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OBJECTIVE: To test if supplemental dietary selenium is associated with changes
in the incidence of prostate cancer. PATIENTS AND METHOD: A total of 974 men
with a history of either a basal cell or squamous cell carcinoma were randomized to either a daily supplement of 200 microg of selenium or a placebo. Patients were treated for a mean of 4.5 years and followed for a mean of 6.5 years. RESULTS: Selenium treatment was associated with a significant (63%) reduction in the secondary endpoint of prostate cancer incidence during 1983-93. There were 13 prostate cancer cases in the selenium-treated group and 35 cases in the placebo group (relative risk, RR=0.37, P=0.002). Restricting the analysis to the 843 patients with initially normal levels of prostate-specific antigen (< or = 4 ng/mL), only four cases were diagnosed in the selenium-treated group and 16 cases were diagnosed in the placebo group after a 2 year treatment lag, (RR=0.26 P=0.009). There were significant health benefits also for the other secondary endpoints of total cancer mortality, and the incidence of total, lung and colorectal cancer. There was no significant change in incidence for the primary endpoints of basal and squamous cell carcinoma of the skin. In light of these results, the 'blinded' phase of this trial was stopped early. CONCLUSIONS: Although selenium shows no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin, the selenium-treated group had substantial reductions in the incidence of prostate cancer, and total cancer incidence and mortality that demand further evaluation in well-controlled prevention trials.

Chemoprevention is a recently introduced and rapidly growing area of oncology
that is identifying agents with a potentially preventive role in cancer. Several clinical trials have recently shown the feasibility of this approach in reducing the risk of major human cancers. In the USA, a large trial that demonstrated a reduction of approximately 50% in the risk of developing breast cancer led to Food and Drug Administration (FDA) approval of tamoxifen as a preventive agent in women at increased risk. Although the results could not be reproduced in two smaller European trials, further investigations into this agent are clearly warranted. Raloxifene, another selective oestrogen receptor modulator which has reduced the risk of breast cancer in a trial in women with osteoporosis, is being compared with tamoxifen in a large primary prevention trial in at-risk women. Retinoids are a group of compounds that have proved especially effective in reducing the occurrence of second primary tumours in subjects with skin, head and neck or liver cancer. Fenretinide, a synthetic retinoic acid derivative, has recently been shown to decrease the occurrence of a second breast malignancy in premenopausal women. Results with non-steroidal anti-inflammatory drugs (NSAIDs) have proved consistently encouraging in epidemiological studies in lowering the incidence of colorectal cancer. Clinical trials with selective cyclo-oxygenase inhibitors potentially devoid of gastrointestinal (GI) toxicity are currently
underway in at-risk subjects. Calcium and selenium have also received much
attention as chemopreventive agents. Originally investigated against skin
cancer, selenium showed efficacy in reducing prostate, lung and colon cancer
incidence. Similarly, vitamin E was effective in reducing prostate cancer
incidence and mortality in a lung cancer prevention trial in heavy smokers. The challenges of conducting well-designed and unequivocal chemoprevention trials are considerable, but advances in techniques of identification of at-risk subjects and establishing surrogate endpoint biomarkers should contribute greatly to future studies. Current knowledge suggests that a pharmacological approach to preventing cancer, using natural or synthetic agents, could become an important way forward.

The hypothesis that a dietary supplement of selenium (Se) may reduce cancer risk was tested experimentally in humans. Patients with histories of basal/squamous cell carcinomas of the skin were assigned randomly in double-blind fashion to daily oral supplements of either Se-enriched yeast (200 micrograms Se/day), or a low-Se yeast placebo. A total of 1312 patients recruited in 1983-1990 were followed with regular dermatologic examinations through 1993 for a total of 8269 person-years of observation. Skin cancer diagnoses were confirmed histologically. Plasma Se concentration was determined at 6-12 months intervals. All deaths and patient-reported illnesses were recorded; reported cancers were confirmed and documented by consultation with the patient medical care providers. The results indicate that Se did not significantly affect the primary endpoints: incidences of recurrent basal/squamous cell carcinomas of the skin. However, Se-treatment was associated with reductions in several secondary endpoints: total mortality, mortality from all cancers combined, as well as the incidence of all cancers combined, lung cancer, colorectal cancer and prostate cancer. The consistencies of these associations over time, between study clinics and for the leading cancer sites strongly suggests benefits of
Se-supplementation for this cohort of patients, supporting the hypothesis that
supplemental Se can reduce cancer risk. Although Se did not shown protective
effects against non-melanoma skin cancers, the suggested reductions in risks to other frequent cancers demand further evaluation in well controlled clinical intervention trials.

PATIENTS AND METHOD: In order to test the hypothesis that a dietary supplement
of selenium (Se) may reduce cancer risk, 1312 patients with histories of
basa/squamous cell carcinomas of the skin were assigned in random, double-blind fashion to daily oral supplements of either Se-enriched yeast (200 micrograms Se/day), or a low-Se yeast placebo. Patients were recruited in 1983 to 1990 and were followed with regular dermatologic examinations through, 1993 for a total of 8269 person-years of observation. Skin cancer diagnoses were confirmed histologically and plasma Se concentration was determined at 6 to 12 months intervals. All deaths and patient-reported illnesses were confirmed and documented by consultation with the patient medical care providers. RESULTS: Results showed that Se-supplementation did not significantly affect the incidences of recurrent basal/squamous cell carcinomas of the skin. However, Se-treatment was associated with reductions in total cancer mortality and in the incidences of lung, colorectal, prostate and total cancers. These effects were consistent over time and between study clinics. CONCLUSION: The results strongly suggest benefits of Se-supplementation for this cohort of patients and support the hypothesis that supplemental Se can reduce risks to at least some types of cancer.

Nitrosamines have been suspected in the etiology of esophageal/gastric cardia
cancer in the high incidence area of Linxian of the Henan Province in northern
China, but marginal deficiencies in riboflavin, vitamins A and C, and other
micronutrients may also be involved. A joint U.S.-China nutritional intervention study with investigators from the Cancer Institute of the Chinese Academy of Medical Sciences and the U.S. National Cancer Institute tested the effects of the following four combinations of nutrients on 29,584 subjects in an eight-group design: 1) retinol and zinc; 2) riboflavin and niacin; 3) vitamin C and molybdenum; and 4) vitamin E, beta-carotene and selenium. Supplementation with Group 4 nutrients significantly decreased mortality rate from stomach cancer, primarily due to the decrease in deaths resulting from adenocarcinomas of the gastric cardia; it lowered the total mortality rate and showed signs of other beneficial effects. Another study of nutrition and gastric cancer in a high incidence area of Linqu of the Shangdong province in northern China (in collaboration with the Beijing Institute for Cancer Research and the U. S. National Institutes of Health) found significantly lower serum concentrations of vitamin C and beta-carotene among individuals with intestinal metaplasia; an intervention trial with vitamins C and E and selenium (combined) is ongoing in Linqu. Other studies are also elucidating the mechanisms for the pathogenesis of adenocarcinoma at the gastroesophageal junction with the use of a rat model. Such studies are expected to shed light on the etiology and prevention of gastroesophageal cancers in humans.

The objective of this cross-sectional study was to determine whether plasma
selenium concentration predicts the prevalence of adenomatous polyps of the
colon and rectum. The source population for the study was 101 patients
undergoing sequential colonoscopies at the Veterans Affairs Medical Center,
Tucson, AZ. The study population was then limited to the 48 patients (all male)undergoing their initial colonoscopy who did not have a diagnosis of colorectal cancer. For each of these patients, a prediagnostic fasting plasma selenium concentration was determined. The data from this study suggest that fasting plasma selenium concentrations may be an important risk factor for colorectal adenomas. Patients with fasting plasma selenium concentrations below the median (< 128 mcg/liter) were significantly more likely to have one or more adenomatous polyps (prevalence odds ratio 4.2) and more adenomatous polyps (3.5 times) per patient. There was also a suggestion of a more proximal distribution of adenomatous polyps in the patients with a lower level of selenium. These associations were not confounded by age or smoking. The results of this study are consistent with the experimental animal studies, geographic mortality studies, and prospective cohort studies of selenium and colorectal cancer.

The potential protective effect of selenium status on the risk of developing
cancer has been examined in animal and epidemiologic studies. This ecological
study investigated the association between U.S. county forage selenium status
and site- and sex-specific county cancer mortality rates (1950-1969) using
weighted least squares regression. Consistent, significant (p less than .01)
inverse associations were observed for cancers of the lung, rectum, bladder,
esophagus, and cervix in a model limited to rural counties and for cancers of
the lung, breast, rectum, bladder, esophagus, and corpus uteri in a model of all counties. No consistent significant positive associations were observed in the rural county models. This remarkable degree of consistency for the inverse
associations strengthens the likelihood of a causal relationship between low
selenium status and an increased risk of cancer mortality.

The essential trace element selenium retards the growth of certain chemically
induced tumors in animals. The addition of subtoxic amounts of this element in
form of selenite to the supply water lowers the incidence of spontaneous mammary tumors in female C3H mice significantly without affecting the health and life-span of the animals. Arsenic, a selenium antagonist, administered in form of arsenite in the supply water, also lowers the tumor incidence at dosage levels of 10 ppm, but those animals which develop spontaneous mammary tumors under these conditions demonstrate dramatically enhanced tumor growth rates. The results of initial epidemiological studies suggest that the human cancer mortality is lower in areas providing an adequate dietary intake of selenium as estimated from the selenium content in grains and forage crops in various regions of the United States, or the dietary selenium intakes as calculated from food consumption data in various countries.

Both experimental and epidemiologic studies have linked a low dietary intake of
selenium with an increased risk of cancer. The authors examined the association between plasma selenium levels and risk of hepatocellular carcinoma (HCC) among chronic carriers of hepatitis B and/or C virus in a cohort of 7,342 men in Taiwan who were recruited by personal interview and blood draw during 1988-1992. After these men were followed up for an average of 5.3 years, selenium levels in the stored plasma were measured by using hydride atomic absorption spectrometry for 69 incident HCC cases who were positive for hepatitis B surface antigen (HBsAg) and/or antibodies against hepatitis C virus (mostly HBsAg positive) and 139 matched, healthy controls who were HBsAg positive. Mean selenium levels were significantly lower in the HCC cases than in the HBsAg-positive controls (p = 0.01). Adjusted odds ratios of HCC for subjects in increasing quintiles of plasma selenium were 1.00, 0.52, 0.32, 0.19, and 0.62, respectively. The inverse association between plasma selenium levels and HCC was most striking among cigarette smokers and among subjects with low plasma levels of retinol or various carotenoids. There was no clear evidence for an interaction between selenium and alpha-tocopherol in relation to HCC risk.

BACKGROUND: There has been an increase in the number of adults seeking liver transplantation for hepatitis C in the last few years and the count is going up rapidly. There is no reliable and effective therapy for chronic hepatitis C
since interferon and antivirals work no more than 30% of the time, and liver
transplant surgery is uncertain and tentative over the long run. This is
because, ultimately, residual hepatitis C viremia infects the new liver.
Furthermore, liver transplantation can be painful, disabling and extremely
costly. TREATMENT PROGRAM: The author describes a low cost and efficacious treatment program in 3 patients with cirrhosis, portal hypertension and esophageal varices secondary to chronic hepatitis C infection. This effective
and conservative regimen combines 3 potent antioxidants (alpha-lipoic acid
[thioctic acid], silymarin, and selenium) that possess antiviral, free radical
quenching and immune boosting qualities. CONCLUSION: There are no remarkably effective treatments for chronic hepatitis C in general use. Interferon and antivirals have less than a 30% response rate and because of the residual
viremia, a newly transplanted liver usually becomes infected again. The triple
antioxidant combination of alpha-lipoic acid, silymarin and selenium was chosen
for a conservative treatment of hepatitis C because these substances protect the liver from free radical damage, increase the levels of other fundamental
antioxidants, and interfere with viral proliferation. The 3 patients presented
in this paper followed the triple antioxidant program and recovered quickly and
their laboratory values remarkably improved. Furthermore, liver transplantation
was avoided and the patients are back at work, carrying out their normal
activities, and feeling healthy. The author offers a more conservative approach
to the treatment of hepatitis C, that is exceedingly less expensive. One year of
the triple antioxidant therapy described in this paper costs less than $2,000,
as compared to mor than $300,000 a year for liver transplant surgery. It appears
reasonable, that prior to liver transplant surgery evaluation, or during the
transplant evaluation process, the conservative triple antioxidant treatment
approach should be considered. If these is a significant betterment in the
patient's condition, liver transplant surgery may be avoided.