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Methods
Study Population
As reported previously, the VITamins And Lifestyle study is a prospective study designed to investigate the association between vitamins, minerals, and other dietary supplements and cancer risk. Briefly, men and women aged 50–76 years at baseline who lived in the 13-county region in western Washington State covered by the Surveillance, Epidemiology, and End Results cancer registry were eligible to participate. Between October 2000 and December 2002, baseline questionnaires were mailed to 364,418 individuals who were identified by a commercial mailing list. Among them, 77,719 (21.3%) individuals returned questionnaires and satisfied eligibility requirements.
Exclusion criteria for these analyses included patients with the following: a history of CRC at baseline (n=971) or with missing baseline CRC information (n=213); a history of ulcerative colitis or Crohn's disease (n=1,030); intestinal polyposis (n=273); diagnosis with in situ CRC over the period of follow-up (n=12); cancer noted on death certificate only with no diagnosis date available (n=1); and a diagnosis with CRC of certain rare morphologies (listed below, n=33). In addition, individuals with missing information on all four exposure variables (n=15) were excluded, leaving 75,214 patients for analyses. The above-listed exclusions are not mutually exclusive, and hence individuals may have been excluded for more than one reason. Study participants provided informed consent and study procedures were approved by the Fred Hutchinson Cancer Research Center Institutional Review Board.
Exposure Assessment
Vitamins and Lifestyle participants completed a self-administered, sex-specific, 24-page questionnaire on supplement use, medication use, health history, risk factors, and diet.
Closed-ended questions were used to ascertain 10-year average history of constipation (Over the past 10 years, how often did you feel constipated enough to take something, such as a laxative, enema, or prunes?) and non-fiber laxative use (Over the past 10 years, about how many times have you taken non-fiber laxatives (such as Ex-lax, Correctol, or milk of magnesia)?). Response options (never or less than once per year, 1–4 times per year, 5–11 times per year, 1–3 times per month, or 1 time per week or more) were then categorized into three groups by combining the last three categories. Bowel movement frequency, which was ascertained by asking participants a closed-ended question (How often do you usually have a bowel movement?), was combined into four categories (<5 times per week, 5–6 times per week, 1 time per day, and 2 or more times per day).
Fiber laxative use was ascertained by asking separate questions on frequency and duration of use of "fiber products such as Metamucil, Citrucel, FiberCon, or Fiberall" in the 10-year period before baseline. Fiber laxative use was then categorized into three groups: high use (4+ days per week for 4+ years), low use (<4 days per week odds ratio (OR) <4 years), or no use. These categories were created a priori so that the highest level of exposure is defined by high frequency (4+ days per week) and substantial duration (4+ years) of use.
Participants also reported on personal characteristics as part of the baseline questionnaire, including age, sex, ethnicity, education, height, weight, dietary intake, recreational physical activity, cigarette smoking, alcohol consumption, family history of cancer, and medical history. Dietary intakes were assessed using a semiquantitative food frequency questionnaire, adapted from instruments developed for the Women's Health Initiative and other studies. Participants reported their usual frequency and portion size (small, medium, or large relative to a given portion size and to photographs of portion sizes) of 120 foods and beverages consumed during the year before baseline. Body mass index was calculated from a self-report of height and weight. Recreational physical activity was measured as average total metabolic equivalent hours per week over the past 10 years, based on the reported years, frequency, and estimated energy expenditure for different moderate/vigorous activities.
Ascertainment of Case Status, Site, and Stage
Cohort members were followed up for incidence of CRC (ICD-O-3 codes of 18.0–20.9) from enrollment to 31 December 2008, by linking the study cohort to the western Washington Surveillance, Epidemiology and End Results cancer registry. After excluding in situ cases, carcinoid tumors, neuroendocrine carcinomas, and lymphomas, there were 558 eligible invasive cancers of the colon and rectum. Stage was based on Surveillance, Epidemiology, and End Results stage, which defines localized cancer as cancer that is limited to the organ in which it began, regional as beyond the original site to nearby lymph nodes or organs and tissues, and distant as cancer that has spread to distant organs or distant lymph nodes. Colon cancer cases included those with ICD-O-3 codes of 18.0–18.9 and rectal cancer cases were those with ICD-O-3 codes of 19.9 and 20.9. Cases were followed up until date of CRC diagnosis and non-cases were censored at whichever occurred earlier: date of death (6.7%), date of emigration out of the Surveillance, Epidemiology, and End Results catchment area (5.5%), date of requested removal from study (0.03%), or end of follow-up period, 31 December 2008 (87.8%). Deaths occurring within the state of Washington were identified by linkage to the state death file, whereas emigrations out of area were identified by linkage to the National Change of Address System and by telephone calls and mailings.
Statistical Analysis
Logistic regression was used to calculate ORs with 95% confidence intervals (95% CI) to evaluate associations between baseline study participant characteristics and laxative use.
Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs for the associations of bowel habits and laxative use with the risk for CRC. Age was the time metric in regression models, with participants entering at the age of completing the baseline questionnaire and exiting at their age at the end of follow-up. P-value for trend was modeled by treating the categorical exposure variable as continuous.
Covariates included in multivariate analyses were selected a priori and included factors associated with CRC. The multivariate model included the following covariates: age, sex, race/ethnicity, education, body mass index (kg/m), physical activity, smoking history, energy intake, total calcium intake, alcohol consumption, multivitamin use, dietary fiber intake, fruit/vegetable intake excluding potatoes, red/processed meat intake, and hormone replacement therapy, as well as aspirin use and non-aspirin nonsteroidal anti-inflammatory drug use. Analyses also included adjustment for family history of CRC among first-degree relatives, history of sigmoidoscopy/colonoscopy in the 10 years before baseline, and history of polyp removal. In addition, HRs were estimated with models mutually adjusted for all exposure variables (constipation, bowel movement frequency, fiber laxative use, and non-fiber laxative use).
Stratified analyses were performed to examine the association between laxative use and CRC risk by sex. P-values for interaction by sex were calculated by including a single cross-product term between laxative use, modeled as a continuous categorical variable, and sex in the unstratified, mutually adjusted multivariate model.
We also evaluated heterogeneity of the laxative–CRC association by cancer site (colon vs. rectum) and cancer stage (local vs. regional/distal) at the time of diagnosis. Logistic regression limited to cases was used to determine the statistical significance of subsite- and stage-specific differences. In addition, a sensitivity analysis, which excluded all cases diagnosed within 1 year of follow-up, was performed to address the possibility that preclinical CRC may influence bowel habits and laxative use. The 1-year follow-up period was selected as CRC diagnoses usually occur within 1 year of onset of symptoms.
All reported P-values are two-sided, and a P-value <0.05 was considered statistically significant. All analyses were carried out using STATA 11 (StataCorp, College Station, TX).
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