A Scottish study of 1,598 patients diagnosed with stage I to III colorectal cancer (CRC) found an association between plasma concentrations of 25-hydroxyvitamin D (25-OHD) and CRC survival.
The study (J Clin Oncol 2014;32[23]:2430-2439, PMID: 25002714) involved patients who were part of a larger national study identifying genetic and environmental factors in CRC. Blood was drawn after definitive surgical treatment (median time to sampling, 105 days), and samples were standardized to a single month (May) to adjust for seasonal differences in vitamin D. Total 25-OHD was measured by liquid chromatography/mass spectrometry, and blood leukocyte DNA was genotyped for polymorphisms at the vitamin D receptor (VDR) gene locus.
The researchers reported that 49.7% of patients met the criteria for vitamin D deficiency (25-OHD <10 ng/mL) and 26.8% were at high risk for deficiency (10-16 ng/mL), thought to be the result of increasingly indoor lifestyles, as well as Scotland’s northern latitude.
Plasma 25-OHD levels were significantly associated with CRC-specific (P=0.008) and all-cause (P=0.003) mortality. Comparing CRC mortality between the one-third of patients with the highest 25-OHD levels and patients in the lowest tertile, the adjusted hazard ratio was 0.68 (95% confidence interval, 0.50-0.90; P=0.004). CRC-specific mortality reached 10% after 2.5 years for patients in the lowest vitamin D tertile and 6.6 years for patients in the highest tertile. These trends were similar for all-cause mortality.
A gene–environment interaction was found between increased 25-OHD levels and the presence of VDR variant rs11568820. The authors speculated that this variant might serve as a prognostic biomarker.
EXPERT INSIGHT
Celina Ang, MD
Assistant Professor of Medicine, Hematology and Medical Oncology
Mount Sinai Health System
New York, New York
Although seemingly less sophisticated than contemporary molecularly targeted agents, vitamin D boasts an expansive and versatile repertoire of biologic activities. Typically known for its role in maintaining bone health and calcium homeostasis, vitamin D also has been shown to have antiproliferative, pro-apoptotic, pro-differentiative, anti-inflammatory and antiangiogenic properties, which have generated interest in its utility as an antineoplastic agent.
In this observational study, investigators reported a significant inverse relationship between 25-OHD concentrations and CRC mortality, with a 32% reduction in risk for death among patients with the highest compared with the lowest 25-OHD concentrations. Of note, the relationship was most pronounced among patients with stage II CRC and those who did not receive chemotherapy. The findings are even more remarkable considering that the differences were seen at concentrations that would be considered deficient (<20 ng/mL), as well as the relatively small differential (6 ng/mL) separating the highest and lowest concentration categories. This suggests that even greater benefits may be achieved with vitamin D sufficiency.
The study adds to the growing body of data suggesting that vitamin D plays a protective role against CRC, although it remains to be determined if there is a true cause-and-effect relationship between vitamin D status and CRC outcomes. Several questions deserve further evaluation. First, will correcting vitamin D deficiency improve survival and lower the CRC mortality in this patient population? Second, given the observation that the protective effects of high 25-OHD were greater in those who did not receive chemotherapy than in those who did, is there a negative interaction between chemotherapy and vitamin D, and can this be overcome by supplementation? Third, do current guidelines for vitamin D supplementation in the general population apply to patients with CRC? Fourth, given the strong prognostic effect of vitamin D status in the stage II subset, should 25-OHD concentrations be considered in risk-stratifying these patients to determine whether adjuvant chemotherapy should be given? Finally, what is the role of VDR polymorphisms in modulating response to vitamin D supplementation and chemotherapy?
In summary, vitamin D supplementation appears promising as a relatively low-risk therapeutic adjunct for CRC with broader health benefits. However, additional studies are needed to ascertain its precise role in the management of this disease.