BACKGROUND:Colonic epithelial cell proliferation is increased in patients at high risk for colon cancer. Calcium administration has ameliorated the proliferative changes in rodents, and findings in small, uncontrolled clinical trials have suggested similar effects in humans. PURPOSE: This preliminary, double-blind, randomized clinical trial was designed 1) to investigate whether supplemental calcium will reduce colonic epithelial cell proliferation in patients with sporadic adenomas who consume a high-fat, Western-style diet; 2) to determine the sample size (number of scorable crypts per person) needed to achieve adequate statistical power; and 3) to evaluate the feasibility of full-scale clinical trials. METHODS:Twenty-one sporadic adenoma patients were treated daily with placebo or 1200 mg of supplemental calcium. To determine colonic epithelial cell proliferation, we used tritiated thymidine labeling of colon crypt epithelial cells in rectal biopsy specimens and calculated the percentage of labeled cells (labeling index [LI]). Two pathology technician "readers" independently scored each specimen, and inter-reader reliability was determined. Subjects remained on their usual diet during the study, and intake of calories, calcium, total fat, and vitamin D did not differ substantially among them. We calculated curves for statistical power to determine the number of scorable crypts needed per person for detection of a statistically significant difference (P < .05) of 1.0% in mean LI. RESULTS: The pooled baseline LI was 4.7%. In the calcium-treated group, the LI increased 0.6% (proportional increase, 12.8%); in the placebo-treated group, it decreased 0.5% (proportional decrease, 10.6%). The difference between change in the mean LI from baseline to 8 weeks' follow-up in the placebo group versus the calcium group was not statistically significant. The intraclass correlation coefficient for inter-reader reliability for the baseline LI was .66. Analyses indicated scoring eight crypts sufficient for estimates of the LI adequate for between-group comparisons, a level achieved in 81% of biopsy specimens. CONCLUSIONS:Calcium carbonate supplements delivering 1200 mg elemental calcium daily may not decrease colonic epithelial cell proliferation over an 8-week period in sporadic adenoma patients. In future trials measuring the LI, consideration should be given to ensuring adequate numbers of scorable crypts and to the impact of inadequate biopsy procedures, labeling failure, reader reliability, and participant withdrawal. Our findings support the feasibility of a full-scale clinical trial to further study the relationships among dietary calcium, colonic epithelial cell proliferation, and colorectal cancer.
RCT Entities:
BACKGROUND: Colonic epithelial cell proliferation is increased in patients at high risk for colon cancer. Calcium administration has ameliorated the proliferative changes in rodents, and findings in small, uncontrolled clinical trials have suggested similar effects in humans. PURPOSE: This preliminary, double-blind, randomized clinical trial was designed 1) to investigate whether supplemental calcium will reduce colonic epithelial cell proliferation in patients with sporadic adenomas who consume a high-fat, Western-style diet; 2) to determine the sample size (number of scorable crypts per person) needed to achieve adequate statistical power; and 3) to evaluate the feasibility of full-scale clinical trials. METHODS: Twenty-one sporadic adenomapatients were treated daily with placebo or 1200 mg of supplemental calcium. To determine colonic epithelial cell proliferation, we used tritiated thymidine labeling of colon crypt epithelial cells in rectal biopsy specimens and calculated the percentage of labeled cells (labeling index [LI]). Two pathology technician "readers" independently scored each specimen, and inter-reader reliability was determined. Subjects remained on their usual diet during the study, and intake of calories, calcium, total fat, and vitamin D did not differ substantially among them. We calculated curves for statistical power to determine the number of scorable crypts needed per person for detection of a statistically significant difference (P < .05) of 1.0% in mean LI. RESULTS: The pooled baseline LI was 4.7%. In the calcium-treated group, the LI increased 0.6% (proportional increase, 12.8%); in the placebo-treated group, it decreased 0.5% (proportional decrease, 10.6%). The difference between change in the mean LI from baseline to 8 weeks' follow-up in the placebo group versus the calcium group was not statistically significant. The intraclass correlation coefficient for inter-reader reliability for the baseline LI was .66. Analyses indicated scoring eight crypts sufficient for estimates of the LI adequate for between-group comparisons, a level achieved in 81% of biopsy specimens. CONCLUSIONS:Calcium carbonate supplements delivering 1200 mg elemental calcium daily may not decrease colonic epithelial cell proliferation over an 8-week period in sporadic adenomapatients. In future trials measuring the LI, consideration should be given to ensuring adequate numbers of scorable crypts and to the impact of inadequate biopsy procedures, labeling failure, reader reliability, and participant withdrawal. Our findings support the feasibility of a full-scale clinical trial to further study the relationships among dietary calcium, colonic epithelial cell proliferation, and colorectal cancer.