Orthomolecular Medicine News Service, July 15, 2019
by William B. Grant
(OMNS July 15, 2019) The results of a phase 2 randomized controlled trial (RCT) of high- vs. low-dose vitamin D3 supplementation for 139 patients with advanced colorectal cancer taking chemotherapy was recently reported in JAMA [Ng et al., 2019]. The high-dose vitamin D treatment was 8000 IU/d vitamin D3 for two weeks, then 4000 IU/d thereafter. The low-dose treatment group received 400 IU/d vitamin D3. The length of time before the disease worsened was 13 months in the high-dose treatment group and 11 months in the low-dose group. Further, high-dose vitamin D3 supplementation significantly reduced the risk of death by 36% (P = 0.02). In secondary analyses, the length of time before the disease worsened was significantly longer for patients in the treatment group who maintained a healthy weight, or had more metastatic sites.
The rate of diarrhea was 12% in the low-dose group, but only 1% in the high-dose group. This finding is consistent with the role of vitamin D in maintenance of gut mucosal barrier integrity.
The findings from this RCT are supported by results from the recently-reported VITAL trial [Manson, 2019]. In that RCT, the treatment group received 2000 IU/d vitamin D3 and another group received a placebo. In the analysis of the entire 25,000-person group, the risk of cancer was not significantly reduced. However, evidently higher vitamin D levels take time to have an effect, because when the data from the first one or two years were omitted, there was a 25% significant reduction in the all-cancer mortality rate. In the secondary analyses, the effect of a higher vitamin D intake was to lower the all-cancer incidence rate by 24% for those with BMI < 25 kg/m2 (i.e. with "normal weight"), and by 23% (P = 0.06) for blacks.
To put these two studies in historical perspective, the UVB-vitamin D-cancer hypothesis was first proposed in 1980 by the brothers Cedric and Frank Garland after seeing the map of colon cancer mortality rates in the U.S. and noting that the region with the lowest rates was the sunny southwest [Garland & Garland, 1980]. Subsequently, after a more detailed cancer atlas became available [Devessa, 1999], incidence of many cancer types was found to be inversely correlated with solar UVB doses [Grant, 2002; Grant & Garland, 2006]. The mechanisms whereby vitamin D reduces the risk of cancer incidence and death are well known, and include effects on cells, angiogenesis around tumors, and metastasis [Moukayed & Grant, 2013, 2017].
There is also strong evidence that higher 25-hydroxyvitamin D concentrations reduce the risk of all types of cancer, including breast cancer [Grant & Boucher, 2017; McDonnell et al., 2016, 2018]. Thus, those interested in reducing risk of cancer would be well-advised to take several thousand IU/d vitamin D3 to achieve 25-hydroxyvitamin D concentrations above 40 ng/ml. Those diagnosed with cancer may want to include high-dose vitamin D3 supplementation in addition to the standard care of treatment.
Along with supplementing with vitamin D, you can further reduce your risk for cancer by not smoking and by avoiding alcohol, maintaining a healthy weight, exercising regularly, and eating an excellent diet with fruits, vegetables, whole grains [Aune et al., 2009a; Schwingshackl et al., 2017] and low amounts of meat [Aune et al., 2009b]. It is also important to eat raw vegetables and fruits containing fiber, along with adequate doses of the essential nutrients including vitamins and minerals.
Aune D, De Stefani E, Ronco A, et al. (2009a) Fruits, vegetables and the risk of cancer: a multisite case-control study in Uruguay. Asian Pac J Cancer Prev. 10(3):419-28. http://journal.waocp.org/article_24939_7fcab7713313f3f4a332ddcec7d9dc2c.pdf
Aune D, De Stefani E, Ronco A, et al. (2009b). Meat consumption and cancer risk: a case-control study in Uruguay. Asian Pac J Cancer Prev. 10(3):429-36. http://journal.waocp.org/article_24940_fdc21f9ea72e2cd3d0e1106cf564e346.pdf
Devesa SS, Grauman DJ, Blot WJ, Pennello GA, Hoover RN, Fraumeni JF Jr (1999) Atlas of Cancer Mortality in the United States, 1950-1994. NIH Publication No. 99-4564, 1999. https://academic.oup.com/ije/article/29/3/602/771347
Garland CF, Garland FC. (1980) Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. ;9:227-231. https://academic.oup.com/ije/article/35/2/217/694653
Grant WB, Boucher BJ. (2017) Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PLos One. 12(5):e0176448. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176448
Grant WB, Garland CF. (2006) The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res. 26:2687-2699. https://www.ncbi.nlm.nih.gov/pubmed/16886679
Grant WB. (2002) An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002 Mar 15;94(6):1867-75. https://www.ncbi.nlm.nih.gov/pubmed/11920550
Manson JE, Cook NR, Lee IM, et al. (2019); VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med.. 380:33-44. https://www.ncbi.nlm.nih.gov/pubmed/30415629
McDonnell SL, Baggerly CA, French CB, et al. (2018) Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations ≥ 60 vs < 20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort. PLoS One. 13(6):e0199265. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199265
McDonnell SL, Baggerly C, French CB, et al. (2016) Serum 25-Hydroxyvitamin D Concentrations ≥ 40 ng/ml Are Associated with > 65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. PLoS One. 11(4):e0152441. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152441
Moukayed M, Grant WB. (2013) Molecular link between vitamin D and cancer prevention. Nutrients. 5:3993-4023. https://www.mdpi.com/2072-6643/5/10/3993
Moukayed M, Grant WB. (2017) The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: a review of the epidemiology, clinical trials, and mechanisms. Rev Endocr Metab Disord. 18:167-182. https://www.ncbi.nlm.nih.gov/pubmed/28213657
Ng K, Nimeiri HS, McCleary NJ, et al. (2019) Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial. JAMA. 321:1370-1379. doi: 10.1001/jama.2019.2402 https://jamanetwork.com/journals/jama/article-abstract/2730112
Schwingshackl L, Schwedhelm C, Galbete C, Hoffmann G. (2017) Adherence to Mediterranean Diet and Risk of Cancer: An Updated Systematic Review and Meta-Analysis. Nutrients. 9(10). pii: E1063. doi: 10.3390/nu9101063. https://www.mdpi.com/2072-6643/9/10/1063
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