From Medscape CME Clinical Briefs
High Vitamin D Levels Linked to Reduced Risk for Colon Cancer CME
News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD

February 9, 2010 — High vitamin D levels are linked to lower risk for colon cancer, according to the results of a nested case-control study reported Online First in the January 22 issue of the BMJ.

"An effect of vitamin D on cancer may be important in the colorectum because both normal and neoplastic colon cells can produce the active hormone from the main circulating form 25-hydroxy-vitamin D(25-(OH) D), suggesting that it may play a direct role in controlling the growth of normal and neoplastic colonic cells," write Mazda Jenab, from the International Agency for Research on Cancer (IARC-WHO), in Lyon, France, and colleagues. "However, the epidemiological evidence is not conclusive and almost no pre-diagnostic data are available from European populations."

The goal of this study was to evaluate the association between prediagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk for colorectal cancer in European populations, using the European Prospective Investigation into Cancer and Nutrition (EPIC) study cohort of more than 520,000 participants from 10 western European countries. After enrollment into the EPIC cohort, incident colorectal cancer developed in 1248 patients, and these case patients were matched to 1248 control subjects.

Primary study endpoints were circulating vitamin D concentration (25-[OH]D) measured by enzyme immunoassay, and dietary and lifestyle data collected with questionnaires. Multivariate conditional logistic regression models adjusted for potential dietary and other confounders allowed estimation of incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of the risk for colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake. Mid-level concentration of 25-(OH)D was predefined as 50.0 to 75.0 nmol/L.

There was a strong inverse, linear dose-response association of 25-(OH)D concentration with the risk for colorectal cancer (P for trend < .001). Compared with mid levels of 25-(OH)D, lower levels were associated with a greater risk for colorectal cancer (< 25.0 nmol/L:IRR, 1.32; 95% CI, 0.87 - 2.01 vs 25.0 - 49.9 nmol/L: IRR, 1.28; 95% CI, 1.05 - 1.56). Higher 25-(OH)D levels were associated with lesser risk (75.0 - 99.9 nmol/L: IRR, 0.88; 95% CI, 0.68 - 1.13 vs ≥ 100.0 nmol/L: IRR, 0.77; 95% CI, 0.56 - 1.06).

Compared with patients in the lowest quintile of 25-(OH)D concentration, those in the highest quintile had a 40% lower risk for colorectal cancer (P < .001). In subgroup analyses, there was a strong association of 25-(OH)D level with colon cancer but not with rectal cancer (P for heterogeneity, .048).

Although higher dietary intake of calcium was associated with a lower risk for colorectal cancer, dietary vitamin D intake was not associated with disease risk. Sex, season, and month of blood donation did not affect the findings.

Limitations of this study include limited power for consideration of 25-(OH)D and diet interactions, fairly short follow-up time, observational design, and possible residual or uncontrolled confounding.

"The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations," the study authors write. "However, before any public health recommendations can be made for vitamin D supplementation, new randomised trials are needed to test the hypothesis that increases in circulating 25-(OH)D concentration are effective in reducing colorectal cancer risk without inducing serious adverse events."

The World Cancer Research Fund funded the present study. The EPIC study was supported by the Europe Against Cancer Programme of the European Commission; Ligue contre le Cancer (France); Mutuelle Générale de l'Education Nationale; Institut National de la Santé et de la Recherche Médicale; German Cancer Aid; German Cancer Research Center; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund of the Spanish Ministry of Health; the participating regional governments and institutions of Spain; The ISCIII Red de Centro RCESP; Cancer Research UK; Medical Research Council, UK; the Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; the Wellcome Trust, UK; Greek Ministry of Health and Social Solidarity; Hellenic Health Foundation and Stavros Niarchos Foundation; Greek Ministry of Education; Italian Association for Research on Cancer; Italian National Research Council; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); Swedish Cancer Society; Swedish Scientific Council; Regional Governments of Skane and Vasterbotten, Sweden; and Norwegian Cancer Society. The study authors have disclosed no relevant financial relationships.

BMJ. Published online January 22, 2010. Abstract

Clinical Context

Although epidemiologic research has suggested an inverse relationship between calcium and vitamin D and the risk for colorectal cancer, an analysis of the Women's Health Initiative cohort by Wactawski-Wende and colleagues suggested that oral supplementation of calcium and vitamin D might not ameliorate the risk for colorectal cancer among women. Specifically, the results of the study, which were published in the February 16, 2006, issue of the New England Journal of Medicine, found that daily calcium supplements at a dose of 1000 mg with vitamin D3 400 IU were not superior to placebo in reducing the risk for colorectal cancer. This result was unchanged on subgroup analysis.

In addition to being consumed through the diet, vitamin D is synthesized through sun exposure. The current study focuses the association between circulating levels of vitamin D, in the form of 25-(OH)D, diet, and the risk for colorectal cancer in a large cohort of European adults.

Study Highlights

Study data were drawn from the EPIC cohort, which observes 520,000 individuals in 23 centers.
Participants underwent a baseline evaluation, including physical examination, 12-month dietary recall, and laboratory testing between 1992 and 1998. National registries followed cancer and mortality outcomes for the cohort.
1248 patients with first incidental colorectal cancer (785 colon cancer and 463 rectal cancer) were compared vs 1248 control subjects matched for age, sex, study center, and (for women) menopausal status.
The main study outcome was the relationship between serum levels of 25-(OH)D and the risk for colorectal cancer. This result was adjusted to account for demographic, health habit, and physical confounding variables.
The mean age of participants at recruitment was 59 years. The average time between blood collection and the diagnosis of colorectal cancer was slightly less than 4 years.
There was a linear inverse trend between higher levels of 25-(OH)D and a lower risk for colorectal cancer. Compared with a mid-level concentration of 25-(OH)D of 50 to 75 nmol/L, the IRR of cancer for participants with a 25-(OH)D level less than 25 nmol/L was 1.32. The respective IRRs for subjects with 25-(OH)D levels of 75 to 99 nmol/L and 100 nmol/L or more were 0.88 and 0.77.
Comparing the highest and lowest quintile of 25-(OH)D levels yielded a IRR of 0.60 for colorectal cancer.
There was no significant difference in the risk for colorectal cancer among subjects in the 2 highest quintiles of 25-(OH)D levels.
Higher 25-(OH)D levels were associated with lower rates of colon, but not rectal, cancer.
Dietary vitamin D intake did not affect the risk for colorectal cancer. However, dietary calcium intake was inversely and significantly related to the risk for colorectal cancer.
The inverse relationship between 25-(OH)D levels and the risk for colorectal cancer remained valid across different levels of dietary calcium consumption. Participants' sex did not affect the main study conclusion.

Clinical Implications

A previous analysis of the Women's Health Initiative trial failed to demonstrate that calcium plus vitamin D supplementation reduced the risk for colorectal cancer.
The current study demonstrates that higher levels of 25-(OH)D as well as higher dietary calcium consumption were associated with a lower risk for colorectal cancer. However, dietary vitamin D intake did not affect the risk for colorectal cancer.

CME Test

Questions answered incorrectly will be highlighted.

What was the main conclusion of the previous trial of calcium and vitamin D supplementation for the prevention of colorectal cancer by Wactawski-Wende and colleagues?

Only calcium supplementation reduced the risk for colorectal cancer
Supplementation reduced the risk for colon, but not rectal, cancer
Supplementation had no significant effect on the risk for colorectal cancer
Supplementation reduced the risk for cancer among men only

Which of the following variables was associated with a reduced risk for colorectal cancer in the current study by Jenab and colleagues?

Higher consumption of dietary vitamin D only
Higher consumption of dietary calcium and vitamin D only
Higher consumption of dietary calcium and higher levels of 25-(OH)D only
Higher consumption of dietary calcium