endocrine therapy were older (RR = 0.81, 95% CI 0.77-0.85 for age 75+ vs. 55-64), Black (RR = 0.93, 95% CI 0.87-1.00 vs. white), and had stage I disease (RR = 0.88, 95% CI 0.85-0.91 vs. stage III).<h4>Conclusions</h4>Despite an increase in AI use over time, at least one in six eligible women did not initiate endocrine therapy, highlighting opportunities for improving endocrine therapy uptake in breast cancer survivors.
<b><i>Background:</i></b> In response to evidence of overdiagnosis and overtreatment of papillary thyroid carcinoma (PTC), the 2009 and 2015 American Thyroid Association (ATA) adult guidelines recommended less extensive surgery (lobectomy vs. total thyroidectomy) and more restricted use of postsurgical radioactive iodine (RAI) in management of PTC at low risk of recurrence. In 2015, active surveillance was suggested as a viable option for some <1-cm PTCs, or microcarcinomas. The 2015 ATA pediatric guidelines similarly shifted toward more restricted use of RAI for low-risk PTCs. The impact of these recommendations on low-risk adult and pediatric PTC management remains unclear, particularly after 2015. <b><i>Methods:</i></b> Using data from 18 Surveillance, Epidemiology, and End Results (SEER) U.S. registries (2000-2018), we described time trends in reported first-course treatment (total thyroidectomy alone, total thyroidectomy+RAI, lobectomy, no surgery, and other/unknown) for 105,483 patients diagnosed with first primary localized PTC (without nodal/distant metastases), overall and by demographic and tumor characteristics. <b><i>Results:</i></b> The declining use of RAI represented the most pronounced change in management of PTCs <4 cm (44-18% during the period 2006-2018), including microcarcinomas (26-6% during the period 2007-2018). In parallel, an increasing proportion of PTCs were managed with total thyroidectomy alone (35-54% during the period 2000-2018), while more subtle changes were observed for lobectomy (declining from 23% to 17% during the period 2000-2006, stabilizing, and then rising from 17% to 24% during the period 2015-2018). Use of nonsurgical management did not meaningfully change over time, impacting <1% of microcarcinomas annually during the period 2000-2018. Similar treatment trends were observed by sex, age, race/ethnicity, metropolitan vs. nonmetropolitan residence, and insurance status. For pediatric patients (<20 years), use of RAI peaked in 2009 (59%), then decreased markedly to 11% (2018), while use of total thyroidectomy alone and, to a lesser extent, lobectomy increased. No changing treatment trends were observed for ≥4-cm PTCs. <b><i>Conclusions:</i></b> The declining use of RAI in management of low-risk adult and pediatric PTC is consistent with changing recommendations from the ATA practice guidelines. Post-2015 trends in use of lobectomy and nonsurgical management of low-risk PTCs, particularly microcarcinomas, were more subtle than expected; however, these trends may change as evidence regarding their safety continues to emerge.
This commentary is written in response to a recent commentary in Carcinogenesis that provides several viewpoints on the International Agency for Research on Cancer's (IARC) Monographs program on cancer hazard identification. This commentary offers an alternative viewpoint of the role of cancer hazard identification derived from cancer epidemiology studies in risk characterization, as well as clarification on the previous commentary's interpretation of the purpose of the Monographs and other programs of cancer hazard identification and how IARC communicates the findings of the Monographs.
<h4>Background</h4>In response to the US opioid epidemic, the Centers for Disease Control and Prevention updated their guideline on prescription opioids for chronic pain management in March 2016. The aim of this study was to provide detailed analysis of trends in opioid claims among cancer patients in the United States during 2013-2018.<h4>Methods</h4>We analyzed pharmaceutical dispensing data from Symphony Health's Integrated Dataverse database, which covers approximately 80% of the US population. We examined annual trends in dispensed opioids in cancer patients during 2013-2018. We examined quarterly trends of the prevalence, mean number of days, and dose (stated as morphine milligram equivalents) of opioid dispensing in cancer patients.<h4>Results</h4>Dispensing records of an average of over 3.7 million cancer patients contributed to the study annually in 2013-2018. The annual prevalence of opioid dispensing claims declined from 40.2% in 2013 to 34.5% in 2018. Annual declines occurred across cancer sites, and particularly among patients with metastatic cancer (decline of 19.8%), breast cancer (18.2%), and lung cancer (13.8%). By quarter, the prevalence of opioid claims declined statistically significantly from 26.6% in Q1 2013 to 21.2% in Q4 2018; this decline was more pronounced after Q3 2016 (2-sided <i>P </i>=<i> </i>.004). Both quarterly trends in mean days and morphine milligram equivalents of opioids supplied showed a gradual decline from 2013 to 2018, with a slightly larger decline after 2016.<h4>Conclusions</h4>We observed a decline in opioid use among cancer patients, particularly after 2016, coinciding with the publication of the Centers for Disease Control and Prevention's guideline on prescription opioids for chronic pain management.
Use of computed tomography (CT) scanning has increased substantially since its introduction in the 1990s. Several authors have reported increased risk of leukemia and brain tumors associated with radiation exposure from CT scans. However, reverse causation is a concern, particularly for brain cancer; in other words, the CT scan may have been taken because of preexisting cancer and therefore not have been a cause. We assessed the possibility of reverse causation via a simulation study focused on brain tumors, using a simplified version of the data structure for recent CT studies. Five-year-lagged and unlagged analyses implied an observed excess risk per scan up to 70% lower than the true excess risk per scan, particularly when more than 10% of persons with latent cancer had increased numbers of scans or the extra scanning rate after development of latent cancer was greater than 2 scans/year; less extreme values of these parameters imply little risk attenuation. Without a lag and when more than 20% of persons with latent cancer had increased scans-an arguably implausible scenario-the excess risk per scan was increased over the true excess risk per scan by up to 35%-40%. This study suggests that with a realistic lag, reverse causation results in downwardly biased risk, a result of induced classical measurement error, and is therefore unlikely to produce a spurious positive association between cancer and radiation dose from CT scans.
<h4>Purpose</h4>To inform prevention efforts, we sought to determine which cancer types contribute the most to cancer mortality disparities by individual-level education using national death certificate data for 2017.<h4>Methods</h4>Information on all US deaths occurring in 2017 among 25-84-year-olds was ascertained from national death certificate data, which include cause of death and educational attainment. Education was classified as high school or less (≤ 12 years), some college or diploma (13-15 years), and Bachelor's degree or higher (≥ 16 years). Cancer mortality rate differences (RD) were calculated by subtracting age-adjusted mortality rates (AMR) among those with ≥ 16 years of education from AMR among those with ≤ 12 years.<h4>Results</h4>The cancer mortality rate difference between those with a Bachelor's degree or more vs. high school or less education was 72 deaths per 100,000 person-years. Lung cancer deaths account for over half (53%) of the RD for cancer mortality by education in the US.<h4>Conclusion</h4>Efforts to reduce smoking, particularly among persons with less education, would contribute substantially to reducing educational disparities in lung cancer and overall cancer mortality.
Radiation doses of parents exposed from the Chornobyl accident as cleanup workers or evacuees were estimated in the National Cancer Institute-National Research Center for Radiation Medicine trio (i.e. father, mother, offspring) study aimed at investigating the radiation effects on germline<i>de novo</i>mutations in children as well as other outcomes. Paternal (testes) and maternal (ovaries) gonadal doses were calculated along with associated uncertainty distributions for the following exposure pathways: (a) external irradiation during the cleanup mission, (b) external irradiation during residence in Pripyat, and (c) external irradiation and (d) ingestion of radiocesium isotopes, such as<sup>134</sup>Cs and<sup>137</sup>Cs, during residence in settlements other than Pripyat. Gonadal doses were reconstructed for 298 trios for the periods from the time of the accident on 26 April 1986 to two time points before the child's date of birth (DOB): 51 (DOB-51) and 38 (DOB-38) weeks. The two doses, DOB-51 and DOB-38 were equal (within 1 mGy) in most instances, except for 35 fathers where the conception of the child occurred within 3 months of exposure or during exposure. The arithmetic mean of gonadal DOB-38 doses was 227 mGy (median: 11 mGy, range 0-4080 mGy) and 8.5 mGy (median: 1.0 mGy, range 0-550 mGy) for fathers and mothers, respectively. Gonadal doses varied considerably depending on the exposure pathway, the highest gonadal DOB-38 doses being received during the cleanup mission (mean doses of 376 and 34 mGy, median of 144 and 7.4 mGy for fathers and mothers, respectively), followed by exposure during residence in Pripyat (7.7 and 13 mGy for mean, 7.2 and 6.2 mGy for median doses) and during residence in other settlements (2.0 and 2.1 mGy for mean, 0.91 and 0.81 mGy for median doses). Monte Carlo simulations were used to estimate the parental gonadal doses and associated uncertainties. The geometric standard deviations (GSDs) in the individual parental stochastic doses due to external irradiation during the cleanup mission varied from 1.2 to 4.7 (mean of 1.8), while during residence in Pripyat they varied from 1.4 to 2.8 (mean of 1.8), while the mean GSD in doses received during residence in settlements other than Pripyat was 1.3 and 1.4 for external irradiation and ingestion of radiocesium isotopes, respectively.
There is limited evidence that non-leukaemic lymphoid malignancies are radiogenic. As radiation-related cancer risks are generally higher after childhood exposure, we analysed pooled lymphoid neoplasm data in nine cohorts first exposed to external radiation aged <21 years using active bone marrow (ABM) and, where available, lymphoid system doses, and harmonised outcome classification. Relative and absolute risk models were fitted. Years of entry spanned 1916-1981. At the end of follow-up (mean 42.1 years) there were 593 lymphoma (422 non-Hodgkin (NHL), 107 Hodgkin (HL), 64 uncertain subtype), 66 chronic lymphocytic leukaemia (CLL) and 122 multiple myeloma (MM) deaths and incident cases among 143,136 persons, with mean ABM dose 0.14 Gy (range 0-5.95 Gy) and mean age at first exposure 6.93 years. Excess relative risk (ERR) was not significantly increased for lymphoma (ERR/Gy = -0.001; 95% CI: -0.255, 0.279), HL (ERR/Gy = -0.113; 95% CI: -0.669, 0.709), NHL + CLL (ERR/Gy = 0.099; 95% CI: -0.149, 0.433), NHL (ERR/Gy = 0.068; 95% CI: -0.253, 0.421), CLL (ERR/Gy = 0.320; 95% CI: -0.678, 1.712), or MM (ERR/Gy = 0.149; 95% CI: -0.513, 1.063) (all p-trend > 0.4). In six cohorts with estimates of lymphatic tissue dose, borderline significant increased risks (p-trend = 0.02-0.07) were observed for NHL + CLL, NHL, and CLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.
<h4>Background</h4>Mutually increased risks for thyroid and breast cancer have been reported, but the contribution of etiologic factors versus increased medical surveillance to these associations is unknown.<h4>Methods</h4>Leveraging large-scale US population-based cancer registry data, we used standardized incidence ratios (SIRs) to investigate the reciprocal risks of thyroid and breast cancers among adult females diagnosed with a first primary invasive, non-metastatic breast cancer (N = 652,627) or papillary thyroid cancer (PTC) (N = 92,318) during 2000-2017 who survived ≥1-year.<h4>Results</h4>PTC risk was increased 1.3-fold [N = 1434; SIR = 1.32; 95 % confidence interval (CI) = 1.25-1.39] after breast cancer compared to the general population. PTC risk declined significantly with time since breast cancer (Poisson regression = P<sub>trend</sub> <0.001) and was evident only for tumors ≤2 cm in size. The SIRs for PTC were higher after hormone-receptor (HR)+ (versus HR-) and stage II or III (versus stage 0-I) breast tumors. Breast cancer risk was increased 1.2-fold (N = 2038; SIR = 1.21; CI = 1.16-1.26) after PTC and was constant over time since PTC but was only increased for stage 0-II and HR + breast cancers.<h4>Conclusion</h4>Although some of the patterns by latency, stage and size are consistent with heightened surveillance contributing to the breast-thyroid association, we cannot exclude a role of shared etiology or treatment effects.
<h4>Motivation</h4>Mortality Tracker is an in-browser application for data wrangling, analysis, dissemination and visualization of public time series of mortality in the United States. It was developed in response to requests by epidemiologists for portable real time assessment of the effect of COVID-19 on other causes of death and all-cause mortality. This is performed by comparing 2020 real time values with observations from the same week in the previous 5 years, and by enabling the extraction of temporal snapshots of mortality series that facilitate modeling the interdependence between its causes.<h4>Results</h4>Our solution employs a scalable 'Data Commons at Web Scale' approach that abstracts all stages of the data cycle as in-browser components. Specifically, the data wrangling computation, not just the orchestration of data retrieval, takes place in the browser, without any requirement to download or install software. This approach, where operations that would normally be computed server-side are mapped to in-browser SDKs, is sometimes loosely described as Web APIs, a designation adopted here.<h4>Availabilityand implementation</h4>https://episphere.github.io/mortalitytracker; webcast demo: youtu.be/ZsvCe7cZzLo.<h4>Supplementary information</h4>Supplementary data are available at Bioinformatics online.
<h4>Purpose</h4>The role of established breast cancer risk factors and clinical characteristics of the first breast cancer in the development of contralateral breast cancer (CBC) among postmenopausal women is unclear.<h4>Methods</h4>We identified 10,934 postmenopausal women diagnosed with a first primary breast cancer between 1995 and 2011 in the NIH-AARP Diet and Health Study. CBC was defined as a second primary breast cancer diagnosed in the contralateral breast ≥ 3 months after the first breast cancer. Exposures included pre-diagnosis risk factors (lifestyle, reproductive, family history) and clinical characteristics of the first breast cancer. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).<h4>Results</h4>Over a median follow-up of 6.8 years, 436 women developed CBC. We observed an increasing trend in CBC risk by age (p-trend = 0.002) and decreasing trend by year of diagnosis (p-trend = 0.001) of the first breast cancer. Additional risk factor associations were most pronounced for endocrine therapy (HR 0.68, 95% CI 0.53-0.87) and family history of breast cancer (HR 1.38, 95% CI 1.06-1.80, restricted to invasive first breast cancer). No associations were found for lifestyle (body mass index, physical activity, smoking, alcohol) or reproductive factors (age at menarche, parity, age at first birth, age at menopause).<h4>Conclusions</h4>This study suggests that clinical characteristics of the first breast cancer and family history of breast cancer, but not pre-diagnosis lifestyle and reproductive factors, are strongly associated with CBC risk among postmenopausal women. Future studies are needed to understand how these factors contribute to CBC etiology and to identify further opportunities for prevention.
The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.
<h4>Background</h4>Excess death estimates quantify the full impact of the coronavirus disease 2019 (COVID-19) pandemic. Widely reported U.S. excess death estimates have not accounted for recent population changes, especially increases in the population older than 65 years.<h4>Objective</h4>To estimate excess deaths in the United States in 2020, after accounting for population changes.<h4>Design</h4>Surveillance study.<h4>Setting</h4>United States, March to August 2020.<h4>Participants</h4>All decedents.<h4>Measurements</h4>Age-specific excess deaths in the United States from 1 March to 31 August 2020 compared with 2015 to 2019 were estimated, after changes in population size and age were taken into account, by using Centers for Disease Control and Prevention provisional death data and U.S. Census Bureau population estimates. Cause-specific excess deaths were estimated by month and age.<h4>Results</h4>From March through August 2020, 1 671 400 deaths were registered in the United States, including 173 300 COVID-19 deaths. An average of 1 370 000 deaths were reported over the same months during 2015 to 2019, for a crude excess of 301 400 deaths (128 100 non-COVID-19 deaths). However, the 2020 U.S. population includes 5.04 million more persons aged 65 years and older than the average population in 2015 to 2019 (a 10% increase). After population changes were taken into account, an estimated 217 900 excess deaths occurred from March through August 2020 (173 300 COVID-19 and 44 600 non-COVID-19 deaths). Most excess non-COVID-19 deaths occurred in April, July, and August, and 34 900 (78%) were in persons aged 25 to 64 years. Diabetes, Alzheimer disease, and heart disease caused the most non-COVID-19 excess deaths.<h4>Limitation</h4>Provisional death data are underestimated because of reporting delays.<h4>Conclusion</h4>The COVID-19 pandemic resulted in an estimated 218 000 excess deaths in the United States between March and August 2020, and 80% of those deaths had COVID-19 as the underlying cause. Accounting for population changes substantially reduced the excess non-COVID-19 death estimates, providing important information for guiding future clinical and public health interventions.<h4>Primary funding source</h4>National Cancer Institute.
<h4>Background</h4>Estimates of contralateral breast cancer (CBC) risk in the modern treatment era by year of diagnosis and characteristics of the first breast cancer are needed to assess the impact of recent advances in breast cancer treatment and inform clinical decision making.<h4>Methods</h4>We examined CBC risk among 419,818 women (age 30-84 years) who were diagnosed with a first unilateral invasive breast cancer and survived ≥ 1 year in the US Surveillance, Epidemiology, and End Results program cancer registries from 1992 to 2015 (follow-up through 2016). CBC was defined as a second invasive breast cancer in the contralateral breast ≥ 12 months after the first breast cancer. We estimated standardized incidence ratios (SIRs) of CBC by year of diagnosis, age at diagnosis, and tumor characteristics for the first breast cancer. Cumulative incidence of CBC was calculated for women diagnosed with a first breast cancer in the recent treatment era (2004-2015, follow-up through 2016).<h4>Results</h4>Over a median follow-up of 8 years (range 1-25 years), 12,986 breast cancer patients developed CBC. Overall, breast cancer patients had approximately twice the risk of developing cancer in the contralateral breast when compared to that expected in the general population (SIR = 2.21, 95% CI = 2.17-2.25). SIRs for CBC declined by year of first diagnosis, irrespective of age at diagnosis and estrogen receptor (ER) status (p-trends < 0.001), but the strongest decline was after an ER-positive tumor. The 5-year cumulative incidence of CBC ranged from 1.01% (95% CI = 0.90-1.14%) in younger women (age < 50 years) with a first ER-positive tumor to 1.89% (95% CI = 1.61-2.21%) in younger women with a first ER-negative tumor.<h4>Conclusion</h4>Declines in CBC risk are consistent with continued advances in breast cancer treatment. The updated estimates of cumulative incidence inform breast cancer patients and clinicians on the risk of CBC and may help guide treatment decisions.
Although transgenerational effects of exposure to ionizing radiation have long been a concern, human research to date has been confined to studies of disease phenotypes in groups exposed to high doses and high dose rates, such as the Japanese atomic bomb survivors. Transgenerational effects of parental irradiation can be addressed using powerful new genomic technologies. In collaboration with the Ukrainian National Research Center for Radiation Medicine, the US National Cancer Institute, in 2014-2018, initiated a genomic alterations study among children born in selected regions of Ukraine to cleanup workers and/or evacuees exposed to low-dose-rate radiation after the 1986 Chornobyl (Chernobyl) nuclear accident. To investigate whether parental radiation exposure is associated with germline mutations and genomic alterations in the offspring, we are collecting biospecimens from father-mother-offspring constellations to study de novo mutations, minisatellite mutations, copy-number changes, structural variants, genomic insertions and deletions, methylation profiles, and telomere length. Genomic alterations are being examined in relation to parental gonadal dose, reconstructed using questionnaire and measurement data. Subjects are being recruited in exposure categories that will allow examination of parental origin, duration, and timing of exposure in relation to conception. Here we describe the study methodology and recruitment results and provide descriptive information on the first 150 families (mother-father-child(ren)) enrolled.
Children undergoing computed tomography (CT) scans have an increased risk of cancer in subsequent years, but it is unclear how much of the excess risk is due to reverse causation bias or confounding, rather than to causal effects of ionising radiation. An examination of the relationship between excess cancer risk and organ dose can help to resolve these uncertainties. Accordingly, we have estimated doses to 33 different organs arising from over 900 000 CT scans between 1985 and 2005 in our previously described cohort of almost 12 million Australians aged 0-19 years. We used a multi-tiered approach, starting with Medicare billing details for government-funded scans. We reconstructed technical parameters from national surveys, clinical protocols, regulator databases and peer-reviewed literature to estimate almost 28 000 000 individual organ doses. Doses were age-dependent and tended to decrease over time due to technological improvements and optimisation.
<h4>Purpose</h4>Previous studies have shown an overall decreased risk of second cancers among prostate cancer survivors, but this has not been comprehensively examined by race/ethnicity. We conducted a retrospective cohort study of 716,319 one-year survivors of prostate cancer diagnosed at ages 35-84 during 2000-2015 as reported to 17 US Surveillance, Epidemiology and End Results (SEER) registries.<h4>Methods</h4>We estimated standardized incidence ratios (SIRs) for second primary non-prostate malignancies by race/ethnicity (non-Latino white, Black, Asian/Pacific Islander [API] and Latino), by Gleason, and by time since prostate cancer diagnosis. Poisson regression models were used to test heterogeneity between groups with the expected number as the offset.<h4>Results</h4>60,707 second primary malignancies were observed. SIRs for all second cancers combined varied significantly by race/ethnicity: SIR<sub>white</sub>: 0.88 (95% confidence interval: 0.87-0.89), SIR<sub>Latino</sub>: 0.92 (0.89-0.95), SIR<sub>Black</sub>: 0.97 (0.95-0.99), and SIR<sub>API</sub>: 1.05 (1.01-1.09) (p-heterogeneity < 0.001). SIRs for all cancers combined were higher among survivors of higher vs. lower Gleason prostate cancers irrespective of race/ethnicity. We observed significant heterogeneity by race/ethnicity in SIRs for 9 of 14 second cancer types investigated including lung, bladder, kidney, and liver.<h4>Conclusions</h4>Our results confirm that most prostate cancer survivors have lower risks of second cancers than expected, but the magnitude varied by race/ethnicity. Exceptionally, API men had small but significantly increased risk. Further research to understand drivers of the observed race/ethnicity heterogeneity is warranted.
<h4>Purpose</h4>To investigate the relationship between oesophagus dose-volume distribution and long-term risk of oesophageal cancer after radiation therapy for breast cancer.<h4>Materials and methods</h4>In a case-control study nested within a cohort of 289,748 ≥5-year survivors of female breast cancer treated in 1943-2003 in five countries, doses to the second primary cancer (D<sub>SPC</sub>) and individual dose-volume histograms (DVH) to the entire oesophagus were reconstructed for 252 oesophageal cancer cases and 488 matched controls (median follow-up time: 13, range: 5-37 years). Using conditional logistic regression, we estimated excess odds ratios (EOR) of oesophageal cancer associated with DVH metrics. We also investigated whether DVH metrics confounded or modified D<sub>SPC</sub>-related -risk estimates.<h4>Results</h4>Among the DVH metrics evaluated, median dose (D<sub>median</sub>) to the entire oesophagus had the best statistical performance for estimating risk of all histological types combined (EOR/Gy = 0.071, 95% confidence interval [CI]: 0.018 to 0.206). For squamous cell carcinoma, the most common subtype, the EOR/Gy for D<sub>median</sub> increased by 31% (95% CI: 3% to 205%) for each increment of 10% of V30 (p = 0.02). Adjusting for DVH metrics did not materially change the EOR/Gy for D<sub>SPC</sub>, but there was a borderline significant positive interaction between D<sub>SPC</sub> and V30 (p = 0.07).<h4>Conclusion</h4>This first study investigating the relationship between oesophagus dose-volume distribution and oesophageal cancer risk showed an increased risk per Gy for D<sub>median</sub> with larger volumes irradiated at high doses. While current techniques allows better oesophagus sparing, constraints applied to D<sub>median</sub> and V30 could potentially further reduce the risk of oesophageal cancer.
<h4>Background & aims</h4>Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.<h4>Methods</h4>We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.<h4>Results</h4>During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.<h4>Conclusion</h4>We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.<h4>Lay summary</h4>Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
<h4>Importance</h4>Life expectancy has decreased in the US, driven largely by increases in drug poisoning, suicide, and alcohol-induced deaths. Assessing whether patterns of these causes differ is required to inform public health interventions.<h4>Objective</h4>To compare patterns and trends in drug poisoning, suicide, and alcohol-induced death rates by geography and demographic characteristics.<h4>Design, setting, and participants</h4>This serial cross-sectional study used national vital statistics data from the entire US population from January 1, 2000, to December 31, 2017, among US residents aged 20 to 64 years. Data were analyzed from January through August 2019.<h4>Exposures</h4>Age, sex, race/ethnicity, county-level percentage of unemployment, rurality, and geography.<h4>Main outcomes and measures</h4>Deaths were categorized as due to drug poisoning, suicide, or alcohol-induced causes based on underlying cause of death. Age-standardized incidence rates and annual percentage changes (APCs) in rates were estimated. Clusters of high-rate counties were identified with hot spot analysis. Excess deaths during 2001 to 2017 were estimated for each cause as the difference between the number of deaths observed and expected if rates had remained stable starting in 2000.<h4>Results</h4>During 2000 to 2017, 1 446 177 drug poisoning, suicide, and alcohol-induced premature deaths occurred in the US, including 563 765 drug poisoning deaths (age-standardized rate: 17.6 per 100 000 person-years [PYs]), 517 679 suicides (age-standardized rate: 15.8 per 100 000 PYs), and 364 733 alcohol-induced deaths (age-standardized rate: 10.5 per 100 000 PYs), totaling 451 596 more deaths than expected based on 2000 rates. High drug poisoning death rates were clustered in the Northeast through Appalachia, yet rates of suicide and alcohol-induced deaths were highest in the West. Only suicide death rates were highest in rural areas. Drug poisoning death rates were highest among people aged 35 to 49 years (age-standardized rate: 23.7 per 100 000 PYs), whereas suicide and alcohol-induced death rates peaked among people aged 50 to 64 years (suicide age-standardized rate: 19.6 per 100 000 PYs; alcohol-induced age-standardized death rate: 26.8 per 100 000 PYs). Increases occurred over time across racial/ethnic groups, although trajectories and inflection years varied. Drug poisoning (2013-2017 APC, 15.0% [95% CI, 11-8%-18.3%] per year) and alcohol-induced death rates (2012-2017 APC, 4.1% [95% CI, 3.3%-4.9%] per year) have accelerated recently, while increases in suicide death rates have largely increased at a constant trajectory (2000-2017 APC, 1.8% [95% CI, 1.7%-1.9%] per year).<h4>Conclusions and relevance</h4>This cross-sectional study found that demographic characteristics and geographic patterns varied by cause of death, suggesting that increasing death rates from these causes were not concentrated in 1 group or region. Specialized interventions tailored for the underlying drivers of each cause of death are urgently needed.
<h4>Background</h4>Outcome assessment problems and errors that could lead to biased risk estimates in low-dose radiation epidemiological studies of cancer risks have not been systematically evaluated.<h4>Methods</h4>Incidence or mortality risks for all cancers or all solid cancers combined and for leukemia were examined in 26 studies published in 2006-2017 involving low-dose (mean dose ≤100 mGy) radiation from environmental, medical, or occupational sources. We evaluated the impact of loss to follow-up, under- or overascertainment, outcome misclassification, and changing classifications occurring similarly or differentially across radiation dose levels.<h4>Results</h4>Loss to follow-up was not reported in 62% of studies, but when reported it was generally small. Only one study critically evaluated the completeness of the sources of vital status. Underascertainment of cancers ("false negatives") was a potential shortcoming for cohorts that could not be linked with high-quality population-based registries, particularly during early years of exposure in five studies, in two lacking complete residential history, and in one with substantial emigration. False positives may have occurred as a result of cancer ascertainment from self- or next-of-kin report in three studies or from enhanced medical surveillance of exposed patients that could lead to detection bias (eg, reporting precancer lesions as physician-diagnosed cancer) in one study. Most pediatric but few adult leukemia studies used expert hematopathology review or current classifications. Only a few studies recoded solid cancers to the latest International Classification of Diseases or International Classification of Diseases for Oncology codes. These outcome assessment shortcomings were generally nondifferential in relation to radiation exposure level except possibly in four studies.<h4>Conclusion</h4>The majority of studies lacked information to enable comprehensive evaluation of all major sources of outcome assessment errors, although reported data suggested that the outcome assessment limitations generally had little effect on risk or biased estimates towards the null except possibly in four studies.
<h4>Background</h4>Low-dose, penetrating photon radiation exposure is ubiquitous, yet our understanding of cancer risk at low doses and dose rates derives mainly from high-dose studies. Although a large number of low-dose cancer studies have been recently published, concern exists about the potential for confounding to distort findings. The aim of this study was to describe and assess the likely impact of confounding and selection bias within the context of a systematic review.<h4>Methods</h4>We summarized confounding control methods for 26 studies published from 2006 to 2017 by exposure setting (environmental, medical, or occupational) and identified confounders of potential concern. We used information from these and related studies to assess evidence for confounding and selection bias. For factors in which direct or indirect evidence of confounding was lacking for certain studies, we used a theoretical adjustment to determine whether uncontrolled confounding was likely to have affected the results.<h4>Results</h4>For medical studies of childhood cancers, confounding by indication (CBI) was the main concern. Lifestyle-related factors were of primary concern for environmental and medical studies of adult cancers and for occupational studies. For occupational studies, other workplace exposures and healthy worker survivor bias were additionally of interest. For most of these factors, however, review of the direct and indirect evidence suggested that confounding was minimal. One study showed evidence of selection bias, and three occupational studies did not adjust for lifestyle or healthy worker survivor bias correlates. Theoretical adjustment for three factors (smoking and asbestos in occupational studies and CBI in childhood cancer studies) demonstrated that these were unlikely to explain positive study findings due to the rarity of exposure (eg, CBI) or the relatively weak association with the outcome (eg, smoking or asbestos and all cancers).<h4>Conclusion</h4>Confounding and selection bias are unlikely to explain the findings from most low-dose radiation epidemiology studies.
<h4>Background</h4>Ionizing radiation is an established carcinogen, but risks from low-dose exposures are controversial. Since the Biological Effects of Ionizing Radiation VII review of the epidemiological data in 2006, many subsequent publications have reported excess cancer risks from low-dose exposures. Our aim was to systematically review these studies to assess the magnitude of the risk and whether the positive findings could be explained by biases.<h4>Methods</h4>Eligible studies had mean cumulative doses of less than 100 mGy, individualized dose estimates, risk estimates, and confidence intervals (CI) for the dose-response and were published in 2006-2017. We summarized the evidence for bias (dose error, confounding, outcome ascertainment) and its likely direction for each study. We tested whether the median excess relative risk (ERR) per unit dose equals zero and assessed the impact of excluding positive studies with potential bias away from the null. We performed a meta-analysis to quantify the ERR and assess consistency across studies for all solid cancers and leukemia.<h4>Results</h4>Of the 26 eligible studies, 8 concerned environmental, 4 medical, and 14 occupational exposure. For solid cancers, 16 of 22 studies reported positive ERRs per unit dose, and we rejected the hypothesis that the median ERR equals zero (P = .03). After exclusion of 4 positive studies with potential positive bias, 12 of 18 studies reported positive ERRs per unit dose (P = .12). For leukemia, 17 of 20 studies were positive, and we rejected the hypothesis that the median ERR per unit dose equals zero (P = .001), also after exclusion of 5 positive studies with potential positive bias (P = .02). For adulthood exposure, the meta-ERR at 100 mGy was 0.029 (95% CI = 0.011 to 0.047) for solid cancers and 0.16 (95% CI = 0.07 to 0.25) for leukemia. For childhood exposure, the meta-ERR at 100 mGy for leukemia was 2.84 (95% CI = 0.37 to 5.32); there were only two eligible studies of all solid cancers.<h4>Conclusions</h4>Our systematic assessments in this monograph showed that these new epidemiological studies are characterized by several limitations, but only a few positive studies were potentially biased away from the null. After exclusion of these studies, the majority of studies still reported positive risk estimates. We therefore conclude that these new epidemiological studies directly support excess cancer risks from low-dose ionizing radiation. Furthermore, the magnitude of the cancer risks from these low-dose radiation exposures was statistically compatible with the radiation dose-related cancer risks of the atomic bomb survivors.
Whether low-dose ionizing radiation can cause cancer is a critical and long-debated question in radiation protection. Since the Biological Effects of Ionizing Radiation report by the National Academies in 2006, new publications from large, well-powered epidemiological studies of low doses have reported positive dose-response relationships. It has been suggested, however, that biases could explain these findings. We conducted a systematic review of epidemiological studies with mean doses less than 100 mGy published 2006-2017. We required individualized doses and dose-response estimates with confidence intervals. We identified 26 eligible studies (eight environmental, four medical, and 14 occupational), including 91 000 solid cancers and 13 000 leukemias. Mean doses ranged from 0.1 to 82 mGy. The excess relative risk at 100 mGy was positive for 16 of 22 solid cancer studies and 17 of 20 leukemia studies. The aim of this monograph was to systematically review the potential biases in these studies (including dose uncertainty, confounding, and outcome misclassification) and to assess whether the subset of minimally biased studies provides evidence for cancer risks from low-dose radiation. Here, we describe the framework for the systematic bias review and provide an overview of the eligible studies.
<h4>Importance</h4>The long-term health effects of radioactive iodine (RAI) and antithyroid drug (ATD) treatments compared with surgery for hyperthyroidism remain uncertain.<h4>Objective</h4>To compare solid cancer mortality rates associated with RAI and ATD treatments vs surgical management for hyperthyroidism.<h4>Design, setting, and participants</h4>This multicenter cohort study assessed patients treated for hyperthyroidism from January 1, 1946, to December 31, 1964, with follow-up through December 31, 2014. Data analysis was performed from August 1, 2019, to April 23, 2020.<h4>Exposures</h4>Management with RAI, ATDs, surgical intervention, or combinations of these treatments.<h4>Main outcomes and measures</h4>Comparisons of solid cancer mortality rates in each treatment group with expected rates from the general population were assessed using standardized mortality ratios (SMRs), and internal comparisons were assessed using hazard ratios (HRs) adjusted for age, sex, and underlying diagnosis (Graves disease or toxic nodular goiter).<h4>Results</h4>Of 31 363 patients (24 894 [79.4%] female; mean [SD] age, 46.9 [14.8] years) included in the study, 28 523 (90.9%) had Graves disease. The median follow-up time was 26.0 years (interquartile range, 12.3-41.9 years). Important differences in patient characteristics existed across treatment groups at study entry. Notably, the drug-only group (3.6% of the cohort) included a higher proportion of patients with prior cancers (7.3% vs 1.9%-4.0%), contributing to an elevated SMR for solid cancer mortality. After excluding prior cancers, solid cancer SMRs were not elevated in any of the treatment groups (SMR for surgery only, 0.82 [95% CI, 0.66-1.00]; SMR for drugs only, 0.90 [95% CI, 0.74-1.09]; SMR for drugs and surgery, 0.88 [95% CI, 0.84-0.94]; SMR for RAI only, 0.90 [95% CI, 0.84-0.96]; SMR for surgery and RAI, 0.66 [95% CI, 0.52-0.85]; SMR for drugs and RAI, 0.94 [95% CI, 0.89-1.00]; and SMR for drugs, surgery, and RAI, 0.85 [95% CI, 0.75-0.96]), and no significant HRs for solid cancer death were observed across treatment groups. Among RAI-treated patients, HRs for solid cancer mortality increased significantly across levels of total administered activity (1.08 per 370 MBq; 95% CI, 1.03-1.13 per 370 MBq); this association was stronger among patients treated with only RAI (HR, 1.19 per 370 MBq; 95% CI, 1.09-1.30 per 370 MBq).<h4>Conclusions and relevance</h4>After controlling for known sources of confounding, the study found no significant differences in the risk of solid cancer mortality by treatment group. However, among RAI-treated patients, a modest positive association was observed between total administered activity and solid cancer mortality, providing further evidence in support of a dose-dependent association between RAI and solid cancer mortality.
<h4>Objective</h4>The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed.<h4>Methods and materials</h4>Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites.<h4>Results</h4>Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma (<i>n</i> = 349), ependymoma (<i>n</i> = 309), and glial/astrocytoma tumors (<i>n</i> = 279). The most common non-CNS diagnoses are rhabdomyosarcoma (<i>n</i> = 284), Ewing's sarcoma (<i>n</i> = 153), and neuroblastoma (<i>n</i> = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study.<h4>Conclusions</h4>The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research.<h4>Advances in knowledge</h4>For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.
<h4>Importance</h4>Premature death rates vary in the United States by race/ethnicity. Despite their socioeconomic disadvantages, US Latino populations have lower premature mortality rates than do US white populations, a phenomenon termed the "Latino or Hispanic paradox."<h4>Objective</h4>To investigate whether there is a broader Latin American paradox by comparing premature mortality rates in the United States according to race/ethnicity with rates in Latin America and Puerto Rico from 2001 to 2015.<h4>Design, setting, and participants</h4>This descriptive cross-sectional study used mortality data from the World Health Organization Mortality Database. All deaths occurring in individuals aged 20 to 64 years among US Latino, African American, white, and Puerto Rican and 12 other Latin American populations from January 2001 to December 2015 were selected. The data analysis began in October 2018.<h4>Exposures</h4>Age, sex, race/ethnicity, and country.<h4>Main outcomes and measures</h4>All-cause mortality, cause-specific mortality, age-standardized mortality rates (AMSRs), and average annual percentage change in mortality rates during 2001 to 2015.<h4>Results</h4>During 2001 to 2015, 22 million deaths (8 million women and 14 million men) occurred among individuals aged 20 to 64 years in the selected populations. Among women, US Latina individuals had the lowest premature mortality rates (ASMR for 2015, 144 deaths per 100 000 population) and US African American women had the highest premature mortality rate (ASMR for 2015, 340 deaths per 100 000 population) of the 16 populations studied. Rates among US white women shifted from the sixth lowest in 2001 (ASMR, 231 deaths per 100 000 population) to the 12th lowest in 2015 (ASMR, 235 deaths per 100 000 population). Among men, Peru had the lowest premature mortality rates (ASMR for 2015, 219 deaths per 100 000 population), and Belize had the highest premature mortality rates (ASMR for 2015, 702 deaths per 100 000 population). White men in the United States shifted from the fifth lowest rates in 2001 (ASMR, 396 deaths per 100 000 population) to the eighth lowest rates in 2015 (ASMR, 394 deaths per 100 000 population). Rates for both women and men decreased in all the populations studied from 2001 to 2015 (average annual percentage change range, 0.4% to 3.8% per year) except among US white populations, for which the rate plateaued (average annual percentage change, 0.02% per year [95% CI, -0.3% to 0.2% per year] for women; -0.2% per year [95% CI, -0.4% to 0.0% per year] for men) and among Nicaraguan men, for whom the rates increased (0.6% per year [95% CI, 0.2% to 1.0% per year]). The populations with the lowest mortality rates in 2015 had lower rates from all major causes, but rates were particularly lower for heart disease (21 deaths per 100 000 population) and cancer (50 deaths per 100 000 population).<h4>Conclusions and relevance</h4>Premature mortality rates are lower for US Latino populations and several Latin American countries than for US white populations, suggesting that there may be a broader Latin American paradox. This analysis also highlights the high premature mortality rates among US African American populations, especially women, compared with many Latin American populations.
<h4>Purpose</h4>To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity.<h4>Methods</h4>Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend (<i>P</i> < .05) and 95% CIs (< 1.0).<h4>Results</h4>A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types.<h4>Conclusion</h4>Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
<h4>Importance</h4>Notable increases in mortality from alcohol-induced causes over the past 2 decades in the United States have been reported. However, comprehensive assessments of trends in alcohol-induced mortality by sex, age, race/ethnicity, and social and geographic factors are lacking.<h4>Objective</h4>To examine trends in alcohol-induced mortality rates from 2000 to 2016, comparing results by demographic characteristics including sex, race/ethnicity, age, county-level socioeconomic status, and geographic location.<h4>Design, setting, and participants</h4>This serial cross-sectional study used US national vital statistics data for years 2000 to 2016 for all US residents older than 15 years. Data analysis was conducted from January to September 2019.<h4>Exposures</h4>Trends in alcohol-induced mortality by sex, race/ethnicity, age, county-level socioeconomic status (ie, median income, percentage of unemployed residents, percentage of residents with a bachelor's degree), rurality level, and US state.<h4>Main outcomes and measures</h4>Alcohol-induced mortality, ie, deaths for which alcohol holds a population-attributable fraction of 1. Deaths were expressed per 100 000 residents as absolute and age-standardized rates. Mortality trends were measured as average annual percentage changes (AAPCs) for the entire period (ie, 2000-2016) and annual percentage changes (APCs) for individual periods of change within the study period.<h4>Results</h4>A total of 425 045 alcohol-induced deaths were identified from 2000 to 2016 (2000: 19 627 deaths; 14 979 [76.3%] men; 2016: 34 857 deaths; 25 213 [73.3%] men). The rate of alcohol-induced deaths increased substantially among men (AAPC, 1.4%; 95% CI, 1.0% to 1.8%) and women (AAPC, 3.1%; 95% CI, 2.6% to 3.6%) and accelerated recently (men, 2012-2016: APC, 4.2%; 95% CI, 3.1% to 5.3%; women, 2013-2016: APC, 7.1%; 95% CI, 5.1% to 9.1%). The largest increases by race/ethnicity were observed among American Indian and Alaska Native men (AAPC, 3.3%; 95% CI, 2.6% to 4.0%), American Indian and Alaska Native women (AAPC, 4.2%; 95% CI, 3.8% to 4.6%), and white women (AAPC, 4.1%; 95% CI, 3.6% to 4.7%). Despite initial declines among black women, black men, and Latino men (eg, Latino men, 2000-2003: APC, -5.1%; 95% CI, -9.8% to -0.1%; 2003-2013: APC, -0.6%; 95% CI, -1.4% to 0.2%), increases occurred later in the study period (eg, Latino men, 2013-2016: APC, 4.1%; 95% CI, 0.3% to 8.1%). The rates of increase varied by age group and in turn by racial/ethnic group. Among white individuals, large absolute increases occurred in midlife (eg, men aged 55-59 years, 2000-2003: 25.5 deaths per 100 000 residents; 2013-2016: 43.3 deaths per 100 000 residents; women aged 50-54 years, 2000-2003: 7.4 deaths per 100 000 residents; 2013-2016: 16.5 deaths per 100 000 residents), although APCs were also large for ages 25 to 34 years, ranging from 4.6% to 6.9% per year among men and from 7.3% to 12.0% among women. Among American Indian and Alaska Native individuals, increases throughout the age range were observed, with the largest absolute increase occurring for ages 45 to 49 years among men (2000-2013: 113.6 deaths per 100 000 residents; 2013-2016: 193.1 deaths per 100 000 residents) and for ages 50 to 54 among women (2000-2013: from 56.1 deaths per 100 000 residents; 2013-2016: 105.1 deaths per 100 000 residents).<h4>Conclusions and relevance</h4>This study found large increases in alcohol-induced death rates across age and racial/ethnic subgroups of the US population, which have accelerated over recent years. Large increases in alcohol-induced deaths among younger age groups may be associated with future increases in alcohol-related disease.
<h4>Background</h4>While radiotherapy is a major risk factor for thyroid cancer after childhood cancer, factors contributing to increased thyroid cancer risk after adulthood cancer remain unclear.<h4>Methods</h4>We evaluated second primary papillary thyroid cancer (PTC) risk among 3,175,216 ≥ 1-year adult survivors of non-thyroid malignancies from US population-based cancer registries (2000-2015), using standardized incidence ratios (SIRs). Because heightened surveillance may increase detection of indolent thyroid tumors and earlier detection of advanced tumors, we examined SIRs by PTC stage and time since first cancer (latency).<h4>Results</h4>SIRs for second primary PTC (N = 4333) were statistically-significantly 1.2-3.5-fold elevated overall and after 23/27 first cancer types evaluated, with generally similar risks for localized and regional/distant PTC. SIRs for regional/distant PTC (N = 1501) were highest after pancreatic (SIR = 3.7; 95% confidence interval [CI] = 1.9-6.5) and soft tissue (SIR = 4.2; 95%CI = 2.8-6.2) cancers, followed by melanoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, and larynx, kidney, and brain/central nervous system (SIRs = 2.0-2.9) cancers. SIRs typically decreased with increasing latency but remained statistically-significantly elevated for regional/distant-PTC ≥5 years after diagnosis of cancers of the rectum, pancreas, lung/bronchus, soft tissue, female breast, uterine corpus, prostate, and kidney, and after melanoma, Hodgkin lymphoma, CLL/SLL, and follicular lymphoma. Neither total nor regional/distant PTC were clearly associated with initial course of radiotherapy or chemotherapy.<h4>Conclusions</h4>PTC risk was elevated after a range of first primary adult cancers but was not clearly related to treatment. Although surveillance may contribute to elevated short-term risks of PTC, longer-term elevations in regional/distant PTC may be attributable to shared risk factors.
<h4>Purpose</h4>Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.<h4>Patients and methods</h4>We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based <i>P</i> values using a Bonferroni-corrected significance threshold of <i>P</i> < 8.06 × 10<sup>-5</sup>.<h4>Results</h4>Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; <i>P</i> = 4.79 × 10<sup>-5</sup>), most notably but nonsignificantly for <i>FANCM</i> (patient cases, 4.0%; matched controls, 0.6%; <i>P</i> = 9.64 × 10<sup>-5</sup>). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; <i>P</i> = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with <i>EXO1</i> variants (patient cases, 1.8%; controls, 0.4%; <i>P</i> = 3.31 × 10<sup>-5</sup>), another gene implicated in DNA double-strand break repair.<h4>Conclusion</h4>In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.
<h4>Purpose</h4>The long-term risks and benefits of radiotherapy for ductal carcinoma in situ (DCIS) remain unclear. Recent data from the Surveillance, Epidemiology and End Results (SEER) registries showed that DCIS-associated radiotherapy treatment significantly increased risk of second non-breast cancers including lung cancer. To help understand those observations and whether breast cancer risk factors are related to radiotherapy treatment decision-making, we examined associations between lifestyle and clinical factors with DCIS radiotherapy receipt.<h4>Methods</h4>Among 1628 participants from the NIH-AARP Diet and Health Study, diagnosed with incident DCIS (1995-2011), we examined associations between lifestyle and clinical factors with radiotherapy receipt. Radiotherapy and clinical information were ascertained from state cancer registries. Odds ratios (ORs) and 95% confidence intervals (CIs) for radiotherapy receipt (yes/no) were estimated from multivariable logistic regression.<h4>Results</h4>Overall, 45% (n = 730) received radiotherapy. No relationships were observed for most lifestyle factors and radiotherapy receipt, including current smoking (OR 0.97, 95%CI 0.70, 1.34). However positive associations were observed for moderate alcohol consumption and infrequent physical activity. The strongest associations were observed for radiotherapy receipt and more recent diagnoses (2005-2011 vs. 1995-1999; OR 1.60, 95%CI 1.14, 2.25), poorly versus well-differentiated tumors (OR 1.69, 95%CI 1.16, 2.46) and endocrine therapy (OR 3.37, 95%CI 2.56, 4.44).<h4>Conclusions</h4>Clinical characteristics were the strongest determinants of DCIS radiotherapy. Receipt was largely unrelated to lifestyle factors suggesting that the previously observed associations in SEER were likely not confounded by these lifestyle factors. Further studies are needed to understand mechanisms driving radiotherapy-associated second malignancies following DCIS, to identify prevention opportunities for this growing population.
Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.
<h4>Background</h4>Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear.<h4>Methods</h4>We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided.<h4>Results</h4>Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers.<h4>Conclusions</h4>Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
<h4>Importance</h4>Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States. Despite substantial declines in CVD mortality rates during past decades, progress against cardiovascular deaths in midlife has stagnated, with rates increased in some US racial/ethnic groups.<h4>Objective</h4>To examine the trends in premature (ages 25-64 years) mortality from CVD from 2000 to 2015 by demographics and county-level factors, including education, rurality, and the prevalence of smoking, obesity, and diabetes.<h4>Design, setting, and participants</h4>This descriptive study used US national mortality data from the Surveillance, Epidemiology, and End Results data set and included all CVD deaths among individuals ages 25 to 64 years from January 2000 to December 2015. The data analysis began in February 2018.<h4>Exposures</h4>Age, sex, race/ethnicity, and county-level factors.<h4>Main outcomes and measures</h4>Age-standardized mortality rates and average annual percent change (AAPC) in rates by age, sex, race/ethnicity, and county-level factors (in quintiles) and relative risks of CVD mortality across quintiles of each county-level factor.<h4>Results</h4>In 2000 to 2015, 2.3 million CVD deaths occurred among individuals age 25 to 64 years in the United States. There were significant declines in CVD mortality for black, Latinx, and Asian and Pacific Islander individuals (AAPC: range, -1.7 to -3.2%), although black people continued to have the highest CVD mortality rates. Mortality rates were second highest for American Indian/Alaskan Native individuals and increased significantly among those aged 25 to 49 years (AAPC: women, 2.1%; men, 1.3%). For white individuals, mortality rates plateaued among women age 25 to 49 years (AAPC, 0.05%). Declines in mortality rates were observed for most major CVD subtypes except for ischemic heart disease, which was stable in white women and increased in American Indian/Alaska Native women, hypertensive heart disease, for which significant increases in rates were observed in most racial/ethnic groups, and endocarditis, for which rates increased in white individuals and American Indian/Alaska Native men. Counties with the highest prevalence of diabetes (quintile 5 vs quintile 1: relative risk range 1.6-1.8 for white individuals and 1.4-1.6 for black individuals) had the most risk of CVD mortality.<h4>Conclusions and relevance</h4>There have been substantial declines in premature CVD mortality in much of the US population. However, increases in CVD mortality before age 50 years among American Indian/Alaska Native individuals, flattening rates in white people, and overall increases in deaths from hypertensive disease suggest that targeted public health interventions are needed to prevent these premature deaths.
<h4>Importance</h4>Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied.<h4>Objectives</h4>To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status.<h4>Design, setting, and participants</h4>In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018.<h4>Exposures</h4>Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents.<h4>Main outcomes and measures</h4>Odds ratios (ORs) for subsequent breast cancer by ER status.<h4>Results</h4>A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use.<h4>Conclusions and relevance</h4>This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.
<h4>Introduction</h4>A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer.<h4>Methods</h4>We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events.<h4>Ethics and dissemination</h4>The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets.<h4>Trial registration number</h4>NCT02603341.
<h4>Aim</h4>To determine cumulative scan frequencies and estimate lens dose for paediatric computed tomography (CT) head examinations in the context of potential cataract risk.<h4>Materials and methods</h4>The cumulative number of head-region CT examinations among a cohort of 410,997 children and young adults who underwent CT in the UK between 1985 and 2014 was calculated. Images from a sample of these head examinations (n=668) were reviewed to determine the level of eye inclusion. Lens dose per scan was estimated using the computer program, NCICT V1.0, for different levels of eye inclusion and exposure settings typical of past and present clinical practice.<h4>Results</h4>In total 284,878 patients underwent 448,108 head-region CT examinations. The majority of patients (72%) had a single recorded head-region examination. A small subset (∼1%, n=2,494) underwent ≥10 examinations, while 0.1% (n=387) underwent ≥20. The lens was included within the imaged region for 57% of reviewed routine head examinations. In many cases, this appeared to be intentional, i.e. protocol driven. In others, there appeared to have been an attempt to exclude the eyes through gantry angulation. Estimated lens doses were 20-75 mGy (mean: 47 mGy) where the eye was fully included within the examination range and 2-7 mGy (mean: 3.1 mGy) where the lens was fully excluded. Potential cumulative lens doses ranged from ∼3 mGy to ∼4,700 mGy, with 2,335 patients potentially receiving >500 mGy.<h4>Conclusion</h4>The majority of young people will receive cumulative lens doses well below 500 mGy, meaning the risk of cataract induction is likely to be very small.
Excess sarcoma risks after childhood cancer are well established, but risks among young adulthood cancer survivors are poorly understood. Using US population-based cancer registry data, we compared bone and soft-tissue sarcoma risk vs the general population among 186 351 individuals who were diagnosed with nonsarcoma first primary malignancies at ages 20-39 years from 1975 to 2014 (follow-up through 2015) and survived at least 1 year. Bone sarcomas were rare (n = 50), but risk was statistically significantly elevated overall (2.9-fold) and greater than fivefold after Hodgkin lymphoma, non-Hodgkin lymphoma, and central nervous system tumors. Soft-tissue sarcomas were more common (n = 284) and risks were statistically significantly elevated approximately twofold overall and after melanoma and carcinomas of the breast, thyroid, and testis, and greater than fourfold after Hodgkin lymphoma and central nervous system tumors. Risks varied markedly by subtype, with the highest risks (greater than fourfold) for osteosarcoma and the soft-tissue subtypes of rhabdomyosarcoma and blood vessel and nerve sheath sarcomas. These data demonstrate elevated risk for sarcoma after a range of young adulthood cancers.
Disparities in cancer mortality by county-level income have increased. It is unclear whether these widening disparities have affected older and younger adults equally. National death certificate data were utilized to ascertain cancer deaths during 1999-2015. Average annual percent changes in mortality rates and mortality rate ratios (RRs) were estimated by county-level income quintile and age (25-64 vs ≥65 years). Among 25- to 64-year-olds, cancer mortality rates were 30% higher (RR = 1.30, 95% confidence interval [CI] = 1.29 to 1.31) in the lowest-vs the highest-income counties in 1999-2001 and 56% higher (RR = 1.56, 95% CI = 1.55 to 1.57) in 2013-2015; the disparities among those 65 years and older were smaller but also widened over time (RR1999-2001 = 1.04, 95% CI = 1.03 to 1.05; RR2013-2015 = 1.14, 95% CI = 1.13 to 1.14). Widening disparities occurred across cancer sites. If all counties had the mortality rates of the highest-income counties, 21.5% of cancer deaths among 25- to 64-year-olds and 7.3% of cancer deaths in those 65 years and older would have been avoided in 2015. These results highlight an ongoing need for equity-focused interventions, particularly among younger adults.
<h4>Importance</h4>Radioactive iodine (RAI) has been used extensively to treat hyperthyroidism since the 1940s. Although widely considered a safe and effective therapy, RAI has been associated with elevated risks of total and site-specific cancer death among patients with hyperthyroidism.<h4>Objective</h4>To determine whether greater organ- or tissue-absorbed doses from RAI treatment are associated with overall and site-specific cancer mortality in patients with hyperthyroidism.<h4>Design, setting, and participants</h4>This cohort study is a 24-year extension of the multicenter Cooperative Thyrotoxicosis Therapy Follow-up Study, which has followed up US and UK patients diagnosed and treated for hyperthyroidism for nearly 7 decades, beginning in 1946. Patients were traced using records from the National Death Index, Social Security Administration, and other resources. After exclusions, 18 805 patients who were treated with RAI and had no history of cancer at the time of the first treatment were eligible for the current analysis. Excess relative risks (ERRs) per 100-mGy dose to the organ or tissue were calculated using multivariable-adjusted linear dose-response models and were converted to relative risks (RR = 1 + ERR). The current analyses were conducted from April 28, 2017, to January 30, 2019.<h4>Exposures</h4>Mean total administered activity of sodium iodide I 131 was 375 MBq for patients with Graves disease and 653 MBq for patients with toxic nodular goiter. Mean organ or tissue dose estimates ranged from 20 to 99 mGy (colon or rectum, ovary, uterus, prostate, bladder, and brain/central nervous system), to 100 to 400 mGy (pancreas, kidney, liver, stomach, female breast, lung, oral mucosa, and marrow), to 1.6 Gy (esophagus), and to 130 Gy (thyroid gland).<h4>Main outcomes and measures</h4>Site-specific and all solid-cancer mortality.<h4>Results</h4>A total of 18 805 patients were included in the study cohort, and the mean (SD) entry age was 49 (14) years. Most patients were women (14 671 [78.0%]), and most had a Graves disease diagnosis (17 615 [93.7%]). Statistically significant positive associations were observed for all solid cancer mortality (n = 1984; RR at 100-mGy dose to the stomach = 1.06; 95% CI, 1.02-1.10; P = .002), including female breast cancer (n = 291; RR at 100-mGy dose to the breast = 1.12; 95% CI, 1.003-1.32; P = .04) and all other solid cancers combined (n = 1693; RR at 100-mGy dose to the stomach = 1.05; 95% CI, 1.01-1.10; P = .01). The 100-mGy dose to the stomach and breast corresponded to a mean (SD) administered activity of 243 (35) MBq and 266 (58) MBq in patients with Graves disease. For every 1000 patients with hyperthyroidism receiving typical doses to the stomach (150 to 250 mGy), an estimated lifetime excess of 19 (95% CI, 3-40) to 32 (95% CI, 5-66) solid cancer deaths could occur.<h4>Conclusions and relevance</h4>In RAI-treated patients with hyperthyroidism, greater organ-absorbed doses appeared to be modestly positively associated with risk of death from solid cancer, including breast cancer. Additional studies are needed of the risks and advantages of all major treatment options available to patients with hyperthyroidism.
Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m<sup>2</sup> increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.
<h4>Background</h4>Pediatric differentiated thyroid cancer (DTC) rates have increased over time in the United States and worldwide. Improvements in imaging for the diagnosis of DTC have been hypothesized as a potential driver of these increases. This study stratifies temporal trends in pediatric DTC by stage and tumor size to assess whether rates of large, late-stage cancers, which are likely to be clinically meaningful, are increasing over time.<h4>Methods</h4>Age-standardized incidence rates (ASRs) of DTC and annual percent changes (APCs) in primary DTC rates were estimated for 0- to 19-year-olds with data from 39 US cancer registries during 1998-2013.<h4>Results</h4>During 1998-2013, 7296 cases of DTC were diagnosed (6652 papillary cases and 644 follicular cases). APCs of pediatric DTCs significantly increased by 4.43%/y [95% CI, 3.74%/y-5.13%/y], primarily because of increases in papillary histologies. Increasing trends were observed for children aged 10 to 19 years for both sexes and for non-Hispanic whites, non-Hispanic blacks, and Hispanics. Rates increased significantly over the time period for all tumor stages (APC<sub>localized</sub> , +4.06%/y [95% CI, 2.84%/y-5.29%/y]; APC<sub>regional</sub> , +5.68%/y [95% CI, 4.64%/y-6.73%/y]; APC<sub>distant</sub> , +8.55%/y [95% CI, 5.03%/y-12.19%/y]) and across tumor sizes (APC<sub><1 cm</sub> , +9.46%/y [95% CI, 6.13%/y-12.90%/y]; APC<sub>1-2 cm</sub> , +6.92%/y [95% CI, 4.31%/y-9.60%/y]; APC<sub>>2 cm</sub> , +4.69%/y [95% CI, 2.75%/y-6.67%/y]).<h4>Conclusions</h4>Significantly increasing rates of DTC over time among 10- to 19-year-olds in the United States are unlikely to be entirely explained by increases in medical surveillance during childhood because rates of large and late-stage DTC are increasing over time. Future studies should examine environmental and other factors that may be contributing to rising DTC rates.
<h4>Background</h4>Available evidence on diet and glioma risk comes mainly from studies with retrospective collection of dietary data. To minimize possible differential dietary recall between those with and without glioma, we present findings from 3 large prospective studies.<h4>Methods</h4>Participants included 692 176 from the UK Million Women Study, 470 780 from the US National Institutes of Health-AARP study, and 99 148 from the US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox regression yielded study-specific adjusted relative risks for glioma in relation to 15 food groups, 14 nutrients, and 3 dietary patterns, which were combined, weighted by inverse variances of the relative risks. Separate analyses by <5 and ≥5 years follow-up assessed potential biases related to changes of diet before glioma diagnosis.<h4>Results</h4>The 1 262 104 participants (mean age, 60.6 y [SD 5.5] at baseline) were followed for 15.4 million person-years (mean 12.2 y/participant), during which 2313 incident gliomas occurred, at mean age 68.2 (SD 6.4). Overall, there was weak evidence for increased glioma risks associated with increasing intakes of total fruit, citrus fruit, and fiber and healthy dietary patterns, but these associations were generally null after excluding the first 5 years of follow-up. There was little evidence for heterogeneity of results by study or by sex.<h4>Conclusions</h4>The largest prospective evidence to date suggests little, if any, association between major food groups, nutrients, or common healthy dietary patterns and glioma incidence. With the statistical power of this study and the comprehensive nature of the investigation here, it seems unlikely we have overlooked major effects of diet on risk of glioma that would be of public health concern.
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.
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.
<h4>Purpose</h4>Consistent follow-up and data collection are necessary to identify long-term benefits/detriments of proton radiotherapy. Obtaining comprehensive clinical follow-up can be difficult and time-intensive for proton centers. Here we evaluate what factors affect maximum follow-up time among MGH Pediatric Proton Consortium Registry (PPCR) participants.<h4>Patients and methods</h4>Enrollment in the PPCR was offered to any patient <22 years receiving protons. Patients were excluded from analysis if they were taken off study due to death or withdrawal. Distance from MGH was calculated by the great-circle formula. We utilized both univariate and multivariate analyses to determine risk factors associated with follow-up time.<h4>Results</h4>333 PPCR patients enrolled between 10/2012 and 03/2017 were included. Median follow-up was 2.4 years (<1-5.5), and median distance away from the proton center was 256.4 km (<1.6-16,949.6). Distance from MGH significantly predicted follow-up time: patients living outside the Boston Metropolitan Statistical Area, >121 km from the proton center, had average follow-up that was 0.53 years less compared to those living within 121 km (p = 0.0002). Loss in average follow-up was also associated with Medicaid insurance, treatment delay due to insurance, and non-White race. Those co-enrolled on a proton trial or seen at a facility had significantly increased follow-up by almost one year (p < 0.0001).<h4>Conclusion</h4>Patients living further from treating proton center have shorter follow-up durations. Increased distance from treating centers may adversely affect clinical outcomes research. Enhanced sharing of medical information among care providers and improved collection methods are needed to effectively evaluate the benefits of proton therapy.
<h4>Background</h4>Brain and other central nervous system (CNS) cancers are the leading cause of U.S. pediatric cancer mortality. Incidence trends can provide etiologic insight. We report trends in incidence rates of pediatric malignant CNS cancers and pilocytic astrocytoma (nonmalignant but historically registered) in the United States.<h4>Methods</h4>Age-standardized incidence rates and annual percent changes (APC) in rates during 1998 to 2013 were calculated for children aged 0 to 19, stratified by subtype, age, sex, and for gliomas, histology and location. We estimated the absolute change in number of cases diagnosed U.S.-wide during 2013 compared with the expected number of cases had 1998 rates remained stable.<h4>Results</h4>Rates of all pediatric malignant CNS cancer combined (<i>n</i> = 18,612) did not change [APC: 0.16; 95% confidence interval (CI): -0.21-0.53]. There were statistically significant changes in several subtypes; however, glioma incidence (<i>n</i> = 10,664) increased by 0.77% per year (95% CI: 0.29-1.26), embryonal cancer rates (<i>n</i> = 5,423) decreased by 0.88% per year (95% CI: -1.33 to -0.43), and pilocytic astrocytoma rates (<i>n</i> = 6,858) increased by 0.89% per year (95% CI: 0.21-1.58). Of the 1,171 malignant tumors and 450 pilocytic astrocytomas diagnosed in U.S. children in 2013, we estimated 120 excess gliomas, 94 excess pilocytic astrocytomas, and 72 fewer embryonal CNS tumors than would be expected had 1998 rates remained stable.<h4>Conclusions</h4>The gradual changes in incidence we observed for specific types of pediatric CNS cancers are likely due to a combination of changes in classification and diagnosis and true changes in CNS cancer.<h4>Impact</h4>Continued surveillance of pediatric CNS tumors should remain a priority, given their significant contribution to pediatric cancer-related deaths.
<h4>Purpose</h4>To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years.<h4>Materials & methods</h4>Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types.<h4>Results</h4>Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were <5 years of age, and 50% <10 years. More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents.<h4>Conclusion</h4>To our knowledge, this survey provides the first worldwide assessment of proton therapy use for pediatric cancer management. Since previous estimates in the United States and Europe, CNS tumors remain the cancer types most commonly treated with protons in 2016. However, the proportion of extra-cranial tumors is growing worldwide. The typically low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients.
<h4>Background</h4>Increasing premature mortality among some groups of Americans has been largely driven by increases in drug poisoning deaths. However, to our knowledge, a formal descriptive study by race and ethnicity, socioeconomic status, rurality, and geography has not been done. In this study, we examined US trends in premature all-cause and drug poisoning mortality between 2000 and 2015 at the county level among white, black, and Latino people.<h4>Methods</h4>We used US mortality data for the period Jan 1, 2000, to Dec 31, 2015, including underlying cause of death and demographic data, collected from death certificates by the Centers for Disease Control and Prevention National Center for Health Statistics, and ascertained county attributes from the 2011-15 Census American Community Survey. We categorised counties into quintiles on the basis of the percentage of people unemployed, the percentage of people with a bachelor's degree, median income, and rurality. We estimated premature (ie, deaths in those aged 25-64 years) age-standardised mortality for all causes (by race and ethnicity) and drug poisoning, by county, for the periods of 2000-03 and 2012-15. We estimated annual percentage changes in mortality (2000-15) by county-level characteristics.<h4>Findings</h4>Premature mortality declined from 2000-03 to 2012-15 among black and Latino people, but increased among white people in many US counties. Drug poisoning mortality increased in counties throughout the country. Significant increases between 2000 and 2015 occurred across low and high socioeconomic status and urban and rural counties among white people aged 25-64 years (annual percentage change range 4·56% per year [95% CI 3·56-5·57] to 11·51% per year [9·41-13·65]), black people aged 50-64 years (2·27% per year [0·42-4·16] to 9·46% per year [7·02-11·96]), Latino women aged 25-49 years (2·43% per year [1·18-3·71] to 5·01% per year [3·80-6·23]), and Latino men aged 50-64 years (2·42% per year [0·53-4·34] to 5·96% per year [3·86-8·11]). Although drug poisoning mortality increased rapidly in counties with the lowest socioeconomic status and in rural counties, most deaths during 2012-15 occurred in the largest metropolitan counties (121 395 [76%] in metropolitan counties with ≥250 000 people vs 2175 [1%] in the most rural counties), reflecting population size.<h4>Interpretation</h4>Premature mortality has declined among black and Latino people in the USA, and increased among white people, particularly in less affluent and rural counties. Increasing drug poisoning mortality was not limited to poor white people in rural areas. Rapid increases have occurred in communities throughout the USA regardless of race and ethnicity, socioeconomic status, or rurality. Widespread public health interventions are needed to addess this public health emergency.<h4>Funding</h4>National Institutes of Health.
Purpose To assess the potential ionizing radiation exposure from CT scans for both screening and surveillance of patients with von Hippel-Lindau (VHL) syndrome. Materials and Methods For this retrospective study, abdomen-pelvic (AP) and chest-abdomen-pelvic (CAP) CT scans were performed with either a three-phase (n = 1242) or a dual-energy virtual noncontrast protocol (VNC; n = 149) in 747 patients with VHL syndrome in the National Institutes of Health Clinical Center between 2009 and 2015 (mean age, 47.6 years ± 14.6 [standard deviation]; age range, 12-83 years; 320 women [42.8%]). CT scanning parameters for patients with pancreatic neuroendocrine tumors (PNETs; 124 patients and 381 scans) were compared between a tumor diameter-based surveillance protocol and a VHL genotype and tumor diameter-based algorithm (a tailored algorithm) developed by three VHL clinicians. Organ and lifetime radiation doses were estimated by two radiologists and five radiation scientists. Cumulative radiation doses were compared between the PNET surveillance algorithms by analyses of variance, and a two-tailed P value less than .05 indicated statistical significance. Results Median cumulative colon doses for annual CAP and AP CT scans from age 15 to 40 years ranged from 0.34 Gy (5th-95th percentiles, 0.18-0.75; dual-energy VNC CT) to 0.89 Gy (5th-95th percentiles, 0.42-1.0; three-phase CT). For the current PNET surveillance protocol, the cumulative effective radiation dose from age 40 to 65 years was 682 mSv (tumors < 1.2 cm) and 2125 mSv (tumors > 3 cm). The tailored algorithm could halve these doses for patients with initial tumor diameter less than 1.2 cm (P < .001). Conclusion CT screening of patients with von Hippel-Lindau syndrome can lead to substantial radiation exposures, even with dual-energy virtual noncontrast CT. A genome and tumor diameter-based algorithm for pancreatic neuroendocrine tumor surveillance may potentially reduce lifetime radiation exposure. © RSNA, 2018 Online supplemental material is available for this article.
Although increased risk of acute myeloid leukemia (AML) has been observed after chemotherapy and radiotherapy, less is known about radiotherapy-related risks of specific AML subtypes and other specific myeloid neoplasms. We used the US population-based cancer registry data to evaluate risk of myeloid neoplasms among three cohorts of cancer survivors initially treated with radiotherapy only. We included 1-year survivors of first primary thyroid (radioiodine only, stages I-IV; N = 49 879), prostate (excluding stage IV; N = 237 439), or uterine corpus cancers (stage I-II; N = 16 208) diagnosed during 2000-2013. We calculated standardized incidence ratios (SIRs) and excess absolute risks (EARs). Thyroid cancer survivors had significantly elevated risks of total AML (SIR = 2.77, 95% CI: 1.99-3.76), AML with cytogenetic abnormalities (SIR = 3.90, 95% CI: 1.57-8.04), AML with myelodysplasia-related changes (SIR = 2.87, 95% CI: 1.05-6.25), and BCR-ABL1-positive chronic myelogenous leukemia (CML) (SIR = 5.38, 95% CI: 2.58-9.89). Irradiated prostate and uterine corpus cancer survivors were at elevated risk for total AML (SIR = 1.14, 95% CI: 1.03-1.27 and SIR = 1.77, 95% CI: 1.01-2.87, respectively), AML with cytogenetic abnormalities (SIR = 2.52, 95% CI: 1.84-3.37 and SIR = 7.21, 95% CI: 2.34-16.83, respectively), and acute promyelocytic leukemia (SIR = 3.20, 95% CI: 2.20-4.49 and SIR = 8.88, 95% CI: 2.42-22.73, respectively). In addition, prostate cancer survivors were at increased risk of BCR-ABL1-positive CML (SIR = 2.11, 95% CI: 1.52-2.85). Our findings support the importance of diagnostic precision in myeloid neoplasm classification since susceptibility following radiotherapy may vary by myeloid neoplasm subtype, thereby informing risk/benefit discussions in first primary cancer treatment.
<h4>Importance</h4>The United States has higher infant and youth mortality rates than other high-income countries, with striking disparities by racial/ethnic group. Understanding changing trends by age and race/ethnicity for leading causes of death is imperative for focused intervention.<h4>Objective</h4>To estimate trends in US infant and youth mortality rates from 1999 to 2015 by age group and race/ethnicity, identify leading causes of death, and compare mortality rates with Canada and England/Wales.<h4>Design, setting, and participants</h4>This descriptive study analyzed death certificate data from the US National Center for Health Statistics, Statistics Canada, and the UK Office of National Statistics for all deaths among individuals younger than 25 years. The study took place from January 1, 1999, to December 31, 2015, and analyses started in September 2017.<h4>Exposures</h4>Race/ethnicity.<h4>Main outcomes and measures</h4>Average annual percent changes in mortality rates from 1999 to 2015 and absolute rate change between 1999 to 2002 and 2012 to 2015 for each age group, race/ethnicity, and cause of death.<h4>Results</h4>Among individuals from birth to age 24 years, 1 169 537 deaths occurred in the United States, 80 540 in Canada, and 121 183 in England/Wales from 1999 to 2015. In the United States, 64% of deaths occurred in male individuals and 52.6% occurred in white individuals (25.1% deaths occurred in black individuals and 17.9% in Latino individuals). All-cause mortality declined for all age groups (infants younger than 1 year [38.5% of deaths], children aged 1-9 years [10.6%], early adolescents aged 10-14 years [5%], late adolescents aged 15-19 years [17.7%], and young adults aged 20-24 years [28.1%]) in the United States, Canada, and England/Wales from 1999 to 2015. However, rates were highest in the United States. Within the United States, annual declines in all-cause mortality rates occurred among all age groups of black, Latino, and white individuals, except for white individuals aged 20 to 24 years, whose rates remained stable. Mortality rates declined across most major causes of death from 1999 to 2002 and 2012 to 2015, with notable declines observed for sudden infant death syndrome, unintentional injury death, and homicides. Among infants, unintentional suffocation and strangulation in bed increased (difference between 2012-2015 and 1999-2002 range, 6.11-29.03 per 100 000). Further, suicide rates among Latino and white individuals aged 10 to 24 years (range, 0.21-2.63 per 100 000) and black individuals aged 10 to 19 years (range, 0.10-0.45 per 100 000) increased, as did unintentional injury deaths in white young adults (0.79 per 100 000). The rise in unintentional injury deaths is attributed to increases in drug poisonings and was also observed in black and Latino young adults.<h4>Conclusions and relevance</h4>Mortality rates in the United States have generally declined for infants and youths from 1999 to 2015 owing to reductions in sudden infant death syndrome, unintentional injury death, and homicides. However, US mortality rates remain higher than Canada and England/Wales, with particularly elevated rates among black and American Indian/Alaskan Native youth. Further, there is a concerning increase in suicide and drug poisoning death rates among US adolescents and young adults.
<h4>Background</h4>Although life expectancy has been projected to increase across high-income countries, gains for the USA are anticipated to be among the smallest, and overall US death rates actually increased from 2014 to 2015, with divergence for specific US populations. Therefore, projecting future premature mortality is essential for clinical and public health service planning, curbing rapidly increasing causes of death, and sustaining progress in declining causes of death. We aimed to project premature mortality (here defined as deaths of individuals aged 25-64 years) trends through 2030, and to estimate the total number of projected deaths, the projected number of potential years of life lost due to premature mortality, and the effect of reducing projected accidental death rates by 2% per year.<h4>Methods</h4>We obtained death certificate data for the US population aged 25-64 years for 1990-2015 from the US Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. We obtained US mortality data for 2016 for non-American Indian or Alaska native groups from CDC WONDER; data for 2016 were not available for American Indians or Alaska natives. Our analysis focused on all-cause premature mortality and the commonest causes of premature death (cancer, heart disease, accidents, suicide, and chronic liver disease or cirrhosis) among white, black, Hispanic, Asian or Pacific islanders, and American Indian or Alaska native men and women. We estimated age-standardised premature mortality and corresponding annual percentage changes for 2017-30 by sex and race or ethnic origin by use of age-period-cohort forecasting models. We also did a sensitivity analysis projecting future mortality from cross-sectional mortality and a JoinPoint of the (log) period rate ratio curve. We calculated absolute death counts by use of corresponding age-specific and year-specific US census population projections, and estimated years of potential life lost.<h4>Findings</h4>During 2017-30, all-cause deaths are projected to increase among white women and American Indians or Alaska natives, resulting in 239 700 excess premature deaths relative to 2017 rates (a 10% increase). Mortality declines in white men and black, Hispanic, and Asian or Pacific islander men and women will result in 945 900 fewer deaths (a 14% reduction). Cancer mortality rates are projected to decline among white, black, Hispanic, and Asian or Pacific islander women and men, with the largest declines among black women (age-standardised premature mortality rate 2016: 104·5 deaths per 100 000 woman-years; 2030: 77·1 per 100 000 woman-years) and men (2016: 116·8 per 100 000 man-years; 2030: 81·6 per 100 000 man-years). Heart disease death rates are projected to increase in American Indian or Alaska native men (2015: 150·9 per 100 000 man-years; 2030: 175·9 per 100 000 man-years) and decline in other groups, albeit only slightly in white (2016: 35·6 per 100 000 woman-years; 2030: 31·1 per 100 000 woman-years) and American Indian or Alaska native women (2015: 64·4 per 100 000 woman-years; 2030: 62·8 per 100 000 woman-years). Accidental death rates are projected to increase in all US populations except Asian or Pacific islander women, and will increase most rapidly among white women (2030: 60·5 per 100 000 woman-years) and men (2030: 101·9 per 100 000 man-years) and American Indian or Alaska native women (2030: 97·5 per 100 000 woman-years) and men (2030: 298·7 per 100 000 man-years). Suicide rates are projected to increase for all groups, and chronic liver disease and cirrhosis deaths are projected to increase for all groups except black men. A 2% per year reduction in projected accidental deaths would eliminate an estimated 178 700 deaths during 2017-30.<h4>Interpretation</h4>To reduce future premature mortality, effective interventions are needed to address rapidly rising mortality rates due to accidents, suicides, and chronic liver disease and cirrhosis.<h4>Funding</h4>National Cancer Institute Intramural Research Program.
<h4>Background</h4>Substantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (<100 mSv) radiation is less certain, although this is the dose range most relevant to the general population. We aimed to estimate the risk of leukaemia associated with low-dose radiation exposure in childhood (age <21 years).<h4>Methods</h4>In this analysis of historical cohort studies, we pooled eligible cohorts reported up to June 30, 2014. We evaluated leukaemia and myeloid malignancy outcomes in these cohorts with the relevant International Classification of Diseases and International Classification of Diseases for Oncology definitions. The cohorts included had not been treated for malignant disease, had reported at least five cases of the relevant haematopoietic neoplasms, and estimated individual active bone marrow (ABM) doses. We restricted analysis to individuals who were younger than 21 years at first irradiation who had mean cumulative ABM doses of less than 100 mSv. Dose-response models were fitted by use of Poisson regression. The data were received in fully anonymised form by the statistical analyst.<h4>Findings</h4>We identified nine eligible cohorts from Canada, France, Japan, Sweden, the UK, and the USA, including 262 573 people who had been exposed to less than 100 mSv enrolled between June 4, 1915, and Dec 31, 2004. Mean follow-up was 19·63 years (SD 17·75) and mean cumulative ABM dose was 19·6 mSv (SD 22·7). 154 myeloid malignancies were identified (which included 79 acute myeloid leukaemias, eight myelodysplastic syndromes, and 36 chronic myeloid leukaemias, in addition to other unspecified myeloid malignancies) and 40 acute lymphoblastic leukaemias, with 221 leukaemias (including otherwise unclassified leukaemias but excluding chronic lymphocytic leukaemia) identified overall. The fitted relative risks at 100 mSv were 3·09 (95% CI 1·41-5·92; p<sub>trend</sub>=0·008) for acute myeloid leukaemia and myelodysplastic syndromes combined, 2·56 (1·09-5·06; p<sub>trend</sub>=0·033) for acute myeloid leukaemia, and 5·66 (1·35-19·71; p<sub>trend</sub>=0·023) for acute lymphoblastic leukaemia. There was no clear dose-response for chronic myeloid leukaemia, which had a relative risk at 100 mSv of 0·36 (0·00-2·36; p<sub>trend</sub>=0·394). There were few indications of between-cohort heterogeneity or departure from linearity. For acute myeloid leukaemia and myelodysplastic syndromes combined and for acute lymphoblastic leukaemia, the dose-responses remained significant for doses of less than 50 mSv. Excess absolute risks at 100 mSv were in the range of 0·1-0·4 cases or deaths per 10 000 person-years.<h4>Interpretation</h4>The risks of acute myeloid leukaemia and acute lymphoblastic leukaemia were significantly increased after cumulative doses of ionising radiation of less than 100 mSv in childhood or adolescence, with an excess risk also apparent for cumulative radiation doses of less than 50 mSv for some endpoints. These findings support an increased risk of leukaemia associated with low-dose exposure to radiation and imply that the current system of radiological protection is prudent and not overly protective.<h4>Funding</h4>National Cancer Institute Intramural Research Program, National Cancer Institute, and US National Institutes for Health.
<h4>Purpose</h4>Ionizing radiation and high levels of circulating estradiol are known breast cancer carcinogens. We investigated the risk of first primary postmenopausal breast cancer in relation to the combined effects of whole-body ionizing radiation exposure and prediagnostic levels of postmenopausal sex hormones, particularly bioavailable estradiol (bE<sub>2</sub>).<h4>Materials and methods</h4>A nested case-control study of 57 incident breast cancer cases matched with 110 controls among atomic bomb survivors. Joint effects of breast radiation dose and circulating levels of sex hormones were assessed using binary regression and path analysis.<h4>Results and conclusion</h4>Radiation exposure, higher levels of bE<sub>2</sub>, testosterone and progesterone, and established reproductive risk factors were positively associated with postmenopausal breast cancer risk. A test for mediation of the effect of radiation via bE<sub>2</sub> level suggested a small (14%) but significant mediation (p = 0.004). The estimated interaction between radiation and bE<sub>2</sub> was large but not significant (interaction = 3.86; p = 0.32). There is accumulating evidence that ionizing radiation not only damages DNA but also alters other organ systems. While caution is needed, some portion of the radiation risk of postmenopausal breast cancer appeared to be mediated through bE<sub>2</sub> levels, which may be evidence for cancer risks due to both direct and indirect effects of radiation.
<h4>Background</h4>Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking.<h4>Methods</h4>We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided.<h4>Results</h4>Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts.<h4>Conclusions</h4>Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.
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.
The last decade has introduced a new era of epidemiologic studies of low-dose radiation facilitated by electronic record linkage and pooling of cohorts that allow for more direct and powerful assessments of cancer and other stochastic effects at doses below 100 mGy. Such studies have provided additional evidence regarding the risks of cancer, particularly leukemia, associated with lower-dose radiation exposures from medical, environmental, and occupational radiation sources, and have questioned the previous findings with regard to possible thresholds for cardiovascular disease and cataracts. Integrated analysis of next generation genomic and epigenetic sequencing of germline and somatic tissues could soon propel our understanding further regarding disease risk thresholds, radiosensitivity of population subgroups and individuals, and the mechanisms of radiation carcinogenesis. These advances in low-dose radiation epidemiology are critical to our understanding of chronic disease risks from the burgeoning use of newer and emerging medical imaging technologies, and the continued potential threat of nuclear power plant accidents or other radiological emergencies.
<h4>Background</h4>Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.<h4>Objectives</h4>The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed.<h4>Discussion</h4>We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.<h4>Conclusions</h4>The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
The RERF International Low-Dose Symposium was held on 5-6 December 2013 at the RERF campus in Hiroshima, Japan, to discuss the issues facing the Life Span Study (LSS) and other low-dose studies. Topics included the current status of low-dose risk detection, strategies for low-dose epidemiological and statistical research, methods to improve communication between epidemiologists and biologists, and the current status of radiological studies and tools. Key points made by the participants included the necessity of pooling materials over multiple studies to gain greater insight where data from single studies are insufficient; generating models that reflect epidemiological, statistical, and biological principles simultaneously; understanding confounders and effect modifiers in the current data; and taking into consideration less studied factors such as the impact of dose rate. It is the hope of all participants that this symposium be used as a trigger for further studies, especially those using pooled data, in order to reach a greater understanding of the health effects of low-dose radiation.
<h4>Background</h4>Infections with certain human herpesviruses have been established as risk factors for some cancer types. For example, Epstein-Barr Virus is considered a cause of Burkitt's lymphoma and other immunosuppression related lymphomas, Hodgkin lymphoma, and nasopharyngeal cancer. Several other human herpesviruses have been linked to cancers but the totality of evidence is inconclusive.<h4>Methods</h4>We conducted a systematic sub-study from within an ongoing case control study of adult black South Africans to investigate the relationship between antibodies to six human herpesviruses and seven cancer groups that may be caused by infectious agents. Subjects had incident cancers of the oral cavity (n = 88), the cervix (n = 53), the prostate (n = 66), Hodgkin lymphoma (n = 83), non-Hodgkin lymphoma (n = 80), multiple myeloma (n = 94) or leukaemia (n = 203). For comparison, patients with other cancers (n = 95) or cardiovascular disease (n = 101) were randomly selected from within the study. Patients were interviewed and their blood was tested for IgG antibodies against HSV-1, HSV-2, VZV, EBV-EBNA, CMV and HHV-6 using enzyme linked immunosorbent assays. Because these viruses are highly prevalent in this population, optical density results from the assays were used as an indirect, quantitative measure of antibody level.<h4>Results</h4>There was significant variation in the mean log antibody measures for HSV-2, VZV, CMV and HHV-6 between the disease groups. However, none of the specific cancer groups had significantly higher mean log antibody measures for any of the viruses compared to either control group. In a more detailed examination of seven associations between cancers and herpesviruses for which there had been prior reports, two statistically significant associations were found: a decreasing risk of myeloid leukaemia and an increasing risk of oral cancer with increasing tertiles of antibodies against HHV-6 compared to all other patients (p-trend = 0.03 and 0.02, respectively). Odds ratios for the top tertile compared to the bottom tertile were 0.58 (95%CI 0.3-1.0) for myeloid leukaemia and 2.21 (95% CI 1.1-4.3) for oral cancer.<h4>Conclusion</h4>In this population, using these tests for IgG, neither mean antibody measure nor high antibody measure against human herpesviruses 1-6 was strongly associated with any of the seven cancer groups. However, we may not have had sufficient power to detect weak associations or associations with a sub-type of cancer if they were present.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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).<h4>Interpretation</h4>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.<h4>Funding</h4>US National Cancer Institute and UK Department of Health.
Radiation exposure, particularly at a young age, is an established cause of breast cancer. It is not known whether radiation-related breast cancer risk varies by molecular subtype. We characterized the relative risk (RR) of contralateral breast cancer (CBC) related to radiotherapy by histology and estrogen receptor (ER) status of the CBC in five-year survivors in the Surveillance, Epidemiology, and End Results database using Poisson regression models adjusted for attained age and calendar year, age at and year of treatment, ER status of the first breast cancer, and disease stage. 205,316 female breast cancer survivors were followed for an average of 10 years from 1973 until 2007, during which time 6924 women developed a subsequent primary invasive breast cancer in the contralateral breast. The overall RR (and 95% confidence interval (CI)) of radiotherapy-related CBC was 1.11 (1.05-1.16). There was no heterogeneity in risk according to histology of the CBC (P > 0.50) for all ages or young age at exposure, but case numbers were small for subtypes other than ductal and lobular carcinomas. Information on ER status was available from 1990 onwards for 3546 CBC cases, of which 2597 (73%) were ER+ and 949 (27%) were ER-. The RRs were 1.10 (1.02-1.19) for ER+ CBC and 1.19 (1.04-1.35) for ER- CBC (P (difference) = 0.33). Among women treated age <35 years, radiation-related risk of CBC was non-significantly elevated for ER- (RR = 1.38, 95% CI: 0.96-1.97) but not for ER+ tumors (RR = 0.80, 95% CI: 0.47-1.35) (P (difference) = 0.09). We did not find clear evidence that radiation-related risk varies by histology or ER status, but our findings, which were the first to examine this question, were suggestive of possible differences by ER status that may merit further investigation.
Background. Although using computed tomography (CT) can be greatly beneficial, the associated relatively high radiation doses have led to growing concerns in relation to potential associations with risk of future cancer. Very little has been published regarding the trends of CT use in young people. Therefore, our objective was to assess temporal and other patterns in CT usage among patients aged under 22 years in Great Britain from 1993 to 2002. Methods. Electronic data were obtained from the Radiology Information Systems of 81 hospital trusts within Great Britain. All included patients were aged under 22 years and examined using CT between 1993 and 2002, with accessible radiology records. Results. The number of CT examinations doubled over the study period. While increases in numbers of recorded examinations were seen across all age groups, the greatest increases were in the older patients, most notably those aged 15-19 years of age. Sixty percent of CT examinations were of the head, with the percentages varying with calendar year and patient age. Conclusions. In contrast to previous data from the North of England, the doubling of CT use was not accompanied by an increase in numbers of multiple examinations to the same individual.
<h4>Importance</h4>Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved.<h4>Objective</h4>To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk.<h4>Design, setting, and participants</h4>Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020.<h4>Exposures</h4>Radiation and chemotherapy dose changes over time.<h4>Main outcomes and measures</h4>Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age.<h4>Results</h4>Among 11 550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence.<h4>Conclusions and relevance</h4>Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies.
<h4>Background</h4>Soft tissue sarcoma is a rare but serious side-effect of radiotherapy to treat breast cancer, and rates are increasing in the USA. We evaluated potential co-factors in two complimentary cohorts of US breast cancer survivors.<h4>Methods</h4>In this retrospective cohort study, we sourced data from the Kaiser Permanente (KP) cohort and the Surveillance, Epidemiology, and End Results (SEER) 13 registries cohort, both in the USA. The KP cohort included 15 940 women diagnosed with breast cancer from Jan 1, 1990, to Dec 31, 2016, in KP Colorado, KP Northwest (which serves Oregon and Southwest Washington state), or KP Washington, with detailed treatment data and comorbidities (including hypertension and diabetes at or before breast cancer diagnosis) from electronic medical records. The SEER cohort included 457 300 women diagnosed with breast cancer from Jan 1, 1992, to Dec 31, 2016, within the 13 SEER registries across the USA, with initial treatment data (yes vs no or unknown). Eligibility criteria in both cohorts were female breast cancer survivors (stage I-III) aged 20-84 years at diagnosis who had breast cancer surgery, and had survived at least 1 year after breast cancer diagnosis. The outcome of interest was any second thoracic soft tissue sarcoma (angiosarcomas and other subtypes) that developed at least 1 year after breast cancer diagnosis. Risk factors for thoracic soft tissue sarcoma were assessed using multivariable Poisson regression models.<h4>Findings</h4>In the KP cohort, median follow-up was 9·3 years (IQR 5·7-13·9) and 19 (0·1%) of 15 940 eligible, evaluable women developed a thoracic soft tissue sarcoma (11 angiosarcomas, eight other subtypes). Most (94·7%; 18 of 19) thoracic soft tissue sarcomas occurred in women treated with radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (relative risk [RR] 8·1 [95% CI 1·1-60·4]; p=0·0052), but there was no association with prescribed dose, fractionation, or boost. The RR of angiosarcoma after anthracyclines was 3·6 (95% CI 1·0-13·3; p=0·058). Alkylating agents were associated with an increased risk of developing other sarcomas (RR 7·7 [95% CI 1·2-150·8]; p=0·026). History of hypertension (RR 4·8 [95% CI 1·3-17·6]; p=0·017) and diabetes (5·3 [1·4-20·8]; p=0·036) were each associated with around a five-times increased risk of angiosarcoma. In the SEER cohort, 430 (0·1%) of 457 300 patients had subsequent thoracic soft tissue sarcomas (268 angiosarcomas and 162 other subtypes) after a median follow-up of 8·3 years (IQR 4·3-13·9). Most (77·9%; 335 of 430) cases occurred after radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (RR 3·0 [95% CI 2·4-3·8]; p<0·0001) and, for angiosarcomas, the RR for breast-conserving surgery plus radiotherapy versus mastectomy plus radiotherapy was 1·9 (1·1-3·3; p=0·012). By 10 years after radiotherapy, the cumulative incidence of thoracic soft tissue sarcoma was 0·21% (95% CI 0·12-0·34) in the KP cohort and 0·15% (95% CI 0·13-0·17) in SEER.<h4>Interpretation</h4>Radiotherapy was the strongest risk factor for thoracic soft tissue sarcoma in both cohorts. This finding, along with the novel findings for diabetes and hypertension as potential risk factors for angiosarcomas, warrant further investigation as potential targets for prevention strategies and increased surveillance.<h4>Funding</h4>US National Cancer Institute and National Institutes of Health.
<h4>Importance</h4>Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy.<h4>Objective</h4>To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk.<h4>Design, setting, and participants</h4>This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022.<h4>Exposures</h4>Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses.<h4>Main outcomes and measures</h4>The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy).<h4>Results</h4>The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose.<h4>Conclusions and relevance</h4>These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.
<h4>Background</h4>Disparities in cardiovascular disease mortality among breast cancer survivors are documented, but geographic factors by county-level socioeconomic status (SES) and rurality are not well described.<h4>Methods</h4>We analyzed 724 518 women diagnosed with localized or regional stage breast cancer between 2000 and 2017 within Surveillance, Epidemiology, and End Results Program-18 with follow-up until 2018. We calculated relative risks (RRs) of cardiovascular disease mortality using Poisson regression, accounting for age- and race-specific rates in the general population, according to county-level quintiles of SES (measured by Yost index), median income, and rurality at breast cancer diagnosis. We also calculated 10-year cumulative mortality risk of cardiovascular disease accounting for competing risks.<h4>Results</h4>Cardiovascular disease mortality was 41% higher among breast cancer survivors living in the lowest SES (RR = 1.41, 95% confidence interval [CI] = 1.36 to 1.46, Ptrend < .001) and poorest (RR = 1.41, 95% CI = 1.36 to 1.47, Ptrend < .001) counties compared with the highest SES and wealthiest counties, and 24% higher for most rural relative to most urban counties (RR = 1.24, 95% CI = 1.17 to 1.30, Ptrend < .001). Disparities for the lowest SES relative to highest SES counties were greatest among younger women aged 18-49 years (RR = 2.32, 95% CI = 1.90 to 2.83) and aged 50-59 years (RR = 2.01, 95% CI = 1.77 to 2.28) and within the first 5 years of breast cancer diagnosis (RR = 1.53, 95% CI = 1.44 to 1.64). In absolute terms, however, disparities were widest for women aged 60+ years, with approximately 2% higher 10-year cumulative cardiovascular disease mortality risk in the poorest compared with wealthiest counties.<h4>Conclusions</h4>Geographic factors at breast cancer diagnosis were associated with increased cardiovascular disease mortality risk. Studies with individual- and county-level information are needed to inform public health interventions and reduce disparities among breast cancer survivors.
<h4>Background</h4>Racial and ethnic disparities in heart disease mortality by initial treatment type among breast cancer survivors have not been well described.<h4>Methods</h4>We included 739 557 women diagnosed with first primary invasive breast cancer between 2000 and 2017 (aged 18-84 years, received surgery, survived ≥1 year, followed through 2018) in the Surveillance, Epidemiology, and End Results-18 database. Standardized mortality ratios (SMRs; observed over expected) were calculated by race and ethnicity (non-Hispanic/Latina Asian American, Native Hawaiians, and other Pacific Islanders [AANHPI]; non-Hispanic/Latina Black [Black]; Hispanic/Latina [Latina]; and non-Hispanic/Latina White [White]) and initial treatment (surgery only; chemotherapy with surgery; chemotherapy, radiotherapy, with surgery; and radiotherapy with surgery) compared with the racial- and ethnic-matched general population, and by clinical characteristics. Cumulative heart disease mortality was estimated accounting for competing risks.<h4>Results</h4>SMRs were elevated for Black and Latina women treated with surgery only and chemotherapy with surgery (SMR range = 1.15-1.21) and AANHPI women treated with chemotherapy, radiotherapy, with surgery (SMR = 1.29; 95% confidence interval [CI] = 1.11 to 1.48), whereas SMRs were less than 1 for White women (SMR range = 0.70-0.96). SMRs were especially high for women with advanced (regional or distant) stage among Black women for all treatment (range = 1.15-2.89) and for AANHPI and Latina women treated with chemotherapy with surgery (range = 1.28-3.61). Non-White women diagnosed at younger than age 60 years had higher SMRs, as did Black and AANHPI women diagnosed with estrogen receptor-positive breast cancers. Black women had the highest 10-year cumulative risk of heart disease mortality: aged younger than 60 years (Black: 1.78%, 95% CI = 1.63% to 1.94%) compared with White, AANHPI, and Latina women (<1%) and aged 60 years and older (Black: 7.92%, 95% CI = 7.53% to 8.33%) compared with White, AANHPI, and Latina women (range = 3.90%-6.48%).<h4>Conclusions</h4>Our findings illuminated striking racial and ethnic disparities in heart disease mortality among Black, AANHPI, and Latina breast cancer survivors, especially after initial chemotherapy receipt.
Data sharing is essential for reproducibility of epidemiologic research, replication of findings, pooled analyses in consortia efforts, and maximizing study value to address multiple research questions. However, barriers related to confidentiality, costs, and incentives often limit the extent and speed of data sharing. Epidemiological practices that follow Findable, Accessible, Interoperable, Reusable (FAIR) principles can address these barriers by making data resources findable with the necessary metadata, accessible to authorized users, and interoperable with other data, to optimize the reuse of resources with appropriate credit to its creators. We provide an overview of these principles and describe approaches for implementation in epidemiology. Increasing degrees of FAIRness can be achieved by moving data and code from on-site locations to remote, accessible ("Cloud") data servers, using machine-readable and nonproprietary files, and developing open-source code. Adoption of these practices will improve daily work and collaborative analyses and facilitate compliance with data sharing policies from funders and scientific journals. Achieving a high degree of FAIRness will require funding, training, organizational support, recognition, and incentives for sharing research resources, both data and code. However, these costs are outweighed by the benefits of making research more reproducible, impactful, and equitable by facilitating the reuse of precious research resources by the scientific community.
<h4>Background</h4>Computed tomography (CT) scans make substantial contributions to low-dose ionizing radiation exposures, raising concerns about excess cancers caused by diagnostic radiation.<h4>Methods</h4>Deidentified medicare records for all Australians aged 0-19 years between 1985-2005 were linked to national death and cancer registrations to 2012. The National Cancer Institute CT program was used to estimate radiation doses to the brain from CT exposures in 1985-2005, Poisson regression was used to model the dependence of brain cancer incidence on brain radiation dose, which lagged by 2 years to minimize reverse causation bias.<h4>Results</h4>Of 10 524 842 young Australians, 611 544 were CT-exposed before the age of 20 years, with a mean cumulative brain dose of 44 milligrays (mGy) at an average follow-up of 13.5 years after the 2-year lag period. 4472 were diagnosed with brain cancer, of whom only 237 had been CT-exposed. Brain cancer incidence increased with radiation dose to the brain, with an excess relative risk of 0.8 (95% CI 0.57-1.06) per 100 mGy. Approximately 6391 (95% CI 5255, 8155) persons would need to be exposed to cause 1 extra brain cancer.<h4>Conclusions</h4>For brain tumors that follow CT exposures in childhood by more than 2 years, we estimate that 40% (95% CI 29%-50%) are attributable to CT Radiation and not due to reverse causation. However, because of relatively low rates of CT exposure in Australia, only 3.7% (95% CI 2.3%-5.4%) of all brain cancers are attributable to CT scans. The population-attributable fraction will be greater in countries with higher rates of pediatric scanning.
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Findings</h4>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.<h4>Interpretation</h4>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.<h4>Funding</h4>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.
On February 2, 2022, President Biden and First Lady Dr. Biden reignited the Cancer Moonshot, setting a new goal to reduce age-standardized cancer mortality rates by at least 50% over the next 25 years in the United States. We estimated trends in U.S. cancer mortality during 2000 to 2019 for all cancers and the six leading types (lung, colorectum, pancreas, breast, prostate, liver). Cancer death rates overall declined by 1.4% per year from 2000 to 2015, accelerating to 2.3% per year during 2016 to 2019, driven by strong declines in lung cancer mortality (-4.7%/year, 2014 to 2019). Recent declines in colorectal (-2.0%/year, 2010-2019) and breast cancer death rates (-1.2%/year, 2013-2019) also contributed. However, trends for other cancer types were less promising. To achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. We reviewed opportunities to prevent, detect, and treat these common cancers that could further reduce population-level cancer death rates and also reduce disparities.<h4>Significance</h4>We reviewed opportunities to prevent, detect, and treat common cancers, and show that to achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. See related commentary by Bertagnolli et al., p. 1049. This article is highlighted in the In This Issue feature, p. 1027.
<h4>Purpose</h4>The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need.<h4>Methods and materials</h4>We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks.<h4>Results</h4>For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s).<h4>Conclusions</h4>Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy.
<h4>Background</h4>Breast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking.<h4>Methods</h4>We identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis.<h4>Results</h4>Over a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62-1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37-1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65-6.33), soft tissue (SIR = 3.32, 95%CI = 2.51-4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82-3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18-3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89-5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31-1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01-1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17-4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78-0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01-8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38-0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers.<h4>Conclusions</h4>Elevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.
<h4>Background</h4>Starting in 2018, national death certificates included a new racial classification system that accounts for multiple-race decedents and separates Native Hawaiian and Pacific Islander (NHPI) individuals from Asian individuals. We estimated cancer death rates across updated racial and ethnic categories, sex, and age.<h4>Methods</h4>Age-standardized US cancer mortality rates and rate ratios from 2018 to 2020 among individuals aged 20 years and older were estimated with national death certificate data by race and ethnicity, sex, age, and cancer site.<h4>Results</h4>In 2018, there were approximately 597 000 cancer deaths, 598 000 in 2019, and 601 000 in 2020. Among men, cancer death rates were highest in Black men (298.2 per 100 000; n = 105 632), followed by White (250.8; n = 736 319), American Indian/Alaska Native (AI/AN; 249.2; n = 3376), NHPI (205.6; n = 1080), Latino (177.2; n = 66 167), and Asian (147.9; n = 26 591) men. Among women, Black women had the highest cancer death rates (206.5 per 100 000; n = 104 437), followed by NHPI (192.1; n = 1141), AI/AN (189.9; n = 3239), White (183.0; n = 646 865), Latina (128.4; n = 61 579), and Asian (111.4; n = 26 396) women. The highest death rates by age group occurred among NHPI individuals aged 20-49 years and Black individuals aged 50-69 and 70 years and older. Asian individuals had the lowest cancer death rates across age groups. Compared with Asian individuals, total cancer death rates were 39% higher in NHPI men and 73% higher in NHPI women.<h4>Conclusions</h4>There were striking racial and ethnic disparities in cancer death rates during 2018-2020. Separating NHPI and Asian individuals revealed large differences in cancer mortality between 2 groups that were previously combined in vital statistics data.
Forecasting methods are notoriously difficult to interpret, particularly when the relationship between the data and the resulting forecasts is not obvious. Interpretability is an important property of a forecasting method because it allows the user to complement the forecasts with their own knowledge, a process which leads to more applicable results. In general, mechanistic methods are more interpretable than non-mechanistic methods, but they require explicit knowledge of the underlying dynamics. In this paper, we introduce EpiForecast, a tool which performs interpretable, non-mechanistic forecasts using interactive visualization and a simple, data-focused forecasting technique based on empirical dynamic modelling. EpiForecast's primary feature is a four-plot interactive dashboard which displays a variety of information to help the user understand how the forecasts are generated. In addition to point forecasts, the tool produces distributional forecasts using a kernel density estimation method-these are visualized using color gradients to produce a quick, intuitive visual summary of the estimated future. To ensure the work is FAIR and privacy is ensured, we have released the tool as an entirely in-browser web-application.
<b>Motivation:</b> Epidemiological studies face two important challenges: the need to ingest ever more complex data types, and mounting concerns about participant privacy and data governance. These two challenges are compounded by the expectation that data infrastructure will eventually need to facilitate cross-registration of participants by multiple epidemiological studies. <b>Implementation:</b> The portable web-service epiDonate was developed using the serverless model known as FaaS (Function-as-a-Service). The reference implementation uses nodejs. The implementation relies on a simple tokenization scheme, mediated by a public API, that a) distinguishes admin from participant roles, with b) extensible permission configuration operating a read/write structure. <b>General Features:</b> The critical design feature of epiDonate is the absence of business logic on the server-side (the web service). The simplicity removes the need to customize virtual machines and enables ecosystems of multiple web Applications backed by one or more data donation deployments. <b>Availability:</b> https://episphere.github.io/donate.
<h4>Background</h4>Many high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear.<h4>Methods</h4>We conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted.<h4>Results</h4>Of 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0-5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59-2.85), CML (n = 61) = 1.77 (95% CI 0.38-4.50), and ALL (n = 71) = 6.65 (95% CI 2.79-14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards.<h4>Discussion</h4>We found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.
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.
<h4>Background</h4>Online questionnaires are commonly used to collect information from participants in epidemiological studies. This requires building questionnaires using machine-readable formats that can be delivered to study participants using web-based technologies such as progressive web applications. However, the paucity of open-source markup standards with support for complex logic make collaborative development of web-based questionnaire modules difficult. This often prevents interoperability and reusability of questionnaire modules across epidemiological studies.<h4>Results</h4>We developed an open-source markup language for presentation of questionnaire content and logic, Quest, within a real-time renderer that enables the user to test logic (e.g., skip patterns) and view the structure of data collection. We provide the Quest markup language, an in-browser markup rendering tool, questionnaire development tool and an example web application that embeds the renderer, developed for The Connect for Cancer Prevention Study.<h4>Conclusion</h4>A markup language can specify both the content and logic of a questionnaire as plain text. Questionnaire markup, such as Quest, can become a standard format for storing questionnaires or sharing questionnaires across the web. Quest is a step towards generation of FAIR data in epidemiological studies by facilitating reusability of questionnaires and data interoperability using open-source tools.
<h4>Background</h4>The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results.<h4>Methods</h4>Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs.<h4>Results</h4>During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10-11 years; HR, 1.28; 95% CI, 1.00-1.64), younger (<40; HR, 1.31; 95% CI, 1.05-1.62) and older (≥55; HR, 1.33; 95% CI, 1.05-1.68) ages at menopause (vs 40-44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02-1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13-1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00-1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76-0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70-0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles.<h4>Conclusions</h4>Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight.
<h4>Background</h4>It has been well-established that acute radiation exposures increase the risk of leukemia. However, it is still unknown whether these leukemia risk estimates could be extrapolated to occupational populations who receive repeated low-dose radiation exposure. The purpose of this study was to estimate quantified associations between low-dose radiation exposures and leukemia.<h4>Methods</h4>The Chinese medical X-ray worker study (CMXW) included 27,011 medical X-ray workers employed at major hospitals in 24 provinces in China from 1950 to 1980, and a control population of 25,782 physicians matched by hospital, who were unexposed to X-ray equipment. Poisson regression models were used to estimate the excess relative risk (ERR) and excess absolute risk (EAR) for the incidence of leukemia associated with cumulative doses. A meta-analysis of the published literature on low-dose occupational radiation exposure and leukemia risk was also conducted.<h4>Results</h4>The incidence rates of leukemia in X-ray workers and the control group were 6.70 and 3.39 per 100,000 person-years, respectively. Among X-ray workers, the average cumulative red bone marrow dose was 0.046 Gy. We found a positive relationship between 2-year lagged cumulative red bone marrow dose and risk of leukemia excluding chronic lymphocytic leukemia (CLL) (ERR = 0.66 per 100 mGy, 90% CI: 0.09, 1.53; EAR = 0.29 per 10<sup>4</sup> PY-100 mGy, 90% CI: 0.07, 0.56). The excess risk was largely driven by myeloid leukemia (ERR = 1.06 per 100 mGy, 90% CI: 0.22, 2.51). Based on the meta-analysis, the pooled ERR at 100 mGy was 0.19 (95% CI: 0.08, 0.31).<h4>Conclusion</h4>This study provides strong evidence of a positive and linear doseresponse relationship between cumulative red bone marrow dose and the incidence of non-CLL leukemia.
<h4>Background</h4>A high body mass index (BMI, kg/m<sup>2</sup>) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology.<h4>Methods</h4>We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy.<h4>Results</h4>The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO.<h4>Conclusion</h4>The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.
Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.
Breast cancer survivors have an increased risk of developing second primary cancers, yet risks by race and ethnicity have not been comprehensively described. We evaluated second primary cancer risks among 717,335 women diagnosed with first primary breast cancer (aged 20-84 years and survived ≥1-year) in the SEER registries using standardized incidence ratios (SIRs; observed/expected). SIRs were estimated by race and ethnicity compared with the racial- and ethnic-matched general population, and further stratified by clinical characteristics of the index breast cancer. Poisson regression was used to test for heterogeneity by race and ethnicity. SIRs for second primary cancer differed by race and ethnicity with the highest risks observed among non-Hispanic/Latina Asian American, Native Hawaiian, or other Pacific Islander (AANHPI), non-Hispanic/Latina Black (Black), and Hispanic/Latina (Latina) survivors and attenuated risk among non-Hispanic/Latina White (White) survivors (SIR<sub>AANHPI</sub> = 1.49, 95% CI = 1.44-1.54; SIR<sub>Black</sub> = 1.41, 95% CI = 1.37-1.45; SIR<sub>Latina</sub> = 1.45, 95% CI = 1.41-1.49; SIR<sub>White</sub> = 1.09, 95% CI = 1.08-1.10; p-heterogeneity<.001). SIRs were particularly elevated among AANHPI, Black, and Latina survivors diagnosed with an index breast cancer before age 50 (SIRs range = 1.88-2.19) or with estrogen receptor-negative tumors (SIRs range = 1.60-1.94). Heterogeneity by race and ethnicity was observed for 16/27 site-specific second cancers (all p-heterogeneity's < .05) with markedly elevated risks among AANHPI, Black, and Latina survivors for acute myeloid and acute non-lymphocytic leukemia (SIRs range = 2.68-3.15) and cancers of the contralateral breast (SIRs range = 2.60-3.01) and salivary gland (SIRs range = 2.03-3.96). We observed striking racial and ethnic differences in second cancer risk among breast cancer survivors. Additional research is needed to inform targeted approaches for early detection strategies and treatment to reduce these racial and ethnic disparities.
<h4>Background</h4>Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking.<h4>Methods</h4>We conducted a retrospective cohort study of 10 211 women diagnosed with first primary unilateral breast cancer in Kaiser Permanente Washington or Colorado (aged 20 years and older, survived ≥1 year). We estimated multivariable adjusted hazard ratios (HRs) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [referent]) and CVD risk, adjusted for patient characteristics, other treatments, and CVD risk factors. Cumulative incidence was calculated considering competing events.<h4>Results</h4>After 5.79 median years, 14.67% of women developed CVD (cardiomyopathy and/or heart failure [HF], ischemic heart disease, stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (adjusted HR = 1.53, 95% confidence interval [CI] = 1.31 to 1.79), persisting at least 5 years postdiagnosis (adjusted HR5-<10 years = 1.85, 95% CI = 1.44 to 2.39; adjusted HR≥10 years = 1.83, 95% CI = 1.34 to 2.49). Cardiomyopathy and/or HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for those aged younger than 65 years (adjusted HR20-54years = 2.97, 95% CI = 1.72 to 5.12; adjusted HR55-64years = 2.21, 95% CI = 1.52 to 3.21), differing for older women (adjusted HR≥65 years = 1.32, 95% CI = 0.97 to 1.78), and at least 5 years postdiagnosis (adjusted HR5-<10years = 1.89, 95% CI = 1.35 to 2.64; adjusted HR≥10 years = 2.21, 95% CI = 1.52 to 3.20). Anthracyclines and/or trastuzumab receipt was associated with increased ischemic heart disease risks after 5 or more years (adjusted HR5-<10years = 1.51, 95% CI = 1.06 to 2.14; adjusted HR≥10 years = 1.86, 95% CI = 1.18 to 2.93) with no clear age effects, and stroke risk (adjusted HR = 1.33, 95% CI = 1.05 to 1.69), which did not vary by time or age. There was some evidence of long-term cardiomyopathy and/or HF and ischemic heart disease risks with other chemotherapies. Among women aged younger than 65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10 years (20-54 years = 6.91%; 55-64 years = 16.00%), driven by cardiomyopathy and/or HF (20-54 years = 3.90%; 55-64 years = 9.78%).<h4>Conclusions</h4>We found increased long-term risks of cardiomyopathy and/or HF and ischemic heart disease among breast cancer survivors treated with anthracyclines and/or trastuzumab and increased cardiomyopathy and/or HF risk among women aged younger than 65 years.
<h4>Purpose</h4>Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR).<h4>Methods</h4>We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status.<h4>Results</h4>Genetically predicted BMI was positively associated with non-dense area (IVW: β = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10<sup>-63</sup>) and inversely associated with dense area (IVW: β = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10<sup>-7</sup>). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (β = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (β = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches.<h4>Conclusion</h4>Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.
Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m<sup>-</sup><sup>2</sup>: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m<sup>-2</sup> cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m<sup>-</sup><sup>2</sup>, HR: 2.33 for 300-399 mg m<sup>-</sup><sup>2</sup> and HR: 2.78 for ≥400 mg m<sup>-</sup><sup>2</sup>). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m<sup>-</sup><sup>2</sup> of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m<sup>-</sup><sup>2</sup> cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.
<h4>Background</h4>It is important to understand the impact of the COVID-19 pandemic on cancer death rates in 2020 in the US. We estimated whether there were larger-than-expected changes in cancer mortality rates from March to December 2020 after accounting for temporal and seasonal patterns using data from January 2011 to February 2020 by cancer type and age.<h4>Methods</h4>We obtained death counts and underlying causes of death by cancer type, month/year (2011-2020), and age group from the National Center for Health Statistics and population estimates from the US Census Bureau. Poisson regression was used to test for significant changes in cancer death rates from March to December 2020 compared with prior years.<h4>Results</h4>After accounting for temporal trends and seasonal patterns, total cancer death rates were significantly lower than expected during March to December 2020 among 55- to 64-year-olds and ≥75-year-olds, but not in other age groups. Cancer death rates were 2% lower than expected from March to June among 55- to 64-year-olds and 2% to 3% lower from March to July and December among ≥75-year-olds. Among ≥75-year-olds, colorectal cancer death rates were lower from March to June [rate ratios (RR) = 0.94-0.96; P < 0.05]; however, lung cancer death rates were 5% lower across each month (all RRs = 0.95; P < 0.05).<h4>Conclusions</h4>In the US, cancer death rates based on the underlying cause of death were broadly similar to expected rates from March to December 2020. However, cancer death rates were lower than expected among 55- to 64-year-olds and ≥75-year-olds, likely due to COVID-19 as a competing cause of death.<h4>Impact</h4>Cancer mortality rates from 2020 should be interpreted with caution.
Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (<sup>131</sup>I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.
<h4>Background</h4>Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk.<h4>Methods</h4>Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use.<h4>Findings</h4>During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005).<h4>Interpretation</h4>The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.<h4>Funding</h4>Medical Research Council, Cancer Research UK.
<h4>Background</h4>Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors.<h4>Methods</h4>Individual participant datasets were sought from principal investigators and provided centrally for 27 276 women with endometrial cancer (cases) and 115 743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy.<h4>Findings</h4>The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27 276 cases and 45 625 (39%) of 115 743 controls had ever used oral contraceptives, for median durations of 3·0 years (IQR 1-7) and 4·4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0·76 (95% CI 0·73-0·78; p<0·0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased, with no apparent decrease between the RRs for use during the 1960s, 1970s, and 1980s, despite higher oestrogen doses in pills used in the early years. However, the reduction in risk associated with ever having used oral contraceptives differed by tumour type, being stronger for carcinomas (RR 0·69, 95% CI 0·66-0·71) than sarcomas (0·83, 0·67-1·04; case-case comparison: p=0·02). In high-income countries, 10 years use of oral contraceptives was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2·3 to 1·3 per 100 women.<h4>Interpretation</h4>Use of oral contraceptives confers long-term protection against endometrial cancer. These results suggest that, in developed countries, about 400 000 cases of endometrial cancer before the age of 75 years have been prevented over the past 50 years (1965-2014) by oral contraceptives, including 200 000 in the past decade (2005-14).<h4>Funding</h4>Medical Research Council, Cancer Research UK.
<h4>Background</h4>Postmenopausal women who use hormone-replacement therapy (HRT) containing oestrogen alone are at increased risk of endometrial cancer. To minimise this risk, many HRT users who have not had a hysterectomy use combined oestrogen-progestagen preparations or tibolone. Limited information is available on the incidence of endometrial cancer in users of these therapies.<h4>Methods</h4>716,738 postmenopausal women in the UK without previous cancer or previous hysterectomy were recruited into the Million Women Study in 1996-2001, provided information about their use of HRT and other personal details, and were followed up for an average of 3.4 years, during which time 1320 incident endometrial cancers were diagnosed.<h4>Findings</h4>320,953 women (45%) reported at recruitment that they had used HRT, among whom 69,577 (22%) last used continuous combined therapy (progestagen added daily to oestrogen), 145,486 (45%) last used cyclic combined therapy (progestagen added to oestrogen, usually for 10-14 days per month), 28,028 (9%) last used tibolone, and 14,204 (4%) last used oestrogen-only HRT. These HRT types had sharply contrasting effects on the overall risk of endometrial cancer (p<0.0001 for heterogeneity). Compared with never users of HRT, risk was: reduced with last use of continuous combined preparations (relative risk 0.71 [95% CI 0.56-0.90]; p=0.005); increased with last use of tibolone (1.79 [1.43-2.25]; p<0.0001) and oestrogen only (1.45 [1.02-2.06]; p=0.04); and not significantly altered with last use of cyclic combined preparations (1.05 [0.91-1.22]; p=0.5). A woman's body-mass index significantly affected these associations, such that the adverse effects of tibolone and oestrogen-only HRT were greatest in non-obese women, and the beneficial effects of combined HRT were greatest in obese women.<h4>Interpretation</h4>Oestrogens and tibolone increase the risk of endometrial cancer. Progestagens counteract the adverse effect of oestrogens on the endometrium, the effect being greater the more days every month that they are added to oestrogen and the more obese that women are. However, combined oestrogen-progestagen HRT causes a greater increase in breast cancer than the other therapies do. Thus, when endometrial and breast cancers are added together, there is a greater increase in total cancer incidence with use of combined HRT, both continuous and cyclic, than with use of the other therapies.
Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.
<h4>Purpose</h4>Trials demonstrating benefits of tamoxifen for women with ductal carcinoma in situ (DCIS) were published > 20 years ago; yet subsequent uptake of endocrine therapy was low. We estimated endocrine therapy initiation in women with DCIS between 2001 and 2018 in a community setting, reflecting more recent years of diagnosis than previous studies.<h4>Methods</h4>This retrospective cohort included adult females ≥ 20 years diagnosed with first primary DCIS between 2001 and 2018, followed through 2019, and enrolled in one of three U.S. integrated healthcare systems. We collected data on endocrine therapy dispensings (tamoxifen, aromatase inhibitors [AIs]) from electronic pharmacy records within 12 months after DCIS diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated endocrine therapy initiation rates over time and by patient, tumor (including estrogen receptor [ER] status), and treatment characteristics.<h4>Results</h4>Among 2020 women with DCIS, 587 (29%) initiated endocrine therapy within 12 months after diagnosis (36% among 1208 women with ER-positive DCIS). Among women who used endocrine therapy, 506 (86%) initiated tamoxifen and 81 (14%) initiated AIs. Age-adjusted endocrine therapy initiation declined from 34 to 21% between 2001 and 2017; between 2015 and 2018, AI use increased from 8 to 35%. Women less likely to initiate endocrine therapy were ER-negative or had borderline/unknown or no ER test results, ≥ 65 years at diagnosis, Black, and received no radiotherapy.<h4>Conclusion</h4>One-third of women diagnosed with DCIS initiated endocrine therapy, and use decreased over time. Understanding why women eligible for endocrine therapy do not initiate is important to maximizing disease-free survival following DCIS diagnosis.
In this article we review the history of key epidemiological studies of populations exposed to ionizing radiation. We highlight historical and recent findings regarding radiation-associated risks for incidence and mortality of cancer and non-cancer outcomes with emphasis on study design and methods of exposure assessment and dose estimation along with brief consideration of sources of bias for a few of the more important studies. We examine the findings from the epidemiological studies of the Japanese atomic bomb survivors, persons exposed to radiation for diagnostic or therapeutic purposes, those exposed to environmental sources including Chornobyl and other reactor accidents, and occupationally exposed cohorts. We also summarize results of pooled studies. These summaries are necessarily brief, but we provide references to more detailed information. We discuss possible future directions of study, to include assessment of susceptible populations, and possible new populations, data sources, study designs and methods of analysis.