CaDvMAP: Calcium and Vitamin D vs Markers of Adenomatous Polyps

Study Details

Study Description

Brief Summary

The purpose of this study is to test whether calcium and/or vitamin D supplementation favorably affects a set of biomarkers of risk for colon cancer in persons who are at higher than average risk for colon cancer (ie, have already undergone the removal of adenomatous polyps, which are known to be precursors to developing colon cancer).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Adenomatous Polyps	Dietary Supplement: Calcium and vitamin D3 combined Drug: Placebo Dietary Supplement: Calcium Dietary Supplement: Vitamin D3	Phase 2

Detailed Description

There is strong biologic plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial in humans (yet the previously reported observational evidence, although generally supportive, is inconsistent), and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, other than a possible reduction of colorectal epithelial cell proliferation by calcium, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown. There have been no clinical trials involving vitamin D individually or jointly with calcium related to colorectal cancer chemoprevention in humans. There are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer other than the possible exception of proliferation markers that, at best, have limited usefulness as individual markers. Based on recent advances in understanding the molecular basis of colorectal cancer, we developed a panel of newer, plausible, reliable, immunohistochemically detected biomarkers that provides molecular phenotyping of the normal appearing colorectal epithelium: 1) inflammation (COX-2), 2) the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the two major colorectal carcinogenesis pathways (APC, MSH2, MLH1), and 3) a more complete picture of the cell cycle events in colorectal epithelial crypt cells (short and long-term proliferation: MIB-1 and telomerase; differentiation: p21; apoptosis inhibition and promotion: bcl-2, bax, and bak) that has not yet been tested in a chemoprevention trial.

To address these needs, we will conduct a preliminary, randomized, double-blind, placebo-controlled, 2 x 2 factorial chemoprevention trial (n = 88) of calcium 2,000 mg/day and vitamin D3 800 IU/day, alone and in combination vs placebo over 6 months in patients with recent removal of sporadic adenomatous colorectal polyps, to investigate their effects on the individual components and aggregate profile of our colorectal cancer risk biomarker panel. We will also examine study results stratified by NSAID use and Bsm I vitamin D receptor genotypes. The preliminary estimates of treatment effect sizes and variabilities will be used to refine the biomarker panel and study design and to calculate the needed sample size for a potential full-scale study.

We assert that using biological measurements of risk, as they have for ischemic heart disease, will result in a decline in colorectal cancer incidence and mortality. The proposed project is borne of this vision, and has intertwined missions of exploring the efficacy of two plausible and evidentially well-supported dietary agents, calcium and vitamin D, on the modulation of a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia.

Study Design

Study Type:

Interventional

Actual Enrollment :

92 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Calcium, Vitamin D, and Colon Cancer Risk Biomarkers

Study Start Date :

May 1, 2005

Actual Primary Completion Date :

Sep 1, 2006

Actual Study Completion Date :

Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Calcium Calcium 2,000 mg/day as calcium carbonate in two divided doses with food	Dietary Supplement: Calcium Calcium 2,000 mg/day as calcium carbonate in two divided doses with meals over 6 months
Experimental: Vitamin D3 Vitamin D3 800 IU given as 400 IU twice daily with food over 6 months	Dietary Supplement: Vitamin D3 Vitamin D3 800 IU given as 400 IU twice daily with food over 6 months
Experimental: Calcium and vitamin D3 combined Calcium 2,000 mg (as calcium carbonate) + vitamin D3 800 IU given in equal divided doses twice daily with meals over 6 months	Dietary Supplement: Calcium and vitamin D3 combined Calcium 2,000 mg (as calcium carbonate) + vitamin D3 800 IU given in equal divided doses twice daily with food over 6 months
Placebo Comparator: Placebo	Drug: Placebo Placebo

Outcome Measures

Primary Outcome Measures

Biomarkers of Risk for Colorectal Neoplasms [6 months]
A panel of putative biomarkers of risk for colorectal neoplasms in biopsies of normal appearing rectal mucosa: COX-2, APC, MSH-2, MLH1, MIB-1, telomerase, p21, bcl-2, bax, bak, β-catenin, E-cadherin, TGFα, TGFβ1, calcium sensing receptor, vitamin D receptor, CYP27B1, CYP24, 8-OH-dG

Secondary Outcome Measures

Vitamin D metabolites [6 months]
serum 25-OH-vitamin D3 and 1,25-OH-vitamin D3
Circulating inflammation markers [6 months]
serum CRP, TNF-α, IL-6, IL-1β, IL-8 and IL-10