In this application we propose to complete CA098286, a double-blind, randomized, controlled trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. The study builds on extensive epidemiological and experimental data indicating that both vitamin D and calcium have anti-neoplastic effects in the large bowel and that these agents interact, each requiring the other for full effect. Despite the strong supporting data, randomized trials are needed to confirm the purported efficacy of vitamin D, clarify its persistence, and assess the possible interaction with calcium. Experience with previous candidate chemopreventive agents for large bowel neoplasia shows that observation of a single colonoscopic surveillance cycle provides an incomplete evaluation of efficacy. Some agents have shown maximal effects only with longer follow-up;others have shown "rebound" increases in adenoma risk after treatment ends. Eligible subjects for the trial had a recent adenoma and no known polyps remaining in the large bowel. A total of 2259 subjects have been randomized to calcium carbonate (1200 mg calcium/day), vitamin D (1000 IU/day), both agents, or placebo. Women were offered the choice of being randomized to calcium alone or calcium plus vitamin D. Colonoscopic follow-up is either 3 years or 5 years after the qualifying exam, as planned by each subject's gastroenterologist. The main endpoint of the study is one or more neoplastic polyps of the bowel on follow-up;advanced lesions and multiple lesions are secondary endpoints. After completion of study treatment, subjects are followed for one subsequent colonoscopic surveillance cycle. The study has successfully met its milestones during the first 10 years of funding. Enrollment proceeded according to schedule and subjects have shown very good compliance with study procedures and agents. Recruitment into the post-treatment follow-up has been excellent. We now request funds for the final phases of the study: completion of treatment for a few subjects, post- treatment follow-up, and analyses of on-treatment and post-treatment adenoma occurrence. In our main analyses, we will assess the effect of vitamin D alone vs. placebo and that of vitamin D + calcium vs. calcium alone and also test whether there is a "rebound" in adenoma risk after cessation of vitamin D treatment. Under conservative assumptions, we will have greater than 95% power to detect a 20% reduction in adenoma recurrence with vitamin D vs. placebo, 89% power to detect a 25% reduction with calcium plus vitamin D vs. calcium alone and 80% power to reject a non-inferiority hypothesis regarding vitamin D vs. placebo, with an inferiority margin of 0.065 during post-treatment follow-up. Our secondary analyses will address advanced and multiple lesions, the interaction of calcium and vitamin D, and the modifying effects of baseline 25-OH vitamin D levels and polymorphisms in the vitamin D receptor on vitamin D treatment effects.
Colorectal cancer is one of the most common cancers in the U.S. This study aims to confirm in a clinical trial that supplementation with calcium or vitamin D can reduce the risk of colorectal adenomas, benign tumors that can evolve into cancer if left in place. The study agents are safe, so if they are effective in interfering with carcinogenesis in th large bowel, they could have a substantial beneficial effect on public health.
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