The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

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A prospective study of the prognostic significance of the labelling index (LI) was undertaken in 1972. The LI of the primary tumor was measured consecutively on 128 patients with mammary carcinoma at the time of initial treatment, following in vitro incubation of specimens with tritiated thymidine. The follow-up for all patients has now extended over 10 years. Relapse-free survival and total survival are significantly higher in patients with a low LI. A multivariate analysis of the prognostic factors, carried out with Cox's model, showed that LI is the most predictive indicator with respect to survival. The size of the tumor is the second most predictive indicator, while histological grading and the number of involved lymph nodes are less predictive. These results strongly suggest that proliferative activity as assessed by LI is directly related to metastatic dissemination probability, independent of other prognostic factors.

The relationship between breast cancer and radiation treatment for cervical cancer was evaluated in an international study of 953 women who subsequently developed breast cancer and 1,806 matched controls. Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed for exposed subjects on the basis of their original radiotherapy records. Overall, 88% of the breast cancer cases and 89% of the controls received radiation treatment [relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.7-1.2]. Among women with intact ovaries (561 cases, 1,037 controls), radiotherapy was linked to a significant 35% reduction in breast cancer risk, attributable in all likelihood to the cessation of ovarian function. Ovarian doses of 6 Gy were sufficient to reduce breast cancer risk but larger doses did not reduce risk further. This saturation-type response is probably due to the killing of a critical number of ovarian cells. Cervical cancer patients without ovaries (145 cases, 284 controls) were analyzed separately because such women are at especially low natural risk for breast cancer development. In theory, any effect of low-dose breast exposure, received incidentally during treatment for cervical cancer, should be more readily detectable. Among women without ovaries, there was a slight increase in breast cancer risk (RR = 1.07; 95% CI = 0.6-2.0), and a suggestion of a dose response with the RR being 1.0, 0.7, 1.5 and 3.1 for breast doses of 0, 0.01-0.24, 0.25-0.49 and 0.50+ Gy, respectively. However, this trend of increasing RR was not statistically significant. If low-dose radiation increases the risk of breast cancer among women over age 40 years, it appears that the risk is much lower than would be predicted from studies of younger women exposed to higher doses.

Thymidine labelling index (LI) was prospectively assayed in vitro in a series of 128 consecutive patients with breast cancer. The follow-up was longer than 15 years for all patients. The distribution of LI was log normal and patients were subdivided into 3 groups (patients with LI = m +/- sigma, lower than m - sigma and greater than m + sigma where m is the geometrical mean). The incidence of relapse and death remained significantly lower in the group with a low LI than in the 2 other groups, whereas the difference between the 2 other groups faded away when follow-up exceeded 10 years. Multivariate analyses show that LI is one of the two most important independent prognostic indicators for relapse or death, the other being histological grading. Data concerning 2,648 patients treated at our Institute, prior to the introduction of chemotherapy into treatment protocols, have been used to investigate the influence of tumor growth rate on the probability of distant dissemination. A model of the natural history was used, in order to generate metastasis appearance curves, in 3 subgroups of patients, according to the value of the tumor doubling time (TDT). Our results show that after a follow-up exceeding 8 years, there is no longer any difference between the subgroups of patients with rapid or intermediate growth rate, whereas after 25 years large and highly significant differences in relapse and survival between the slow-growing tumors and the other two subgroups still remain. These two sets of data concur to show that tumor growth rate or proliferation rate correlates with the probability of metastatic dissemination.

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