Observational studies show predominantly and consistently an inverse association between selenium exposure and the risk of some cancer types [Vinceti 2018; Cai 2016]. The evidence from some 70 observational studies indicates that higher levels of exposure to selenium are associated with lower levels of cancer incidence and mortality [Vinceti 2018]. What the observational studies haven’t shown thus far is a systematic pattern suggesting specific dose-response relationships. [Vinceti 2018].
The evidence from observational studies also indicates that there may be a U-shaped form to the relationship between selenium exposure and disease risk. For example, one study suggests that the best serum selenium range for protection against prostate cancer is between 119 and 137 micrograms per liter [Chiang 2010]. A second study shows that the risk of prostate cancer decreases gradually as the selenium concentrations increase in the range from 60 micrograms of selenium per liter of plasma up to 170 micrograms per liter. Above 170 micrograms per liter, the protection ceases [Hurst 2012].
The evidence from randomized controlled trials (RCT) is less unequivocal than the evidence from observational studies. The latest Cochrane review analyzes the results from 11 randomized controlled studies of selenium supplementation and cancer risk with a total of 44,743 study participants (94% men). It concludes that selenium supplementation did not significantly reduce overall cancer incidence or mortality [Vinceti 2018].
To an extent, this is a puzzling result. Why, one wonders, does the evidence from the 11 randomized controlled studies differ so markedly from the evidence from the 70 observational studies analyzed in the review?
The effect of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) on the Cochrane review
The 800-pound gorilla in the Cochrane review is the SELECT study, which was a randomized, placebo-controlled study of selenium and/or vitamin E supplementation for the prevention of prostate cancer [Lippman 2009].
34,888 male SELECT study participants completed the study. Those 34,888 study participants make up 78% of the total number of study participants considered in the RCT portion of the Cochrane Review.
The authors of the Cochrane Review state: “The SELECT study had the strongest influence on the effect estimate” for any cancer risk, for colorectal cancer risk, for bladder cancer risk, and for prostate cancer risk [Vinceti 2018].
Note: The SELECT trial was halted early when data indicated that neither vitamin E nor selenium supplements were associated with the prevention of prostate cancer.
Suggested reasons for the failure of the SELECT trial
Selenium researchers have advanced two possible explanations for the failure of the SELECT trial to replicate the promising reduction-of-prostate-cancer-risk results of the earlier Nutritional Prevention of Cancer (NPC) trial [Duffield-Lillico 2002].
- The form of the selenium supplement: in the SELECT study, the researchers used a synthetic selenomethionine supplement whereas the researchers had used a selenized yeast supplement in the NPC study.
- The baseline selenium status of the study participants: the SELECT study participants (average: 135 micrograms per liter) had baseline selenium status much higher than the baseline selenium status of the NPC study participants (average: 114 micrograms per liter). The best cancer prevention results were seen in the study participants who had baseline plasma selenium status below 121.6 micrograms per liter [Duffield-Lillico 2002].
The importance of the form of the selenium supplement
One general conclusion from the results of the SELECT study is that the preferred formulation of selenium supplement is the form used in the Nutritional Prevention of Cancer (NPC) study: the selenized yeast formulation, also known as the high-selenium yeast formulation.
Selenized yeast supplements – high-selenium yeast supplements – are supplements produced by growing a strain of yeast in a selenium-rich medium. The selenium atoms in the medium are incorporated into the proteins in the yeast and become organically bound to the yeast. The yeast cells are dried and are dead and inactive in the high-selenium yeast supplements.
Good quality selenized yeast supplements contain approximately 60% natural selenomethionine and as many as 30 more different species of selenium, some or many of which seem to have important biological functions and may be responsible for the cancer prevention seen in the NPC study.
Note: Contrast the variety of natural species of selenium in the selenized yeast preparations with the 100% synthetic selenomethionine composition used in the SELECT study. Contrast too the baseline serum selenium levels in the two different types of studies.
Note, furthermore, that a New Zealand study has shown that a dose of 200 micrograms per day of selenized yeast is a safer supplementation option than a similar dose of synthetic selenomethionine [Karunasinghe 2013].
Comparing the selenized yeast studies separately
In certain respects, then, mixing together and analyzing the results of cancer studies using synthetic selenomethionine and the results of cancer studies using selenized yeast seems like comparing apples and oranges.
What happens if the studies using selenized yeast are analyzed separately, on their own, apart from the synthetic selenomethionine studies?
The selenized yeast and cancer studies
Algotar [2013], 699 participants = no significant results over five years on prostate cancer incidence in men at high-risk for prostate cancer from the start of the study
Dreno [2007], 184 participants = no significant prevention over three years of skin lesions linked to human papilloma virus (HPV)
Duffield-Lillico [2002], 1312 participants = significantly reduced total cancer incidence and prostate cancer incidence over six years of follow-up with the strongest beneficial effects in study participants with baseline plasma selenium concentrations below 121.6 micrograms per liter
Karp [2013], 1561 participants = no significant reduction in incidence over five years of second primary tumors in patients with resected non-small-cell lung cancer
Reid [2008], 423 participants = significantly reduced total cancer incidence (by 25%) when supplemented with 200 micrograms daily; no significant reduction when supplemented with 400 micrograms daily
Yu [1991], 2474 participants = significantly reduced primary liver cancer incidence (by 35%) during 8-year follow-up
Yu [1997], 226 participants = significantly inhibited primary liver cancer and hepatitis B virus infections over four years
There have been other selenized yeast and cancer studies that were RCTs and that showed significant beneficial results of the supplementation. These studies were not analyzed in the Cochrane review because the studies investigated selenium’s effect on cancer in combination with other antioxidants:
- Linxian Nutritional Intervention Trials: significantly lower cancer mortality and lower stomach cancer mortality [Blot 1993]
- Indian Oral Cancer Trial: significantly reduced risk of oral cancer [Prasad 1995]
- Su.Vi.Max. Trial: significantly lower total cancer incidence and all-cause mortality in men [Hercberg 2004]
Preliminary conclusions about the selenized yeast and cancer studies
What do we see?
The selenized yeast and cancer studies comprise only 16% of the total participants in the Cochrane Review. The synthetic selenomethionine and cancer studies, the SELECT study [Lippman 2009] and the Marshall study [2011], comprise 78% of the total participants in the Cochrane Review [Vinceti 2018]. The remaining 6% of RCTs analyzed in the Cochrane Review are studies using inorganic selenite preparations [Vinceti 2018].
- There are too few studies and too few participants in the selenized yeast and cancer studies to conclude definitively that selenized yeast supplements do not significantly reduce overall cancer incidence or mortality.
- The results of the Nutritional Prevention of Cancer study [Duffield-Lillico 2002; Reid 2008] are encouraging as are the results of the Yu studies [1991; 1997], the Linxian studies [Blot 1993] and the Su.Vi.Max. study [Hercberg 2004]. These studies tested the use of a different form of selenium supplement in study participants with much lower baseline serum selenium concentrations.
More funding needed for more studies of selenized yeast and cancer
We would like to see funding for replication studies of these results, using high-selenium yeast preparations in low-selenium status populations and testing adequate numbers of both men and women. It is premature to write off selenium supplements for cancer prevention because of the results of the SELECT study.
Sources
Algotar, A. M., Stratton, M. S., Stratton, S. P., Hsu, C., & Ahmann, F. R. (2010). No effect of selenium supplementation on serum glucose levels in men with prostate cancer. The American Journal of Medicine, 123(8), 765-768.
Blot, W. J., Li, J. Y., Taylor, P. R., Guo, W., Dawsey, S., Wang, G. Q., et al. (1993). Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. Journal of The National Cancer Institute, 85(18), 1483-1492.
Cai, X., Wang, C., Yu, W., Fan, W., Wang, S., Shen, N., & Wang, F. (2016). Selenium exposure and cancer risk: an updated meta-analysis and meta-regression. Scientific Reports, 619213.
Chiang, E. C., Shuren, S., Kengeri, S. S., Xu, H., Combs, Jr., G. F., Morris, J. S., Bostwick, D. G., & Waters, D. J. (2010). Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis. Dose Response, 8(3): 285–300. doi: 10.2203/dose-response.09-036.
Clark, L. C., Combs, G. J., Turnbull, B. W., Slate, E. H., Chalker, D. K., Chow, J., & Taylor, J. R. (1996). Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA, 276(24), 1957-1963.
Dréno, B., Euvrard, S., Frances, C., Moyse, D., & Nandeuil, A. (2007). Effect of selenium intake on the prevention of cutaneous epithelial lesions in organ transplant recipients. European Journal of Dermatology: EJD, 17(2), 140-145.
Duffield-Lillico, A. J., Reid, M. E., Turnbull, B. W., Combs, G. J., Slate, E. H., Fischbach, L. A., & … Clark, L. C. (2002). Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiology, Biomarkers & Prevention, 11(7), 630-639.
Hercberg, S., Galan, P., Preziosi, P., Bertrais, S., Mennen, L., Malvy, D., & Briançon, S. (2004). The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Archives of Internal Medicine, 164(21), 2335-2342.
Hurst, R., Hooper, L., Norat, T., Lau, R., Aune, D., Greenwood, D. C., & Fairweather-Tait, S. J. (2012). Selenium and prostate cancer: systematic review and meta-analysis. The American Journal of Clinical Nutrition, 96(1), 111-122. doi:10.3945/ajcn.111.033373
Karp, D. D., Lee, S. J., Keller, S. M., Wright, G. S., Aisner, S., Belinsky, S. A., & Khuri, F. R. (2013). Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597. Journal of Clinical Oncology, 31(33), 4179-4187.
Karunasinghe, N., Han, D.Y., Zhu, S., Duan, H., Ko, Y.J., Yu, J.F., Triggs, C.M. & Ferguson, L.R. (2013). Effects of supplementation with selenium, as selenized yeast, in a healthy male population from New Zealand. Nutr Cancer, 65(3):355-66. doi: 10.1080/01635581.2013.760743.
Lippman, S.M., Klein, E.A., Goodman, P.J., Lucia, M.S., Thompson, I.M., Ford, L.G., et al. (2009). Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 301(1):39–51.
Prasad, M. P., Mukunda, M. A., & Krishnaswamy, K. (1995). Micronuclei and carcinogen DNA adducts as intermediate end points in nutrient intervention trial of precancerous lesions in the oral cavity. Eur. J. Cancer B Oral Oncol, 31B: 155-159.
Reid, M.E., Duffield-Lillico, A.J., Slate, E., et al. The nutritional prevention of cancer: 400 μg per day selenium treatment. Nutr Cancer. 2008;60(2):155-163.
Vinceti, M., Filippini, T., Del Giovane, C., Dennert, G., Zwahlen, M., Brinkman, M., & … Crespi, C. M. (2018). Selenium for preventing cancer. The Cochrane Database of Systematic Reviews, 1CD005195. doi:10.1002/14651858.CD005195.pub4
Yu, S.Y., Zhu, Y.J. & Li, W.G. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res. 1997;56(1):117-124.
Yu, S. Y., Zhu, Y. J., Li, W. G., Huang, Q. S., Huang, C. Z., Zhang, Q. N., & Hou, C. (1991). A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China. Biological Trace Element Research, 29(3), 289-294.
Disclaimer: The information presented in this review article is not intended as medical advice and should not be construed as such.