Trial Information

Calcium, Vitamin D, and Colon Cancer Risk Biomarkers

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.