George B. Hutchison

Radiation dose and second cancer risk in patients treated for cancer of the cervix

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-Hodgkins 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, Hodgkins 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.

Factors affecting the association of oral contraceptives and ovarian cancer.

We investigated the relation between epithelial ovarian cancer and the use of oral contraceptives in a case-control study of 144 white women under the age of 60 who had ovarian cancer and 139 white women under 60 who were selected from the general population. We observed a decreased risk for ovarian cancer associated with the use of oral contraceptives in subjects 40 through 59 years of age at the time of the study. The relative risk, adjusted for parity, was 0.11, with 95 per cent confidence limits of 0.04 to 0.33. In contrast to the findings in older women, a decreased risk for ovarian cancer associated with oral-contraceptive use was not found in women under 40. In this group, the adjusted relative risk associated with any use of oral contraceptives was 1.98, with 95 per cent confidence limits of 0.74 to 5.27. The lowest risk for ovarian cancer associated with the use of oral contraceptives was observed in older parous subjects and in women who had discontinued use more than 10 years previously.

Coronary heart disease mortality after irradiation for Hodgkin's disease

The authors conducted a study designed to evaluate the hypothesis that irradiation to the heart in the treatment for Hodgkins disease (HD) is associated with increased coronary heart disease (CHD) mortality. This report describes 957 patients diagnosed with HD in 1942–75 and analyzes follow‐up findings through December 1977. Twenty‐five coronary heart disease deaths have been observed, and 4258.2 person‐years of experience at risk have been accrued. The relative death rate (RDR), defined as the CHD mortality for heart‐irradiated subjects divided by the mortality for nonirradiated subjects, was estimated. After adjustment for the effect of interval of observation, age, stage, and class, the RDR estimate is 1.5 but does not differ significantly from unity (95% confidence limits: 0.59, 3.7).

Coffee Drinking and Death Due to Coronary Heart Disease

For a series of 649 patients who died of coronary heart disease within 24 hours of onset of symptoms, and an equal number of neighborhood controls, information was obtained on a large number of variables, including coffee consumption. An analysis using multivariate risk scores to control for all available variables yields a maximum likelihood estimate of the risk ratio associated with coffee drinking of 1.1 (95 per cent two-sided confidence limits, 0.8 to 1.6). The estimate of the risk ratio depends somewhat on the number and nature of variables controlled for in the analysis. Overall, our findings, limited to low-risk and middle-risk patients, suggest that the risk, if any, of death from coronary heart disease associated with coffee drinking is small.

Late neoplastic changes following medical irradiation

New additions since 1968 to the literature on radiation carcinogenesis in man support the earlier conclusion of an approximately linear increase in cancer incidence in a broad intermediate dose range for most sites of cancer. Questions are raised regarding the nature of the dose‐response relation at very low and at very high dose exposures. Analyses of some data on exposure to radiation from internal deposits of radioactive material suggest that the dose‐response curve at low and intermediate ranges is concave up, implying a smaller effect per unit exposure at very low doses than at intermediate ranges. Data on exposure to the very high but anatomically limited doses of radiation used in cancer therapy give conflicting results, suggesting in one report a continuation of the linear relation into the high‐dose range. Other reports suggest a lesser effect per unit dose at high doses than at intermediate doses. Extensive laboratory studies of exposure of experimental animals indicate that over broad dose ranges, exceptions to simple linear relations are the rule, and that factors of dose rate and fractionation also affect the dose‐response relation.

Radiotherapy of stage I and II Hodgkin's disease. A collaborative study

Four hundred sixty patients enrolled in a randomized trial of involved field (IF) and extended field (EF) radiotherapy for Hodgkins disease Stages I and II in the years 1967 to 1973 have been followed to a maximum of 13 years. Minimum time at risk is 6 years, and median follow‐up is 8 years. Actuarial survivals are 85% IF and 87% EF at 5 years. The overall standardized risk ratio comparing IF with EF is 1.3, implying a 30% excess mortality in IF, a nonsignificant difference. For males the risk ratio is 1.7 and significant, whereas for females it is 0.6, a nonsignificant reduction in risk with IF therapy. Extension‐free survival was significantly better in the EF group than in the IF within 2 years after treatment, and that benefit persists to the current follow‐up, with extension‐free survivals of 42% IF and 64% EF at 5 years. The risk ratio is 1.7. Favorable survival is significantly correlated with initial characteristics of female sex, age younger than 40 years, and histologic type nodular sclerosis or lymphocyte predominance. Histologic type is the most powerful predictor in the total series, but its prognostic value is not seen in patients staged with laparotomy. Six cases of leukemia have been reported in this series, among whom less than one case would be expected at general population rates. All leukemias have occurred in 167 patients who required chemotherapy for extension of Hodgkins disease after initial radiotherapy, implying an increased risk following chemotherapy of more than 200‐fold.

Correcting a Bias

Horwitz and Feinstein, in an article in this issue of the Journal, suggest that a selection bias explains the strong association between exogenous estrogens and endometrial cancer reported by many ...