Elaine Ron

A pooled analysis of case–control studies of thyroid cancer: cigarette smoking and consumption of alcohol, coffee, and tea

Objective: To analyze the role of smoking, alcohol, coffee and tea in relation to thyroid cancer, we conducted a pooled analysis of 14 case–control studies conducted in the United States, Europe, and Asia. Methods: The sample consisted of 2725 thyroid cancer cases (2247 females, 478 males) and 4776 controls (3699 females, 1077 males). Conditional logistic regression with stratification on study, age at diagnosis, and gender was used to compute odds ratios and 95% confidence intervals. Results: Thyroid cancer risk was reduced in persons who had ever smoked. The relationship was more pronounced in current smokers (OR = 0.6, 95% CI = 0.6–0.7) than former smokers (OR = 0.9, 95% CI = 0.8–1.1). There were significant trends of reduced risk with greater duration and frequency of smoking. For consumption of wine and beer, there was a significant trend of decreasing thyroid cancer risk (p = 0.02) that was not maintained after adjustment for current smoking (p = 0.12). Thyroid cancer risk was not associated with consumption of coffee or tea. These findings were consistent in both gender-specific and histology-specific (papillary and follicular) analyses. Conclusions: Pooled analyses of these geographically diverse case–control data indicate a reduced thyroid cancer risk associated with current smoking. A reduced risk associated with alcohol was eliminated after adjustment for smoking, and caffeinated beverages did not alter thyroid cancer risk.

Ionizing radiation and cancer risk : Evidence from epidemiology

Epidemiological studies provide the primary data on the carcinogenic effects of radiation in humans. Much of what is known has come from studies of the atomic bomb survivors, and to a lesser extent from patients receiving radiotherapy. These studies demonstrate that exposure to moderate to high doses of radiation increases the risk of cancer in most organs. For all solid cancers combined, cancers of the thyroid, breast and lung, and leukemia, risk estimates are fairly precise, and associations have been found at relatively low doses (<0.2 Gy). Associations between radiation and cancers of the salivary glands, stomach, colon, bladder, ovary, central nervous system and skin have also been reported, but the relationships are not as well quantified. Associations between radiation and cancers of the liver and esophagus, and to a lesser extent multiple myeloma and non-Hodgkins lymphoma, have been reported in a few studies, but results are inconsistent. Chronic lymphocytic leukemia, Hodgkins disease, and cancers of the pancreas, prostate, testis and cervix have rarely been linked to radiation exposure. A linear no-threshold model adequately describes the dose-response relationship for solid cancers, although at extremely high doses the risk appears to flatten out. Because few populations have been followed until the end of life, the temporal patterns of risk are not completely known. An increased risk, however, does continue for several decades. In contrast, radiation-related leukemias begin to occur shortly (2-3 years) after exposure and, at least in the A-bomb survivors, a linear-quadratic dose response seems to fit the data better than a pure linear model. Radiation does not act entirely in isolation. It can interact with other carcinogens, e.g. tobacco or chemotherapeutic agents, and with host factors such as age at exposure, gender or reproductive history. Interactions with medical interventions or with certain heritable mutations have also been suggested. While the studies of high-dose exposures are essential for understanding the overall biological consequences of radiation exposure, the public is more concerned about the long-term health effects from protracted exposures at low doses. Unfortunately, the inherent limitations of epidemiology make it extremely difficult to directly quantify health risks from these exposures. While most epidemiological data are compatible with linear extrapolations from exposures at high doses or high dose rates, they cannot entirely exclude other possibilities. As the field of epidemiology advances, understanding more about the health effects of prolonged and low-dose exposures will be the next challenge.

Cancer incidence in the U.S. radiologic technologists health study, 1983–1998

Workers exposed to low doses of radiation can provide information regarding cancer risks that are of public concern. However, characterizing risk at low doses requires large populations and ideally should include a large proportion of women, both of which rarely are available.

A pooled analysis of case-control studies of thyroid cancer II. Menstrual and reproductive factors

Objective: It has been suggested that female hormones, and hence menstrual and reproductive factors, play a role in thyroid cancer etiology. Epidemiological data, however, are limited and inconsistent, partly because of the small number of cases included in each study. To clarify the etiology of thyroid cancer, we conducted a pooled analysis of original data from 14 case-control studies, 4 from the United States, 2 from Asia, and 8 from Europe.Methods: This analysis included a total of 2,247 female cases of thyroid cancer (80% papillary) and 3,699 control women. Pooled odds ratios (OR) were estimated using logistic regression, conditioning on study and (i) matching sets for individually matched studies, or (ii) quinquennia of age for the other studies. Additional terms for age and history of radiation exposure were included in the regression equations.Results: The OR per year of later menarche was 1.04 (95% confidence interval (CI) 1.0–1.1). Compared to pre-menopausal women, the OR was 1.3 for women with natural menopause, and 1.8 for those with artificial menopause, but the studies were heterogeneous and the association may be due, at least in part, to diagnostic or ascertainment bias. Parity, spontaneous or induced abortions and history of infertility were not associated with thyroid cancer risk. The OR was above unity in women reporting later age at first birth (OR=1.1, 95% CI 1.0–1.3 for 5-year delay) and higher in the first years after a birth.Conclusions: The associations of menstrual and reproductive factors with thyroid cancer risk were generally weak, but appeared stronger among women diagnosed with thyroid cancer at younger ages.

Dose Reconstruction for Therapeutic and Diagnostic Radiation Exposures: Use in Epidemiological Studies

Abstract Stovall, M., Weathers, R., Kasper, C., Smith, S. A., Travis, L., Ron, E. and Kleinerman, R. Dose Reconstruction for Therapeutic and Diagnostic Radiation Exposures: Use in Epidemiological Studies. Radiat. Res. 166, 141–157 (2006). This paper describes methods developed specifically for reconstructing individual organ- and tissue-absorbed dose of radiation from past exposures from medical treatments and procedures for use in epidemiological studies. These methods have evolved over the past three decades and have been applied to a variety of medical exposures including external-beam radiation therapy and brachytherapy for malignant and benign diseases as well as diagnostic examinations. The methods used for estimating absorbed dose to organs in and outside the defined treatment volume generally require archival data collection, abstraction and review, and phantom measurements to simulate past exposure conditions. Three techniques are used to estimate doses from radiation therapy: (1) calculation in three-dimensional mathematical computer models using an extensive database of out-of-beam doses measured in tissue-equivalent materials, (2) measurement in anthropomorphic phantoms constructed of tissue-equivalent material, and (3) calculation using a three-dimensional treatment-planning computer. For diagnostic exposures, doses are estimated from published data and software based on Monte Carlo techniques. We describe and compare these methods of dose estimation and discuss uncertainties in estimated organ doses and potential for future improvement. Seven epidemiological studies are discussed to illustrate the methods.

Second solid cancers after radiotherapy for breast cancer in SEER cancer registries

Background: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.Methods:We evaluated long-term second cancer risks among 182u2009057 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.Results:By the end of 2005 (median follow-up=13.0 years), 15u2009498 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+u2009Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04–1.15) for contralateral breast cancer (≈1u2009Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5–0.99u2009Gy, RR=0.89 (0.74–1.06)) or low doses (<0.5u2009Gy, 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.Conclusions:Most second solid cancers in breast cancer survivors are not related to radiotherapy.

Acromegaly and cancer risk: A cohort study in Sweden and Denmark

Objective: Several studies have suggested that patients with acromegaly have an increased risk of benign and malignant neoplasms, especially of the colon. To further investigate this relationship we evaluated cancer risk in population-based cohorts of acromegaly patients in Sweden and Denmark. Methods: Nationwide registry-based cohorts of patients hospitalized for acromegaly (Denmark 1977–1993; Sweden 1965–1993) were linked to tumor registry data for up to 15–28 years of follow-up, respectively. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated to estimate cancer risk among 1634 patients with acromegaly. Results: The patterns of cancer risk in Sweden and Denmark were similar. After excluding the first year of follow-up, 177 patients with acromegaly had a diagnosis of cancer compared with an expected number of 116.5 (SIR = 1.5, 95% CI = 1.3–1.8). Increased risks were found for digestive system cancers (SIR = 2.1, 95% CI = 1.6–2.7), notably of the small intestine (SIR = 6.0, 95% CI = 1.2–17.4), colon (SIR = 2.6, 95% CI = 1.6–3.8), and rectum (SIR = 2.5, 95% CI = 1.3–4.2). Risks were also elevated for cancers of the brain (SIR = 2.7, 95% CI = 1.2–5.0), thyroid (SIR = 3.7, 95% CI = 1.8–10.9), kidney (SIR = 3.2, 95% CI = 1.6–5.5), and bone (SIR = 13.8, 95% CI = 1.7–50.0). Conclusions: The increased risk for several cancer sites among acromegaly patients may be due to the elevated proliferative and anti-apoptotic activity associated with increased circulating levels of insulin-like growth factor-1 (IGF-1). Pituitary irradiation given to some patients may have contributed to the excess risks of brain tumors and thyroid cancer. Our findings indicate the need for close medical surveillance of patients with acromegaly, and further studies of the IGF-1 system in the etiology of various cancers.

Radiation-Induced Skin Carcinomas of the Head and Neck

Radiation exposures to the scalp during childhood for tinea capitis were associated with a fourfold increase in skin cancer, primarily basal cell carcinomas, and a threefold increase in benign skin tumors. Malignant melanoma, however, was not significantly elevated. Overall, 80 neoplasms were identified from an extensive search of the pathology logs of all major hospitals in Israel and computer linkage with the national cancer registry. Radiation dose to the scalp was computed for over 10,000 persons irradiated for ringworm (mean 7 Gy), and incidence rates were contrasted with those observed in 16,000 matched comparison subjects. The relative risk of radiogenic skin cancer did not differ significantly between men or women or by time since exposure; however, risk was greatest following exposures in early childhood. After adjusting for sex, ethnic origin, and attained age, the estimated excess relative risk was 0.7 per Gy and the average excess risk over the current follow-up was 0.31/10(4) PY-Gy. The risk per Gy of radiation-induced skin cancer was intermediate between the high risk found among whites and no risk found among blacks in a similar study conducted in New York City (Shore et al., Radiat. Res. 100, 192-204, 1984). This finding suggests the role that subsequent exposure to uv radiation likely plays in the expression of a potential radiation-induced skin malignancy.

Cancer Mortality Risk among Workers at the Mayak Nuclear Complex

Abstract Shilnikova, N. S., Preston, D. L., Ron, E., Gilbert, E. S., Vassilenko, E. K., Romanov, S. A., Kuznetsova, I. S., Sokolnikov, M. E., Okatenko, P. V., Kreslov, V. V. and Koshurnikova, N. A. Cancer Mortality Risk among Workers at the Mayak Nuclear Complex. Radiat. Res. 159, 787–798 (2003). At present, direct data on risk from protracted or fractionated radiation exposure at low dose rates have been limited largely to studies of populations exposed to low cumulative doses with resulting low statistical power. We evaluated the cancer risks associated with protracted exposure to external whole-body γ radiation at high cumulative doses (the average dose is 0.8 Gy and the highest doses exceed 10 Gy) in Russian nuclear workers. Cancer deaths in a cohort of about 21,500 nuclear workers who began working at the Mayak complex between 1948 and 1972 were ascertained from death certificates and autopsy reports with follow-up through December 1997. Excess relative risk models were used to estimate solid cancer and leukemia risks associated with external γ-radiation dose with adjustment for effects of plutonium exposures. Both solid cancer and leukemia death rates increased significantly with increasing γ-ray dose (P < 0.001). Under a linear dose–response model, the excess relative risk for lung, liver and skeletal cancers as a group (668 deaths) adjusted for plutonium exposure is 0.30 per gray (P < 0.001) and 0.08 per gray (P < 0.001) for all other solid cancers (1062 deaths). The solid cancer dose–response functions appear to be nonlinear, with the excess risk estimates at doses of less than 3 Gy being about twice those predicted by the linear model. Plutonium exposure was associated with increased risks both for lung, liver and skeletal cancers (the sites of primary plutonium deposition) and for other solid cancers as a group. A significant dose response, with no indication of plutonium exposure effects, was found for leukemia. Excess risks for leukemia exhibited a significant dependence on the time since the dose was received. For doses received within 3 to 5 years of death the excess relative risk per gray was estimated to be about 7 (P < 0.001), but this risk was only 0.45 (P = 0.02) for doses received 5 to 45 years prior to death. External γ-ray exposures significantly increased risks of both solid cancers and leukemia in this large cohort of men and women with occupational radiation exposures. Risks at doses of less than 1 Gy may be slightly lower than those seen for doses arising from acute exposures in the atomic bomb survivors. As dose estimates for the Mayak workers are improved, it should be possible to obtain more precise estimates of solid cancer and leukemia risks from protracted external radiation exposure in this cohort.

Skin tumor risk among atomic-bomb survivors in Japan

Objectives: Elevated risks of skin cancer following high doses of ionizing radiation have long been known. Recent reports on atomic-bomb survivors indicate that nonmelanoma skin cancer can be induced at low to medium doses. We studied atomic-bomb survivors to determine the effects of radiation on specific histologic types of skin cancer and to describe the dose-response relationship.Methods: Cases of melanoma, nonmelanoma skin cancers, and Bowens disease were ascertained between 1958 and 1987 for the 80,000 cohort members through the population-based Hiroshima and Nagasaki (Japan) tumor registries augmented by searches of other records.Results: An excess of basal cell carcinoma (n=80), with some suggestion of a non-linear dose-response, was observed. The excess risk decreased markedly as age at exposure increased, and there was no evidence for an interaction between ionizing and ultraviolet radiation. No dose-response was found for squamous cell carcinoma (n=69). The excess relative risk point-estimates were large, but statistically nonsignificant for both melanoma (n=10) and Bowens disease (n=26).Conclusions: The basal layer of the epidermis appears to be quite sensitive to radiation carcinogenesis, particularly at a young age. The suprabasal layer seems to be more resistant, as shown by the lack of an association for squamous cell carcinomas.