Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (ie, radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (ie, dose-response relationships). Major conclusions of the NCRP include: 1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and 2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include 1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; 2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; 3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; 4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and 5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.
Second 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.
Objective
To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.
Design, Setting, and Subjects
Matched 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 Measures
Relative 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.
Results
Breast 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<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5;P= .03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P= .003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses.
Conclusions
Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.
of having both a minimum latency of 17 years (compared with the 10-year lag of Gilbert et al.) and a minimum exposure age of 62 years (compared with no exclusions, as in the analysis of Gilbert et al.). This table also shows that the trend statistic (3.90) was much higher than the value of Gilbert et al. for Hanford workers (2.19). In the summary of their paper Gilbert and her associates are inclined to attribute their significant findings for high death ages to biases in the data that are not well understood. Therefore, it is interesting to consider what might have been the effects of faulty recording of cancer deaths and/or faulty recording of radiation doses. Faults of both kinds were possible, and the first would only require doctors who knew of the nuclear industry connection to be repeatedly overrecording cancer as the cause of death of workers who combined high doses with high death ages. However, when we added to the other controlling factors the age on leaving the industry, we found that for exposures after 60 years of age, with a lag period of 15 years (i.e. 75 years as the minimum age for a radiogenic cancer death), the trend statistic (3.51) was still much higher than the value of Gilbert et al. Therefore, faulty recording of cancer deaths could have been the cause of the suspected bias only if it had distinguished between workers with low and high doses who had in common both the age when they left the industry and the age when they died. Finally, although faulty recording of radiation doses was possible, it is difficult to see how this could have effects which were less obvious for deaths within 10 years of leaving the industry than for deaths with longer post-employment intervals.
Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse.
These analyses are based on data from a lifespan study of beagle dogs exposed to inhaled plutonium being conducted at Pacific Northwest Laboratory. An important goal of this study is to increase understanding of health risk resulting from this exposure, with particular attention to lung cancer risks. Data on humans exposed to plutonium are inadequate for achieving this goal.
Gilbert, E. S., Koshurnikova, N. A., Sokolnikov, M. E., Shilnikova, N. S., Preston, D. L., Ron, E., Okatenko, P. V., Khokhryakov, V. F., Vasilenko, E. K., Miller, S., Eckerman, K. and Romanov, S. A. Lung Cancer in Mayak Workers. Radiat. Res. 162, 505–516 (2004).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.
The mortality of workers at the Hanford Plant in southeastern Washington who have been exposed to penetrating external ionizing radiation is studied. Deaths are analyzed statistically and compared to standardized mortality ratios. Cancer deaths in particular are examined. (ACR)
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