This trial focused on men potentially at an elevated risk of PC based on biopsy-identified HGPIN. The study extends SELECT, which randomized average-risk subjects to selenomethionine and/or vitamin E (alpha-tocopherol; ref. 39
) and showed that neither agent had any effect in preventing PC. Fleshner et al. (46
) also found no effect on the progression of HGPIN to PC in a trial of a putative prevention cocktail containing vitamin E, selenium, and soy in HGPIN patients.
These results differ strikingly from those of the NPC, in which selenium supplementation was associated with a 50% decrease in PC incidence (35
). The effect of selenium supplementation on PC risk appeared early enough in the NPC trial to suggest that a three-year treatment period in the present trial would be adequate to reveal a protective effect. The benefit of selenium supplementation in the NPC trial was confined to subjects in the lowest two tertiles of baseline plasma selenium. In general, the NPC participants had much lower baseline blood selenium levels (mean 114 ng/ml; refs. 35
) than did the HGPIN patients in the present trial (over 135 ng/ml). There was no protective effect of selenium among NPC participants with baseline selenium levels comparable to those of generally replete subjects in the present trial (36
). The levels in our study, as in SELECT, were well above even the mean of 123 ng/ml estimated for the U.S. population (47
). Selenium was not protective, however, even in HGPIN patients in the lowest baseline selenium quartile (an upper boundary of 106 ng/ml), although the risk was nonsignificantly reduced in this group. Although selenium had no effect in the second quartile, the levels in this quartile ranged from 106 to 132 ng/ml, which substantially overlaps the highest tertile of the NPC study. The NPC study tested selenized yeast, whereas selenomethionine was tested in our present study and SELECT; nonetheless, if there was a protective organoselenium compound other than selenomethionine in this yeast, it remains to be identified (37
A key limitation of the NPC results—a substantial number of patients with elevated PSA tests were not biopsied—has been reported (36
). More critical, subjects on selenium were less likely than subjects on placebo to have a biopsy following an elevated PSA test (36
). The NPC investigators attempted to adjust for this difference between the arms statistically, and the association between selenium supplementation and decreased risk persisted in spite of the adjustment (36
). Nonetheless, the association between selenium supplementation and PC in NPC was a secondary trial endpoint that could have resulted from confounding due to an unmeasured or imperfectly measured factor or to statistical error inherent in secondary analyses; it could have been a chance occurrence.
Our present study focused strictly on PC and was not powered or otherwise designed to evaluate other chronic disease endpoints such as diabetes. The NPC study found that selenium was associated with a statistically significantly higher rate of diabetes than was placebo. In SELECT, a slight, statistically nonsignificant excess of diabetes was observed in patients who received selenium alone (versus placebo) although the excess was much smaller than that in NPC. Additional analyses of the SELECT data are ongoing.
Although family history of PC is linked to PC risk, the present study was not powered to control for family history. We relied on randomization to balance a number of potential confounding factors between the selenium and placebo arms, and the congruence of our present results with those of SELECT (39
) and Fleshner et al. (46
) strongly suggests that they were not confounded by family history.
In the present study, 29 men proposed by the clinical sites to be eligible for enrollment and randomization were deemed ineligible by centralized pathology review of their biopsy samples or other reasons following their randomization. However, no subject was ruled ineligible on the basis of a condition that developed after randomization, and excluding these ineligible subjects likely did not lead to a study bias.
This study's 36% period prevalence of PC in three years suggests that its HGPIN patients were at a higher PC risk than were men recruited to other PC prevention trials. Men in the PCPT were believed to be at a low risk with no known HGPIN and a PSA level of ≤ 3.0 ng/ml at study entry (2
), and 24% (placebo) were diagnosed with PC within the approximately 7 year study period. In the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (PSA eligibility 2.5–10.0 ng/ml), 25% of men were diagnosed with PC within the four years of the trial (3
). Although secondary analyses of variables—including the number of biopsy cores positive for HGPIN, baseline micronutrient status, body mass index, and potential germline and somatic molecular biomarkers (48
)—that may have predicted progression of HGPIN to invasive disease are beyond the scope of this report, we plan to conduct such analyses within the present trial's population for a future report.
We minimized the enrollment of men with PC (accompanying HGPIN) that was missed at the baseline biopsy. At the beginning of the study, subjects whose initial biopsy showed HGPIN and no cancer were required to undergo a second, negative biopsy of six or more cores before they could be randomized. After November 2002, subjects whose initial biopsy of 10 or more cores showed HGPIN and no cancer were not required to be re-biopsied. The rationale for this change was that 10-or-more core biopsies were coming into use in 2002 and substantially lowered the probability that PC would be missed on a single biopsy. It is likely that a few small cancers were missed at study entry, both before and after 2002, but it is unlikely that they hampered the trial's ability to assess selenium for PC prevention.
PC that developed in the present trial was in large part low grade, with Gleason score 6 or lower in 70.8% of graded cancers in the selenium arm and in 75.5 % in the placebo arm. In the placebo arm of the 7-year PCPT, 78% of graded cancers were Gleason score 6 or lower. In the placebo arm of REDUCE, about 73% of PC were Gleason score 6 or lower (3
). In SELECT, 53% of diagnosed PCs were Gleason score 6 or lower, likely reflecting the fact that biopsies in SELECT were not mandated but were triggered by clinical criteria. These collective findings suggest that the presence of HGPIN does not signal an increased risk of high-grade or aggressive disease.
Although the endpoint for over 60% of men in the present trial was definitively assessed per protocol (by biopsy within 90 days of ending the three-year duration of study), this percentage was not as high as we had intended. The percentage of endpoint assessments, however, was virtually identical for selenium and placebo participants and is in line with the rates of endpoint assessment in the PCPT (60%, finasteride arm, and 63%, placebo arm; ref. 2
) and in the four-year REDUCE (58% protocol-directed biopsy rate at 25–48 months, although 82% had at least one biopsy, and 80% had a protocol-directed biopsy at 19–24 months; ref. 3
). Men who had a negative interim biopsy but no end-of-study biopsy were not counted as having complied with the end-of-study biopsy requirement. Counting these 35 interim-biopsy patients and assuming that a three-year biopsy also would have been negative raises the biopsy-defined endpoint rates to 69% for selenium and 74% for placebo patients. An alternate analysis expanded the end-of-study window to ± 180 days and provided further evidence that PC risk was similar in the selenium and placebo arms.
Recruitment to cancer therapy trials or to prevention trials in non-IEN people (like PCPT and SELECT) is generally easier than is recruitment to trials designed for IEN patients, and our HGPIN trial was no exception to the rule. Major hindrances to IEN-patient recruitment include the fact that IEN patients generally are not seen in cooperative cancer treatment (primarily) groups or tertiary academic referral centers and that IEN trials involve complexities (e.g., in sampling and monitoring) not common to prevention trials in generally healthy volunteers. Recruitment during our first one to two years was very slow. We successfully addressed this problem in several ways, including doubling the initial enrollment payment from 500 to 1000 dollars and adding more recruitment sites. We have previously reported the obstacles to recruitment and our solutions to them in completing accrual to the present trial in ref. 43
, where we would refer readers interested in further information on this critical issue of clinical cancer prevention.
Despite advances in PC therapy, it still imposes significant human costs and complications for men diagnosed with PC (49
). Ambiguities in the management of men with low-grade, low-volume PC and over-screening for PC persist (50
). PC prevention would lessen the need for patients to undergo treatment and would bear on the debate over the value of aggressive screening and therapy for low-grade, low-volume PC (52
). An increased preventive focus on HGPIN as a marker of an increased PC risk, as shown in the present trial, is warranted. Selenium (200 mcg/day) in the form of selenomethionine is clearly ineffective for reducing PC risk in selenium-replete men with HGPIN. However, men with HGPIN might well be treated with agents, such as 5-alpha reductase inhibitors or other molecular-targeted agents, that would not be acceptable for those at average or low risk. The present trial's suggestion of a selenium benefit in selenium-deficient men, which is consistent with earlier NPC findings, and selenium pharmacogenetics (53
) may identify men who would benefit from selenium, suggesting an approach for future study of selenium. As the largest randomized controlled trial of a preventive agent in HGPIN patients, the present study extends the findings of the massive SELECT in showing that selenium does not prevent prostate cancer in selenium-replete men, which is an important contribution to the public health.