What were the results of the SELECT (Seletion of Vitamins and Minerals to Enhance Cancer Treatment) trial regarding selenium and vitamin E for prostate cancer prevention?

SELECT Trial Summary

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) demonstrated that neither selenium nor vitamin E, alone or in combination, prevented prostate cancer in healthy men, and extended follow-up revealed that vitamin E supplementation significantly increased prostate cancer risk by 17%. 1, 2, 3

Trial Design and Population

SELECT was a phase III randomized, double-blind, placebo-controlled trial with a 2×2 factorial design that enrolled 35,533 men from 427 sites across the United States, Canada, and Puerto Rico between August 2001 and June 2004. 1, 2

Eligibility criteria included: 1, 2

• Age ≥55 years (≥50 years for African American men)
• PSA ≤4 ng/mL
• Normal digital rectal examination (not suspicious for prostate cancer)
• No previous prostate cancer diagnosis

Randomization groups: 2, 3

• Selenium alone: 200 μg/day L-selenomethionine
• Vitamin E alone: 400 IU/day all rac-α-tocopheryl acetate
• Both selenium and vitamin E
• Placebo (both matched placebos)

The planned follow-up was a minimum of 7 years and maximum of 12 years. 2, 4

Primary Results

At the initial analysis (median follow-up 5.46 years, study closure October 2008): 2, 5

The hazard ratios for prostate cancer compared to placebo (n=416 cases) were:

• Vitamin E alone: HR 1.13 (99% CI: 0.95-1.35; n=473 cases; P=0.06)
• Selenium alone: HR 1.04 (99% CI: 0.87-1.24; n=432 cases; P=0.62)
• Selenium + Vitamin E: HR 1.05 (99% CI: 0.88-1.25; n=437 cases; P=0.52)

No significant differences were found in any other prespecified cancer endpoints. 2

Extended Follow-Up Results

With longer follow-up through July 2011 (54,464 additional person-years and 521 additional prostate cancer cases): 3

The hazard ratios for prostate cancer compared to placebo (n=529 cases) were:

• Vitamin E alone: HR 1.17 (99% CI: 1.004-1.36; n=620 cases; P=0.008) - statistically significant increased risk
• Selenium alone: HR 1.09 (99% CI: 0.93-1.27; n=575 cases; P=0.18)
• Selenium + Vitamin E: HR 1.05 (99% CI: 0.89-1.22; n=555 cases; P=0.46)

The absolute increase in prostate cancer risk per 1,000 person-years compared to placebo was: 3

• 1.6 for vitamin E alone
• 0.8 for selenium alone
• 0.4 for the combination

Additional Safety Signals

A statistically nonsignificant trend toward increased risk of newly diagnosed type 2 diabetes mellitus was observed with selenium alone (relative risk 1.07; 99% CI: 0.94-1.22; P=0.16). 2, 5

Clinical Implications

The U.S. Preventive Services Task Force incorporated SELECT findings into their 2014 recommendations, concluding with moderate certainty that vitamin E supplementation has zero net benefit for cancer prevention, and that vitamin E should not be used for prostate cancer prevention. 1

The American Cancer Society guidelines similarly cite SELECT as a prototypical example of how high-dose single nutrient supplementation can be harmful, contrasting with the potential benefits of consuming whole foods containing these nutrients. 1

The American College of Chest Physicians guidelines on lung cancer chemoprevention also reference SELECT's negative findings for selenium, recommending against selenium use as a general cancer prevention strategy. 1

Important Caveats

The null and harmful findings may be explained by several factors: 6

• The specific formulation and dose of selenium (L-selenomethionine at 200 μg/day)
• Baseline selenium status of participants (benefit may only occur in selenium-deficient populations)
• The relatively healthy, well-nourished cohort enrolled
• Age and genetic variations in selenoprotein metabolism

Unlike the Prostate Cancer Prevention Trial (PCPT), SELECT did not mandate prostate biopsies; participants underwent annual PSA testing (approximately 85%) and DRE (approximately 70%) according to local standards and patient preference, making it more representative of real-world screening practices. 1