Abstract
Garland et al. first reported in 1980 a link between vitamin D deficiency and an increased risk of colorectal cancer (CRC) [1]. Garland confirmed the increased risk in geographic locations with low sunlight exposure and in cities with increased risk of rickets, both considered measures of low vitamin D levels [1]. Subsequent studies have suggested a link between vitamin D status, as reflected by 25-OH vitamin D3 level (25-D3), and the risk of CRC. A meta-analysis of studies evaluating the impact of serum 25-D3 and CRC confirmed a statistically significant increased risk of CRC in the vitamin D3-deficient population. This meta-analysis suggested that for every 10 ng/ml increase in 25-D3 levels, there was a 26% reduction in the risk of CRC [2]. An association between vitamin D deficiency and colorectal carcinogenesis is supported further by several case control and observational studies that have linked an increased risk of colorectal adenoma and vitamin D deficiency [3–5]. In addition, a meta-analysis of studies investigating dietary vitamin D intake and risk of CRC has suggested a modest, but statistically significant, association between D3 intake and risk of CRC [2]. These data have been considered hypothesis generating. Note that no large-scale randomized prospective studies have yet shown any advantage to vitamin D3 supplementation for the prevention of CRC. To the contrary, the Women’s Health Initiative study failed to show any benefit from vitamin D3 and calcium supplementation in the prevention of CRC [6]. However, this study was criticized for the low dose of 400 IU vitamin D3 supplementation [7]. There is a strong rationale for the consideration of vitamin D3 supplementation in the prevention of CRC. 1,25-hydroxy-D3 (1,25-D3) has an antitumor and prodifferentiating activity through its binding to vitamin D receptor. Vitamin D receptor expression is present in normal and malignant colonic tissue [8–10]. Vitamin D 1α-hydroxylase, the enzyme responsible for the transformation of 25-D3 to the active form 1,25-D3 is expressed in colon tissue. The expression appears equally prominent in normal colon, polyps and differentiated colonic adenocarcinomas [10]. However, the expression of 1αhydroxylase appears to be decreased in higher grade CRC [11,12]. These findings may suggest a differential impact of vitamin D3 in the prevention setting compared with the more advanced, metastatic CRC [13]. Nonetheless, several studies have now investigated the impact of vitamin D3 status on patients with established CRC. Analysis of the Nurse Health Study and the Health Professional Follow-up Study showed an improved overall survival (OS) following a diagnosis of CRC in patients with the highest quartile of 25-D3 levels [14]. Given the dominance of earlier stages of CRC in this study, extrapolation to more advanced metastatic disease is
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