J. D. Boice

BACKGROUND: Children diagnosed with retinoblastoma, a rare cancer of the eye, tend to develop and die of second primary cancers in childhood and adolescence, but few investigations have followed patients into adulthood. Retinoblastoma is frequently caused by inherited mutations of the RB1 tumor suppressor gene. Most patients with germline (hereditary) mutations have bilateral disease. PURPOSE: We sought to quantify the mortality from second malignancies among long-term survivors of retinoblastoma and to identify factors that predispose to these deaths. METHODS: A retrospective cohort study examined mortality among 1603 patients enrolled at 1 year after diagnosis of retinoblastoma during the period 1914-1984. Data on demography, family history, and retinoblastoma treatment were collected by medical chart review and questionnaire interview. Number of deaths, by cause, was compared with the corresponding expected figure based on U.S. mortality data for the general population for 1925-1990. RESULTS: Follow-up was complete for 1458 patients (91%) for a median of 17 years after retinoblastoma diagnosis. A total of 305 deaths occurred, 167 of them from retinoblastoma. There were 96 deaths from second primary tumors (relative risk [RR] = 30), 21 from other known causes (RR = 1.0), and 21 from ill-defined or unknown causes. Statistically significant excess mortality was found for second primary cancers of bone, connective tissue, and malignant melanoma and benign and malignant neoplasms of brain and meninges. Among 919 children with bilateral retinoblastoma, 90 deaths from second primary tumors occurred (RR = 60). Deaths from second tumors were more frequent among females (RR = 39) than males (RR = 22) (P = .007). The cumulative probability of death from second primary neoplasms was 26% at 40 years after bilateral retinoblastoma diagnosis, and additional cancer deaths occurred thereafter. Radiotherapy for retinoblastoma further increased the risk of mortality from second neoplasms. An excess of mortality from a second cancer, not seen in prior studies, was found among the 684 children with unilateral disease (RR = 3.1; 95% confidence interval = 1.0-7.3). CONCLUSIONS: These findings implicate germinal mutations in the retinoblastoma gene in second cancer mortality. Radiotherapy treatment for retinoblastoma appears to further enhance the inborn susceptibility to development of a second cancer. IMPLICATIONS: Patients with retinoblastoma, particularly bilateral retinoblastoma, should have careful follow-up, and interventions should be developed to reduce mortality from a second cancer.

BACKGROUND: Studies of underground miners exposed to radioactive radon and its decay products have found that exposure increases risk of lung cancer. Consequently, when radon was found to accumulate in houses, there was concern about the public health impact from exposure to a known carcinogen. Estimates on the basis of studies of underground miners suggest that indoor radon may account for 6000-36,000 lung cancer deaths each year in the United States. Because of differences between working in underground mines and living in houses, estimates are subject to major uncertainties. Numerous case-control studies were launched to assess directly the lung cancer risk from indoor radon. Some studies report positive or weakly positive findings, while others report no increased risk. Thus, the potential hazard from indoor radon remains answered only indirectly through miner studies, experimental animal studies, and cellular studies. PURPOSE: To provide more information on the risk of lung cancer from indoor radon, we conducted a meta-analysis of all case-control studies that included at least 200 case subjects each and that used long-term indoor radon measurements. METHODS: Eight studies were available and included a total of 4263 lung cancer case subjects and 6612 control subjects. From the published results of each study, confounder-adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for categories of radon concentration were obtained, and weighted linear regression analyses were performed. RESULTS: The combined trend in the RR was significantly different from zero (two-sided P = .03), and an estimated RR of 1.14 (95% CI = 1.0-1.3) at 150 Bq/m3 was found. An influence analysis indicated that no single study dominated the combined results. The exposure-response trend was similar to model-based extrapolations from miners and to RRs computed directly from miners with low cumulative exposures. However, there were significant differences in the study-specific estimates of the exposure response (two-sided P < .001), which were not explained by study differences in percent of the defined exposure interval covered by radon measurements, mean number of residences per subject, and other factors. CONCLUSIONS: Meta-analyses are valuable for identifying differences among studies and for summarizing results, but they should be interpreted cautiously when expected RRs are low as with indoor radon exposure, when there is study heterogeneity and where there is the potential for confounding and exposure misclassification. Nonetheless, the results of this meta-analysis suggest that the risk from indoor radon is not likely to be markedly greater than that predicted from miners and indicate that the negative exposure response reported in some ecologic studies is likely due to model misspecification or uncontrolled confounding and can be rejected. IMPLICATIONS: Until ongoing case-control studies of indoor radon are completed and the data are pooled and analyzed, the studies of underground miners remain the best source of data to use to assess risk from indoor radon. This meta-analysis provides support for their general validity.

BACKGROUND: Radioactive radon is an inert gas that can migrate from soils and rocks and accumulate in enclosed areas, such as homes and underground mines. Studies of miners show that exposure to radon decay products causes lung cancer. Consequently, it is of public health interest to estimate accurately the consequences of daily, low-level exposure in homes to this known carcinogen. Epidemiologic studies of residential radon exposure are burdened by an inability to estimate exposure accurately, low total exposure, and subsequent small excess risks. As a result, the studies have been inconclusive to date. Estimates of the hazard posed by residential radon have been based on analyses of data on miners, with recent estimates based on a pooling of four occupational cohort studies of miners, including 360 lung cancer deaths. PURPOSE: To more fully describe the lung cancer risk in radon-exposed miners, we pooled original data from 11 studies of radon-exposed underground miners, conducted a comprehensive analysis, and developed models for estimating radon-associated lung cancer risk. METHODS: We pooled original data from 11 cohort studies of radon-exposed underground miners, including 65,000 men and more than 2700 lung cancer deaths, and fit various relative risk (RR) regression models. RESULTS: The RR relationship for cumulative radon progeny exposure was consistently linear in the range of miner exposures, suggesting that exposures at lower levels, such as in homes, would carry some risk. The exposure-response trend for never-smokers was threefold the trend for smokers, indicating a greater RR for exposure in never-smokers. The RR from exposure diminished with time since the exposure occurred. For equal total exposure, exposures of long duration (and low rate) were more harmful than exposures of short duration (and high rate). CONCLUSIONS: In the miners, about 40% of all lung cancer deaths may be due to radon progeny exposure, 70% of lung cancer deaths in never-smokers, and 39% of lung cancer deaths in smokers. In the United States, 10% of all lung cancer deaths might be due to indoor radon exposure, 11% of lung cancer deaths in smokers, and 30% of lung cancer deaths in never-smokers. This risk model estimates that reducing radon in all homes exceeding the U. S. Environmental Protection Agency's recommended action level may reduce lung cancer deaths about 2%-4%. These estimates should be interpreted with caution, because concomitant exposures of miners to agents such as arsenic or diesel exhaust may modify the radon effect and, when considered together with other differences between homes and mines, might reduce the generalizability of findings in miners.

A population-based case-control interview study of thyroid cancer (159 cases and 285 controls) was conducted in Connecticut. Prior radiotherapy to the head or neck was reported by 12% of the cases and 4% of the controls [odds ratio (OR) = 2.8; 95% confidence interval = 1.2-6.9]. Risk was inversely related to age at irradiation and was highest among children exposed under age 10. Few persons born after 1945 received prior radiotherapy, consistent with the declining use of radiation to treat benign conditions in the 1950's. Among females the radiogenic risk appeared to be potentiated by the number of subsequent live-births. Other significant risk factors included a history of benign thyroid nodules (OR = 33) or goiter (OR = 5.6). Miscarriage and multiparity increased risk but only among women who developed thyroid cancer before age 35 years. Consumption of shellfish (a rich source of iodine) seemed to increase the risk of follicular thyroid cancer, whereas consumption of goitrogen-containing vegetables appeared to reduce risk of total thyroid cancer, possibly because of their cruciferous nature. A significantly low risk was observed among persons of English descent, whereas Italian ancestry appeared to increase risk. No significant associations were found with a number of suspected risk factors: diagnostic x-rays, radioactive isotope scans, occupational radiation exposure, tonsillectomy, Jewish ethnicity, alcohol intake, cigarette smoking, oral contraceptives, lactation suppressants, menopausal estrogens, most other common medications, and water source. New associations were suggested for obesity among females (OR = 1.5), surgically treated benign breast disease (OR = 1.6), use of spironolactone (OR = 4.3) or vitamin D supplements (OR = 1.8), and a family history of thyroid cancer (OR = 5.2). About 9% of the incident thyroid cancers could be attributed to prior head and neck irradiation, 4% to goiter, and 17% to thyroid nodular disease, leaving the etiology of most thyroid cancers yet to be explained.

Several studies have shown that survivors of Hodgkin's disease have increased risk of lung cancer, but the factors responsible for this excess risk are not well known. This study was undertaken to investigate the effects of radiation dose, chemotherapy, and smoking on the risk of lung cancer following treatment of Hodgkin's disease. We conducted a case-control study in a cohort of 1939 patients treated for Hodgkin's disease from 1966 through 1986 in The Netherlands. Detailed treatment information was collected from the medical records for 30 case patients with lung cancer following Hodgkin's disease and 82 matched control subjects who had not developed lung cancer. Multiple sources were used to obtain as complete smoking histories of the study participants as possible. For each case-control set, the radiation dose received by the area of the lung where the case patient developed the tumor was estimated on the basis of radiotherapy charts and experimental simulations of treatments. The estimates of relative risk (RR) for lung cancer associated with specific exposures were obtained from logistic regression methods, and all tests of statistical significance were two-sided. A statistically significant increase in risk of lung cancer was observed with increasing radiation dose ( P for trend =.01) with an RR of 9.6 (95% confidence interval [CI] = 0.93–98) for patients who received 9 Gy or more compared with those who received less than 1 Gy. Patients who smoked more than 10 pack-years after the diagnosis of Hodgkin's disease had a sixfold increase in the risk of lung cancer compared with patients who smoked less than 1 pack-year ( P =.03). Positive interaction on a multiplicative scale was observed between the carcinogenic effects of smoking and radiation. The increase in risk of lung cancer with increasing radiation dose was much greater among the patients who smoked after diagnosis of Hodgkin's disease than among those who refrained from smoking ( P =.04). There was no increase in lung cancer risk in relation to the number of cycles of chemotherapy or the cumulative doses of the drugs mechlorethamine and procarbazine. The excess risk of lung cancer in Hodgkin's disease patients treated with radiotherapy is related to the radiation dose received by the affected area of the lung. Smokers experience a significantly greater risk attributable to radiotherapy than nonsmokers. Physicians in charge of patient treatment should make a special effort to dissuade Hodgkin's disease patients from smoking after receiving radiotherapy. [J Natl Cancer Inst 1995; 87:1530–7]