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estimated an ERR per gray of 0.33 (< −0.2, 5.8) for women with no ovaries and of −0.2 (< −0.2, 0.3) overall.
A cohort study of second cancer risk following radiation therapy for cancer of the uterine cervix was also carried out in Japan among 11,855 patients (Arai and others 1991). Significant excesses of leukemia and of cancers of the rectum, bladder, and lung were observed. No estimation of organ dose is available.
The large radiation therapy fields used to treat HD and the young age and long survival of patients provide an opportunity to study the risk of second cancer after exposure to ionizing radiation. Most patients, however, in the past 20 years, have been treated with a combination of radiotherapy and chemotherapy.
Following a first report by Arseneau and collaborators (1972), a number of authors have studied the risk of second cancer following treatment for HD (Boivin and others 1984). Initial reports focused mainly on the risk of leukemia following this treatment, but as longer follow-up periods were considered, an excess risk of a number of solid cancers (in particular breast and lung) became apparent.
The results of the first multinational study were published in 1987 by Kaldor and collaborators. The study involved the follow-up (based on 11 cancer registries in seven countries: Denmark, Finland, Norway, Sweden, Slovenia, Canada, and the United Kingdom) of a cohort of 28,462 patients treated for HD between 1950 (in the earliest countries) and 1984. Increases in the risk of NHL, leukemia, lung, bladder, and breast cancer were reported in this cohort. No treatment information was available in this study, and no information is provided on radiation risks. Nested case-control studies of leukemia and of lung cancer were carried out, allowing reconstruction of individual doses for the subjects and estimation of site-specific cancer risks (Kaldor and others 1990a, 1992).
The case-control study of leukemia included 163 cases and 455 controls. Radiation dose to the active bone marrow was estimated for subjects who had undergone radiotherapy, and doses were classified into three categories (<10, 10–20, and 20+ Gy). Among patients who did not receive chemotherapy, a significant increase in the risk of leukemia was seen at doses of more than 20 Gy (Kaldor and others 1990a).
Another case-control study from the same collaborative group involved 98 cases of lung cancer occurring between 1960 and 1987 and 259 matched controls (Kaldor and others 1992). Radiation dose to the lung as a whole was estimated for the 60 cases and 275 controls who had undergone radiotherapy, and doses were classified into three categories (<1, 1–2.5, and 2.5+ Gy). Among patients treated with radiotherapy alone, there was a nonsignificant increase in risk in relation to radiation dose level. It is noted that the follow-up was short in this study, with three-quarters of the lung cancer cases having been diagnosed within 10 years of their initial disease (Kaldor and others 1992).
In 1995, Boivin and collaborators published results of a joint Canada-U.S. study of second cancer risk among 10,472 patients treated for HD between 1940 and 1987. A total of 122 leukemia and 438 solid tumors were found, and nested case-control studies were carried out. Significant increases in the risk of cancers of the respiratory system, intrathoracic organs, and female genital system were observed among patients followed for 10 years or more after surgery. Estimates of organ doses were not available, and analyses by level of radiation dose are not shown.
Van Leeuwen and collaborators (1995) conducted a case-control study of lung cancer nested in a cohort of 1939 patients treated for HD between 1966 and 1986 in the Netherlands. Radiation dose to the parenchyma, bronchi, and trachea were estimated for patients who had received radiotherapy (30 cases and 82 controls). A statistically significant increase in the risk of lung cancer was observed, with an RR of 9.6 (95% CI 0.93, 98.0) for patients who had received 9 Gy or more compared to patients who had received less than 1 Gy. The increase was greater among those who either continued smoking or started smoking after diagnosis, and a multiplicative interaction was observed between radiation dose and tobacco smoking.
Swerdlow and collaborators (2001) carried out a nested case-control study of lung cancer in a cohort of 5519 patients with HD treated in Britain between 1963 and 1993. The study included 88 cases and 176 controls for whom treatment and other risk factor information was abstracted from medical records. An increased risk of lung cancer following radiotherapy was observed. No individual reconstruction of dose to the lung was carried out.
Travis and colleagues (2002) carried out a case-control study of lung cancer nested within a multinational cohort of 19,046 HD patients diagnosed between 1965 and 1994 and reported to population-based cancer registries in Connecticut, Iowa, Denmark, Finland, the Netherlands, Sweden, and Canada (Ontario). The study included 222 cases and 444 matched controls. Nineteen of the cases were included in the previous case-control study by Kaldor and coworkers (1992). Dose to the specific location of the lung where the tumor had developed (and to a comparable location for matched controls) was calculated from radiotherapy records. The mean dose was 27.2 Gy in cases and 21.8 Gy in controls. In subjects who had not undergone chemotherapy, a significantly increased risk of lung cancer was observed (odds ratio [OR]3 5.9; 95% CI 2.7, 13.5) for a dose of 5 Gy or more. A significant trend in risk was observed with increasing dose.
In a follow-up to this study, Gilbert and colleagues (2003) analyzed radiation effects among 227 lung cancer cases and