tionated doses, and studies of these patients provide the potential to study the effects of exposure fractionation and protraction.

Radiotherapy for Malignant Disease

Studies of second cancer following radiotherapy have generally focused on patients treated for cervical cancer, breast cancer, Hodgkin’s disease (HD), and childhood cancers (i.e., patients that generally have a favorable long-term prognosis). Survivors of these cancers may live long enough to develop a second, treatment-related malignancy. It should be noted that chemotherapy and/or hormonal therapy used in the treatment of cancers is a potential confounding factor in investigations of the risk of a second primary cancer.

Cervical Cancer

The treatment of cervical cancer involves external beam radiotherapy or radium or cesium in applicators to deliver high local doses of X-rays and gamma rays to the cervix uteri and adjacent organs in the abdomen and pelvic area. Treatment is usually successful, and patients survive for years after radiotherapy. Although doses to the cervix are very high (typically 40–150 Gy), doses to distant organs are significantly lower: of the order of 0.1 Gy to the thyroid, 0.3 Gy to the breast and the lung, 2 Gy to the stomach, and 7 Gy to the active bone marrow (Kleinerman and others 1995).

Most of the information on second cancers following radiotherapy for cervical cancer comes from an international cohort study of approximately 200,000 women treated for cervical cancer. The study involved the follow-up, based on 15 cancer registries in eight countries (Canada, Denmark, Finland, Norway, Sweden, the United Kingdom, the United States, and Yugoslavia [Slovenia]), of a multinational cohort of nearly 200,000 women patients treated for cancer of the cervix after 1960. In 1985, Boice and colleagues reported on 5146 second cancers that were diagnosed in this cohort up to 1980 and showed an increased risk of cancer following radiotherapy at a number of sites (Boice and others 1985). Kleinerman and coworkers (1995) extended the follow-up of this cohort, adding an additional 10 years of incident cases. Several registries from the original study were retained, and other registries were added to increase the number of nonexposed comparison subjects. A total of 7543 cases were included. This study confirmed earlier findings of increased risk of malignancies following radiotherapy and the persistence of increased risk over time.

Case-control studies of specific cancer types, nested within this cohort, allowed the reconstruction of individual doses to specific organs and the estimation of site-specific cancer risks (Boice and others 1987, 1988, 1989). These studies are based on incidence data; the numbers of exposed and unexposed patients were large; there was long and complete follow-up (hundreds of cases and controls, with followup of 10–20 years or more); chemotherapy was rarely used; and the existence of radiotherapy records facilitated the development of a comprehensive dose reconstruction system to estimate individual doses.

In an expanded case-control study nested within this international cohort (Boice and others 1988), radiation doses for selected organs were reconstructed from original radiotherapy records. Very high doses, of the order of several hundred grays delivered to the cervix, significantly increased the risks for cancers of the bladder, rectum, and vagina and possibly bone, uterine corpus, cecum, and non-Hodgkin’s lymphoma (NHL). Doses of several grays increased the risks for stomach cancer and for leukemia. The ERR1 for stomach cancer was 0.54 Gy−1 (90% CI 0.05, 1.5), with an excess attributable risk of 3.16 per 104 person-years (PY) per gray (0.05, 10.4), based on 348 cases and 658 controls. A nonsignificant twofold increase in the risk of thyroid cancer was observed, with an average dose of 0.11 Gy (43 cases and 81 controls).

More detailed dose-response investigations were carried out for leukemia and breast cancer after treatment for cervical cancer. The case-control study of leukemia risk (Boice and others 1987) included 195 cases and 745 controls, of whom 181 and 672, respectively, had received radiotherapy. Radiation dose to the active bone marrow was estimated from detailed radiotherapy records of the subjects. Radiation exposure did not affect the risk of chronic lymphocytic leukemia (CLL; 52 cases). For other forms of leukemia taken together (143 cases), there was a significant twofold increase in risk associated with radiotherapy; the risk increased with increasing dose up to about 4 Gy and then decreased at higher doses and was modeled adequately by a linear-exponential function. The linear term of this model for leukemia other than CLL provides an estimate of the ERR per gray in the low-dose range, where cell killing is negligible; this estimate is 0.88 Gy−1 (standard error = 0.69).

The case-control study of breast cancer included 953 cases and 1806 controls (Boice and others 1989). Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed from original radiotherapy records. Overall, there was no association between radiotherapy and risk of breast cancer. Among women with intact ovaries (561 cases), radiotherapy was associated with a significant reduction of risk, probably attributable to cessation of ovarian function. Among women with no ovaries, there was a slight increase in breast cancer risk and a suggestion of a dose-response with a relative risk (RR)2 of 1.0, 0.7, 1.5, and 3.1, respectively, for the dose groups 0, 0.01–0.24, 0.25–0.49, and 0.5 + Gy. From these data, UNSCEAR (2000b)


ERR is the rate of disease in an exposed population divided by the rate of disease in an unexposed population minus 1.0.


RR is the rate of disease in an exposed population divided by the rate of disease in an unexposed population.

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