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"Ron, Elaine"
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Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries
Improvements in cancer survival have made the long-term risks from treatments more important, including the risk of developing a second cancer after radiotherapy. We aimed to estimate the proportion of second cancers attributable to radiotherapy in adults with data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries.
We used nine of the SEER registries to systematically analyse 15 cancer sites that are routinely treated with radiotherapy (oral and pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye and orbit, brain and CNS, and thyroid). The cohort we studied was composed of patients aged 20 years or older who were diagnosed with a first primary invasive solid cancer reported in the SEER registries between Jan 1, 1973, and Dec 31, 2002. Relative risks (RRs) for second cancer in patients treated with radiotherapy versus patients not treated with radiotherapy were estimated with Poisson regression adjusted for age, stage, and other potential confounders.
647 672 cancer patients who were 5-year survivors were followed up for a mean 12 years (SD 4·5, range 5–34); 60 271 (9%) developed a second solid cancer. For each of the first cancer sites the RR of developing a second cancer associated with radiotherapy exceeded 1, and varied from 1·08 (95% CI 0·79–1·46) after cancers of the eye and orbit to 1·43 (1·13–1·84) after cancer of the testes. In general, the RR was highest for organs that typically received greater than 5 Gy, decreased with increasing age at diagnosis, and increased with time since diagnosis. We estimated a total of 3266 (2862–3670) excess second solid cancers that could be related to radiotherapy, that is 8% (7–9) of the total in all radiotherapy patients (≥1 year survivors) and five excess cancers per 1000 patients treated with radiotherapy by 15 years after diagnosis.
A relatively small proportion of second cancers are related to radiotherapy in adults, suggesting that most are due to other factors, such as lifestyle or genetics.
US National Cancer Institute.
Journal Article
Non-malignant Thyroid Diseases after a Wide Range of Radiation Exposures
The thyroid gland is one of the most radiosensitive human organs. While it is well known that radiation exposure increases the risk of thyroid cancer, less is known about its effects in relation to non-malignant thyroid diseases. The aim of this review is to evaluate the effects of high- and low-dose radiation on benign structural and functional diseases of the thyroid. We examined the results of major studies from cancer patients treated with high-dose radiotherapy or thyrotoxicosis patients treated with high doses of iodine-131, patients treated with moderate- to high-dose radiotherapy for benign diseases, persons exposed to low doses from environmental radiation, and survivors of the atomic bombings who were exposed to a range of doses. We evaluated radiation effects on structural (tumors, nodules), functional (hyper- and hypothyroidism), and autoimmune thyroid diseases. After a wide range of doses of ionizing radiation, an increased risk of thyroid adenomas and nodules was observed in a variety of populations and settings. The dose response appeared to be linear at low to moderate doses, but in one study there was some suggestion of a reduction in risk above 5 Gy. The elevated risk for benign tumors continues for decades after exposure. Considerably less consistent findings are available regarding functional thyroid diseases including autoimmune diseases. In general, associations for these outcomes were fairly weak, and significant radiation effects were most often observed after high doses, particularly for hypothyroidism. A significant radiation dose–response relationship was demonstrated for benign nodules and follicular adenomas. The effects of radiation on functional thyroid diseases are less clear, partly due to the greater difficulties encountered in studying these diseases.
Journal Article
Cancer Risks Attributable to Low Doses of Ionizing Radiation: Assessing What We Really Know
High doses of ionizing radiation clearly produce deleterious consequences in humans, including, but not exclusively, cancer induction. At very low radiation doses the situation is much less clear, but the risks of low-dose radiation are of societal importance in relation to issues as varied as screening tests for cancer, the future of nuclear power, occupational radiation exposure, frequent-flyer risks, manned space exploration, and radiological terrorism. We review the difficulties involved in quantifying the risks of low-dose radiation and address two specific questions. First, what is the lowest dose of x- or γ-radiation for which good evidence exists of increased cancer risks in humans? The epidemiological data suggest that it is ≈10-50 mSv for an acute exposure and ≈50-100 mSv for a protracted exposure. Second, what is the most appropriate way to extrapolate such cancer risk estimates to still lower doses? Given that it is supported by experimentally grounded, quantifiable, biophysical arguments, a linear extrapolation of cancer risks from intermediate to very low doses currently appears to be the most appropriate methodology. This linearity assumption is not necessarily the most conservative approach, and it is likely that it will result in an underestimate of some radiation-induced cancer risks and an overestimate of others.
Journal Article
A Pooled Analysis of Thyroid Cancer Incidence Following Radiotherapy for Childhood Cancer
Childhood cancer five-year survival now exceeds 70–80%. Childhood exposure to radiation is a known thyroid carcinogen; however, data are limited for the evaluation of radiation dose-response at high doses, modifiers of the dose-response relationship and joint effects of radiotherapy and chemotherapy. To address these issues, we pooled two cohort and two nested case-control studies of childhood cancer survivors including 16,757 patients, with 187 developing primary thyroid cancer. Relative risks (RR) with 95% confidence intervals (CI) for thyroid cancer by treatment with alkylating agents, anthracyclines or bleomycin were 3.25 (0.9–14.9), 4.5 (1.4–17.8) and 3.2 (0.8–10.4), respectively, in patients without radiotherapy, and declined with greater radiation dose (RR trends, P = 0.02, 0.12 and 0.01, respectively). Radiation dose-related RRs increased approximately linearly for <10 Gy, leveled off at 10–15-fold for 10–30 Gy and then declined, but remained elevated for doses >50 Gy. The fitted RR at 10 Gy was 13.7 (95% CI: 8.0–24.0). Dose-related excess RRs increased with decreasing age at exposure (P < 0.01), but did not vary with attained age or time-since-exposure, remaining elevated 25+ years after exposure. Gender and number of treatments did not modify radiation effects. Thyroid cancer risks remained elevated many decades following radiotherapy, highlighting the need for continued follow up of childhood cancer survivors.
Journal Article
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-Hodgkin's lymphoma, have been reported in a few studies, but results are inconsistent. Chronic lymphocytic leukemia, Hodgkin's 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.
Journal Article
The Ukrainian-American Study of Leukemia and Related Disorders among Chornobyl Cleanup Workers from Ukraine: III. Radiation Risks
Romanenko, A. Ye., Finch, S. C., Hatch, M., Lubin, J. H., Bebeshko, V. G., Bazyka, D. A., Gudzenko, N., Dyagil, I. S., Reiss, R. F., Bouville, A., Chumak, V. V., Trotsiuk, N. K., Babkina, N. G., Belyayev, Yu., Masnyk, I., Ron, E., Howe, G.;thR. and Zablotska, L. B. The Ukrainian-American Study of Leukemia and Related Disorders among Chornobyl Cleanup Workers from Ukraine: III. Radiation Risks. Radiat. Res. 170, 711–720 (2008). Leukemia is one of the cancers most susceptible to induction by ionizing radiation, but the effects of lower doses delivered over time have not been quantified adequately. After the Chornobyl (Chernobyl) accident in Ukraine in April 1986, several hundred thousand workers who were involved in cleaning up the site and its surroundings received fractionated exposure, primarily from external γ radiation. To increase our understanding of the role of protracted low-dose radiation exposure in the etiology of leukemia, we conducted a nested case-control study of leukemia in a cohort of cleanup workers identified from the Chornobyl State Registry of Ukraine. The analysis is based on 71 cases of histologically confirmed leukemia diagnosed in 1986–2000 and 501 age- and residence-matched controls selected from the same cohort. Study subjects or their proxies were interviewed about their cleanup activities and other relevant factors. Individual bone marrow radiation doses were estimated by the RADRUE dose reconstruction method (mean dose = 76.4 mGy, SD = 213.4). We used conditional logistic regression to estimate leukemia risks. The excess relative risk (ERR) of total leukemia was 3.44 per Gy [95% confidence interval (CI) 0.47–9.78, P < 0.01]. The dose response was linear and did not differ significantly by calendar period of first work in the 30-km Chornobyl zone, duration or type of work. We found a similar dose–response relationship for chronic and non-chronic lymphocytic leukemia [ERR = 4.09 per Gy (95% CI < 0–14.41) and 2.73 per Gy (95% CI < 0–13.50), respectively]. To further clarify these issues, we are extending the case-control study to ascertain cases for another 6 years (2001–2006).
Journal Article
Subclinical Hypothyroidism after Radioiodine Exposure: Ukrainian-American Cohort Study of Thyroid Cancer and Other Thyroid Diseases after the Chornobyl Accident (1998-2000)
Background: Hypothyroidism is the most common thyroid abnormality in patients treated with high doses of iodine-131 (¹³¹I). Data on risk of hypothyroidism from low to moderate ¹³¹I thyroid doses are limited and inconsistent. Objective: This study was conducted to quantify the risk of hypothyroidism prevalence in relation to ¹³¹I doses received because of the Chornobyl accident. Methods: This is a cross-sectional (1998-2000) screening study of thyroid diseases in a cohort of 11,853 individuals < 18 years of age at the time of the accident, with individual thyroid radioactivity measurements taken within 2 months of the accident. We measured thyroid-stimulating hormone (TSH), free thyroxine, and antibodies to thyroid peroxidase (ATPO) in serum. Results: Mean age at examination of the analysis cohort was 21.6 years (range, 12.2-32.5 years), with 49% females. Mean ¹³¹I thyroid dose was 0.79 Gy (range, 0-40.7 Gy). There were 719 cases with hypothyroidism (TSH > 4 mIU/L), including 14 with overt hypothyroidism. We found a significant, small association between ¹³¹I thyroid doses and prevalent hypothyroidism, with the excess odds ratio (EOR) per gray of 0.10 (95% confidence interval, 0.03-0.21). EOR per gray was higher in individuals with ATPO ≤ 60 U/mL compared with individuals with ATPO > 60 U/mL (p < 0.001). Conclusions: This is the first study to find a significant relationship between prevalence of hypothyroidism and individual ¹³¹I thyroid doses due to environmental exposure. The radiation increase in hypothyroidism was small (10% per Gy) and limited largely to subclinical hypothyroidism. Prospective data are needed to evaluate the dynamics of radiation-related hypothyroidism and clarify the role of antithyroid antibodies.
Journal Article