REPORTS

Prospective Study of Talc Use and Ovarian Cancer

Dorota M. Gertig, David J. Hunter, Daniel W. Cramer, Graham A. Colditz, Frank E. Speizer, Walter C. Willett, Susan E. Hankinson

Affiliations of authors: D. M. Gertig, F. E. Speizer,Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; D. J. Hunter, G. A. Colditz, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health, Boston, and Harvard Center for Cancer Prevention, Boston; D. W. Cramer, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital; W. C. Willett, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Departments of Epidemiology and Nutrition, Harvard School of Public Health; S. E. Hankinson, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health.

Correspondence to: Dorota M. Gertig, MB.BS., MHSc., ScD., Centre for Genetic Epidemiology, University of Melbourne, 200 Berkeley St., Carlton 3053, Australia (e-mail: Dorota.Gertig{at}channing.harvard.edu).


    ABSTRACT
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Notes
 References
 
BACKGROUND: Perineal talc use has been associated with an increased risk of ovarian cancer in a number of case-control studies; however, this association remains controversial because of limited supporting biologic evidence and the potential for recall bias or selection bias in case-control studies. In this study, we conducted a prospective analysis of perineal talc use and the risk of ovarian cancer. METHODS: The Nurses' Health Study is a prospective study of 121 700 female registered nurses in the United States who were aged 30-55 years at enrollment in 1976. Talc use was ascertained in 1982 by use of a self-administered questionnaire: after exclusions, 78 630 women formed the cohort for analysis. Three hundred seven epithelial ovarian cancers subsequently diagnosed in this cohort through June 1, 1996, were confirmed by medical record review and met inclusion criteria. Proportional hazards models by use of pooled logistic regression were used to derive relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: In 1982, 40.4% (n = 31 789) of the cohort reported ever using talc, and 14.5% (n = 11 411) reported ever using talc daily. We observed no overall association with ever talc use and epithelial ovarian cancer (multivariate RR = 1.09; 95% CI = 0.86-1.37) and no increase in risk of ovarian cancer with increasing frequency of use. There was a modest elevation in risk for ever talc use and invasive serous ovarian cancer (multivariate RR = 1.40; 95% CI = 1.02-1.91). The risk of epithelial ovarian cancer for talc users was not greater among women who had never had a tubal ligation (multivariate RR = 0.97; 95% CI = 0.71-1.32). CONCLUSION: Our results provide little support for any substantial association between perineal talc use and ovarian cancer risk overall; however, perineal talc use may modestly increase the risk of invasive serous ovarian cancer.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Notes
 References
 
Talc was originally implicated as a possible ovarian carcinogen because of its chemical similarity to asbestos, which has been linked to ovarian cancer in occupational settings and is associated with mesotheliomas histologically resembling epithelial ovarian cancers (1-3). Perineal use of talcum powder has been positively associated with ovarian cancer risk in a number of case-control studies (4-13), although the magnitude of the associations has been modest, with odds ratios ranging from 1.2 to 1.9, and not all results reached statistical significance (5,6,8). Despite this relative consistency among studies, the limited supporting biologic evidence, together with the possibility of recall and selection bias in case-control studies (1), has raised questions about the plausibility of the association. We, therefore, prospectively examined the relationship between perineal talc use and ovarian cancer risk in a large cohort of U.S. women.


    METHODS
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Notes
 References
 
The Nurses' Health Study, established in 1976, is a prospective cohort of 121 700 registered nurses living in 11 of the larger states in the United States. Questionnaires were mailed to married, female nurses aged 30-55 years, requesting information on health-related issues, including medical history and potential risk factors for cancer. Follow-up questionnaires have been mailed every 2 years to update information on exposures and to ascertain newly diagnosed diseases. The study was approved by the Human Research Committee at the Brigham and Women's Hospital, Boston, MA.

Ascertainment of cases. We sought medical records from all women who reported a diagnosis of ovarian cancer or who were deceased in each follow-up cycle. Records were reviewed by physicians unaware of exposure status. Histologic subtypes were determined from pathology reports, and epithelial ovarian cancers were classified as serous cancers (including cystadenocarcinoma and papillary adenocarcinoma), mucinous cancers (including adenocarcinoma and mucinous papillary adenocarcinoma), and endometrioid cancers (clear cell and other types, including mixed epithelial tumors). Borderline histologic tumors are included in the analysis. Deaths are reported by relatives and postal authorities, as well as a search of the National Death Index. Mortality follow-up is estimated to be 98% complete in this cohort (14). Cases of epithelial ovarian cancer (International Classification of Diseases Code, ICD183.0), confirmed by medical record review or death certificate, occurring between the return of the 1982 questionnaire and June 1, 1996, were included in the analysis.

Exclusions. Women who did not respond to the question on talc use in 1982 were excluded from this analysis. We also excluded women who had reported a diagnosis of cancer (other than nonmelanoma skin cancer) before 1982, as well as women who reported bilateral oophorectomy, surgery with an unknown number of ovaries removed, and a history of radiation therapy. Validity of self-reported surgical menopause has been assessed previously, and agreement with medical records was more than 97% (15). These exclusions were updated every 2 years. At baseline, 78 630 women were eligible for the analysis. The resulting population after exclusions contributed 984 212 person-years of follow-up and 307 cases of epithelial ovarian cancer.

Ascertainment of talc exposure. Use of talcum powder was ascertained on the 1982 questionnaire in the following ways: "Have you ever commonly used talcum, baby powder, or deodorizing powder a) to apply to perineal (private) area? No, daily, one to six times per week, or less than once per week or b) to apply on sanitary napkins? No, Yes." We classified "ever talc use" as ever talc use on either the perineal area or sanitary napkins.

Other covariates. Potential risk factors and confounders of the association between ovarian cancer and exposures of interest in this analysis also were obtained from the biennial questionnaires and were updated every 2 years where relevant. Oral contraceptive use was asked every 2 years from 1976 through 1982, by which time use was rare. Tubal ligation history was asked as part of a question on methods of contraception from 1976 through 1984, and, in 1994, women were asked if they had ever had a tubal ligation and, if so, at what age. Family history of ovarian cancer was not asked until 1992. Parity was defined as the number of pregnancies lasting 6 months or more and was asked through 1984.

Statistical analysis. Incidence rates (number of cases for each category of exposure divided by person months of follow-up in that cycle) were calculated for each category, adjusting for age in 5-year intervals. Proportional hazards models by use of pooled logistic regression were used to derive relative risks (RRs) and 95% confidence intervals (CIs) of disease for each exposure category (16). For age-adjusted analyses, we categorized variables as follows: parity (0, 1-2, or >=3), oral contraceptive use (never, past, or current), tubal ligation (yes or no), postmenopausal hormone use (never, past, or current), cigarette smoking (never, past, or current), and body mass index, i.e., weight in kilograms/height in meters squared (<21, 21.0-22.9, 23.0-24.9, 25.0-28.9, or >=29 kg/m2). In multivariate analyses, we adjusted for age (years) and for potential risk factors by use of indicator variables for each category as described above, except for parity (0, 1-2, 3-4, or >=5) and duration of oral contraceptive use (never or <3, 3-5, or >5 years), for which we used a larger number of categories to more appropriately control for confounding. In addition we controlled for age at menarche, duration of breast-feeding, and age at menopause. However, since this did not alter the estimates for talc use, further models did not control for these variables. Body mass index and duration of oral contraceptive use were also entered as continuous variables, and similar estimates were obtained. All RRs reported are multivariate unless otherwise stated. P values reported are two-sided.


    RESULTS
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Notes
 References
 
Three hundred seven women developed ovarian cancer in the cohort from 1982 through 1996 who responded to the 1982 questionnaire on talc use. In 1982, 40.4% (n = 31 789) of the baseline cohort reported ever using talc, of which 14.5% (n = 11 411) were ever daily talc users. Talc use was associated with higher body mass index and inversely associated with current cigarette smoking (Table 1Go).


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Table 1. Age-standardized prevalence of ovarian cancer risk factors according to perineal talc use in 1982*

 
We did not observe an overall association with ever use of talc and epithelial ovarian cancer (RR = 1.09; 95% CI = 0.86-1.37). There was also no elevation in risk among daily users of perineal talc, and no trend was seen with increasing frequency of use (Table 2Go). Talc use on sanitary napkins was inversely related to ovarian cancer, but the association was statistically nonsignificant. Exclusion of use of talc on sanitary napkins from the ever use of talc variable did not substantially alter the results. We also evaluated the risk for women who used both perineal talc and talc on sanitary napkins but did not see an effect compared with never users of talc (RR = 0.90; 95% CI = 0.59-1.37).


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Table 2. Talc use and ovarian cancer: 1982 through 1996 (all subtypes included)*

 
When we stratified by histologic subtype, we observed a modest increase in risk for ever talc use for serous invasive cancers (RR =1.40; 95% CI =1.02-1.91) but not for all serous cancers (including borderline cancers), endometrioid cancers, or mucinous cancers (Table 3Go). For women who reported ever daily use of talc, the RR of invasive serous cancer was 1.49 (95% CI = 0.98-2.26). The RRs for ever talc users of less than once per week and one to six times per week were 1.29 (95% CI = 0.81-2.04) and 1.49 (95% CI = 0.77-2.11), respectively (P for trend = .05).


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Table 3. Talc use and ovarian cancer: 1982-1996 (by histologic subtype)*

 
Because the talc hypothesis depends on the ability of fibers to migrate up a patent genital tract to the ovaries, we evaluated the risk among women who had reported a tubal ligation and those who had not. Women who were ever talc users and had never had a tubal ligation were not at increased risk of epithelial ovarian cancer compared with women who had not used talc (RR = 0.97; 95% CI = 0.71-1.32). There was no evidence of heterogeneity of RRs between women who had a tubal ligation and women who did not. In addition, when women who had had a tubal ligation or simple hysterectomy were excluded from the analysis, the RR for ever talc use was 1.15 (95% CI = 0.89-1.49). For serous invasive cancers, the RR for women who had never had a tubal ligation was similar to that for women without a tubal ligation; however, the number of case patients who had had a tubal ligation was small (data not shown).

Cosmetic talc may have been more likely to contain asbestos fibers prior to 1976, before voluntary guidelines were proposed (9). As a proxy for early talc use, we assessed risk among women 45 years old or older in 1982. There was no evidence that older women in 1982 were at greater risk of ovarian cancer overall; the RR for ever talc use compared with never talc use for women under 45 years was 0.95 (95% CI = 0.59-1.53) and among women 45 years old or older was 1.13 (95% CI = 0.86-1.47). However, women 45 years old or older in 1982 who ever used talc had a higher risk of serous invasive cancer (RR = 1.51; 95% CI = 1.07-2.15). There was no evidence of effect modification by oral contraceptive use, body mass index, or cigarette smoking for epithelial cancers overall.


    DISCUSSION
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Notes
 References
 
To our knowledge, this is the first prospective analysis of talc use and ovarian cancer, and it addresses some of the potential limitations of previous case-control studies. Because we ascertained talc exposure prior to case diagnosis, the possibility for recall bias, which has been raised as a potential explanation for previous positive findings in case-control studies (1), is eliminated, and selection bias is reduced. We controlled for known or suspected ovarian cancer risk factors in the analysis, such as parity, oral contraceptive use, tubal ligation history, and body mass index, reducing the potential for uncontrolled confounding.

However, there are several important limitations to our study. The questions on talcum powder use referred to ever use, and we cannot determine the age at which women began using talc or the duration of use. Thus, we were unable to assess the potential effect of talc use before first pregnancy, which has been shown to be a stronger risk factor for ovarian cancer than use after pregnancy in one study (13). The number of lifetime applications of talc has also been associated with increased risk of ovarian cancer in some previous studies (9,13). Our relatively short follow-up period may be inadequate to detect an association if the latency for development of ovarian cancer is more than 15 years. Although we controlled for tubal ligation history, the tubal ligation question was asked as part of a question on contraceptive use; therefore, postmenopausal women and some premenopausal women who were not sexually active may not have responded to the question. Substantial residual confounding is unlikely, since there was no overall association between talc use and tubal ligation in this study. In addition, we excluded women who were postmenopausal in 1976 from analyses stratified by tubal ligation history. Finally, the prevalence of talc use in our study is somewhat higher than that in other studies and may reflect the fact that we asked about frequency of ever use rather than current regular use; this may have contributed to an attenuation of risk due to misclassification of exposure.

The potential effect of talc on the ovaries depends on migration of talc fibers through a patent genital tract, and we would, therefore, expect a stronger association among women without a tubal ligation who had used talc. However, no effect modification was seen by history of tubal ligation. Because we did not have the date of tubal ligation, some women may have begun talc use only after tubal ligation, potentially resulting in misclassification of talc use and attenuation of the RRs.

Since the first study showing an almost twofold increase in risk of ovarian cancer with any perineal talc use (4), most case-control studies have demonstrated positive associations with talc use (4-13), although not all have been statistically significant (5,6,8). Several studies (9,17-20) found no overall association between any genital talc use and ovarian cancer. We did not observe a dose-response relationship with talc use, and previous studies also have been inconsistent in this regard. Some studies (9,13,17) have demonstrated statistically insignificant trends in risk with increased frequency of talc use, duration of use, and measures of "total lifetime applications," while other studies (6,8) have not observed a statistically significant dose response.

With regard to histologic subtypes, a recent study by Cramer et al. (13) observed the greatest risk for talc use and invasive serous cancer; however, other studies found increased risks for endometrioid cancers (9,12), serous cancers (7), and invasive cancers of all subtypes (12). Since serous cancers, which account for more than half of all invasive ovarian cancers, most resemble mesotheliomas, it could be hypothesized that this subtype may be most likely associated with talc use. In our stratification by subtype, we did observe a modest positive association with serous invasive cancers and ever talc use as well as a borderline significant trend for increasing frequency of ever use.

The biologic evidence for the association of talc and ovarian cancer is incomplete. Asbestos has been linked to ovarian cancer in occupational settings and is associated with peritoneal tumors similar to ovarian cancer (2,3,21). Because of the chemical similarity of talc and asbestos, talc also has been implicated as a possible ovarian carcinogen. Talc is able to migrate through the genital tract and gain access to the ovaries because talc fibers have been detected in benign and malignant ovarian tissue (22), although no relation between reported levels of talc exposure and ovarian talc counts has been observed (23). There have been few studies (24,25) of talc exposure in animals, and these studies have not demonstrated an increase in ovarian cancer among animals subjected to chronic talc exposure. These data should be interpreted cautiously because there are important anatomic and physiologic differences between rodents and humans, and talc in animals is often administered at high dose via aerosol exposure (24).

In summary, we did not observe an overall association between epithelial ovarian cancer and ever use of talc, and there was no apparent dose response, although we lacked information on duration of talc use. In analyses stratified by histologic subtype, we observed a modest positive association between invasive serous cancer and ever talc use. Our results provide little support for any substantial association between perineal talc use and ovarian cancer risk overall; however, perineal talc use may modestly increase the risk of invasive serous ovarian cancers.


    NOTES
 
Supported by Public Health Service grant CA40356 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

We thank Karen Corsano and Barbara Egan for their expert assistance with the study and Kathleen Fairfield for her help with analysis. We also thank the Nurses' Health Study participants for their continuing dedication and commitment.


    REFERENCES
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Notes
 References
 

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Manuscript received June 17, 1999; revised November 18, 1999; accepted December 2, 1999.



             
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