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Selenium and Cancer Prevention

Promising Results Indicate Further Trials Requiredespite advances in diagnosis and treatment, morbidity andortality from cancer continue to represent a major health

urden. Given the potentially devastating consequences ande fear associated with a diagnosis of cancer, it is not sur-rising that physicians, patients, and the public may holdubstantial optimism for and have considerable interest ineemingly simple and relatively easily implemented mea-ures, such as dietary modification or use ofvitamin and traceement supplementation, that appear rapidly effective for

ancer prevention. Previous studies examining the potentialfects of dietary supplements, such as antioxidant vitamins1,2r prevention of cancer, have produced mixed results. In this

sue of THE JOURNAL, Clark and colleagues3 present prom-ng but preliminary findings from a randomized trial evalu-ing the possible effectiveness of selenium supplementationr cancer prevention.

See also p 1957.

The Nutritional Prevention of Cancer Study by Clark et al3ndomized 1312 patients to receive placebo or 200 \g=m\gof

elenium per day and was designed to evaluate the effect of

is supplementon

risk of developingnew

basal cell andquamous cell skin cancers. In analysis of the primary outomes, selenium supplementation had no effect on reducinge incidence of these skin cancers. However, after prelimi

ary analyses showed a reduction in total carcinoma, therotocol was modified in 1990 to add total and cancer morality, as well as the incidence of lung, colon, rectum, androstate cancers as secondary end points. Analysis of thesend points indicates apparent rapid and large preventivefects for cancers of the lung, prostate, colon, and rectum,

ut no reduction in risk of breast or bladder cancer. Theverall effect, however, when all carcinomas are combinedto a secondary end point, is a statistically significant 39%

duction in incidence and 48% reduction in mortality.Interpretation of secondary end points, like the interpreta

on of subgroups in randomized trials, requires caution.4 Clarkal specified a priori the secondary end points for follow-up

om 1991 to 1993. In this period, the results remained consisnt with those observed during the first 6 years; incidence andortality were both significantly reduced. Additional caution interpretation is needed given that pathology reports were

vailable for only 76% of cancers. And, importantly, this trial

randomized men (approximately 75% of the participants) andwomen (25%). But, because of the relatively fewer womenincluded and the existing epidemiologie data that show no consistent reduction in risk of breast and other cancers specific towomen with higher selenium intake,5 the applicability of theresults to women remains uncertain.

How should the results of prevention studies be interpreted? Preventive inference should not be based solely onrandomized trials. Randomization is helpful but not necessary,6 and consistency with biologic knowledge of the agentand of the time course of disease also should be considered.

Importantly, the time course of prevention should be biologically plausible. That is, the time from initiating a preventive measure should fit with the known biology of specifictumors and with the potential mechanisms of action for thepreventive agent, when these have been described. The studyby Clark et al3 reports that selenium supplementation wasassociated with a reduction in risk of lung cancer within 5years of randomization that is substantially greater than theeffect of smoking cessation.7 As justifications for belief in itsresults, the authors of this randomized trial focus not only onits study design, but also on the potentialbiologic mechanismwhereby selenium acts through molecular mechanisms that

regulate apoptosis (ie, programmed cell death).Reliance on study design alone as justification for changein prevention recommendations is misguided. Results fromrandomized trials must be considered in the context of all theavailable evidence. Other randomized prevention trials usinglower doses of selenium have not shown such substantial

protection against total cancer.8 Whether this inconsistencyis the result of the dose of selenium, the form of selenium, orthe specific cancers studied (cancers of the esophagus andstomach in China vs cancers of the lung, colon, rectum, andprostate in the United States) is unclear. As in clinical treatment trials, decisions are best made when a number of studiesshow consistent findings.

Further, in interpreting the results, the authors emphasizethe effectiveness of selenium in animal tumor model studies,perhaps because of the large effects observed. These studiessuggest a specificity of the molecular mechanisms that is perplexing. Laboratory studies cited tojustify these mechanismsinclude breast cancer cell lines,9 yet this trial and numerousepidemiologie studies found no relation between selenium andrisk of breast cancer.1011 If this possible magic bullet actsthrough mechanisms suggested by the authors, it is not clearwhy it should be specific to only some cancers. Moreover,human populations behave differently from animals, and thelaboratory findings are not consistent with all the human data.

Thus,further work is

requiredto

identifymarkers for the

molecular changes of apoptosis and cell cycle regulation within

From the Department of Medicine, Brigham and Women's Hospital and Harvardnter for Cancer Prevention, Harvard Medical School, Boston, Mass.

Corresponding author: Graham A. Colditz, MBBS, DrPH, Channing Laboratory,Longwood Ave, Boston, MA 02115.

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humans that may better reflect the mechanism of action for

selenium, rather than reliance on animal models or cell lines.The specificity of the relation for only some among many

cancers also raises questions of interpretation of secondaryend points in trials. When multiple subgroups, here specificcancer sites, are examined, the probability of finding chancedifferences increases.12 Importantly, even though the resultsfor lung and colorectal cancers agree with previous epidemiologie studies, little evidence exists to support a relationwith prostate cancer. In addition, a better understanding of

the relation between selenium supplementation at this leveland risk of cancers specific to women is required to rule outadverse effects and safely generalize the results to women.

The dose of selenium used in this trial is not substantiallygreater than the comparisons that can be achieved in analyticepidemiologie studies among free-living individuals in theUnited States. Individuals in high selenium areas (ie, thosewith high selenium soil content, such as North and SouthDakota) will have higher blood levels of selenium than thoseachieved in this trial which selected a low-intake area forrecruitment of study participants. When we have heterogeneity among the results from studies, the variation in dose isclearly one plausible explanation.13 If the dose is central to themagnitude of benefit observed by Clark et al, then additionalstudies will be required to replicate this finding. Simultaneously, a systematic reexamination of the dose relation withinthe existing epidemiologie data would also be informative.

While it is clear that additional randomized trials are nec

essary to confirm or refute the findings of Clark et al,3 possible strategies to implement prevention with selenium forthe broader US population also should be explored. Prevention goals that focus on risk reduction across the entire community, rather than merely cancer-specific approaches, havethe greatest likely benefit.14 Population-wide approaches thatinclude small changes in risk for individuals result in major

changesin the

populationburden of disease.15

How to achievesuch population-wide prevention should selenium prove to besuch a powerful preventive agent requires focused study.

A preventive strategy may be implemented through healthcare professionals (who can administer diagnostic tests, prescribe drugs, or counsel patients about dietary change), throughgovernment regulations that reduce the risks of harm to thepopulation, and through local activities that promote a healthierlifestyle and environment.16 The social strategy developed toincrease folate intake offers one useful example. In March 1996,the Food and Drug Administration changed the recommendeddaily allowance of this nutrient back to 400 g per day. Toensure adequate intake, US food manufacturers will add the

nutrient folie acid to most enriched breads, flours, corn meals,pastas, rice, and other grain products. This simple regulationaims to raise intake for the majority of the US population. Whileit is premature to market selenium based on the results reported by Clark et al,3 a similar population-wide approach shouldlikely be considered for selenium if the results of the currenttrial are substantiated and benefits are also observed amongwomen. However, selenium has known dose-dependent adverse effects, which also must be considered. Supplementationthrough bread flour already has been shown to increase levels

of selenium.17 Such population-wide approaches are most effective if we are to maximize the benefits of prevention strategies and achieve our national goals of reducing the burden ofcancer. Meanwhile, as we await the results of further prevention research, known lifestyle changes that can reduce cancerrisk (such as smoking cessation, consuming adequate amountsof fruits and vegetables each day, reducing intake of animal fat,and increasing physical activity)18 should be implemented.

In conclusion, this promising set of results based on secondary end points from a skin cancer prevention trial by

Clark et al3 require confirmation in further randomized trialsdesigned to test the effect of selenium supplementation oncancer incidence and mortality. Given the results of this study,the expected effect will be large and the time frame will beshort. Therefore, such trials should be feasible, and resultsshould be available in the near future. These trials mustevaluate the influence of dose and must include women todetermine whether these benefits apply to the common carcinomas in women, including breast and ovarian cancers, andso that explicit comparisons of the efficacy of selenium inwomen and men can be made. For now, it is premature tochange individual behavior, to market specific selenium supplements, or to modify public health recommendations based onthe results of this one randomized trial.

Graham A. Colditz, MBBS, DrPH

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