Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group.

CONTEXT: High-dose iodine 131 is the treatment of choice in the United States for most adults with hyperthyroid disease. Although there is little evidence to link therapeutic (131)I to the development of cancer, its extensive medical use indicates the need for additional evaluation. OBJECTIVE: To evaluate cancer mortality among hyperthyroid patients, particularly after (131)I treatment. DESIGN: A retrospective cohort study. SETTING: Twenty-five clinics in the United States and 1 clinic in England. PATIENTS: A total of 35 593 hyperthyroid patients treated between 1946 and 1964 in the original Cooperative Thyrotoxicosis Therapy Follow-up Study; 91 % had Graves disease, 79% were female, and 65% were treated with (131)I. MAIN OUTCOME MEASURE: Standardized cancer mortality ratios (SMRs) after 3 treatment modalities for hyperthyroidism. RESULTS: Of the study cohort, 50.5% had died by the end of follow-up in December 1990. The total number of cancer deaths was close to that expected based on mortality rates in the general population (2950 vs 2857.6), but there was a small excess of mortality from cancers of the lung, breast, kidney, and thyroid, and a deficit of deaths from cancers of the uterus and the prostate gland. Patients with toxic nodular goiter had an SMR of 1.16 (95% confidence interval [CI], 1.03-1.30). More than 1 year after treatment, an increased risk of cancer mortality was seen among patients treated exclusively with antithyroid drugs (SMR, 1.31; 95% CI, 1.06-1.60). Radioactive iodine was not linked to total cancer deaths (SMR, 1.02; 95% CI, 0.98-1.07) or to any specific cancer with the exception of thyroid cancer (SMR, 3.94; 95% CI, 2.52-5.86). CONCLUSIONS: Neither hyperthyroidism nor (131)I treatment resulted in a significantly increased risk of total cancer mortality. While there was an elevated risk of thyroid cancer mortality following (131)I treatment, in absolute terms the excess number of deaths was small, and the underlying thyroid disease appeared to play a role. Overall, (131)I appears to be a safe therapy for hyperthyroidism.

Calcium channel blockers and the risk of cancer.

CONTEXT: Recent epidemiologic studies have raised the concern that calcium channel blocker use may increase the risk of cancer overall and of several specific cancers. OBJECTIVE: To assess whether calcium channel blocker use increases the risk of cancer overall and of specific cancers. DESIGN: Case-control drug surveillance study based on data collected from 1983 to 1996. SETTING: Hospitals in Baltimore, Md, New York, NY, and Philadelphia, Pa. PATIENTS: A total of 9513 patients aged 40 to 69 years with incident cancer of various sites and 6492 controls aged 40 to 69 years admitted for nonmalignant conditions. MAIN OUTCOME MEASURES: Incident cancer overall and 23 specific cancers. RESULTS: Calcium channel blocker use was unrelated to the risk of cancer overall (relative risk [RR], 1.1; 95% confidence interval [CI], 0.9-1.3). Use was not significantly associated with increased risks of individual cancers, including those previously implicated, except cancer of the kidney (RR, 1.8; 95% CI, 1.1 -2.7). Recent use, use for 5 or more years, and use of individual calcium channel blocker drugs were also not associated with cancer incidence. Use of beta-blockers and angiotensin-converting enzyme inhibitors was generally unrelated to cancer overall or individual cancers, but both were associated with kidney cancer (RR, 1.8; 95% CI, 1.3-2.5; and RR, 1.9; 95% CI, 1.2-3.0, respectively). CONCLUSIONS: The present study suggests that the use of calcium channel blockers is unrelated to an increase in the overall risk of cancer or of individual cancers, except kidney cancer, which has been associated with hypertension or drugs to treat hypertension in previous studies.

Transitional cell cancer of the urinary tract and renal cell cancer in relation to acetaminophen use (United States).

Experimental and epidemiologic evidence have suggested that phenacetin use increases the risk of transitional cell cancers of the urinary tract. The drug is no longer marketed but a commonly used metabolite, acetaminophen, has been linked recently to an increased risk of renal cancer. We assessed the relation of acetaminophen use to the risk of transitional cell cancer of the urinary tract and of renal cell cancer with data from a hospital-based study of cancers and medication use conducted from 1976-96 in the eastern United States. We compared 498 cases of transitional cell cancer and 383 cases of renal cell cancer with 8,149 noncancer controls and 6,499 cancer controls and controlled confounding factors with logistic regression. For transitional cell cancer, the relative risk (RR) estimate for regular acetaminophen use that had begun at least a year before admission was 1.1 (95 percent confidence interval [CI] = 0.6-1.9) based on noncancer controls, and 0.9 (CI = 0.5-1.6) based on cancer controls. RR estimates for use that lasted at least five years, and for nonregular use, were also close to 1.0. For renal cell cancer, the corresponding estimates were again close to 1.0. Our results suggest that acetaminophen, as used in present study population, does not influence the risk of transitional cell cancer of the urinary tract or of renal cell cancer.

Induced and spontaneous abortion in relation to risk of breast cancer (United States).

The relation of induced and spontaneous abortion to the risk of breast cancer is evaluated in a hospital-based case-control interview study conducted in three cities in the United States from 1985 through 1995. Cases were 1,803 women aged 25 to 64 years with newly diagnosed invasive breast cancer; controls were 4,182 women of the same ages admitted for conditions unrelated to reproductive factors. Other breast cancer risk-factors were controlled through multiple logistic regression. The reference for all analyses was women who had never had an abortion, either induced or spontaneous. Among parous women, the relative risk (RR) estimate was 1.1 (95 percent confidence interval [CI] = 0.9-1.5) for induced abortion overall, 1.0 (CI = 0.7-1.4) for abortion before the first birth, and 1.3 (CI = 1.0-1.8) for abortion after at least one birth. Among nulliparous women, the relative risk estimate for induced abortion was 1.3 (CI = 0.9-1.9). There was no trend of increased risk with number of abortions, nor was there consistent evidence of an increased risk in any particular subgroup. Spontaneous abortion was not associated with increased risk of breast cancer, either among nulliparous women or among parous women. These findings provide little support for the hypothesis that induced abortion increases breast cancer risk overall or in particular subgroups.

Adult height and risk of breast cancer among white women in a case-control study.

Data from a hospital-based case-control study were analyzed to evaluate the relation of adult height to the risk of breast cancer among white women. The authors compared 5,358 newly diagnosed breast cancer cases and 4,555 controls interviewed from 1976 to 1992 in hospitals located mainly in the United States. Overall, there was no association between stature and risk of breast cancer. In comparison with women whose heights were less than 62 inches (< 158 cm), the adjusted odds ratios were 1.1 (95% confidence interval (Cl) 0.9-1.2), 1.0 (95% Cl 0.9-1.2), 1.0 (95% Cl 0.9-1.1), and 1.0 (95% Cl 0.8-1.2) for women with heights of 62-63, 64-65, 66-67, and > or = 68 inches (equivalent to 158-160, 163-165, 168-170, and > or =173 cm), respectively. There was no consistent evidence of modification of the effect of height by other risk factors. The results suggest that adult stature in white women is not related to the risk of breast cancer.

Case-control study of oral contraceptive use and risk of breast cancer.

The relation of oral contraceptive use to the risk of breast cancer in white women aged 25-59 years was assessed with data collected during 1977-1992 in a case-control surveillance system in hospitals in Boston, New York, and Philadelphia. A total of 3,540 cases with breast cancer were compared with 4,488 controls with nonmalignant nongynecologic conditions unrelated to oral contraceptive use. Relative risk estimates were obtained by unconditional logistic regression with control for major risk factors. For at least 1 year of use relative to less than 1 year, the multivariate relative risk estimate was 1.7 (95% confidence interval (CI) 1.3-2.3) in women aged 25-34 years, 0.9 (95% CI 0.7-1.0) in women aged 35-44 years, and 1.2 (95% CI 1.0-1.4) in women aged 45-59 years (p < 0.01 for the difference across age). Among women aged 25-34 years, the relative risk estimates were greatest for use of long duration, but the trend was not statistically significant (p = 0.17); in addition, the duration of use was correlated with the recency of use, and it was not possible to distinguish their effects. Among women aged 35-44 years, the relative risk estimate decreased with increasing duration of use (p = 0.01). Among women aged 45-59 years, some relative risk estimates were increased, but there was no consistent pattern. The results add to the evidence of an association between oral contraceptive use and an increased risk of breast cancer at young ages.

PIP: The relation of oral contraceptive use to the risk of breast cancer in White women 25-59 years old was assessed with data collected during 1977-1992 in a case-control surveillance system in hospitals in Boston, New York, and Philadelphia. A total of 3540 cases with breast cancer were compared with 4488 controls with nonmalignant nongynecologic conditions unrelated to oral contraceptive use. Relative risk estimates were obtained by unconditional logistic regression with control for major risk factors. For at least 1 year of use relative to less than 1 year, the multivariate relative risk estimate was 1.7 in women 25-34 years old, 0.9 in women 35-44 years old, and 1.2 in women 45-59 years old. Among women 25-34 years old, the duration-specific estimate increased to 2.5. In addition, the duration of use was correlated with the recency of use, and it was not possible to distinguish their effects. Among women 35-44 years old, the point estimate declined with increasing duration of use to 0.6 for 10 or more years of use. For women 45-59 years old, the point risk estimate was elevated for 5-9 years of use but not for 10 or more years of use. The association of 1 or more years of use with risk among women under age 35 differed significantly from that among women 35-44 and 45-59 years old. Among women 25-34 years old, the point estimates among women with a family history of breast cancer were greater than the corresponding estimates in women without such a history. The results add to the evidence of an association between oral contraceptive use and an increased risk of breast cancer at young ages, possibly modified by the duration or recency of use.

Oral contraceptive use and breast cancer risk among African-American women.

Recent epidemiologic studies, most of them in predominantly White populations, have suggested that long duration of oral contraceptive (OC) use may increase the risk of breast cancer at young ages. We assessed the relationship of OC use to the risk of breast cancer in African-American women aged 25 to 59 years, using interview data from a multipurpose hospital-based case-control study. Five hundred and twenty-four cases hospitalized for invasive breast cancer were compared with 1,021 controls with nonmalignant conditions unrelated to OC use. Relative risks (RR) and 95 percent confidence intervals (CI) were estimated relative to a reference category of use for less than 12 months; potential confounders were controlled by multiple logistic regression analysis. Among women under age 45, three or more years of OC use was associated with an increased risk of breast cancer: the RR estimate was 2.8 (CI = 1.5-5.0) for three to four years of use, and declined to 1.5 (CI = 08.3.0) for 10 or more years of use. Recency and timing of use did not explain the observed association. Among women aged 45 to 59, OC use was associated with little or no increase in risk: the RR estimate for three or more years of use was 1.3 (CI = 0.7-2.4). The findings add to the evidence from studies of White women and a recent study of Black women which have suggested an increased risk of breast cancer at young ages for moderate or long duration use of OCs.

Relation of benzodiazepine use to the risk of selected cancers: breast, large bowel, malignant melanoma, lung, endometrium, ovary, non-Hodgkin's lymphoma, testis, Hodgkin's disease, thyroid, and liver.

Some animal data have raised the possibility that benzodiazepines influence the risk of selected cancers. With data collected in 1977-1991 in a US hospital-based study, the authors assessed the relation of benzodiazepine use to the risk of 11 cancers: breast (6,056 patients), large bowel (2,203), malignant melanoma (1,457), lung (1,365), endometrium (812), ovary (767), non-Hodgkin's lymphoma (382), testis (314), Hodgkin's disease (299), thyroid (111), and liver (37). Cases were compared with cancer controls (3,777 patients with other cancers) and noncancer controls (1,919 patients admitted for acute nonmalignant disorders). Relative risks were estimated for benzodiazepine use at least 4 days a week for at least 1 month, initiated at least 2 years before admission (sustained use) by multiple logistic regression with control for confounding factors. Results derived with noncancer controls were similar to those derived with cancer controls. For sustained benzodiazepine use relative to no use, relative risk estimates for all 11 cancers were compatible with 1.0 at the 0.05 level of significance. Relative risk estimates for durations of at least 5 years were also compatible with 1.0, with the exceptions of an increased estimate, of borderline statistical significance, for endometrial cancer, and a decreased estimate for ovarian cancer. Relative risk estimates both for sustained use that continued into the 2-year period before admission and for sustained use that ended up to > or = 10 years previously were compatible with 1.0, suggesting a lack of tumor promotion and no increase in the risk after a latent interval. Results were also null for diazepam, chlordiazepoxide, and other benzodiazepines considered separately. The results suggest absence of association between benzodiazepine use and the cancers considered, with the evidence stronger for the cancers with larger numbers of subjects. The similarity of results derived with cancer and noncancer controls suggests that benzodiazepines do not influence the risk of cancer as a whole.

Adult height and risk of breast cancer among US black women.

Adult height has been positively associated with the risk of breast cancer in a number of recent investigations. The authors assessed height in relation to breast cancer risk in a case-control study of US black women aged 25-69 years; 674 hospital patients with newly diagnosed breast cancer and 1,155 controls hospitalized for nonmalignant conditions unrelated to height were interviewed. After control for multiple confounders, the relative risk estimate for women < 61 inches (< 154.9 cm) tall was 0.5 (95% confidence interval (Cl) 0.3-0.7) relative to the median height of 64-65 inches (162.6-165.1 cm). Among women > or = 61 inches (> or = 154.9 cm) tall, there was little indication of any variation in risk with increasing height. The findings suggest that short stature is associated with a decreased risk of breast cancer in US black women.

The relation of vasectomy to the risk of cancer.

We previously reported a strong positive association between vasectomy and the risk of prostatic cancer that arose in multiple comparisons made within data collected from 1976 to 1988 in an ongoing hospital-based surveillance study of many exposures and diseases. We have reassessed this association with data collected in the surveillance study during 1988-1992 from a new set of patients (355 cases of prostatic cancer and 2,048 controls with nonmalignant conditions). Because some studies have reported increased relative risks of lung cancer and testicular cancer in vasectomized men, we also used the surveillance database (4,126 men with various cancers, 7,027 men with nonmalignant conditions) to assess the relation of vasectomy to the risk of these and other cancers. In the newly collected data, the multivariate relative risk estimate for prostatic cancer in vasectomized men was 1.2 (95% confidence interval (CI) 0.6-2.7). For lung cancer and testicular cancer, the relative risk estimates were 1.3 (95% CI 0.8-2.1) and 0.8 (95% CI 0.4-1.9), respectively; for lung cancer occurring > or = 15 years after vasectomy, the relative risk estimate was 1.9 but it was not statistically significant (95% CI 0.7-5.0). For pancreatic cancer, the relative risk estimate was 1.8 (95% CI 1.0-3.1). For each of the other cancers considered--malignant melanoma, large bowel cancer, bladder cancer, kidney cancer, lymphoma, leukemia, and other cancers--the relative risk estimate was 1.3 or less and compatible with a value of 1.0. The present data provide little support for an association of vasectomy with the risk of prostatic cancer or other cancers. In addition, the data from two sets of cases of prostatic cancer and controls interviewed consecutively illustrate that increased relative risks detected in screening for statistically significant associations may tend to have an upward bias and to be lower in subsequent data.

A case-control study of oral contraceptive use and invasive epithelial ovarian cancer.

The relation of oral contraceptive use to the risk of ovarian cancer was assessed with data collected during 1977-1991 from patients under 65 years of age in hospitals in Boston, New York, Philadelphia, and Baltimore. We compared 441 women with recently diagnosed invasive epithelial ovarian cancer to 2,065 control women. Logistic regression was used to control risk factors for ovarian cancer. The multivariate relative risk estimate decreased with the increasing duration of oral contraceptive use (p < 0.05): the estimate was close to 1.0 for duration categories of less than 3 years; it was reduced for the categories of 3-4 years of use and greater, but it did not decline further as the duration of use increased. For > or = 3 years of use, the estimate was 0.6 (95% confidence interval 0.4-0.8). The inverse association of risk with > or = 3 years of use was consistently present across categories of age, parity, interview year, and geographic area. It was apparent for as long as 15-19 years after cessation. Many different specific oral contraceptive formulations appeared related to a decreased risk; however, data were sparse for the newer types, particularly phasic preparations, and the ability to assess specific preparations in the context of use of multiple preparations was limited. The present data confirm previous reports of an inverse association of ovarian cancer risk with oral contraceptive use of several years in duration. They also suggest that the association may persist for as long as two decades and that it is not confined to any particular type of oral contraceptive formulation.

Oral contraceptive use and risk of cutaneous malignant melanoma.

The relation between cutaneous malignant melanoma (MM) and the use of oral contraceptives (OC) was investigated in a case-control study carried out from 1979 to 1991 among patients in hospitals and clinics in the Philadelphia (PA) and New York City (NY) metropolitan areas (United States). Cases were 615 women under age 70 who recently had been diagnosed with invasive melanoma; controls were 2,107 women of the same ages who had been treated for other conditions unrelated either to OC use or to skin diseases. The cases were categorized as severe or nonsevere based on the depth of invasion of the tumor or the presence or absence of metastases. Among the severe cases, OC use was not associated with MM: the relative risk (RR) estimate for ever-use was 1.1 (95 percent confidence interval [CI] = 0.8-1.5) and the estimate for 10 or more years of use was 1.1 (CI = 0.6-2.1). Nor was risk associated with recent use, long latency, or young age at first use. Among the nonsevere cases, ever-use of oral contraceptives was associated positively with MM (RR = 1.5, CI = 1.1-2.4) but there was no trend with increased duration of use. The findings provide evidence against the hypothesis that OC use increases the risk of malignant melanoma. The elevated estimates among the nonsevere cases most likely reflect selection bias rather than a causal relation.

Estrogen replacement therapy and the risk of breast cancer: results from the case-control surveillance study.

To examine the relation of noncontraceptive estrogen use to the risk of breast cancer among postmenopausal women, the authors conducted a case-control study: 1,686 cases were compared with 2,077 hospital control subjects, of whom 1,120 had non-gynecologic cancers and 957 had nonmalignant (also non-gynecologic) conditions. Data were obtained from 1980 to 1986, by interview of subjects in hospitals in the United States and Canada. The relative risk estimate for any use of replacement estrogens unopposed by progestogens was 1.2 (95% confidence interval (Cl) 1.0-1.4), after adjustment for age and type of menopause; when all known risk factors for breast cancer were taken into account in a multivariate analysis, the estimate was similar. For use of at least 15 years duration, the estimate was 0.9 (95% Cl 0.5-1.9). Most of the unopposed use was of conjugated estrogens: overall, the relative risk (95% Cl) was 1.3 (1.0-1.6); for durations of 15 or more years, it was 0.9 (0.4-1.9); for use of 5 years followed by a latent interval of 15 or more years, it was 1.3 (0.7-2.4); and for current use it was 1.1 (0.7-1.6). There was no evidence of increased breast cancer risk when the conjugated estrogen users were divided according to dose. There was little use of estrogens opposed by progestogens; the relative risk estimate was 1.7 (95% Cl 0.9-3.3). The results of this large study provide no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long durations of use or long latent intervals, but the possibility of a modest increase (less than a doubling) could not be excluded. There were insufficient data to evaluate the effects of nonconjugated estrogens and of combined estrogen and progestogen therapy.

Breast cancer and cigarette smoking: a hypothesis.

In many studies, cigarette smoking has been associated with a small increase in breast cancer risk. The authors evaluated the relation of smoking to breast cancer risk in two case-control studies carried out from 1982 through 1986. In Canada, 607 women with breast cancer and 1,214 controls matched on decade of age and neighborhood were interviewed at home. In the United States, 1,955 cases of breast cancer and 805 controls with other cancers were interviewed in the hospital. In both studies, breast cancer risk was associated weakly with cigarette smoking overall. The odds ratio for women who had smoked 25 or more cigarettes per day as compared with never smokers was 1.2 (95% confidence interval (CI) 0.9-1.6) in the Canadian study and 1.2 (95% Cl 0.9-1.6) in the US study. In both studies, breast cancer risk was more strongly related to commencement of smoking at a young age. Among women who smoked at least 25 cigarettes per day in the most recent year of smoking, the odds ratios for commencement before age 16 years were 1.7 (95% Cl 1.0-2.9) in the Canadian data and 1.8 (95% Cl 1.0-3.4) in the US data, and the odds ratios for commencement at even younger ages were higher. The associations were not explained by duration of smoking, by the time elapsed since commencement, or by factors associated with cigarette smoking such as alcohol consumption or oral contraceptive use. Our findings raise the hypothesis that exposure to cigarette smoke during adolescence may increase a woman's risk of breast cancer. The hypothesis has biologic plausibility: cigarette smoke contains known carcinogens, and the developing breast is especially susceptible to cancer initiation.

Endometrial cancer and age at last delivery: evidence for an association.

Because the role hormonal and reproductive factors play in the etiology of endometrial cancer is incompletely understood, the authors evaluated the risk of this cancer in relation to age at last delivery. The data were obtained in a hospital-based case-control study of 483 women with endometrial cancer (cases) and 693 women with other conditions (controls) conducted in a number of hospitals in the United States and Canada from 1978 to 1985. There was an inverse association between age at last delivery and endometrial cancer risk: Compared with women who last gave birth before age 25 years, the rate ratio was 0.9 (95% confidence interval (CI) 0.5-1.6) for last delivery at ages 25-29 years, 0.6 (95% CI 0.3-1.0) for last delivery at ages 30-34 years, 0.5 (95% CI 0.3-1.0) for last delivery at ages 35-39 years, and 0.4 (95% CI 0.1-0.9) for last delivery at age 40 years or older. The trend of decreasing rate ratio with increasing age at last delivery was statistically significant (p = 0.02). The association was apparent regardless of parity or menopausal status. There was no evidence for an association between age at first pregnancy and risk. These data suggest that women who bear children late in reproductive life may be at lower risk for endometrial cancer than those who complete their families early.

A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and tumor growth in the rodent colon. We assessed NSAID use in relation to risk of human large-bowel cancer in a hospital-based, case-control study of 1326 patients with colorectal cancer and 4891 control patients. For regular NSAID use that continued into the year before interview, the multivariate relative risk estimate was 0.5 (95% confidence interval, 0.4 to 0.8); the estimate decreased as the duration of use increased, but the trend was not statistically significant. Similar results were obtained whether cancer or non-cancer controls were used, and the inverse association was apparent for both colon cancer and rectal cancer in men and women and in subjects younger and older than 60 years. Regular NSAID use that had been discontinued at least 1 year previously and non-regular use were not associated with risk. Almost all regular NSAID use was of aspirin-containing drugs. The present data suggest that the sustained use of NSAIDs reduces the incidence of human large-bowel cancer.

Vasectomy and the risk of prostate cancer.

An unexpected association between history of vasectomy and increased risk of prostate cancer emerged when multiple comparisons were carried out in data collected from 1976-1988 in a US hospital-based case-control study of many diseases and exposures. The association was assessed in detail in these data, in a comparison of 220 men with first episodes of prostate cancer with 571 noncancer controls and 960 cancer controls. The age-adjusted relative risk of prostate cancer was 5.3 (95% confidence interval 2.7-10) when noncancer controls were used and 3.5 (95 percent confidence interval 2.1-6.0) when cancer controls were used. The magnitude of the relative risk estimate appeared to be unrelated to the length of the interval after vasectomy. Allowance for several factors did not alter the estimates, but we did not have information on testosterone level or sexual activity, which may have been confounding factors. The association was stronger among men most likely to have been under more intensive medical surveillance; selective detection of asymptomatic cancer in such men would have led to an excess of cases. Further studies are needed to rule out chance, bias from medical surveillance, and uncontrolled confounding as explanations for the finding.

Diazepam use in relation to breast cancer: results from two case-control studies.

The relation between diazepam use and breast cancer was explored in two case-control studies. The first (1981-1987) was a hospital-based study in the United States of 3,078 cases of breast cancer, 1,259 controls with other malignancies, and 672 controls with nonmalignant conditions. The relative risk estimates for regular diazepam use (at least 4 days per week for at least 6 months) that antedated the diagnosis of breast cancer by at least 12 months were 1.0 (95% confidence interval (CI) 0.6-1.7) using the cancer controls and 0.8 (95% CI 0.4-1.8) using the noncancer controls. Risk factors for breast cancer were taken into account in the estimates. There was no association for regular use lasting at least 5 years or for regular use that took place exclusively in the recent or more distant past. The second study (1982-1986), conducted in Toronto, Ontario, Canada, was community-based, and included 607 cases of breast cancer and 1,214 neighbor controls selected from municipal voting and census records. After control of confounding, the relative risk estimate for regular diazepam use was 0.8 (95% CI 0.5-1.3). Again, there was no association for long-term, past, or recent regular use. The results of both studies suggest that regular diazepam use does not increase the risk of breast cancer. The findings are strengthened by the similarity of the results using three different control groups--women with cancer, women with nonmalignant conditions, and neighbors.

Noncontraceptive estrogen use and epithelial ovarian cancer.

The relation of noncontraceptive estrogen use to epithelial ovarian cancer was evaluated in a case-control study conducted in hospitals mainly in the northeastern United States. There were 377 cases diagnosed within the year before hospital admission and 2,030 hospital controls; data were collected by interview in the hospital. Compared with women who never took noncontraceptive estrogens, the overall relative risk estimate for women whose estrogen use lasted at least one year and was not combined with progestogens or testosterone was 1.2 (95% confidence interval (CI) 0.8-1.9), after taking into account risk factors for ovarian cancer. There were 55 cases of the endometrioid, clear cell, or malignant mixed mesodermal cell type; the corresponding relative risk estimate was 0.9 (95% CI 0.3-3.0). There were 26 cases of undifferentiated cell type, with a relative risk estimate of 3.6 (95% CI 1.2-11). Relative risk estimates were similar in a subset of the cases (57%) for which pathology slides were reviewed. For estrogen use of long duration, use of high-dose preparations, or use in the distant past, the relative risk estimates were not significantly different from 1.0. The estimates were elevated for some categories of use, but not consistently--for example, for an interval of 5-9 years since estrogen use began (relative risk (RR) = 2.7), but not after shorter or longer intervals, and for use of conjugated estrogens with a dose of 0.3 mg (RR = 3.2) or 1.25 mg (RR = 2.4), but not for doses of 0.625 mg or 2.5 mg. The relative risk estimate was also elevated for use by nulliparous women (RR = 2.4). The results suggest that, overall, noncontraceptive estrogen use is not associated with the risk of epithelial ovarian cancer. Furthermore, our data do not support the hypothesis that estrogens increase the risk of endometrioid ovarian cancer. The elevated estimates could be due to multiple stratification of the data, but they should be explored in further studies, given the lethality of ovarian cancer and the common use of estrogens by postmenopausal women.