1970 and 1993 and registered in cancer registries in Iowa, Connecticut, New Jersey, Canada (Ontario), Denmark, Finland, the Netherlands, and Sweden. The study included 36 cases and 106 matched controls. Individual radiation dose to the active bone marrow was estimated from detailed radiotherapy records. In men who did not receive chemotherapy (mean radiation dose to 12.6 Gy), a 3.1-fold elevation of leukemia risk was observed (95% CI 0.7, 22). The risk increased with radiation dose to the active bone marrow, with an OR of 19.7 (95% CI 1.5, 59) for doses of 20 Gy or more (based on four exposed cases). No estimate of ERR or EAR per gray is given.

Thyroid Cancer

A cohort of 834 thyroid cancer patients treated with iodine-131 and of 1121 thyroid cancer patients treated by other means in Sweden between 1950 and 1975 was followed for cancer occurrence (Hall and others 1991). The average 131I cumulative activity administered was 4.55 GBq. The average duration of follow-up was 14 years. A total of 99 second cancers were found 2 years or more after 131I therapy among those treated with this modality and 122 among those treated by other means. The incidence of second malignancy was higher among those treated with 131I. Among women, the overall standardized incidence ratio (SIR)5 was 1.45 (95% CI 1.14, 1.83), and significantly elevated SIRs were found for tumors of the salivary glands, genital organs, kidney, and adrenal gland. A significant trend was seen with increasing 131I activity, with a SIR of 1.80 (95% CI 1.20, 2.58) for administered activities of 3.66 GBq and above.

A cohort of 1771 patients treated with 131I for thyroid cancer was followed up for incidence of second cancers (de Vathaire and others 1997). The average 131I cumulative activity administered was 7.2 GBq, resulting in an estimated average dose of 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukemia was seen. Eighty patients developed a secondary solid cancer, including 13 colorectal cancers. The risk of colorectal cancer was related to the total activity administered (ERR = 0.47 GBq−1; 95% CI 0.1, 1.6). The overall ERR for solid tumors in this study was 0.38 per estimated effective sievert (95% CI −0.22, 1.2); when tumors of the digestive track were excluded, the ERR was reduced to −0.15 Sv−1 (95% CI −0.35, 0.22).

Childhood Cancers

The treatment for childhood cancers, often a combination of both radiotherapy and chemotherapy, has prolonged the life expectancy of children with cancer and increased the chance of development of second cancers. Since childhood cancer is rare, national and international groups such as the Late Effects Study Group (Tucker and others 1987a, 1987b, 1991) and several groups in the United Kingdom (Hawkins and others 1987) and France (de Vathaire and others 1989, 1999) have combined their data to evaluate risks. Results from these cohort studies have indicated that the risk for developing a second cancer in the 25 years after the diagnosis of the first cancer was as high as 12% (Tucker and others 1991). Further, genetic predisposition appears to have a substantial impact on risk of subsequent cancers. Among patients treated for hereditary retinoblastoma, the risk of developing a second cancer in the 50 years after the initial diagnosis was as high as 51% (Wong and others 1997b).

Three nested case-control studies including 64 cases of bone cancer and 209 controls (Tucker and others 1987a), 23 cases of thyroid cancer and 89 controls (Tucker and others 1991), and 25 cases of leukemia and 90 controls (Tucker and others 1987b) were conducted from the Late Effects Study Group cohort of 9170 children who developed a second malignant tumor at least 2 years after diagnosis of the first tumor. A significant increased risk of bone cancer was found among patients who received radiation therapy (RR 2.7; 95% CI 1.0, 7.7), with a sharp dose-response gradient reaching a fortyfold risk following doses to the bone of more than 60 Gy. A significant increased risk of thyroid cancer was also found among patients who had received radiation therapy; most of the increase was among those who had received doses of 2 Gy or more. There was no evidence of a dose-response relationship for leukemia.

In a U.K. cohort of 10,106 3-year survivors of childhood cancer, Hawkins and colleages (1987; Hawkins 1990) reported an excess of second tumors among subjects who had received radiotherapy in comparison with the general population. In addition, two nested case-control studies of 59 cases of second bone cancer and 220 controls (Hawkins and others 1996) and 26 cases of second leukemia and 96 controls (Hawkins and others 1992) were conducted within this cohort, with individual dose reconstruction to the organs of interest. The risk of bone cancer increased substantially with increased cumulative radiation dose to the bone (p < .001), although a decline in risk was seen at doses equal to or greater than 50 Gy. A nonsignificant increased risk of leukemia was observed among those who had received radiotherapy (RR 8.4; 95% CI 0.9, 81.0 based on seven exposed cases). A significant dose-response relationship was observed.

In a cohort study of 634 children treated for childhood cancer from 1942 and 1969 in the Institut Gustave Roussy in Paris, a twofold increase in the risk of second malignancy was seen after doses from radiotherapy of more than 25 Gy, based on two exposed cases (de Vathaire and others 1989). A nonsignificant dose-response was seen based on 13 cases who had received radiotherapy alone.


SIR is the ratio of the incidence rate of a disease in the population being studied divided by the comparable rate in a standard population. The ratio is similar to an RR times 100.

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