Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries.

The numbers of second cancers among 182,040 women treated for cervical cancer that were reported to 15 cancer registries in 8 countries were compared to the numbers expected had the same risk prevailed as in the general population. A small 9% excess of second cancers (5,146 observed vs. 4,736 expected) occurred 1 or more years after treatment. Large radiation doses experienced by 82,616 women did not dramatically alter their risk of developing a second cancer; at most, about 162 of 3,324 second cancers (approximately equal to 5%) could be attributed to radiation. The relative risk (RR = 1.1) for developing cancer in organs close to the cervix that had received high radiation exposures--most notably, the bladder, rectum, uterine corpus, ovary, small intestine, bone, and connective tissue--and for developing multiple myeloma increased with time since treatment. No similar increase was seen for 99,424 women not treated with radiation. Only a slight excess of acute and non-lymphocytic leukemia was found among irradiated women (RR = 1.3), and substantially fewer cases were observed than expected on the basis of current radiation risk estimates. The small risk of leukemia may be associated with low doses of radiation absorbed by the bone marrow outside the pelvis, inasmuch as the marrow in the pelvis may have been destroyed or rendered inactive by very large radiotherapy exposures. There was little evidence of a radiation effect for cancers of the stomach, colon, liver, and gallbladder, for melanoma and other skin cancers, or for chronic lymphocytic leukemia despite substantial exposures. An excess of thyroid cancer possibly was related to the low dose received by this organ. Ovarian damage caused by radiation may have been responsible for a low breast cancer risk (RR = 0.7), which was evident even among postmenopausal women. A substantial excess of lung cancer (RR = 3.7) largely may be due to misclassification of metastases and the confounding influence of cigarette smoking. Women who were under 30 or over 50 years of age when irradiated were at greatest absolute risk for developing a second cancer. The RR, however, was higher among those under age 30 years at exposure (RR = 3.9) than among older women. The expression period for radiation-induced solid tumors appeared to continue to the end of life.

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

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Prognostic factors in the survival of 1,484 stroke cases observed for 30 to 48 months. II. Clinical variables and laboratory measurements.

Using the life table method, 962 cases of infarction, 279 cases of hemorrhage, and 243 cases of undetermined type of stroke, occurring in Manitoba between Jan 1, 1970, and June 30, 1971, were analyzed for factors affecting survival. Survival until Dec 31, 1973, was found to be adversely affected by the presence of coma or unconsciousness and the absence of localizing signs and symptoms. Also, the prognosis was poor if the heart was enlarged on the x-ray film or the ECG was abnormal. On the other hand, the presence of individual clinical entities such as hypertension, hypertensive heart disease, myocardial infarction, atrial fibrillation, or diabetes did not affect the survival significantly. These findings will help in predicting the prognosis and in planning for management of stroke cases.

Prognostic factors in the survival of 1,484 stroke cases observed for 30 to 48 months. I. Diagnostic types and descriptive variables.

Survival and factors affecting survival were studied in 1,484 new cases of acute definite stroke occurring between Jan 1, 1970, and June 30, 1971, in Manitoba. The 962 infarctions, 279 hemorrhages, and 243 unidentified strokes were ascertained from hospital claim reports. Personal, clinical, and laboratory data were collected from hospital medical records, death certificates, and autopsy reports. Cases were followed up until Dec 31, 1973, to determine survival. Survival was significantly better in infarction than in hemorrhage, in subarachnoid hemorrhage than in intracerebral hemorrhage, in men than in women, in the young than in the old, in the married than in the single, in hemorrhage cases from rural areas than from urban areas, and in those discharged home than in those transferred to long-term care hospitals. These data may help in predicting the outcome of stroke and in planning for more efficient care.

Non-Hodgkin's lymphoma and specific pesticide exposures in men: cross-Canada study of pesticides and health.

Our objective in the study was to investigate the putative associations of specific pesticides with non-Hodgkin's Lymphoma [NHL; International Classification of Diseases, version 9 (ICD-9) 200, 202]. We conducted a Canadian multicenter population-based incident, case (n = 517)-control (n = 1506) study among men in a diversity of occupations using an initial postal questionnaire followed by a telephone interview for those reporting pesticide exposure of 10 h/year or more, and a 15% random sample of the remainder. Adjusted odds ratios (ORs) were computed using conditional logistic regression stratified by the matching variables of age and province of residence, and subsequently adjusted for statistically significant medical variables (history of measles, mumps, cancer, allergy desensitization treatment, and a positive history of cancer in first-degree relatives). We found that among major chemical classes of herbicides, the risk of NHL was statistically significantly increased by exposure to phenoxyherbicides [OR, 1.38; 95% confidence interval (CI), 1.06-1.81] and to dicamba (OR, 1.88; 95% CI, 1.32-2.68). Exposure to carbamate (OR, 1.92; 95% CI, 1.22-3.04) and to organophosphorus insecticides (OR, 1.73; 95% CI, 1.27-2.36), amide fungicides, and the fumigant carbon tetrachloride (OR, 2.42; 95% CI, 1.19-5.14) statistically significantly increased risk. Among individual compounds, in multivariate analyses, the risk of NHL was statistically significantly increased by exposure to the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D; OR, 1.32; 95% CI, 1.01-1.73), mecoprop (OR, 2.33; 95% CI, 1.58-3.44), and dicamba (OR, 1.68; 95% CI, 1.00-2.81); to the insecticides malathion (OR, 1.83; 95% CI, 1.31-2.55), 1,1,1-trichloro-2,2-bis (4-chlorophenyl) ethane (DDT), carbaryl (OR, 2.11; 95% CI, 1.21-3.69), aldrin, and lindane; and to the fungicides captan and sulfur compounds. In additional multivariate models, which included exposure to other major chemical classes or individual pesticides, personal antecedent cancer, a history of cancer among first-degree relatives, and exposure to mixtures containing dicamba (OR, 1.96; 95% CI, 1.40-2.75) or to mecoprop (OR, 2.22; 95% CI, 1.49-3.29) and to aldrin (OR, 3.42; 95% CI, 1.18-9.95) were significant independent predictors of an increased risk for NHL, whereas a personal history of measles and of allergy desensitization treatments lowered the risk. We concluded that NHL was associated with specific pesticides after adjustment for other independent predictors.

Household water source and the risk of childhood brain tumours: results of the SEARCH International Brain Tumor Study.

BACKGROUND: The period in utero is a time of increased vulnerability. Offspring of pregnant women exposed to carcinogenic substances in drinking water may be more likely to develop cancer. We examined whether household water source and the presence of nitrates or nitrites in residential water were associated with increased risks of childhood brain tumours (CBT). METHODS: We used data from a multicentre, case-control study with maternal information on residential water source, and nitrate/nitrite levels of tap water measured by dipstick. Subjects included 836 CBT cases and 1485 controls from five countries. RESULTS: The risks of CBT associated with reliance on well water (versus public water) during pregnancy varied widely, with significantly increased risks noted in two (of seven) regions and a decreased risk observed in one region. CBT risk did not increase with increasing nitrate levels. However, our results based on tap water tested in the pregnancy residences suggest the risk of astrocytoma may be associated with increasing levels of nitrite (odds ratio [OR] = 4.3, 95% CI: 1.4, 12.6 for nitrite levels of 1-<5 mg/l nitrite ion; OR = 5.7, 95% CI: 1.2, 27.2 of nitrite > or =5 mg/l). CONCLUSIONS: These results should be interpreted with caution because women's recollection of water sources may have contained inaccuracies, and nitrate and nitrite measurements, available for only a portion of subjects, were often obtained years after the pregnancies occurred. However, our results suggest a need for closer evaluation of well water content in some regions and the possibility that a nitrite-related water exposure may be associated with CBT.

An international case-control study of adult glioma and meningioma: the role of head trauma.

BACKGROUND: Increased brain tumour risk after head trauma suggested by case reports and clinical series has been previously studied epidemiologically with mixed results. An international multicentre case-control study investigated the role of head trauma from injury or sports participation in adult brain tumour risk. METHODS: In all, 1178 glioma and 330 meningioma cases were individually or frequency matched to 2236 controls. Only exposures that occurred at least 5 years before diagnosis and head injuries that received medical attention were considered. RESULTS: Risk for ever having experienced a head injury was highest for male meningiomas (odds ratio [OR] = 1.5, 95% confidence interval [CI] : 0.9-2.6) but was lower for 'serious' injuries, i.e. those causing loss of consciousness, loss of memory or hospitalization (OR = 1.2, 95% CI: 0.6-2.3). Among male meningiomas, latency of 15 to 24 years significantly increased risk (OR = 5.4, 95% CI: 1.7-16.6), and risk was elevated among those who participated in sports most correlated with head injury (OR = 1.9, 95% CI: 0.7-5.3). Odds ratios were lower for male gliomas (OR = 1.2, 95% CI : 0.9-1.5 for any injury; OR = 1.1, 95% CI: 0.7-1.6 for serious injuries) and in females in general. CONCLUSIONS: Evidence for elevated brain tumour risk after head trauma was strongest for meningiomas in men. Findings related to sports should be interpreted cautiously due to cultural variability in our data and our lack of complete data on physical exercise in general which appeared to be protective.

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-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.

Epidemiology of primary intracranial neoplasms in Manitoba, Canada.

The incidence of primary intracranial tumors in Manitoba, Canada was reviewed. From 1980 through 1985, 657 tumors were diagnosed. The crude incidence rates were 10.2/100,000 for males and 10.8/100,000 for females. The three most common tumors were: astrocytoma 281 (43%), meningioma 145 (22%), and pituitary adenoma 111 (17%). Average annual incidence rates for all tumors showed a bimodal distribution with one peak in the 0-4 age group (4.2/100,000), and the other in the 60-69 age group (27.2/100,000). For malignant astrocytoma, the age-specific annual incidence rate increased to the seventh decade where it reached a peak of 14.3/100,000. The incidence of benign astrocytoma remained relatively constant with age at 1.1/100,000. The annual incidence of meningioma increased with age up to the eighth decade reaching 7.2/100,000. Of the 145 meningiomas, 56 (39%) were meningotheliomatous, 48 (33%) transitional, 10 (7%) malignant, 7 (5%) fibroblastic, 6 (4%) psammomatous, 3 (2%) angioblastic, and 15 (10%) lacked pathologic diagnosis. The annual incidence of pituitary adenoma showed two peaks, the first occurring in the third decade (2.6/100,000) and the second in the eighth decade (3.2/100,000). Although the incidence of meningioma was relatively high, the clinical features and pathologic patterns of these tumors were not unlike those previously reported in the literature.

Cancer risks among residents of Manitoba Indian reserves, 1970-79.

A descriptive epidemiologic study of malignant neoplasms among residents of Indian reserves in Manitoba from 1970 to 1979 based on the Manitoba Cancer Registry revealed an unusual pattern. There was a greater risk for kidney cancer in both sexes and for gallbladder and invasive cervical cancer in women. The risk was reduced, however, for cancer of the lung in men and of the breast in women, cancers with a high incidence in the general Canadian population. Overall the risk for cancer was lower in both sexes. The results are compared with those of other studies in Indians, and possible exposure to risk factors in this population is discussed.

Epidemiologic features of cerebrovascular disease in Manitoba: incidence by age, sex and residence, with etiologic implications.

To determine the incidence of and risk factors in cerebrovascular disease in Manitoba, all 1367 new cases in defined areas (population, 660 391) in an 18-month period were studied. Pertinent data were collected from hospital records, death certificates and autopsy reports. The annual incidence of cerebrovascular disease in these areas was 138/100 000 and the incidence was generally higher in men than in women. The incidence of cerebral infarction (INF) and that of hemorrhage (HGE) were similar in men and women less than 50 years old; thereafter the incidence of INF increased faster with age than did that of HGE, the disparity being greater in men than in women, whereas the incidence of HGE increased at similar rates in the two sexes. The incidence of INF was significantly greater in men than in women in urban areas, and in men it was greater in urban than in rural areas. Elevated concentrations of serum lipids and smoking are implicated as risk factors in INF, and hypertension as a risk factor in HGE.

Some descriptive epidemiologic features of central nervous system (CNS) neoplasms in childhood, in Manitoba, Canada.

In an attempt to describe epidemiologic features to generate etiological hypotheses and to study natural history, 121 cases of childhood CNS neoplasms under 15 years of age, occurring during 1950-66 in Manitoba, were analyzed. The incidence of CNS neoplasms in childhood (2.4/100 000 per annum) ranks second only to leukemia in Manitoba. For both sexes somewhat elevated incidences were noted for both extreme age groups; i.e. 0-4 and 10-14. Such peaks were more prominent for gliomas, which may indicate differential factors operation in the genesis of gliomas between early and late childhood. The former may be related to genetic and/or perinatal environmental factors and the latter, to environmental factors, in early childhood. Excess occurrences of gliomas among Irish, Scottish and Icelandic offsprings were observed, which possibly indicates the importance of either genetic or environmental factors peculiar to these ethnic groups. There was no evidence of time clustering (i.e. season and year) by estimated conception or by birth. Further investigation into the relative role of genetic and environmental factor in the genesis of childhood gliomas are in order.

Herpesvirus infection and cervical anaplasia: a seroepidemiological study.

In a cohort of 23,146 pregnant females followed for 37-56 months subsequent to collection of prenatal sera, 57 cases of carcinoma of the cervix were encountered. Three controls were selected for each case from the residual cohort matched to cases for age, residence, number of prior cytology smears taken, and the data of entry to the study. The antibody activity to herpesvirus type 1 and type 2 was examined by the indirect hemagglutination test. The proportion of cases positive for HSV-2 infection was greater than that of the controls; however, the difference was not significant at the 5% level. The relative risk value for the association between HSV-2 infection and carcinoma of the cervix was found to be 2.33. The geometric mean titers of IHAT revealed that the cases of cervical cancer had a higher titer than the controls with respect to HSV-1 as well as HSV-2 antibodies. A sufficiently longer follow-up, yielding a larger sample size, is desired to assess the specific role of HSV-2 infection in development of cervical anaplasia.

Does family history of breast cancer improve survival among patients with breast cancer?

Overall cancer mortality to December 1985 among 291 patients whose breast cancer was diagnosed between 1971 and 1974 and who were interviewed shortly after diagnosis was 39.9% (116 deaths). In this study population a positive maternal family history was strongly associated with breast cancer: The odds ratio for patients versus controls of having a mother with breast cancer was 3.32 (95% confidence limits 1.64 and 6.72); the odds ratio of having a mother, sister, or maternal aunt with breast cancer was 1.92 (95% confidence limits 1.27 and 2.91). However, family history was not associated with stage at diagnosis, which is the most important survival factor (53.6% of patients with a family history and 51.7% without were at a local stage at diagnosis). Survival was better, although not significantly so, among women with maternal relatives with breast cancer. The relative risk of dying of cancer, adjusted for confounding factors, was 1.40 for women without versus with a family history; the difference in survival was not statistically significant.

Relative role of factors associated with cerebral infarction and cerebral hemorrhage. A matched pair case-control study.

Comprehensive ascertainment of all possible new cases of stroke appearing between January 1, 1970 and June 30, 1971, and admitted to three major hospitals in Winnipeg, Manitoba, has been achieved by reviewing the Manitoba Health Services Commission claim reports. The medical records of these cases were reviewed, pertinent data were abstracted, and rigid criteria for diagnosis were followed. Also, data were obtained from death certificates, autopsy reports and long-term hospital records. A total of 606 ascertained cases (410 infarction, 137 hemorrhage, and 59 undetermined type) were matched for age, sex, residence and year of admission with 606 controls from admissions for other than cardiovascular and cerebrovascular disorders. The data were analyzed for elucidating the possible risk factors for infarction (INF) and hemorrhage (HGE). The findings suggested that hypertension was the main risk factor in hemorrhage, whereas in infarction, along with hypertension, other factors such as diabetes, heart enlargement in chest x-ray, ECG abnormalities, and smoking were suggested as risk factors. There was an association also between infarction, on one hand, and the history of receiving anticoagulants, diuretics, and medications for the heart, and the occurrence of myocardial infarction, on the other hand. These features indicate that infarction and ischemic heart disease have similar risk factors. Hemoglobin and hematocrit were higher in infarction cases than in their controls only when measured at stroke admission. No difference was revealed when they were measured prior to stroke. Their association with infraction therefore may be secondary to other factors and of no significance for its risk.