Prostate Cancer: Selenium reduces
prostate cancer incidence and mortality

 

In the U.S., the incidence of prostate cancer increases dramatically with increasing age. It is unusual for prostate cancer to occur in men under the age of 50. Prostate cancer is most common in men over the age of 55, and the average age at diagnosis is 70. The risk of prostate cancer increases exponentially after age 50. In fact, by the age of 60, as many as 34% of men show early evidence of prostate cancer, and 70% of men in their 80s have the disease. Prostate cancer rates are highest among African Americans, intermediate among Caucasians, and lowest among native Japanese and Native Americans. African American men are nearly twice as likely to develop prostate cancer as Caucasian men and are twice as likely to die from the disease. There is increasing evidence that diet plays a role in the development of prostate cancer. Some studies indicate that prostate cancer is more prevalent in populations that consume a diet high in animal fat and/or lacking certain nutrients.

            The dramatic results of the NPC Trial discusses in detain earlier were especially significant for selenium against prostate cancer. (46) As a result, much effort has been directed at understanding the mechanisms involved and further confirmation. The National Cancer Institute has funded several intervention trials including SELECT, the Negative Biopsy Trial (NBT) for men at high risk of Prostate Cancer because of a persistent elevation in PSA above 4 ng/ml and who have had a negative biopsy, the Watchful Waiting Trial for men diagnosed with Prostate Cancer and under 'Watchful Waiting' of a physician for their disease, and the Preprostatectomy Trial (PREP). In Europe, A trial similar to SELECT called The Prevention of Cancer by Intervention with Selenium (PRECISE) is planned and pilot trials have been started. There is government funding for these trials because there is ample credible scientific evidence that selenium reduces the incidence and mortality of prostate cancer.

            As described in the section discussing the details of the NPC Trial, the complete NPC Intervention Trial data for prostate cancer incidence showed that for men with plasma PSA concentrations 32< 4 ng/mL, selenium supplementation was associated with a 65% reduction in prostate cancer risk (P= 0.01) (47). For men entering the trial with PSA < 4 µg/L, there was no significant effect of treatment (RR= 0.88, P= 0.86), nor did Se-treatment reduce elevated PSA values or affect the clinical stage or incidence of advanced prostate cancers. These findings are consistent with a non-treatment, cancer risk reduction from selenium. There was no indication that selenium supplementation affected the stage of prostate disease among men with that diagnosis.

            The NPC Intervention Trial follow-up also showed that the protection by selenium supplementation was most remarkable for “subjects who entered the trial with relatively low baseline plasma selenium levels (53). Those with plasma selenium < 106 µg/L (1.35 µmol/L), i.e., in the lowest tertile of that cohort, showed the strongest effect of Se-treatment (RR= 0.14, P= 0.002) in reducing the risk of being diagnosed with prostate cancers over the subsequent years of follow-up. Subjects in the middle tertile of plasma selenium, 107–123 µg/L (1.37–1.58 µmol/L), showed a more modest, but still protective effect of selenium supplementation (RR= 0.39, P= 0.03); however, subjects in the highest tertile of plasma selenium (>123 µg/L, or >1.58 µmol/L) showed no significant treatment effect (RR = 1.20, P = 0.66). As mentioned in the discussion of the NPC Trial follow-up earlier, Duffield-Lillico et al. explored the possibility of a diagnostic bias with simulated results based on the diagnoses they projected on the basis of comparable biopsy rates between selenium and placebo treatment groups; despite a generally attenuated cancer incidence, their analyses showed significant protection by selenium in the lowest plasma selenium tertile group. (48)

            In 1998, Clark et al. examined data from a trial conducted in the United States and reported a 63% decreased risk of prostate cancer for those receiving 200 mcg of selenium per day versus placebo after 4.5 years of treatment and 6.5 years of follow up (p = 0.002). (47)

            Also in 1998, Yoshizawa et al. used a nested case–control design within a prospective study, i.e., the Health Professionals Follow-Up Study, to investigate the association between risk of prostate cancer and prediagnostic level of selenium in toenails, a measure of long-term selenium intake. (69) In 1986, there were 51,529 male health professionals aged 40–75 years who responded to a mailed questionnaire to form the prospective study. In 1987, there were 33,737 cohort members who provided toenail clippings. When matched case–control data were analyzed, higher selenium levels

were associated with a reduced risk of advanced prostate cancer (odds ratio [OR] for comparison of highest to lowest quintile = 0.49; 95% confidence interval [CI] = 0.25–0.96; P = .11). After additionally controlling for family history of prostate cancer, body mass index, calcium intake, lycopene intake, saturated fat intake, vasectomy, and geographical region, the OR was 0.35 (95% CI = 0.16–0.78; P = .03). The Harvard researchers concluded,Our results support earlier findings that higher selenium intakes may reduce the risk of prostate cancer.” (69)

            In the SU.VI.MAX Intervention Trial supplementation in men was associated with a moderate reduction in prostate cancer rate. (55) There was a statistically significant reduction in prostate cancer incidence in the 94% of men in the trial with a baseline prostate-specific antigen (PSA) concentration <3 µg/L (48% decrease in prostate cancer incidence; hazard ratio = 0.52, 95% CI: 0.29, 0.92) who received the supplements. In 2007, Greenwald et al remarked “this result suggests that supplementation may be beneficial in preventing early stages of prostate carcinogenesis. (70)

            In 2000, Helzlsouer et al. studied over 10,000 Maryland men and prostate cancer. During the study period, 117 men developed prostate cancer. The researchers found that higher levels of selenium in toe nails were associated with a lower risk for developing prostate cancer when the levels of vitamin E were also high. The reduction in risk of prostate cancer with selenium was five-fold when gamma-tocopherol was high and an OR 0.65 when alpha-tocopherol was also high. (71)

            Also in 2000, Nomura et al. examined the protective action of selenium against prostate cancer in a case-control study of 9,345 Japanese-American men examined between 1971 and 1977. (72) At the time of examination, a blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 249 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and

those of 249 matched controls were measured for selenium levels. Odds ratios for prostate cancer, based on quartiles of serum selenium levels, were determined using

the General Estimating Equations approach. The multivariate odds ratio for the highest quartile was 0.5 (95% confidence interval, 0.3– 0.9) with a two-sided P for trend of 0.02. The inverse association was more notable for cases with advanced disease and for cases diagnosed 5–15 years after phlebotomy.

            The study found that selenium cut the risk in half [OR 0.5]. The risk reduction was greatest in cases diagnosed 5 to 15 years after phlebotomy and in current or past smokers. (72)

            In 2003, studies continued to confirm that people with higher levels of selenium in their blood have lower rates of prostate and lung cancers. (73) An additional 2003 study confirmed that selenium supplementation reduces damage to DNA in prostate cells. (74)

            Also in 2003, van den Brandt et al., reported on their study of the association between prostate cancer and baseline toenail selenium level in the Netherlands Cohort Study. (75) This study was conducted among 58,279 men, aged 55-69 years at entry. In September 1986, the cohort members completed a questionnaire on risk factors for cancer and provided toenail clippings for determination of baseline selenium status. After 6.3 years of follow-up, 540 incident prostate carcinoma cases and 1,211 subcohort members with complete toenail selenium data were available for case-cohort analyses. In multivariate survival analysis, an inverse association between toenail selenium level and prostate cancer risk was observed. Incidence rate ratios in increasing selenium quintiles were 1.00 (ref), 1.05, 0.69, 0.75, and 0.69 (95% confidence interval, 0.48-0.99), respectively (P=0.008). This association persisted after exclusion of cases diagnosed during early follow-up. The researchers concluded, “these results confirm the hypothesis that higher selenium intake may reduce prostate cancer risk. Future research on optimum dose level is needed.” (75)

            In 2004, A Harvard group examined the records of physician volunteers in the Harvard Physicians Study. (62) In this study, 586 physicians were tested in 1982 and followed for 13 years. Among other tests was a determination of plasma selenium. The median age at testing was 60 years. These authors reported that “a statistically significant inverse association between pre-diagnostic selenium levels and the risk of advanced prostate cancer.” They also reported that men with PSA levels greater than 4 ng/mL at the beginning of the study appeared to be protected from prostate cancer by a higher plasma level of selenium. They suggest that “selenium may influence tumor progression.” These data and others suggest that selenium can play a major role in reducing the risk of developing prostate cancer.

            In 2006, Brinkman et al. performed a meta-analysis to determine if men with low selenium levels were at increased risk of prostate cancer. Twenty epidemiologic studies were selected. Mean differences were: -5.55 mcg/l (-9.82; -1.27; p=0.01), -0.01 mcg/g (-0.03; 0.006; p=0.19), -0.52 mcg/l (-4.63; 3.58; p=0.80) for serum, toenail and plasma studies, respectively. Overall, the pooled standardized mean difference between cases and controls was; -0.23 (-0.40; -0.05; p=0.01) indicating an inverse association between selenium levels and risk of prostate cancer. (65)

            In 2007, Peters et al, within the PLCO Cancer Screening trial showed serum selenium was associated with prostate cancer risk when subjects had high vitamin E intake (>28 IU/day) [OR 0.58], multivitamin use [OR 0.61] or a history of smoking [OR 0.65]. (76) The missing nutrient was selenium in reducing the relative risk of developing prostate cancer.

            In men with high vitamin E intake (> 28 IU/day) an inverse association was observed, where men in the highest quartile of serum selenium concentration showed a 42% reduced risk of prostate cancer, compared to men in the lowest quartile. A similar inverse association was found among multivitamin users, where men in the highest quartile of serum selenium showed a 39% reduced risk of prostate cancer, compared to men in the lowest quartile. Additionally, among smokers, men in the highest quartile of serum selenium concentration showed a 35% reduced risk of prostate cancer, compared to men in the lowest quartile. The authors of this study conclude that prediagnostic serum selenium concentrations were associated with reduced prostate cancer risks in men who reported a high intake of vitamin E, in multivitamin users, and in smokers."

            In 2008, Cheung et al. as part of an Expert Review reviewed diet and prostate risk reduction and concluded, “selenium and vitamin E may work together in conjunction to lower a person’s risk for prostate cancer. (77)

            It is important to note, too, that the reduced levels of prostate specific antigen (PSA), a commonly used marker for prostate cancer, observed with selenium supplementation is due entirely to the effect of selenium on the cancer cells and not due to selenium interfering with the production of PSA for any reason other than a decrease in cancer cells. "Changes in serum PSA levels in an individual during selenium supplementation is not an effect specific for PSA secretion, but rather is a useful indicator for changes in the disease progression in individual patients." (78)