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PURPOSE Survivors of hereditary retinoblastoma have excellent survival but substantially increased risks of subsequent bone and soft-tissue sarcomas, particularly after radiotherapy. Comprehensive investigation of sarcoma risk patterns would inform clinical surveillance for survivors. PATIENTS AND METHODS In a cohort of 952 irradiated survivors of hereditary retinoblastoma who were originally diagnosed during 1914 to 2006, we quantified sarcoma risk with standardized incidence ratios (SIRs) and cumulative incidence analyses. We conducted analyses separately for bone and soft-tissue sarcomas occurring in the head and neck (in/near the radiotherapy field) versus body and extremities (out of field). RESULTS Of 105 bone and 124 soft-tissue sarcomas, more than one half occurred in the head and neck (bone, 53.3%; soft tissue, 51.6%), one quarter in the body and extremities (bone, 29.5%; soft tissue, 25.0%), and approximately one fifth in unknown/unspecified locations (bone, 17.1%; soft tissue, 23.4%). We noted substantially higher risks compared with the general population for head and neck versus body and extremity tumors for both bone (SIR, 2,213; 95% CI, 1,671 to 2,873 v SIR, 169; 95% CI, 115 to 239) and soft-tissue sarcomas (SIR, 542; 95% CI, 418 to 692 v SIR, 45.7; 95% CI, 31.1 to 64.9). Head and neck bone and soft-tissue sarcomas were diagnosed beginning in early childhood and continued well into adulthood, reaching a 60-year cumulative incidence of 6.8% (95% CI, 5.0% to 8.7%) and 9.3% (95% CI, 7.0% to 11.7%), respectively. In contrast, body and extremity bone sarcoma incidence flattened after adolescence (3.5%; 95% CI, 2.3% to 4.8%), whereas body and extremity soft-tissue sarcoma incidence was rare until age 30, when incidence rose steeply (60-year cumulative incidence, 6.6%; 95% CI, 4.1% to 9.2%), particularly for females (9.4%; 95% CI, 5.1% to 13.8%). CONCLUSION Strikingly elevated bone and soft-tissue sarcoma risks differ by age, location, and sex, highlighting important contributions of both radiotherapy and genetic susceptibility. These data provide guidance for the development of a risk-based screening protocol that focuses on the highest sarcoma risks by age, location, and sex.

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. © RSNA, 2017 Online supplemental material is available for this article.

Purpose To investigate the relationship between oesophagus dose-volume distribution and long-term risk of oesophageal cancer after radiation therapy for breast cancer. Materials and methods 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 (DSPC) 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 DSPC-related -risk estimates. Results Among the DVH metrics evaluated, median dose (Dmedian) 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 Dmedian 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 DSPC, but there was a borderline significant positive interaction between DSPC and V30 (p = 0.07). Conclusion This first study investigating the relationship between oesophagus dose-volume distribution and oesophageal cancer risk showed an increased risk per Gy for Dmedian with larger volumes irradiated at high doses. While current techniques allows better oesophagus sparing, constraints applied to Dmedian and V30 could potentially further reduce the risk of oesophageal cancer.

ObjectivesTo assess radiation exposure-related work history and risk of cataract and cataract surgery among radiologic technologists assisting with fluoroscopically guided interventional procedures (FGIP).MethodsThis retrospective study included 35 751 radiologic technologists who reported being cataract-free at baseline (1994–1998) and completed a follow-up questionnaire (2013–2014). Frequencies of assisting with 21 types of FGIP and use of radiation protection equipment during five time periods (before 1970, 1970–1979, 1980–1989, 1990–1999, 2000–2009) were derived from an additional self-administered questionnaire in 2013–2014. Multivariable-adjusted relative risks (RRs) for self-reported cataract diagnosis and cataract surgery were estimated according to FGIP work history.ResultsDuring follow-up, 9372 technologists reported incident physician-diagnosed cataract; 4278 of incident cases reported undergoing cataract surgery. Technologists who ever assisted with FGIP had increased risk for cataract compared with those who never assisted with FGIP (RR: 1.18, 95% CI 1.11 to 1.25). Risk increased with increasing cumulative number of FGIP; the RR for technologists who assisted with >5000 FGIP compared with those who never assisted was 1.38 (95% CI 1.24 to 1.53; p trend 3 feet (>0.9 m) (RRs for >5000 at ≤3 feet vs never FGIP were 1.48, 95% CI 1.27 to 1.74 and 1.15, 95% CI 0.98 to 1.35, respectively; pdifference=0.04). Similar risks, although not statistically significant, were observed for cataract surgery.ConclusionTechnologists who reported assisting with FGIP, particularly high-volume FGIP within 3 feet of the patient, had increased risk of incident cataract. Additional investigation should evaluate estimated dose response and medically validated cataract type.

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.

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents.We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls.Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide.Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Purpose To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS). Methods and Materials Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology, and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking, and alcohol consumption. Results During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR = 39.4; 95% CI = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking, or alcohol intake. Conclusion Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.

The Chernobyl accident, which occurred April 26, 1986, resulted in a large release of radionuclides, which were deposited over a very wide area, particularly in Europe. Although an increased risk of thyroid cancer in exposed children has been clearly demonstrated in the most contaminated regions, the impact of the accident on the risk of other cancers as well as elsewhere in Europe is less clear. The objective of the present study was to evaluate the human cancer burden in Europe as a whole from radioactive fallout from the accident. Average country- and region-specific whole-body and thyroid doses from Chernobyl were estimated using new dosimetric models and radiological data. Numbers of cancer cases and deaths possibly attributable to radiation from Chernobyl were estimated, applying state-of-the-art risk models derived from studies of other irradiated populations. Simultaneously, trends in cancer incidence and mortality were examined over time and by dose level. The risk projections suggest that by now Chernobyl may have caused about 1,000 cases of thyroid cancer and 4,000 cases of other cancers in Europe, representing about 0.01% of all incident cancers since the accident. Models predict that by 2065 about 16,000 (95% UI 3,400-72,000) cases of thyroid cancer and 25,000 (95% UI 11,000-59,000) cases of other cancers may be expected due to radiation from the accident, whereas several hundred million cancer cases are expected from other causes. Although these estimates are subject to considerable uncertainty, they provide an indication of the order of magnitude of the possible impact of the Chernobyl accident. It is unlikely that the cancer burden from the largest radiological accident to date could be detected by monitoring national cancer statistics. Indeed, results of analyses of time trends in cancer incidence and mortality in Europe do not, at present, indicate any increase in cancer rates -- other than of thyroid cancer in the most contaminated regions -- that can be clearly attributed to radiation from the Chernobyl accident.

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.

Exposure to radioactive iodine ((131)I) from atmospheric nuclear tests conducted in Nevada in the 1950s may have increased thyroid cancer risks. To investigate the long-term effects of this exposure, we analyzed data on thyroid cancer incidence (18,545 cases) from eight Surveillance, Epidemiology, and End Results (SEER) tumor registries for the period 1973-2004. Excess relative risks (ERR) per gray (Gy) for exposure received before age 15 were estimated by relating age-, birth year-, sex- and county-specific thyroid cancer rates to estimates of cumulative dose to the thyroid that take age into account. The estimated ERR per Gy for dose received before 1 year of age was 1.8 [95% confidence interval (CI), 0.5-3.2]. There was no evidence that this estimate declined with follow-up time or that risk increased with dose received at ages 1-15. These results confirm earlier findings based on less extensive data for the period 1973-1994. The lack of a dose response for those exposed at ages 1-15 is inconsistent with studies of children exposed to external radiation or (131)I from the Chernobyl accident, and results need to be interpreted in light of limitations and biases inherent in ecological studies, including the error in doses and case ascertainment resulting from migration. Nevertheless, the study adds support for an increased risk of thyroid cancer due to fallout, although the data are inadequate to quantify it.

Background: Adjuvant radiotherapy is common for uterine corpus cancer patients, yet the long-term carcinogenic effects of different types of radiotherapy have not been studied adequately. Methods: Second primary cancer risks were quantified in a cohort of 60,949 individuals surviving ≥1 year of uterine corpus cancer diagnosed from 1973 to 2003 in Surveillance, Epidemiology and End Results Program cancer registries. Incidence rate ratios (IRR) were estimated by comparing patients treated with surgery plus various types of radiotherapy with patients receiving surgery only. Results: The IRRs of a second cancer were increased among irradiated patients compared with patients having surgery only [combination radiotherapy, IRR = 1.26; 95% confidence interval (CI), 1.16-1.36; external beam therapy, IRR = 1.15; 95% CI CI, 1.08-1.22; brachytherapy, IRR = 1.07; 95% CI, 1.00-1.16]. IRRs were highest for heavily irradiated sites (that is colon, rectum, and bladder) and for leukemia following any external beam therapy, with the largest risks for solid cancers among 10-year survivors. Any external beam therapy had a 44% higher cancer risk at heavily irradiated sites than brachytherapy when the two treatments were directly compared (5-year survivors: IRR = 1.44; 95% CI, 1.19-1.75). We estimated that of 2,012 solid cancers developing ≥5 years after irradiation, 213 (11%) could be explained by radiotherapy. Conclusions: Radiotherapy for uterine cancer increases the risk of leukemia and second solid cancers at sites in close proximity to the uterus, emphasizing the need for continued long-term surveillance for new malignancies. The overall risk of a second cancer was lower following brachytherapy compared with any external beam radiotherapy. Cancer Epidemiol Biomarkers Prev; 19(2); 464–74

Purpose Hodgkin's lymphoma (HL) survivors are known to be at substantially increased risk of solid cancers (SC). However, no investigation has used multivariate modeling to estimate the relative risk (RR), excess absolute risk (EAR), and cumulative incidence for specific attained ages and ages at HL diagnosis. Patients and Methods We identified 18,862 5-year HL survivors from 13 population-based cancer registries in North America and Europe. Poisson regression was used to evaluate the effects of age at diagnosis, attained age, latency, sex, treatment, and year of diagnosis on the RR and EAR of SC. Results Among 1,490 identified SC, 850 were estimated to be in excess. For most cancer sites, both RR and EAR decreased with age at HL diagnosis and showed strong dependencies on attained age. For a patient diagnosed at age 30 years and survived to ≥ 40 years, modeled risks were significantly elevated for cancers of the breast (RR = 6.1), other supradiaphragmatic sites (RR = 6.0), and infradiaphragmatic sites (RR = 3.7); the largest RR (20-fold) was observed for malignant mesothelioma. Thirty-year cumulative risks of SC for men and women diagnosed at 30 years were 18% and 26%, respectively, compared with 7% and 9%, respectively, in the general population. For young HL patients, risks of breast and colorectal cancers were elevated 10 to 25 years before the age when routine screening would be recommended in the general population. Conclusion Multivariable modeling demonstrates for the first time temporal changes in SC risk not evident in unadjusted analyses, and can facilitate the development of individualized risk assessment and the creation of screening strategies for early detection.

To provide direct estimates of cancer risk after low-dose protracted exposure to ionizing radiation, a large-scale epidemiological study of nuclear industry workers was conducted in 15 countries. As part of this study, identification and quantification of errors in historical recorded doses was conducted based on a review of dosimetric practices and technologies in participating facilities. The main sources of errors on doses from "high-energy" photons (100-3000 keV) were identified as the response of dosimeters in workplace exposure conditions and historical calibration practices. Errors related to dosimetry technology and radiation fields were quantified to derive period- and facility-specific estimates of bias and uncertainties in recorded doses. This was based on (1) an evaluation of predominant workplace radiation from measurement studies and dosimetry expert assessment and (2) an estimation of the energy and geometry response of dosimeters used historically in study facilities. Coefficients were derived to convert recorded doses to H(p) (10) and organ dose, taking into account different aspects of the calibration procedures. A parametric, lognormal error structure model was developed to describe errors in doses as a function of facility and time period. Doses from other radiation types, particularly neutrons and radionuclide intake, could not be adequately reconstructed in the framework of the 15-Country Study. Workers with substantial doses from these radiation types were therefore identified and excluded from analyses. Doses from "lower-energy" photons (100 keV) and from "higher-energy" photons (3 MeV) were estimated to be small.

Radiation effects on mortality from solid cancers other than lung, liver, and bone cancer in the Mayak worker cohort: 1948–2008. The cohort of Mayak Production Association (PA) workers in Russia offers a unique opportunity to study the effects of prolonged low dose rate external gamma exposures and exposure to plutonium in a working age population. We examined radiation effects on the risk of mortality from solid cancers excluding sites of primary plutonium deposition (lung, liver, and bone surface) among 25,757 workers who were first employed in 1948–1982. During the period 1948–2008, there were 1,825 deaths from cancers other than lung, liver and bone. Using colon dose as a representative external dose, a linear dose response model described the data well. The excess relative risk per Gray for external gamma exposure was 0.16 (95% CI: 0.07 – 0.26) when unadjusted for plutonium exposure and 0.12 (95% CI 0.03 – 0.21) when adjusted for plutonium dose and monitoring status. There was no significant effect modification by sex or attained age. Plutonium exposure was not significantly associated with the group of cancers analyzed after adjusting for monitoring status. Site-specific risks were uncertainly estimated but positive for 13 of the 15 sites evaluated with a statistically significant estimate only for esophageal cancer. Comparison with estimates based on the acute exposures in atomic bomb survivors suggests that the excess relative risk per Gray for prolonged external exposure in Mayak workers may be lower than that for acute exposure but, given the uncertainties, the possibility of equal effects cannot be dismissed.

Many women develop breast cancer after treatment for Hodgkin lymphoma (HL) at a young age. We estimated this future risk, taking into account age and calendar year of HL diagnosis, HL treatment information, population breast cancer incidence rates, and competing causes of death.Relative risks of breast cancer for categories defined by radiation dose to the chest (0, 20-40 Gy, oror = 40 Gy) and use of alkylating agents (yes or no) were estimated from a case-control study conducted within an international population-based cohort of 3817 female 1-year survivors of HL diagnosed at age 30 years or younger from January 1, 1965, through December 31, 1994. To compute cumulative absolute risks of breast cancer, we used modified standardized incidence ratios to relate cohort breast cancer risks to those in the general population, enabling application of population-based breast cancer rates, and we allowed for competing risks by using population-based mortality rates in female HL survivors.Cumulative absolute risks of breast cancer increased with age at end of follow-up, time since HL diagnosis, and radiation dose. For an HL survivor who was treated at age 25 years with a chest radiation dose of at least 40 Gy without alkylating agents, estimated cumulative absolute risks of breast cancer by age 35, 45, and 55 years were 1.4% (95% confidence interval [CI] = 0.9% to 2.1%), 11.1% (95% CI = 7.4% to 16.3%), and 29.0% (95% CI = 20.2% to 40.1%), respectively. Cumulative absolute risks were lower in women treated with alkylating agents.Breast cancer projections varied considerably by type of HL therapy, time since HL diagnosis, and age at end of follow-up. These estimates are applicable to HL survivors treated with regimens of the past and can be used to counsel such patients and plan management and preventive strategies. Projections should be used with caution, however, in patients treated with more recent approaches, including limited-field radiotherapy and/or ovary-sparing chemotherapy.

ContextSecond cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk.ObjectiveTo quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.Design, Setting, and SubjectsMatched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998.Main Outcome MeasuresRelative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents.ResultsBreast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P

Aspects of radiation-induced lung cancer were evaluated in an international study of Hodgkin's disease. The study population consisted of 227 patients with lung cancer and 455 matched controls. Unique features included dose determinations to the specific location in the lung where each cancer developed and quantitative data on both chemotherapy and tobacco use obtained from medical records. The estimated excess relative risk (ERR) per Gy was 0.15 (95% CI: 0.06-0.39), and there was little evidence of departure from linearity even though lung doses for the majority of Hodgkin's disease patients treated with radiotherapy exceeded 30 Gy. The interaction of radiation and chemotherapy that included alkylating agents was almost exactly additive, and a multiplicative relationship could be rejected (P = 0.017). Conversely, the interaction of radiation and smoking was consistent with a multiplicative relationship, but not with an additive relationship (P < 0.001). The ERR/Gy for males was about four times that for females, although the difference was not statistically significant. There was little evidence of modification of the ERR/Gy by time since exposure (after a 5-year minimum latent period), age at exposure, or attained age. Because of the very high radiation doses received by Hodgkin's disease patients and the immunodeficiency inherent to this lymphoma and that associated with chemotherapy, generalizing these findings to other populations receiving considerably lower doses of radiation should be done cautiously.

Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI = 1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI = 1.2, 2.3) and diseases of blood forming organs (RR = ∞, 95% CI = 3.4, ∞). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95%CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95%CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders.

Background: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose–response relationship are sparse. Methods: In a cohort of 22 269 5-year TC survivors diagnosed during 1959–1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. Results: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7–20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend

Therapy-related acute myeloid leukemia (tAML) is a rare but highly fatal complication of cytotoxic chemotherapy. Despite major changes in cancer treatment, data describing tAML risks over time are sparse. Among 426 068 adults initially treated with chemotherapy for first primary malignancy (9 US population-based cancer registries, 1975-2008), we identified 801 tAML cases, 4.70 times more than expected in the general population (P < .001). Over time, tAML risks increased after chemotherapy for non-Hodgkin lymphoma (n = 158; Poisson regression Ptrend < .001), declined for ovarian cancer (n = 72; Ptrend < .001), myeloma (n = 62; Ptrend = .02), and possibly lung cancer (n = 65; Ptrend = .18), and were significantly heterogeneous for breast cancer (n = 223; Phomogeneity = .005) and Hodgkin lymphoma (n = 58; Phomogeneity = .007). tAML risks varied significantly by age at first cancer and latency and were nonsignificantly heightened with radiotherapy for lung, breast, and ovarian cancers. We identified newly emerging elevated tAML risks in patients treated with chemotherapy since 2000 for esophageal, cervical, prostate, and possibly anal cancers; and since the 1990s for bone/joint and endometrial cancers. Using long-term, population-based data, we observed significant variation in tAML risk with time, consistent with changing treatment practices and differential leukemogenicity of specific therapies. tAML risks should be weighed against the benefits of chemotherapy, particularly for new agents and new indications for standard agents.

Although dose estimates used in epidemiologic studies of nuclear workers are far superior to exposure measures used in many epidemiologic studies, they are subject to several types of bias. These include bias resulting from practices used to measure and record very low doses and from underestimation of dose from neutrons. They also include bias resulting because available dose estimates do not include dose from internally deposited radionuclides, occupational dose received after workers have terminated employment at the facility of interest, or dose from background or medical exposures. These biases can potentially distort dose-response analyses and lead to biased risk estimates and confidence limits. This paper uses data on workers at the Hanford site to investigate the possible effects of these biases on dose-response analyses of leukemia and of all cancer except leukemia. This is accomplished by conducting analyses based on a variety of assumptions regarding the nature and magnitude of these biases. Results were not modified greatly (as compared to those based on the dose as recorded) for any of the 40 sensitivity analyses presented, including some based on fairly extreme assumptions. However, analyses that excluded workers with potential for dose from internal depositions and from neutrons did increase both the risk estimate and upper confidence limits; it may be desirable to emphasize this approach in future presentations. It is recommended that similar sensitivity analyses be performed with data from other worker studies, addressing the specific dosimetry problems that have been identified in those populations.

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

Purpose To assess the dose–response relationship for stomach cancer after radiation therapy for cervical cancer. Methods and Materials We conducted a nested, matched case–control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943 to 1995, from 5 international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 Gy, range 0.03-46.1 and after parallel opposed pelvic fields, 1.63 Gy, range 0.12-6.3). Results More than 90% of women received radiation therapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was nonsignificantly increased (odds ratio 1.27-2.28) for women receiving between 0.5 and 4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (odds ratio 4.20, 95% confidence interval 1.41-13.4, P trend =.047) compared with nonirradiated women. A highly significant radiation dose–response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach ( P trend =.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach ( P trend =.23). Conclusions Our findings show for the first time a significant linear dose–response relationship for risk of stomach cancer in long-term survivors of cervical cancer.

Little is known about long-term cancer risks following in utero radiation exposure. We evaluated the association between in utero radiation exposure and risk of solid cancer and leukemia mortality among 8,000 offspring, born from 1948–1988, of female workers at the Mayak Nuclear Facility in Ozyorsk, Russia. Mother’s cumulative gamma radiation uterine dose during pregnancy served as a surrogate for fetal dose. We used Poisson regression methods to estimate relative risks (RRs) and 95% confidence intervals (CIs) of solid cancer and leukemia mortality associated with in utero radiation exposure and to quantify excess relative risks (ERRs) as a function of dose. Using currently available dosimetry information, 3,226 (40%) offspring were exposed in utero (mean dose = 54.5 mGy). Based on 75 deaths from solid cancers (28 exposed) and 12 (6 exposed) deaths from leukemia, in utero exposure status was not significantly associated with solid cancer: RR = 0.94, 95% CI 0.58 to 1.49; ERR/Gy = −0.1 (95% CI < −0.1 to 4.1), or leukemia mortality; RR = 1.65, 95% CI 0.52 to 5.27; ERR/Gy = −0.8 (95% CI < −0.8 to 46.9). These initial results provide no evidence that low-dose gamma in utero radiation exposure increases solid cancer or leukemia mortality risk, but the data are not inconsistent with such an increase. As the offspring cohort is relatively young, subsequent analyses based on larger case numbers are expected to provide more precise estimates of adult cancer mortality risk following in utero exposure to ionizing radiation.

Background: Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use. Design: Nested case–control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records. Results: The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (Ptrend< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7–28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2–0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking). Conclusions: Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

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.

Studies of Mayak workers and people who lived along the Techa River have demonstrated significant associations between low-dose-rate radiation exposure and increased solid cancer risk. It is of interest to use the long-term follow-up data from these cohorts to describe radiation effects for specific types of cancer; however, statistical variability in the site-specific risk estimates is large. The goal of this work is to describe this variability and provide Bayesian adjusted risk estimates. We assume that the site-specific estimates can be viewed as a sample from some underlying distribution and use Bayesian methods to produce adjusted excess relative risk per gray estimates in the Mayak and Techa River cohorts. The impact of the adjustment is compared to that seen in similar analyses in the atomic bomb survivors. Site-specific risk estimates in the Mayak and Techa River cohorts have large uncertainties. Unadjusted estimates vary from implausibly large decreases to large increases, with a range that greatly exceeds that found in the A-bomb survivors. The Bayesian adjustment markedly reduced the range of the site-specific estimates for the Techa River and Mayak studies. The extreme variability in the site-specific risk estimates is largely a consequence of the small number of excess cases. The adjusted estimates provide a useful perspective on variation in the actual risks. However, additional work on interpretation of the adjusted estimates, extension of the methods used in describing effect modification, and making more use of prior knowledge is needed to make these methods useful.

Development of a second malignancy is one of the most serious late effects in survivors of both childhood and adult-onset cancers. Patterns of second malignancy risk across the age spectrum can differ in terms of the types of second malignancies observed, magnitude of the risks, the latency period, associated risk factors, and modifying influences. Potential explanations for the varying risk patterns by age include differences in susceptibility of individual tissue/organ to carcinogenesis based on stage of development and level of tissue maturity, microenvironment, attained age, and lifestyle factors. A thorough understanding of these differences is essential when considering treatment modifications in newly diagnosed cancer patients that are aimed at reducing the risk of second malignancy and other late effects without compromising cure. Moreover, an understanding of the variations in second cancer risk according to age at treatment is important in customizing patient follow-up.

Substantial improvements in breast cancer treatment and screening signify that nearly 90% of women diagnosed with breast cancer survive for >5 years (Berry et al, 2005; Ries et al, 2008). Currently, an estimated 2.5 million breast cancer survivors live in the United States (Ries et al, 2008), and the long-term health of these women is an important public health issue. A recent descriptive analysis of Surveillance Epidemiology and End Results Program (SEER) cancer registries found that breast cancer survivors have an 18% higher risk of developing a subsequent cancer compared with the general population (Curtis et al, 2006). Shared environmental and genetic factors are likely to be involved, but some of the increased risk is probably a late adverse effect from the cancer treatments such as radiotherapy (Clarke et al, 2005). Randomised trials and cancer registry-based studies have shown that radiotherapy significantly reduces the risk of recurrence and breast cancer mortality, and also increases the risk of second cancers of the lung, oesophagus, soft tissue, contralateral breast and leukaemia (Huang and Mackillop, 2001; Gao et al, 2003; Zablotska and Neugut, 2003; Clarke et al, 2005; Zablotska et al, 2005). Surveillance Epidemiology and End Results Program registries cover the largest population of any national cancer registries and contain information on radiotherapy treatment, tumour characteristics and have long-term follow-up. In this study, we performed the first systematic evaluation of all second solid cancer risks after radiotherapy treatment for invasive breast cancer in the United States using the SEER databases. The large sample size and long-term follow-up enabled evaluation of patterns of effect modification, estimation of the number of excess cases and the proportion of second solid cancers occurring among breast cancer survivors that might be attributable to radiotherapy.

We evaluated 26 901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21 686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial.

Purpose Although cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) are both caused by human papillomavirus (HPV) infection, they differ in cofactors such as cigarette smoking. We assessed whether these cofactor differences translate into differences in second cancer risk. Patients and Methods We assessed second cancer risk among 85,109 cervical SCC and 10,280 AC survivors reported to population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Risks compared to the general population were assessed using standardized incidence ratios (SIR). Results Overall cancer risk was significantly increased among both cervical SCC survivors (n = 10,559 second cancers; SIR, 1.31; 95% CI, 1.29 to 1.34) and AC survivors (n = 920 second cancers; SIR, 1.29; 95% CI, 1.22 to 1.38). Risks of HPV-related and radiation-related cancers were increased to a similar extent among cervical SCC and AC survivors. Although significantly increased in both groups when compared with the general population, risk of smoking-related cancers was significantly higher among cervical SCC than AC survivors (P = .015; SIR for cervical SCC = 2.07 v AC = 1.78). This difference was limited to lung cancer (SIR for cervical SCC = 2.69 v AC = 2.18; P = .026). The increased lung cancer risk among cervical AC survivors was observed for both lung SCC and lung AC. SIRs for second cancers of the colon, soft tissue, melanoma, and non-Hodgkin's lymphoma were significantly higher among cervical AC than SCC survivors. Conclusion The second cancer profiles among cervical SCC and AC survivors mirror the similarities and differences in cofactors for these two histologies. Because smoking is not a cofactor for cervical AC, the increased lung cancer risk suggests a role for additional factors.

Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non–squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.

Background Given the extended survival of patients diagnosed with cervical cancer, the large number of these women treated with radiotherapy, and the presence in this population of established cancer risk factors such as human papillomavirus (HPV) infection and cigarette smoking, it is important to clarify long-term trends in second cancer risk. Methods Using data from 104,760 one-year survivors of cervical cancer reported to 13 population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States, we calculated standardized incidence ratios (SIRs) for second cancers overall and cancers at particular sites among women with cervical cancer, including cervical cancer patients who were treated or not treated with radiation, over more than 40 years of follow-up. Cox regression models were used to assess the time-varying association of radiotherapy with risk of second cancers and to assess the interaction of radiation treatment with age at diagnosis. All statistical tests were two-sided. Results Among 104,760 one-year survivors of cervical cancer, the risk of all second cancers taken together was increased to a statistically significant extent (n = 12,496; SIR = 1.30; 95% confidence interval [CI] = 1.28 to 1.33). Compared with the general population, in both radiotherapy (N = 52,613) and no-radiotherapy groups (N = 27,382), risks for HPV-related cancers (of the pharynx, genital sites, and rectum/anus) and smoking-related cancers (of the pharynx, trachea/bronchus/lung, pancreas, and urinary bladder) were elevated to a statistically significant extent. Cervical cancer patients treated with radiotherapy, but not those who did not receive radiotherapy, were at increased risk for all second cancers and cancers at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, and genital sites) beyond 40 years of follow-up compared with women in the general population. The association of radiotherapy with second cancer risk was modified by age at cervical cancer diagnosis for rectum/anus, genital sites, and urinary bladder, with higher hazard ratios for second cancer at younger ages of cervical cancer. After adjustment for competing mortality, the 40-year cumulative risk of any second cancer was higher among women diagnosed with cervical cancer before age 50 (22.2%; 95% CI = 21.5% to 22.8%) than among women diagnosed after age 50 (16.4%; 95% CI = 16.1% to 16.9%). Conclusion Cervical cancer patients treated with radiotherapy are at increased risk of second cancers at sites in close proximity to the cervix beyond 40 years of follow-up.

Background: Ionizing radiation at very high (radio-therapeutic) dose levels can cause diseases other than cancer, particularly heart diseases. There is increasing evidence that doses of the order of a few sievert (Sv) may also increase the risk of non-cancer diseases. It is not known, however, whether such effects also occur following the lower doses and dose rates of public health concern. Methods: We used data from an international (15-country) nuclear workers cohort study to evaluate whether mortality from diseases other than cancer is related to low doses of external ionizing radiation. Analyses included 275 312 workers with adequate information on socioeconomic status, over 4 million person-years of follow-up and an average cumulative radiation dose of 20.7 mSv; 11 255 workers had died of non-cancer diseases. Results: The excess relative risk (ERR) per Sv was 0.24 [95% CI (confidence intervals) -0.23, 0.78] for mortality from all non-cancer diseases and 0.09 (95% CI -0.43, 0.70) for circulatory diseases. Higher risk estimates were observed for mortality from respiratory and digestive diseases, but confidence intervals included zero. Increased risks were observed among the younger workers (attained age

International audience; A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI

To quantify long-term temporal trends in the excess absolute risk (EAR) of secondary leukemia among breast cancer (BC) survivors, using multivariate analyses to evaluate the effects of subtype, age at BC diagnosis, attained age, and calendar year. We identified 376,825 1-year survivors of BC within 4 nationwide, population-based cancer registries in Sweden, Denmark, Finland, and Norway (1943–2001). Estimates of EAR (per 100,000 person-years) were modeled using Poisson regression methods and cumulative risks calculated using a competing risk model. A total of 687 non-chronic lymphocytic leukemias (EAR = 9.05; 95% confidence interval (CI) = 7.5–10.7) was reported. Significantly elevated risks were observed for the first time for chronic myeloid leukemia (CML) (EAR = 2.06; 95% CI = 1.3–2.9) and acute lymphoblastic leukemia (ALL) (EAR = 0.62; 95% CI = 0.2–1.1), in addition to acute myeloid leukemia (AML) (EAR = 5.00; 95% CI = 3.9–6.2). Excesses of CML, ALL, AML and all leukemias combined persisted over 25 years after BC diagnosis. For all leukemias, EAR decreased with increasing calendar year (P = 0.04) of BC diagnosis. Risk for all leukemia and AML by calendar year of BC diagnosis depended on age at diagnosis. For women diagnosed with BC after 1985, the 10-year cumulative risk of leukemia for those diagnosed before and after age 50 was small, 0.10% and 0.14%, respectively. Although secondary leukemia is a rare event, BC survivors experience statistically significant excesses for at least 25 years after diagnosis, including CML and ALL. Decreasing leukemia risks in recent calendar years likely reflect changes in treatment.

International audience; Radiation protection standards are based mainly on risk estimates from studies of atomic bomb survivors in Japan. The validity of extrapolations from the relatively high-dose acute exposures in this population to the low-dose, protracted or fractionated environmental and occupational exposures of primary public health concern has long been the subject of controversy. A collaborative retrospective cohort study was conducted to provide direct estimates of cancer risk after low-dose protracted exposures. The study included nearly 600,000 workers employed in 154 facilities in 15 countries. This paper describes the design, methods and results of descriptive analyses of the study. The main analyses included 407,391 nuclear industry workers employed for at least 1 year in a participating facility who were monitored individually for external radiation exposure and whose doses resulted predominantly from exposure to higher-energy photon radiation. The total duration of follow-up was 5,192,710 person-years. There were 24,158 deaths from all causes, including 6,734 deaths from cancer. The total collective dose was 7,892 Sv. The overall average cumulative recorded dose was 19.4 mSv. A strong healthy worker effect was observed in most countries. This study provides the largest body of direct evidence to date on the effects of low-dose protracted exposures to external photon radiation. © 2007 by Radiation Research Society.

The cohort of nuclear workers at the Mayak Production Association, located in the Russian Federation, is a unique resource for providing information on the health effects of exposure to plutonium as well as the effects of protracted external dose. Lung cancer mortality risks were evaluated in 21,790 Mayak workers, a much larger group than included in previous evaluations of lung cancer risks in this cohort. These analyses, which included 655 lung cancer deaths occurring in the period 1955‐2000, were the first to evaluate both excess relative risk (ERR) and excess absolute risk (EAR) models and to give detailed attention to the modifying effects of gender, attained age and age at hire. Lung cancer risks were found to be significantly related to both internal dose to the lung from plutonium and external dose, and risks were described adequately by linear functions. For internal dose, the ERR per gray for females was about four times higher than that for males, whereas the EAR for females was less than half that for males; the ERR showed a strong decline with attained age, whereas the EAR increased with attained age until about age 65 and then decreased. Parallel analyses of lung cancer mortality risks in Mayak workers and Japanese A-bomb survivors were also conducted. Efforts currently under way to improve both internal and external dose estimates, and to develop data on smoking, should result in more accurate risk estimates in the future. q 2004 by Radiation Research Society

Bone cancer mortality risks were evaluated in 11,000 workers who started working at the "Mayak" Production Association in 1948-1958 and who were exposed to both internally deposited plutonium and external gamma radiation. Comparisons with Russian and U.S. general population rates indicate excess mortality, especially among females, plutonium plant workers, and workers with external doses exceeding 1 Sv. Comparisons within the Mayak worker cohort, which evaluate the role of plutonium body burden with adjustment for cumulative external dose, indicate excess mortality among workers with burdens estimated to exceed 7.4 kBq (relative risk = 7.9; 95% CI = 1.6-32) and among workers in the plutonium plant who did not have routine plutonium monitoring data based on urine measurements (relative risk = 4.1; 95% CI = 1.2-14). In addition, analyses treating the estimated plutonium body burden as a continuous variable indicate increasing risk with increasing burden (P0.001). Because of limitations in current plutonium dosimetry, no attempt was made to quantify bone cancer risks from plutonium in terms of organ dose, and risk from external dose could not be reliably evaluated.

Background We examined data on death from thyroid cancer across the continental United States and data on incidence from selected areas of the country for evidence of an association between this disease and exposure to radioactive iodine (131I) from nuclear tests in Nevada in the 1950s. Methods Analyses involving 4602 thyroid cancer deaths (1957-1994) and 12 657 incident cases of thyroid cancer (1973-1994) were performed. Excess relative risks (ERRs) per Gray (Gy) of radiation were estimated by relating age-, calendar year-, sex-, and county-specific rates to estimates of dose to the thyroid that take age at exposure into account. Results Analyses of cumulative dose yielded negative ERRs that were not statistically significant. An association was suggested for dose received by children under 1 year of age for both mortality data (ERR per Gy = 10.6; 95% confidence interval [CI] = -1.1 to 29) and incidence data (ERR per Gy = 2.4; 95% CI = -0.5 to 5.6); no association was found for dose received at older ages. For mortality data, but not incidence data, there was an elevated ERR in the 1950-1959 birth cohort of 12.0 (95% CI = 2.8 to 31) per Gy. Conclusions Risk of thyroid cancer from exposure to 131I from atmospheric nuclear tests did not increase with cumulative dose or dose received at ages 1-15 years, but associations were suggested for individuals exposed under 1 year of age and for those in the 1950-1959 birth cohort. The absence of increased risk from dose received at ages 1-15 years is not consistent with studies of children exposed to external radiation sources. This inconsistency may result from the limitations and biases inherent in ecologic studies, including the error introduced when studying a mobile population. These problems preclude making a quantitative estimate of risk due to exposure; however, given such limitations, it is perhaps remarkable that any evidence of the effects of 131I emerges from this study.

Workers at the Mayak nuclear facility in the Russian Federation offer a unique opportunity to evaluate health risks from exposure to inhaled plutonium. Risks of mortality from lung cancer, the most serious carcinogenic effect of plutonium, were evaluated in 14,621 Mayak workers who were hired in the period from 1948–1982, followed for at least 5 years, and either monitored for plutonium or never worked with plutonium. Over the follow-up period from 1953–2008, there were 486 deaths from lung cancer, 446 of them in men. In analyses that were adjusted for external radiation dose and smoking, the plutonium excess relative risk (ERR) per Gy declined with attained age and was higher for females than for males. The ERR per Gy for males at age 60 was 7.4 (95% CI: 5.0–11) while that for females was 24 (95% CI: 11–56). When analyses were restricted to plutonium doses

Objectives: To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. Design: Multinational retrospective cohort study of cancer mortality. Setting: Cohorts of workers in the nuclear industry in 15 countries. Participants: 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. Main outcome measurements: Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. Results: The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. Conclusions: These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

Data from epidemiological studies of humans exposed to potentially harmful substances are usually analyzed using methods that account for the dependence of risks on time-related factors such as age and follow-up period. Recently developed statistical procedures allow modeling of the age-specific risks as a function of dose as well as factors such as age at exposure, time since exposure, exposure duration, and dose rate. These procedures potentially allow more rigorous inferences and clearer understanding of the patterns of risk observed in epidemiological studies than has been available in the past. Statistical procedures that consider time-related factors can also be applied to laboratory animal data, providing information that is useful for the problems involved in extrapolating from animal studies to humans. By applying such procedures to data on exposure to the same substance in different species (including humans) or to different substances in the same species, better understanding of the relationship of risks across species and across substances can be achieved. In addition, such statistical procedures allow appropriate treatment of exposure that is accumulated over time and lead to improved understanding of patterns of risk over time. The approach is illustrated using data from a lifespan study of beagle dogs exposedmore » to inhaled Pu.« less

Analyses of mortality of workers at the Hanford Site were updated to include an additional three years of data (1979-81). Deaths occurring in the state of Washington in the years 1982-85 were also evaluated. Hanford workers continued to exhibit a strong healthy worker effect with death rates substantially below those of the general U.S. population. Comparisons by level of radiation exposure within the Hanford worker population provided no evidence of a positive correlation of radiation exposure and mortality from all cancers combined or of mortality from leukemia. Estimates of cancer risk due to radiation were negative, but confidence intervals were wide, indicating that the data were consistent with no risk and with risks several times larger than estimates provided by major groups concerned with risk assessment. Of 18 categories of cancer analyzed, a correlation of borderline statistical significance was identified for female genital cancers (p = 0.05), but was interpreted as probably spurious. The previously identified correlation for multiple myeloma persisted (p = 0.002).

Liver cancer mortality risks were evaluated in 11,000 workers who started working at the "Mayak" Production Association in 1948-1958 and who were exposed to both internally deposited plutonium and external gamma radiation. Comparisons with Russian liver cancer incidence rates indicate excess risk, especially among those with detectable plutonium body burdens and among female workers in the plutonium plant. Comparisons within the Mayak worker cohort which evaluate the role of plutonium body burden with adjustment for cumulative external dose indicate excess risk among workers with burdens estimated to exceed 7.4 kBq (relative risk = 17; 95% CI = 8. 0-36) and among workers in the plutonium plant who did not have routine plutonium monitoring data based on urine measurements (relative risk = 2.8; 95% CI = 1.3-6.2). In addition, analyses treating the estimated plutonium body burden as a continuous variable indicate increasing risk with increasing burden (P0.001). Relative risks tended to be higher for females than for males, probably because of the lower baseline risk and the higher levels of plutonium measured in females. Because of limitations in current plutonium dosimetry, no attempt was made to quantify liver cancer risks from plutonium in terms of organ dose, and risk from external dose could not be reliably evaluated.

Background: Lung cancer is a frequent cause of death in patients cured of Hodgkin’s disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described.We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. Methods: Within a population-based cohort of 19 046 Hodgkin’s disease patients (diagnosed from 1965 through 1994), a case–control study of lung cancer was conducted.The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients.All statistical tests were twosided. Results: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend

Purpose Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear. Patients and Methods We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location. Results Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m2) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m2 (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m2; however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses. Conclusion Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.