Menopausal Hormone Use and Colorectal Cancer in Saskatchewan: a Record Linkage Cohort Study1

Home , Chlorotrianisene, Methallenestril

Vol. 4, 21-28, January/February 1995 Cancer Epidemiology, Biomarkers & Prevention 21

Menopausal Hormone Use and Colorectal Cancer in Saskatchewan: A Record Linkage Cohort Study1

Harvey A. Risch2 and Geoffrey R. Howe treatment of osteoporosis and the prevention of its sequelae. Department of Epidemiology and Public Health, Yale University School of Estrogen use may have potentially important consequences, Medicine, New Haven, Connecticut 06510 (H. A. RI, and National because long-term usage has been related to increased Cancer Institute of Canada Epidemiology Unit, Department of Preventive incidence of endometrial cancer (1) and possibly breast Medicine and Biostatistics, University of Toronto, Toronto, Ontario cancer (2). It has also been suggested that estrogen use, M5S 1A8, Canada IC. R. H.l through effects on bile acid production, may be associated with the development of colorectal cancer (3), although the Abstrad risks seem to be small and to vary somewhat between studies. If estrogen usage were to be associated with in- It has been suggested that usage of menopausal creased risk, because of the relatively common occurrence estrogens may be associated with risk of colorectal of colorectal cancer among older women and the large cancer. This association was examined in a record number of women using menopausal estrogens, an appre- linkage cohort study using the Saskatchewan Health Plan ciable number of cases could be attributed to this exposure. Databases. All women ages 43-49 who were residents The purpose of the present study was to examine colorectal in Saskatchewan in 1 976 were identified from the cancer incidence and use of estrogens and other meno- Saskatchewan Health master registration file. These pausal hormones among all women (of suitable age) in the 33,003 women were linked by registration beneficiary province of Saskatchewan. number to the Prescription Drug Plan Database for the period January 1 976 through June 1 987, and to the Provincial Cancer Registry Database for the period Subjeds and Methods March 1 960 through December 1 990. Thirty women in The following descriptions apply to the operation of the cohort had colon or redal cancer diagnosed before Saskatchewan Health prior to 1 991 . Since that time, minor 1 976 and were omitted from the analysis; exposures changes have taken place. These changes are of no impor- within 3.5 years of diagnosis or end of follow-up were tance for the present study, and their discussion is omitted. also omitted. Between 1 976 and 1 990, 230 first primary Cohort Definition. Residents of the province become eli- coloredal cancer cases occurred. Women who took gible for health care system benefits once they establish estrogens had nonsignificantly elevated risk of colon residence and apply to Saskatchewan Health for a Health cancer in general (age-adjusted relative risk = 1.29; Services Card. Each person is assigned a unique six-digit 95% confidence interval, 0.86-1 .93) and of cancer of identification number denoting their family unit, and a two- the distal colon (relative risk = 1 .51 ; 95% confidence digit extension identifying them within the family unit. This interval, 0.90-2.54). Women who took p.o. information, plus their name, sex, address, and birthdate, is contraceptives during this follow-up period seemed to stored in a computer registry, the HIRF.’ Saskatchewan be at higher risk of cancer of the proximal colon Health maintains an active follow-up program for review of (relative risk = 2.1 2; 95% confidence interval, 1.00- eligibility and reissuance of the Health Services Card. Be- 4.53), though this apparent association could very well tween January 1989 and December 1990, the review was have occurred by chance. No associations were seen performed biennially; before 1989 it was done annually. between hormone use and risk of redal cancer. This Because family status may have changed over time, the study provides little evidence that usage of menopausal registration beneficiary number for a resident may also have hormones may be related to risk of coloredal cancer changed. For example, children were issued new family (either positively or negatively), though further follow- numbers at age 1 8. After marriage, women took the family up of the cohort appears warranted. number of their husband. Also, individuals may have pen- odically changed name. However, for each person, the Introduction HIRF contains a list of all previous registration numbers, so Among older women, estrogen medications are commonly that individuals may be traced over time through the sys- taken for alleviating menopause symptoms, and for the tem. HIRF information is directly accessible to all of the provincial health care agencies except Vital Statistics. To define the cohort, the HIRF was used to create a list of all women, ages 43-49 years, who were residents of Received 8/1/94; revised 1 0/1 3/94; accepted 1 0/1 3/94.

I Supported by National Health Research and Development Program of Saskatchewan in 1 976. For present purposes, the 30 Health and Welfare Canada Grant 6613-1324-53 (H. A. R.), and by BRSG 507 RR05443 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, NIH.

2 To whom requests for reprints should be addressed, at the Department of

Epidemiology and Public Health, Yale University School of Medicine, 60 3 The abbreviations used are: HIRF, health insurance registration file; RR, College Street, P.O. Box 3333, New Haven, CT 06510. relative risk; Cl, confidence interval.

Table 1 Hormone prescriptions in provincial Drug Plan Database for cohort: 32,973 women ages 43-49 years in 1 976 in Saskatchewan, Canada, 1976-1 987

Hormone No. of prescriptions Percent of total Percent of cohort

Estrogens Conjugated estrogens 1 1 6,427 91 .4 29.0 Estenified estrogens 5,536 4.3 2.1 Piperazine estrone sulfate 3,096 2.4 1 .4 Ethinyl estradiol 1,126 0.9 0.5 Estradiol 612 0.5 0.3 Stilboestrol 355 0.3 0.3 Methallenestril 251 0.2 0.1 Chlorotrianisene 32 0.03 <0.1 Any estrogens 127,435 100.0 30.9

Opposed estrogens Prescriptions on same date 3,585 2.6 Prescriptions >1, 7 days 160 0.04 Prescriptions >7, 14 days 156 0.04

Progestins Medroxyprogesterone acetate 6,724 97.9 4.8 Norethindrone 141 2.0 0.1 Norethindrone acetate 4 0.1 <0.1 Any progestins 6,869 100.0 4.9

Combined agents (p.o. contraceptives) Ethinyl estradiol/D-norgestrel 9,201 27.4 3.1 Ethinyl estradiol/norethindrone 4,524 1 3.4 1 .3 acetate Ethinyl estradiol/ethynodiol 906 2.7 0.3 diacetate Ethinyl estradiol/norethindrone 213 0.6 0.2 Ethinyl estradiol/dimethisterone 1 43 0.4 0.2 Mestranol/norethindrone 1 6,531 49.2 4.5 Mestranol/ethynodiol diacetate 1,810 5.4 0.6 Mestranol/norethynodrel 304 0.9 0.2

Any combined 33,632 100.0 9.0

women with colon or rectal cancer diagnosed before 1976 corded. The various active ingredients of the medications were omitted, leaving 32,973 women in the cohort. found are shown in Table 1. Exposures. The Saskatchewan Prescription Drug Plan was This report concerns usage of p.o. medications. In our initiated in September 1 975, and through June 30, 1 987, all analyses, the term “ever usage” denotes the existence of one residents with a valid Health Services Card were eligible for or more filled prescriptions. Other minimum exposures benefits (4). A nominal part ofeach prescription was paid by were considered for defining ever usage, e.g., 2 prescrip- the consumer, and the Province covered the remainder. tions, 90 tablets, 1 80 tablets, etc.; however, results were Those who could not afford even the nominal cost received very similar and have been omitted. In addition, estrogen benefits without paying. To obtain payment from the Prov- prescriptions were classified as “opposed” if progestin was ince, pharmacists submitted claims to the drug plan, mi- dispensed on the same date; if no such prescriptions were tially on paper forms but later through direct electronic found, the estrogen was considered “unopposed.” Simi- communication from pharmacy computers. The Prescnip- larly, progestin prescriptions were classified with respect to tion Drug Plan Database consists of information compiled estrogen. Allowing up to 1 4 days between dates of estrogen from all prescription claims. This database contains records and progestin prescriptions in the definition of opposed of the HIRF registration number of the consumer; the dis- medications produced essentially no differences in results. pensed drug identification number; the amount of drug and For the analysis of continuous exposures, numbers of tablets date of dispensing; and data regarding the pharmacy, the taken prior to the date of interest were cumulated. This prescriber, and the cost of the prescription. Information measure is closely related to duration of usage. about the active ingredients, strength, and form of prepara- Outcomes. Cohort members were followed by Saskatche- tion may be derived from the drug identification number. wan Health for vital and residence status from January 1, For the present study, we obtained all prescriptions for 1976 through December 31, 1990. Besides the active fol- estrogens, progesti ns, and combi ned estrogen-progestin low-up program used to gather annual data about each agents (p.o. contraceptives) found in the Drug Plan Data- resident (biennial between January 1989 and December

base between January 1 , 1 976, and June 30, 1 987, associ- 1 990), Saskatchewan Health received vital status informa- ated with a HIRF number of a member of the cohort. For tion through death certificates and hospital reports. Notifi- each prescription, the date dispensed, active ingredient cations of registration from the health plans of neighboring number, drug units, dosage form, and strength were re- provinces also provided additional information about emi-

gration. Thus, fact and date of death or emigration from the type of hormone, in cumulating person-years for the ever- province were obtained for the members of the cohort. used and never-used groups, we disregarded usage of the Cancer was made a reportable disease in Saskatche- other kinds of hormones. Thus, for example, some women wan in 1 934, and from 1 944 the Saskatchewan Cancer (and person-years) in both the ever-used p.o. contraceptives Foundation has maintained one of the most complete pro- group and the never-used p.o. contraceptives group reflect vincial cancer registries in Canada (4). Cancer diagnoses usage of noncontraceptive estrogens. Because readers may are reported to the registry through payment claims filed by wish to make comparisons with respect to women in the physicians, through patient registrations at the Regina and cohort who had no prescriptions for any of the various Saskatoon Provincial Cancer Clinics, and through continu- hormones, person-years and rates for this group have been ous review of death certificates and hospital pathology given as well. Finally, we used the GLIM program (Royal reports. Cases ascertained by the registry are identified by Statistical Society, Oxford, UK) with Poisson regression to their HIRF number. The registry database contains informa- calculate age-adjusted relative risks and their confidence tion on date of diagnosis, International Classification of limits. Diseases for Oncology four-digit site code, and five-digit For the multivaniate analysis of continuous measures of histology code for each patient, as well as diagnosis and hormone exposure, Cox regression with time-dependent treatment data. Because of the unique HIRF registration covariates was used (5). A modified version of the program RCOX, based on the one shown in Appendix 3 of Ref. 5, numbers, the cancer registry database can identify multiple was used. Again, an exposure lag of 3.5 years was assumed. cancers in the same patient, at the same or different sites, In this case, for each failure (case diagnosis) time in the and occurring at the same or different times. The database regression, exposure status for a subject was based on the became computerized in the early 1 970s. In addition to the number of tablets taken since 1 976, excluding tablets taken continuous input of new cases, the Cancer Foundation has within the immediately preceding 3.5 years. In cumulating been retrospectively entering older patient files into the the number of tablets taken before a certain date, it was database. At the time that the database file linkages for the assumed that one tablet was taken per day, beginning with present study were performed, cancer diagnoses extending the date dispensed. back through March 1960 were available. Women in the cohort having a first diagnosis of primary colon or rectum cancer [International Classification of Diseases (Ninth Re- Results vision) codes 153 and 154] between January 1, 1976 and Almost one-third of the women in the cohort had estrogen December 31 , 1 990 were considered cases. As noted pre- prescriptions during the 1 1 .5-year period included in the viously, 30 women had a diagnosis of colorectal cancer drug database. The great majority of these prescriptions made between March 1, 1960 and December 31, 1975 and were for conjugated estrogen (Table 1 ). Users of estrogens were excluded from the cohort for the present analysis; had recorded prescriptions totaling on average about 588 incidence of the disease before age 33 (i.e., the age of the tablets each, corresponding to 28 months of usage at 21 oldest women in the cohort in 1960) is essentially zero. tablets/month. On the other hand, p.o. progestins were Thus, the cohort was followed until cancer outcome, death, taken by relatively few women, approximately 5% of the emigration, or the end ofthe study period on December 31, cohort, and in smaller amounts than estrogen, about 1 1 5 1990. tablets (1 6 months at 7 tablets/month) per user. An even Record Linkage. Because the same unique registration smaller fraction of the cohort, 2.6-2.7%, had used estro- numbers were used to identify individuals in the master file gens opposed by progestins. Over 90% opposed estrogen (HIRF), the Prescription Drug Plan Database, and the Can- use reflected estrogen and progestin prescriptions on the cer Foundation Registry, linkage was based on exact match same date. Finally, Table 1 shows that even in the age group of the HIRF registration number. For quality control and of this cohort, there was appreciable usage of p.o. contra- billing purposes, the Saskatchewan Health agencies pen- ceptives: 9% of the women had prescriptions for the com- odically conduct internal linkages of their registries on bined agents, a mean of 472 tablets (22.5 months) per user. name, date of birth, and other identifiers. These linkages Between 1976 and 1990, 230 first primary colorectal have shown the identifying information to be more than cancer cases occurred in the cohort. Ofthese, three had two 99.99% accurate. Therefore, the HIRF registration numbers subsites specified at diagnosis, and two others went on to provide a valid method of identifying the same individual in have a second primary during the follow-up. Age-adjusted the various databases. relative risks for colon and rectal cancer according to ever- Data Analysis. Initially, descriptive analysis of the cohort usage of the various types of hormones are presented in was performed by counting the numbers of prescriptions for Table 2. For both tumor sites grouped together, there was no each of the medications used. To examine associations evidence of increased risk for women using estrogens. between ever/never usage of the various hormones and risk Among the 1 436 women who used estrogens for 5 years or of colon and rectum cancer, numbers of cases and total longer, (7005 person-years), a total of 3 cases occurred, person-years of exposure were cumulated within each giving an age-adjusted relative risk (compared to never use) 1 -year interval of age over the follow-up period for each of of 0.65 (95% Cl, 0.21-2.03). No cases of colon or rectal the exposure groups. Separate analyses were done for ever/ cancer occurred for women who had used estrogens only as never use of estrogens, progestins, and p.o. contraceptives. opposed by progestins, although the number of such Based on biological plausibility grounds, a lag interval of women, 171, was small (540.8 person-years); 1 case of 3.5 years was used. That is, person-years continued to colon cancer occurred among the 648 women who had accrue to each woman in the unexposed category of hor- used both opposed and unopposed estrogens, giving a mone use until 3.5 years after the date of the first prescrip- crude rate of 57.5/1 0 person-years. Three cases of cob- tion. Other lag intervals from 0 to 5 years were considered; rectal cancer occurred among women who had ever used however, the results were essentially unchanged. For each progestins, either as opposed or unopposed. Finally, usage

Table 2 Relative risk of colon or rectal cancer according to previous hormone usage among 32,973 women ages 43-49 years in 1 976 in Saskatchewan, 1976-1990

No. of Crude Age-adjusted Hormone usag& No. of subjects Person-years cases Rate/i 0 RR RR 95% CI

Colon or rectum Estrogens Never 23,145 382,395 187 48.9 1 i Ever 9,828 71,805 43 59.9 1.22 1.04 0.74-1.46

Progestins Never 31,412 446,931 227 50.8 1 1 Ever 1,561 7,270 3 41.3 0.8i 0.64 0.21-2.01

Combined agents (p.o. contraceptives) Never 30,105 425,818 212 49.8 1 1 Ever 2,868 28,383 18 63.4 1.27 1.12 0.69-1.81

Any of the above medications Never 20,870 357,265 171 47.9 1 1 Ever 12,103 96,936 59 60.9 1.27 1.08 0.79-1.46

Colon Estrogens Never 23,138 382,628 ii7 30.6 1 1 Ever 9,835 71,840 32 44.5 1.46 1.29 0.86-1.93

Progestins Never 31,411 447,195 146 32.6 1 1 Ever 1,562 7,273 3 4i.3 1.26 1.04 0.33-3.29

Combined agents (p.o. contraceptives) Never 30,104 426,053 138 32.4 1 1 Ever 2,869 28,415 11 38.7 1.20 1.07 0.58-1.99

Any of the above medications Never 20,863 357,469 107 29.9 1 1 Ever 12,110 96,998 42 43.3 1 .45 1 .28 0.88-1 .86

Rectum Estrogens Never 23,138 382,776 72 18.8 1 1 Ever 9,835 71,956 11 15.3 0.81 0.64 0.33-i.22

Combined agents (p.o. contraceptives) Never 30,104 426,316 76 i7.8 1 1 Ever 2,869 28,415 7 24.6 1.38 1.16 0.53-2.52

Any of the above medications Never 20,864 357,621 66 18.5 1 1 Ever 12,109 97,iio 17 17.5 0.95 0.74 0.43-1.28 a Exposure latency, 3.5 years.

of p.o. contraceptives within the age range of follow-up for the proximal colon, but a somewhat higher, though not exposure in this cohort, 43-61 years, was not significantly statistically significant, 51 % increase in risk was seen for the associated with risk for both sites grouped together. distal colon. An opposing pattern of association appeared For colon cancer considered separately, ever-usage of for ever-usage of p.o. contraceptives, with relative risk less estrogen appeared to be associated with an approximate than unity for the distal colon and greater than unity for the 30% risk increase, which was statistically nonsignificant proximal colon (P = 0.050 for the latter). (P = 0.22). However, use longer than 5 years was not In Table 4, we consider dose-response models of hor- associated with increased risk (RR = 0.70; 95% CI, 0.17- mone usage and risk of colon or rectal cancer. In the Model 2.85). No significant associations were observed for use of 1 5 of this table, for each failure (case diagnosis) time in the the various hormones and risk of rectal cancer. Cox regression, the hormone exposure variables were the In Table 3, age-adjusted relative risks are given for the cumulative number of tablets taken between 1 976 and 3.5 proximal (including cecum through splenic flexure), and years in the past. Neither use of estrogens nor p.o. contra- distal (including descending and sigmoid) colons. Little as- ceptives appeared to be associated with significant trends in sociation with ever-use of estrogens appeared for cancer of risk for colon cancer in general or rectal cancer. We also

Table 3 Relative risk of colon cancer subsites according to previous hormone usage among 32,973 women ages 43-49 years in 1976 in Saskatchewan, 1976-1990

Crude Age -adjusted Hormone usag& No. of subjects Person-years No. of cases Rate/i05 RR RR 95%Cl

Proximal colon5 Estrogens Never 23,133 382,886 43 11.2 1 1 Ever 9,840 71,939 12 16.7 1.49 1.17 0.60-2.25

Progestins Never 31,409 447,544 54 12.1 1 1 Ever 1,564 7,280 1 13.7 1.14 0.80 0.11-S.84

Combined Agents (p.o. contraceptives) Never 30,103 426,397 47 11.0 1 1 Ever 2,870 28,427 8 28.1 2.55 2.12 1.00-4.53

Any of the above medications Never 20,858 357,7i9 37 10.3 1 1 Ever 12,115 97,105 18 18.5 1.79 1.42 0.79-2.55

Distal coIon Estrogens Never 23,136 382,760 69 18.0 1 1 Ever 9,837 71,892 20 27.8 1.54 1.51 0.90-2.54

Progestins Never 31,4ii 447,378 87 19.4 i 1 Ever 1,562 7,274 2 27.5 1.41 1.32 0.32-5.37

Combined Agents (p.o. contraceptives) Never 30,104 426,214 88 20.6 1 1 Ever 2,869 28,437 1 3.52 0.17 0.16 0.02-1.15

Any of the above medications Never 20,862 357,583 67 i8.7 1 1 Ever i2,iil 97,068 22 22.7 1.21 1.16 0.70-1.92 a Exposure latency, 3.5 years. b Proximal colon includes cecum through splenic flexure.

C Distal colon includes descending and sigmoid colon.

found no association between risk of colorectal cancer and the distal colon. Some suggestion of an increase in risk either “current” use of estrogens (i.e., use immediately be- of proximal colon cancer also appeared for usage of fore the lag period of 3.5 years) or average tablet dose of p.o. contraceptives. Neither trend was statistically conjugated estrogen. In order to examine possible patterns significant. of dose-response for levels of usage of estrogens and p.o. contraceptives (Model 2s), the cumulated numbers of tab- letswere divided into categories of use, with roughly similar Discussion numbers of users in each category at the end of the follow- A few points are worth considering before conclusions are up. That is, for each failure time in the regression, a woman drawn from this study. To begin with, the cohort of all was assigned a category of use based on the cumulative women ages 43-49 in 1 976 in the Saskatchewan HIRF, number of tablets taken between 1 976 and 3.5 years in the represents all women of this age range in the province. In past. In these models, some increase in risk of colon cancer actuality, it included about 96% of women at the time, the was seen according to category of estrogen usage, although remaining 4% covered by other health care plans (for fed- the trend (Model 1 ) was not significant. Little evidence of eral or military employees, etc.). Among the women in- trend was present for usage of p.o. contraceptives or for cluded in the cohort, some errors could have occurred in either type of hormone use and rectal cancer. Cox regres- the database information and linkages, and it is possible sion models for colon or colorectal cancer that included that exposures or outcomes could have happened outside categories of estrogen use longer than 5 years in duration of Saskatchewan. However, for the following reasons, the did not show such usage to convey increased risk; the likelihood of substantial errors of these types seems quite relative risks were 0.69 (95% CI, 0.1 7-2.82) and 0.62 (95% small. CI, 0.20-1 .97), respectively. The quality of information in the Saskatchewan HIRF Finally, the Cox regression trend analyses for colon and other provincial databases is excellent, since these cancer subsites are given in Table 5. Similar to the result databases are used for the accounting and financial admin- for colon cancer as a whole, a pattern of increasing risk istration of the provincial health services. It is possible that with category of estrogen use was present for cancer of cases of multiple unconnected HIRF numbers identifying a

Table 4 Relative risk of colon or rectal cancer according to dose-response models of hormone usage among 32,973 women ages 43-49 years in 1976 in Saskatchewan, 1976-1990

Exposure RR At unir’ 95% CI

Colon or rectum Model 1 Age (in 1976) 1.112 lyear i.04-i.i9 Estrogens 0.976 252 tablets” 0.87-i .09 Combined p.o. contraceptives 0.938 252 tablets 0.74-i.i8

Model Age (in 1976) 1.113 1 year 1.04-i.i9 Estrogens 1-252 tabletsc 0.799 yes/no 0.51-i .25 253-504 tablets” 1.033 yes/no 0.51-2.11

505 + tablets’ 0.953 yes/no 0.4-1.69 Combined p.o. contraceptives 1-252 tablets 1.OOi yes/no 0.49-2.03 253-504 tablets 1.780 yes/no 0.79-4.02

505 + tablets 0.790 yes/no 0.29-2.13

Colon Model Age (in 1976) 1.isi 1 year 1.06-1.25 Estrogens i.0i6 252 tablets 0.90-i .1S Combined p.o. contraceptives 0.934 252 tablets 0.69-1.26

Model 2 Age (in 1976) i.15i 1 year 1.06-1.25 Estrogens 1-252 tablets 0.879 yes/no 0.51-i .52 253-504 tablets 1.258 yes/no 0.55-2.88 505 + tablets 1.325 yes/no 0.70-2.49

Combined Oral Contraceptives 1-252 tablets 0.953 yes/no 0.39-2.33 253-504 tablets 1.874 yes/no 0.69-5.08 505 + tablets 0.628 yes/no 0.1 5-2.55

Rectum Model 1 Age (in 1976) 1.052 1 year 0.94-i .17 Estrogens 0.867 252 tablets 0.67-1 .i 2 Combined p.o. contraceptives 0.936 252 tablets 0.6-1.36

Model 2 Age (in 1976) 1.056 1 year 0.95-i .i 8 Estrogens 1-252 tablets 0.639 yes/no 0.29-1.40 253-504 tablets 0.641 yes/no 0.16-2.63 505 + tablets 0.356 yes/no 0.09-1.47

Combined p.o. contraceptives 1-252 tablets 1.066 yes/no 0.33-3.40 253-504 tablets 1.568 yes/no 0.38-6.42 505 + tablets 1.030 yes/no 0.25-4.23

a Exposure variables with number of tablets appearing in this column are continuous and time dependent, and represent cumulative number of tablets between 1 976 and Case Diagnosis Date -3.5 years. Variables with “yes/no” are time-dependent indicators for having reached exactly that category of exposure between 1 976 and Case Diagnosis Date -3.5 years. Age (in 1 976) is continuous but not time dependent in these Cox regression models. b 252 tablets = 21 tablets/month for 12 months.

C Use up to 1 year, assuming 2i tablets/month. d One to 2 years of use, assuming 21 tablets/month.

,. More than 2 years of use, assuming 21 tablets/month.

single person could exist, particularly for women leaving checking of the HIRF. Database information could also the province and returning after a span of more than 2 years. contain errors from incomplete follow-up of individuals These errors are rare, because of the low total emigration who died, moved within Saskatchewan, or emigrated. From rate of less than 0.8%/year for the cohort over the 1 5 years January 1989 through December 1990, individuals in the of follow-up, and because of the frequent internal validity health plan were issued health plan identification cards at

Table 5 Relativerisk of colon-cancer subsites according to dose-response physicians in the province. In addition, even if some pro- models of hormone usage among 32,973 women ages 43-49 years in cedures for cancer diagnosis were performed elsewhere 1976 in Saskatchewan, 1976-1 990 (e.g., Florida), there was a financial incentive for patients to have treatment done in Saskatchewan, thus giving case Exposure RR At unit’ 95% Cl identification. Proximal colon” Also, this study did not record hormone usage prior to Model 1 1 976. Thus, some nondifferential misclassification of the Age (in 1976) 1.079 1 year 0.9S-i .23 menopausal exposures could have occurred, especially for Estrogens 0.905 252 tabletsc 0.69-1 .18 the older women in the cohort, although we estimate that Combined p.o. contraceptives 1.141 252 tablets 0.88-i .48 less than 5% of estrogen use may have been missed (6). Model 2 Nevertheless, on this basis, results could be attenuated Age (in 1976) 1.079 1 year 0.95-1.23 somewhat. Estrogens Another potential error is that an incorrect HIRF regis- 1-252 tablets 1.074 yes/no 0.50-2.30 tration number could have been recorded when a prescnip- 253-S04tablets 0.993 yes/no 0.24-4.13 tion was dispensed at a pharmacy. Between 1976 and 505 + tablets 0.534 yes/no 0.1 3-2.23 1 987, a 1 % random sample of all individuals whose registration numbers were listed on filled prescriptions were sent Combined p.o. contraceptives mail questionnaire cards in which they verified the pre- 1-252 tablets 0.944 yes/no 0.23-3.90 253-504 tablets 5.21 1 yes/no 1 .87-1 4.6 scniption data. This prevented pharmacists from billing the 505 + tablets 1 .534 yes/no 0.37-6.36 drug plan for nonexistent prescriptions, and the results of the questionnaire cards indicated that the prescription and Distal colon” identifying information was appreciably more than 99% Model 1 accurate. Age (in 1976) 1.205 1 year 1.08-i .35 It is also possible that while prescriptions were validly Estrogens 1 .093 252 tablets 0.95-i .26 recorded by the drug plan, the recipients may not have Combined p.o. contraceptives 0.205 252 tablets 0.02-2.45 taken all of the medications. This is an issue for many

Model 2 observational epidemiological studies. Because of the non- Age (in 1976) 1.202 1 year 1.07-i .35 zero cost to the purchaser for each prescription, cohort Estrogens members had some motivation either to use the medica- 1-252 tablets 0.8i0 yes/no 0.37-1.79 tions or to discontinue purchase. Also, women in the cohort 253-504 tablets 1 .61 7 yes/no 0.58-4.49 who obtained hormone prescriptions may have differed in 505 + tablets 2.202 yes/no 1 .07-4.54 their health behaviors, for example with respect to physician visits, as compared to women without such prescnip- Combined p.o. contraceptives tions. However, 96% of women in the cohort had at least 1 Ever-use 0.i65 yes/no 0.02-1.18 database prescription record for some type of medication. a Exposure variables with number of tablets appearing in this column are Finally, over the follow-up period ofthis study, most of continuous and time dependent, and represent cumulative number of tablets the noncontraceptive estrogen use among cohort members between i 976 and Case Diagnosis Date -3.5 years. Variables with “yes/no” are time-dependent indicators for having reached exactly that category of was of unopposed medications. Thus, results for opposed exposure between 1976 and Case Diagnosis Date -3.5 years. Age (in 1976) preparations are limited and may not be the same as those is continuous but not time dependent. for estrogens taken alone. b Proximal colon includes cecum through splenic flexure. C 252 tablets = 21 tablets/month for 1 2 months. Allowing for the previous considerations, the findings d Distal colon includes descending and sigmoid colon. presented here differ little from the results of previous stud- es, in that significant associations have not generally been seen. Most work has shown no relationship between use of noncontraceptive estrogens and risk of colon or colorectal 2-year intervals; before 1989, the cards were issued annu- cancer (7-1 4). Two studies have noted decreased risks (1 5, ally. To track the status of each individual, Saskatchewan 1 6). Slightly increased relative risks, typically in the 1 .4-1 .6 Health used an active follow-up program; using identifica- range, have been seen for rectal cancer in some reports (7, tion card returns by Canada Post, they attempted contact of 8, 1 0, 1 1 , 1 3); however, those associations were not statis- individuals by telephone and by field inspectors, contact of tically significant, and other studies have shown somewhat relatives or neighbors, information from physician death decreased risk with usage (1 7, 1 8). Studies examining risk reports, and through comparisons with town lists. For mdi- separately for cancers of the proximal and distal colon also viduals who moved from Saskatchewan to the neighboring showed little association with estrogen usage (1 0, 1 2, 1 3, provinces of Manitoba, Alberta, or British Columbia and 17), although decreased risk (RR = 0.4-0.5) for the proxi- registered for the health insurance plans there, those prov- mal colon was observed in two reports (1 6, 19). inces notified Saskatchewan Health about the change in Slightly fewer studies have examined risks for women residence. using p.o. contraceptives, particularly in their 40s and SOs. It is possible that some exposures or outcomes could For colon or colorectal cancer overall, one study observed have occurred outside of Saskatchewan. However, from slightly increased risk with usage (7) and two others some- 1976 to 1987, there was a strong financial incentive for what decreased risk (8, 1 7); however, most studies have Saskatchewan residents to obtain prescription medications demonstrated essentially no association with risk (1 1-13, through the drug plan. Similarly, because the health plan 18). Observed relative risks for proximal and distal colon covered the costs of medical work-ups for the conditions subsites have been a little more variable, with studies re- relevant to the hormones considered in this study, a finan- porting both risk increases and decreases, though again cial incentive existed for having these work-ups done by none has been statistically significant (1 1 -1 3).

One concern in the present study is that data on po- estrogen replacement therapy on the risk of breast cancer. JAMA, 265: tentially confounding reproductive and other factors were 1985-1990, 1991. not available to be used in model adjustments for the hor- 3. McMichael, A. J., and Potter, J. D. Reproduction, endogenous and exog- mone variables of interest. For both noncontraceptive es- enous sex hormones, and colon cancer: a review and hypothesis. J. NatI. Cancer Inst., 65: 1201-1207, 1980. trogens and p.o. contraceptives, a number of reports have 4. Strand, L., and West, R. Health data bases in Saskatchewan. In: B. L. Strom given adjusted and unadjusted results or noted differences (ed), Pharmacoepidemiology. New York: Churchill Livingstone, i989. after adjustment, and thus relate to whether our results 5. Kalbfleisch, J. D., and Prentice, R. L. The Statistical Analysis of Failure would be likely to change had we been able to adjust. One Time Data. New York: John Wiley and Sons, 1980. paper, giving relative risk of colorectal cancer according to 6. Persson, I., Adami, H-O., Johansson, E., Lindberg, B., Manell, P., and ever usage of menopausal estrogens, showed a reduction of Westerholm, B. Cohort study of oestrogen treatment and the risk of endo- about 16% (RR changing from 0.57 to 0.49) with adjust- metrial cancer: evaluation of method and its applicability. Eur. J. Clin. ment for parity, hysterectomy, and cholecystectomy (1 7). Pharmacol., 25:625-632, i983. However, the same study showed the relative risk accord- 7. Weiss, N. S., Daling, J. R., and Chow, W-H. Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors. J. ing to ever-usage of p.o. contraceptives to increase toward NatI. Cancer Inst., 67: 57-60, 1981. unity (RR, 0.61-0.80) with adjustment for the same van- 8. Potter, J. D., and McMichael, A. J. Large bowel cancer in women in ables. Overall, most studies have shown essentially no dif- relation to reproductive and hormonal factors: a case-control study. J. NatI. ferences in results controlling for various factors, including Cancer Inst., 71: 703-709, 1983.

dietary variables, parity, family history of colorectal cancer, 9. Wu, A. H., Paganini-Hill, A., Ross, R. K., and Henderson, B. E. Alcohol, socioeconomic status, physical activity, past weight, or physical activity and other risk factors for colorectal cancer: a prospective body-mass index (8, 1 0, 1 1-1 3). Thus, it appears unlikely study. Br. J. Cancer, 55: 687-694, i 987. that the risks related to hormone usage seen in the present 10. Davis, F. C., Furner, S. E., Persky, V., and Koch, M. The influence of work would change appreciably had they been adjusted. parity and exogenous female hormones on the risk of colorectal cancer. Int. J. Cancer, 43: 587-590, 1989. In summary, this cohort study of the Saskatchewan population provides little evidence for increased risk of 1 1 . Kune, C. A., Kune, S., and Watson, L. F. Oral contraceptive use does not colorectal cancer with menopausal usage of either estro- protect against large bowel cancer. Contraception, 41: i9-25, 1990. i2. Peters, R. K., Pike, M. C., Chang, W. W. L., and Mack, T. M. Repro- gens or p.o. contraceptives. No significant dose-response ductive factors and colon cancers. Br. J. Cancer, 61: 741-748, 1990. trends were observed. The one significant risk association, 1 3. Chute, C. C., Willett, W. C., Colditz, C. A., Stampfer, M. J., Rosner, B., between ever-use of p.o. contraceptives and cancer of the and Speizer, F. E. A prospective study of reproductive history and exogenous proximal colon, could very well have occurred by chance estrogens on the risk of colorectal cancer in women. Epidemiology, 2: given the number of independent associations examined. 201-207, 199i. The incidence of colon cancer rises steeply after age 60. 14. Bostick, R. M., Potter, J. D., Kushi, L. H., Sellers, T. A., Steinmetz, K. A., Because of the relatively small numbers of cases in the McKenzie, D. R., Gapstur, S. M., and Folsom, A. R. Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa present study, particularly for the colon subsite analyses, women (United States). Cancer Causes Control, 5: 38-52, 1994. further follow-up of our cohort through the seventh decade 1 5. Newcomb, P. A., Storer, B. E., and Marcus, P. M. Cancer of the large of lifeseems warranted. bowel in relation to use of hormone replacement therapy. Am. J. Epidemiol., 136:958, 1992. Acknowledgments 1 6. Jacobs, E. J., White, E., and Weiss, N. S. Exogenous hormones, reproductive history, and colon cancer (Seattle, Washington, USA). Cancer Causes We gratefully acknowledge the contributions at Saskatchewan Health of Control, 5: 359-366, 1994. Edith Malcolm, Dwayne Senft, Winanne Downey, Diane Robson, Susan Kraft, and Drs. Linda Strand and Roy West. This study is based in part on data 17. Furner, S. E., Davis, F. C., Nelson, R. L., and Haenszel, W. A case- provided by the Saskatchewan Department of Health. The interpretations control study of large bowel cancer and hormone exposure in women. and conclusions contained herein do not necessarily represent those of the Cancer Res., 49:4936-4940, 1989. Government of Saskatchewan, or the Saskatchewan Department of Health. 18. Wu-Williams, A. H., Lee, M., Whittemore, A. S., Gallagher, R. P., Jiao, D-A., Zheng, S., Zhou, L., Wang, X-H., Chen, K., Jung, D., Chong-Ze, T., Ling, C., Xu, J. Y., Paffenbarger, R. S., Jr., and Henderson, B. E. Reproductive References factors and colorectal cancer risk among Chinese females. Cancer Res., 51: 1. Vessey, M. Exogenous hormones. In: M. Vessey and M. Gray (eds.), 2307-2311, 1991. Cancer Risks and Prevention. Oxford, UK: Oxford University Press, 1985. 19. Gerhardsson de Verdier, M., and London, S. Reproductive factors, ex- 2. Steinberg, K. K., Thacker, S. B., Smith, S. J., Stroup, D. F., Zack, M. M., ogenous female hormones, and colorectal cancer by subsite. Cancer Causes Flanders, W. D., and Berkelman, R. L. A meta-analysis of the effect of Control, 3: 355-360, 1992.

Downloaded from cebp.aacrjournals.org on September 25, 2021. © 1995 American Association for Cancer Research. Menopausal hormone use and colorectal cancer in Saskatchewan: a record linkage cohort study.

H A Risch and G R Howe

Cancer Epidemiol Biomarkers Prev 1995;4:21-28.

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