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Effects of Selenium Supplementationfor Cancer Prevention in Patients
With Carcinoma of the SkinA Randomized Controlled TrialLarry C. Clark, MPH, PhD; Gerald F. Combs, Jr, PhD; Bruce W. Turnbull, PhD; Elizabeth H. Slate, PhD;Dan K. Chalker, MD; James Chow, MD; Loretta S. Davis, MD; Renee A. Glover, MD; Gloria F. Graham, MD;Earl G. Gross, MD; Arnon Krongrad, MD; Jack L. Lesher, Jr, MD; H. Kim Park, MD; Beverly B. Sanders, Jr, MD;Cameron L. Smith, MD; J. Richard Taylor, MD; for the Nutritional Prevention of Cancer Study Group
Objective.\p=m-\Todetermine whether a nutritional supplement of selenium will de-crease the incidence of cancer.
Design.\p=m-\Amulticenter, double-blind, randomized, placebo-controlled cancerprevention trial.
Setting.\p=m-\Sevendermatology clinics in the eastern United States.Patients.\p=m-\Atotal of 1312 patients (mean age, 63 years; range, 18-80 years) with
a history of basal cell or squamous cell carcinomas of the skin were randomizedfrom 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) yearsand had a total follow-up of 6.4 (2.0) years.
Interventions.\p=m-\Oraladministration of 200 \g=m\gof selenium per day or placebo.Main Outcome Measures.\p=m-\Theprimary end points for the trial were the inci-
dences of basal and squamous cell carcinomas of the skin. The secondary endpoints, established in 1990, were all-cause mortality and total cancer mortality, to-tal cancer incidence, and the incidences of lung, prostate, and colorectal cancers.
Results.\p=m-\Aftera total
follow-upof 8271
person-years, seleniumtreatment did
not significantly affect the incidence of basal cell or squamous cell skin cancer.There were 377 new cases of basal cell skin cancer among patients in the seleniumgroup and 350 cases among the control group (relative risk [RR], 1.10; 95% con-fidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in theselenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39).Analysis of secondary end points revealed that, compared with controls, patientstreated with selenium had a nonsignificant reduction in all-cause mortality (108deaths in the selenium group and 129 deaths in the control group [RR, 0.83; 95%CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in theselenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]),total cancer incidence (77 cancers in the selenium group and 119 in controls [RR,0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers.
Primarily because of the apparent reductions in total cancer mortality and totalcancer incidence in the selenium group, the blinded phase of the trial was stoppedearly. No cases of selenium toxicity occurred.
Conclusions.\p=m-\Seleniumtreatment did not protect against development of basalor squamous cell carcinomas of the skin. However, results from secondary end-pointanalyses support the hypothesis that supplemental selenium may reduce the inci-dence of, and mortality from, carcinomas of several sites. These effects of seleniumrequire confirmation in an independent trial of appropriate design before new publichealth recommendations regarding selenium supplementation can be made.
JAMA. 1996:276:1957-1963
THE NUTRITIONALLY essential traceelement selenium was first associated withcancer risk in the late 1960s.1"3 Since then,a substantial body of research has elucidated functions of selenium in normal metabolism,2"6 supported the establishmentof a recommended daily allowance,7 anddocumented the cancer prevention potential of selenium supplementation in animals. Selenium compounds have beenshown to have antitumorigenic activitiesin animal models when the drug is administered at levels greater than thoseassociated with nutritional needs.8 Several hypotheses have been proposed toexplain the inhibition of tumorigenesis
by supplemental selenium,912 includingprotection against oxidative damage involving the function of selenium as anessential component of the antioxidantenzyme glutathione peroxidase; alterations in carcinogen metabolism; effectson the endocrine and immune systems;production of cytotoxic selenium metabolites; inhibition of protein synthesis; inhibition of specific enzymes; and stimulation of apoptosis.
For editorial comment see 1984.Geographical studies suggest an in
verse relationship between selenium status and cancer incidence.13 In a study ofthe ecological relationship of environmental selenium levels (forage crop selenium) and county levels of cancer mortality in the United States,14 cancermortality rates were significantly lowerfor total cancer and cancers of the lung,colon and rectum, bladder, esophagus,pancreas, breast, ovary, and cervix incounties with intermediate selenium orhigh selenium levels compared with low-selenium counties.
Affiliations for the named authors and a complete listof the
Nutritional Preventionof
Cancer Study Groupappear at the end of this article.
Corresponding author: Larry C. Clark, MPH, PhD,Arizona
Cancer Center,2504
E Elm St, Tucson,AZ
85716-3417 (e-mail: [email protected]).
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Safety Monitoringand Advisory Committee (SMAC), which were blinded at thattime to the treatment group identities.
End-Point Ascertainment
Incident BCC and SCC were diagnosedby biopsy and confirmed by board-certified dermatopathologists. Recurrent andre-treated skin tumors, and clinically diagnosed skin tumors without biopsy confirmation were excluded from analyses.
The study used individualized, computer-generated patient questionnairesthroughout. These forms displayed previously collected information on the patient's illnesses, medication use, dermatologie diagnoses, and treatments. Thisapproach simplified the collection of newinformation and prompted the review ofpreviously collected information. Patientmedical records from each dermatologistwere reviewed periodically to ascertaininformation from both study and nonstudyvisits to ensure the completeness and accuracy of the information. In addition to
the semiannual clinic visits and the follow-up by the clinical coordinators, annualcontact was attempted with all randomized patients to confirm vital status andidentify diagnoses of new illnesses.
The identification of secondary endpoints in 1990 caused no change in illness-ascertainmentprocedures at the clinic because information on new illnesses andmedication use had been collected routinely since the beginning of the trial.However, at that time, the patient coordination center began an active programto acquire medical records for all significant illnesses that were identified eitherfrom patient interviews, medical histories, or death certificates for both theperiod to 1990 and the post-1990 period.The patient coordinating center beganactive follow-up of all patients who haddiscontinued participation in the trial. TheNational Death Index (NDI) was searchedeach year (1983-1993) for patients forwhom vital status could not be ascertained. In 1994 and 1995, the cancer registry for each clinic state was given a listof study patients and NDI identifiers sothat the 10-year period could be searchedfor diagnosed cases of cancer; thesesearches yielded no additional cases.
When patients reported illnesses ormedical procedures related to the primary, secondary, or safety end points ofthe trial, research nurses requested medical, surgical, and pathology records fromphysicians and hospitals to document theillnesses. An oncologist or appropriatemedical specialist reviewed each recordand made the final diagnosis. Particularcare was taken by the oncologie reviewers to ensure that carcinomas of multiplesites were
distinguishedfrom metastatic
tumors. Death certificates were indepen-
dently coded by an experienced nosolo-gist. Review and coding of all recordswere conducted blindly.
Patient Safety OversightThe SMAC held its first annual meet
ing in 1985. The secondary end points forthe trial were established in 1990 whencancer screening protocols were implemented with approval of the NationalCancer Institute (NCI). The SMAC recommended in December 1994 that thetrial be unblinded and the results be published when the data for the 10-year period were complete and confirmed. Threesenior NCI scientists and 2 data auditorsconducted a trial audit in May 1995. WithNCI approval, the blinded phase of patient treatment and follow-up ended inJanuary 1996.
Statistical AnalysesThe incidence and mortality data were
evaluated using Kaplan-Meier estimatesand log rank tests. Supporting analysesincluded the Cox proportional hazardsmodel, which allowed adjustment for co-variates and permitted a check of the robustness of treatment-effect inferencesbased on the log rank test. The covariatesused for this adjustment were identifiedby a step-wise procedure from the baseline characteristics shown in Table 1. Unless otherwise noted, values are fromlog rank tests, and the relative risks (RRs)are calculated using the ratio of the incidence density for the treatment groups.Consistency of treatment effect acrosssubgroups was evaluated using the signtest. The values are reported as usuallycomputed and not adjusted for multiplicity. These techniques were implementedusing STATA 4.0 (Stata Corp, CollegeStation, Tex).
Each analysis is limited to the diagnosis of the first category-specific, postran-domization cancer. Patients with multiplecancers at different sites are counted onlyonce in the analysis of total cancer andtotal carcinoma, and once in each site-specific analysis in which an incident cancer was diagnosed. The primary analysesof SCC and BCC end
pointswere con
ducted separately from those of other cancers and included a mixed-effects Poissonregression model39 to examine the treatment effect on the occurrence of multipletumors and treatment lag on the occurrence of multiple tumors per patient.40
RESULTS
Patient PopulationTable 1 presents the baseline charac
teristics of the study population, whichconsisted of 1312 randomized patients,
rangingin
agefrom 18 to 80
years.There
are no significant differences between the
Patient Flow
Open-Population RecruitmentEligible: 1316
Randomized: 1312Not Randomized: 4
HZ
Selenium-Treatment Group
Placebo Group
Randomized: 653 Randomized: 659
RegularDermatologie Examon Treatment: 297
RegularDermatologie Examoff Treatment: 126
RegularDermatologie Exam
on Treatment: 297
RegularDermatologie Examoff Treatment: 112
Censored forDermatologie
Follow-up: 142
Censored forDermatologie
Follow-up: 122
Censoredfor SecondaryEnd Points: 5
Censoredfor SecondaryEnd Points: 4
Lost to Follow-up: 0 | Lost to Follow-up: 0
Deceased: 108 Deceased: 129
Figure 1.Enrollment, progress, and outcome ofpatients in the Nutritional Prevention of Cancerstudy as of December 31, 1993.
treatment and placebo groups for thesefactors.
At the end of the study period on December 31,1993, 43.6% of patients werestill on treatment, 18.0% were off treatment but were still having routine dermatologie examinations, 20.1% ofpatientswere censored for dermatologie endpoints but not other end points, and 18.3%had died (Figure 1). After a total of 8271person-years of follow-up, no patientswere lost to vital follow-up and only 9patients (5 in the selenium group and 4in the placebo group) declined to provideadditional illness information for a period of 48 person-years of follow-up (0.6%of the total potential follow-up for thetrial). The range of active patient treatment was 0.0 to 10.3 years.
The
patient-reported complianceindi
cated that 82% of patients in both theselenium and placebo groups had missedtaking a pill less than twice a month. Forboth the selenium and placebo groups,the number of years on treatment (mean[SD]) (4.5 [2.8] vs 4.3 [2.8]) the length ofdermatologie follow-up (5.6 [2.6] vs 5.4[2.6]), and total follow-up (6.4 [2.0] vs 6.2[2.1]) were not significantly different.
Mean plasma selenium concentrationat the time of randomization was 114 ng/mL (SD, 23 ng/mL) (Figure 2), which isin the lower range of normal plasma levels
reportedin the United States. Plasma
selenium concentration of the placebo
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300
Selenium Treatment
0 0.51 23456789 10Time Since Randomization, y
gure 2.Plasma selenium concentrations amongatients receiving selenium (squares) and those reeiving placebo (circles). Values are means and errorars indicate 1 SD. The placebo-treatment lines arefset to allow for examination of overlapping areas.
roup remained constant throughout theial, whereas patients in the selenium-eatment group increased selenium lev
s by approximately 67% to 190 ng/mLwithin 6 to 9 months of supplementation.o patient had plasma selenium levels
ndicative of selenium deficiency (ie,
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Table 4.Total and Cause-Specific Mortality by Treatment Group
Cause, No._Selenium Placebo RR (95% CI)* Value HR (95% Cl)t ValueTotal cancer* 29 57 0.50(0.31-0.80) .002 0.48(0.31-0.76) .001
Lung cancer 12 25 0.47(0.22-0.98) .03 0.47(0.23-0.93) .03Other carcinoma 15 25 0.59(0.29-1.17) .10 0.56(0.30-1.07) .08
Noncarcinoma_2_7 0.28(0.03-1.48) .09 0.26(0.05-1.27) .10Cardiovascular and
cerebrovascular diseases 47 46 1.00(0.66-1.55) .96 0.96(0.64-1.44) .83All other causes 32 26 1.22(0.70-2.12) .47 1.16(0.69-1.95) .57
Respiratory disease 14 11 1.26(0.53-3.06) .57 1.26(0.57-2.77) .57All causes} 108 129 0.83(0.63-1.08) .14 0.79(0.61-1.02) .07
*RR indicates relative risk; and CI, confidence interval. values from the log rank test.tHR Indicates hazard ratio. value from the Cox proportional hazard model adjusted for age, sex, and smoking
status at randomization.These mortality causes are secondary end points.Respiratory disease is the only cause of death that contributed more than 5 deaths to either group.
and lower rates of total cancer incidenceand mortality for 8 years (P=.06).
Exclusion of SCC of the skin diagnosed in the first 2 years of the trialresults in a change in the direction of thetreatment effect for the primary outcome from a nonsignificant excess risk(RR, 1.14; 95% CI, 0.94-1.39; P=.15) toa nonsignificant decreased risk (RR, 0.95;95% CI, 0.75-1.19; P=.79). Exclusion ofcases of BCC from the first 2 years didnot materially change the treatment effect. The treatment effect for total cancer incidence and all-cause mortalitywere unaffected by a treatment lag of 2years, whereas total cancer mortalitywas weakened slightly. The treatmenteffect was enhanced in the 2-year laganalysis for prostate and colon cancerand weakened slightly for lung cancer(data not shown).
The treatment effect on secondary end
points was further evaluated by considering only those events that occurredsubsequent to their formal definition. Thetreatment effects for this time periodwere statistically significant (Table 5) fortotal cancer mortality, total cancer incidence, and cancers of the colon-rectumand the prostate. For lung cancer, thepost-1990 results were consistent withthe overall 10-year lung cancer results,but the treatment effect was not statistically significant.COMMENT
The patient population in this trialwas recruited from the eastern coastalplain of the United States, a region characterized by relatively low selenium levels in soils and crops,1241 and by highrates of SCC and BCC of the skin andcancer mortality.42 Basal cell carcinomaand SCC were selected as primary endpoints because plasma selenium levelshad been associated with these skin cancers in previous case-control and cohortstudies. Each randomized patient had ahistory of BCC or SCC with at least 1cancer within the prior 12 months andwas a patient of a clinical investigator.
The primary purpose of this randomized, double-blind, placebo-controlledtrialwas to test the hypothesis that a nutritional supplement of selenium can reducethe incidences of BCC and SCC of theskin. The results do not support that hypothesis. The primary end points, BCCand SCC of the skin, were not reduced byselenium treatment. One possible explanation for this observation is that thelength of treatment may have been tooshort for prevention of SCC and BCCbecause ultraviolet (UV) radiation increases the risk of SCC and BCC at boththe initiation and promotion-progressionstages of carcinogenesis.
Ultraviolet radiation can induce damage to the p53 gene which inhibits thetransformed cells from undergoing apop-tosis. While this is often a late event inmany carcinomas, it is apparently an earlyevent for SCC of the skin with 69% of
premalignant actinic keratosis and morethan 90% ofSCC expressingUV-inducedmutations of pS.43 In BCC, p53 mutations are less common and occur in 40%to 60% of all lesions.44 The UV radiationalso appears to promote the progressionof p55-mutated cells by inducing apopto-sis of sunburn cells in the epidermisthereby facilitating the clonai expansionof the transformed cells. If the primarycancer preventive effect of seleniumsupplementation is the enhancement ofapoptosis,45 then SCC and BCC of theskin would require a substaintuallylongertreatment period before the manifestation of a protective treatment effect thanwould other types of cancer in which p53mutations are a late stage event. Thiswould occur because a significant proportion of the premalignant skin lesionsalready contain p53 mutations.
The safety of the intervention agentwas an important consideration in thedesign and conduct of the trial. The selenium dose of 200 g/day is within thenormal range of dietary intake of Americans, provides approximately twice the
projected typical dietaryintake of these
patients, and is 3 to 4 times the recom-
1.00
0.00
Selenium Treatment
Placebo Treatment
01 23456789 10
Time Since Randomization, y
Figure 3.Kaplan-Meier curve of total cancer mortality.
mended daily allowance. The absence ofthe dermatologie signs of selenosis46 reinforces the safety of selenium supplementation. Plasma selenium concentrations remained below the no adverse effect
level (1000 ng/mL in whole blood) established by the Environmental ProtectionAgency.6
The results point to the possibility ofprotective effects on the secondary endpoints (total cancer mortality, total cancer incidence, incidences of lung, prostate,and colorectal cancers). Supplementationwith selenium inhibits tumor growth andstimulates apoptosis in cultured tumorcells.47 These observations support the hypothesis that selenium supplementationinhibits the late stage promotion and progression of tumors. Accordingly, seleniumtreatment might be expected to manifestcancer-protective effects within a relatively short time frame.
It appears that regulation of apoptosisis an important determinant of cancerrisk in humans as well as in experimentalsystems. In a cohort of elderly subjects,the use of calcium channel blockers thatinhibit apoptosis increased the risk of cancer in a dose-dependent manner.48 Thus,the enhancement of apoptosis with selenium supplementation may decrease cancer risk particularly in individuals withsuboptimal selenium status. In addition,geographic studies1,12 suggest that, whileit is plausible that selenium might protect against cancer mortality in humans,such effects should not be expected at allsites. The present results are consistentwith the geographic study12 that indicatedno association with noncarcinomas.
The secondary results were consistentacross both clinic and time. The apparently protective effect for total cancerincidence and cancer mortality occurredin 6 of the 7 clinics. These effects alsowere observed in 8 of 10 years of follow-up for total cancer incidence and mortal
ity. The lower number of cancer deaths in
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able 5.Secondary End-Point Analysis Before and After Definition
1983-1989* 1990-1993t
Events, No.
Events, No.
End PointI ISelenium Group Placebo Group RR (95% CI)
I-1Value Selenium Group Placebo Group RR (95% CI) Value
'
ung cancer incidence 16 0.44(0.18-1.06) .06 10 15 0.66(0.30-1.46) .30rostate cancer incidence 0.50(0.15-1.67) 0.33(0.15-0.70)olorectal cancer Incidence 1.20 (0.37-3.95) .76 14 0.14(0.32-0.62) .002otal cancer incidence 0.64(0.39-1.03) 0.63 (0.44-0.90)otal cancer mortality 16 0.44(0.18-1.07) .06 22 0.53(0.31-0.89) .01l-cause mortality 36 0.90(0.57-1.41) 89 0.80(0.58-1.08) .15
'Events prior to secondary end point definition. RR indicates relative risk; and CI, confidence interval. values derived from the log rank test.tEvents after secondary end point definition.
he selenium group was not counterbalnced by an increased risk of death fromther causes, as has been observed inardiovascular prevention trials.49,50 In adtion, the proportion of patients with el
vated prostate-specific antigen levelsas slightly greater inthe seleniumgroup;
hus, the treatment result for prostateancer cannot be explained by a favorble distribution of prostate-specific an
gen levels at randomization.While secondary end points were notormally defined at the beginning of thetudy, the ascertainment of these endoints with patient interviews did nothange during the course of the study.onfirmation ofsecondary end points with
medical record review began in 1987. Aproximately 76% of patients with cancerad their diagnosis confirmed with pahology reports. The uniform searches ofhe NDI and of state cancer registries foreaths and cancer cases decreased theossibility of ascertainment bias explaing the results.Comstock et al51 reviewed 10 cohortudies that obtained prediagnostic serumamples and measured beta carotene, reti-ol, vitamin E, or selenium. All 4 nutrints showed a relatively consistent pat
ern of increased cancer risk associatedwith lower nutrient levels. For selenium,
majority of these studies showed caseubjects had lower levels than control subcts, although most studies showed a case-ontrol difference of less than 10%. Indidual studies of the epidemiology of
elenium and cancer are complex and difcult to interpret because of mthodogie problems. These problems include
he large degree of misclassification ofelenium status with only a single meaurement of blood levels; the relative ho
mogeneity of selenium levels within spefic populations that decrease thetatistical power of studies; the relativelyw power to test hypotheses for indidual sites of cancer because of smalludy populations; and low incidence of
ancer in most of these cohorts defined toudy cardiovascular disease.After considering the results of this
ial, the SMAC recommended unblind-
ing the trial in advance of its plannedtermination in 1998. This decision wasbased on a number of issues, includinglack of effect on the primary end pointsand on reductions in cancer mortality andcancer incidence in the selenium group.It should be noted that, as is typical inlarge clinical and epidemiologie studies, alarge number of statistical tests on thedata were performed and reported herein.
There is no generally agreed upon methodfor adjusting values for the multiplicityofend points considered.52,56 Furthermore,this trial was subject to interim monitoring by the SMAC. In the decision to stopor to continue the trial at each stage, theSMAC entertained a variety of quantitative and qualitative considerations. Informal stopping guidelines were adoptedearly on: values of 3.0 for primary endpoints,56 3.5 for secondary end points, and2.0 for mortality end points. It was agreed,however, that these guidelines would notbe interpreted as rigid stopping rules.
The reported values should be interpreted with great care, since there is nogenerally accepted method for adjusting values when the early stopping is notbased on the primary end point.57,58 However, the significant reductions in cancerincidence and mortality found in this studycannot easily be dismissed as chance observations resulting from multiplicity ofend-point testing. The strength of the associations found and their consistenciesacross clinic, across time, and across allthe major cancer sites for which therewere enough events to allow statisticaltests of adequate power all weigh againstthe role of chance in these findings.
The magnitude of the apparent effectson cancer incidence and cancer mortalitywere unanticipated and should be interpreted with caution consideringconfounding, multiplicity, and generalizability. Thatthere may be important confounding notyet considered is unlikely. The stratifiedrandomization design by clinic should provide balance in potential confounderswithin each clinic for the 2 treatmentgroups. For confounding to have producedthese effects in secondary end points, anyimbalances that may have occurred would
have to have been replicated across mostor all of the clinics; for this, we have noevidence. The stratified randomization byclinic provides balance for such potentialconfounders as type of clinic, and localscreening and diagnostic methods. In addition, the baseline characteristics listedin Table 1 were not imbalanced, and ad
justment for them did not materially affect the results. That this cohort consisted
of subjects at high risk of BCC, SCC, orboth, who showed relatively high cancerrates, may limit the generalizability ofthese findings to other populations. Confirmation of the apparently protective effects of selenium supplementation shownin the study remains necessary. Therefore, additional studies should be conducted to determine whether selenium
supplementation can protect against cancer in other populations and among particular subgroups of individuals withknown cancer risk factors.
CONCLUSIONThe results of this randomized con
trolled trial do not support the hypothesis that selenium supplementation reduces the risk of BCC or SCC of the skin,showing no statistically significant treatment effect on their incidence. However,selenium supplementation was found tobe associated with significant reductionsin secondary end points of total cancerincidence (all-sites combined), lung, colorectal and prostate cancer incidences,and lung cancer mortality. These apparent beneficial effects of selenium supplementation require confirmation in independent trials of appropriate designbefore public health recommendations regarding selenium supplementation canbe made.
From the Arizona Cancer Center, College ofMedicine, University of Arizona, Tucson (Dr Clark);the Division of Nutritional Sciences (Dr Combs) andthe Statistics Center (Drs Tumbull and Slate), Cornell University, Ithaca, NY; the Georgia Dermatology and Skin Cancer Clinic, Macon (Drs Chalker andSanders); Columbia Skin Clinic, Columbia, SC (DrChow); the Medical College of Georgia, Augusta (DrsDavis and Lesher); the Wilson Dermatology Clinic,
Wilson,NC
(DrsGlover and Graham); the Division
of Dermatology, School of Medicine, University of
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North Carolina at Chapel Hill (Dr Graham); the Division of Dermatology, University of ConnecticutSchool of Medicine, Farmington (Dr Gross); School ofMedicine and the Veterans Administration MedicalCenter (Drs Kongrad and Taylor), University of Miami, Fla; Department of Pathology (Dr Park) and theDepartment of Medicine, Division of Dermatology(Dr Smith), School of Medicine, East Carolina University, Greenville, NC; Eastern Dermatology,Greenville, NC (Drs Park and Smith).
The Nutritional Prevention of Cancer StudyGroup: David S. Alberts, MD, Bruce L. Dalkin, MD,Arizona Cancer Center, College of Medicine, University of Arizona, Tuscon; Richard J. Allison Jr, MD,College of Medicine, University of South Carolina,Columbia; James C. Bradshaw, DO, Warner Robins,Ga; David Curtis, MD, Medical College of Georgia,Augusta; Davey R. Deal, MD, Division of Dermatology, Coliseum Hospital, Macon, Ga; Mark Dellasega,MD, Quadrangle Medical Specialists, Greenville, NC;John D. Hendrix, MD, Department of Medicine, Division of Dermatology, East Carolina University,Greenville, NC; James H. Herlong, MD, ColumbiaUrological Specialists, PA, Columbia, SC; Lee J.Hixson, MD, Dixie Medical Center, St George, Utah;Fred Kight, MD, Augusta, Ga; James Moore, MD,South Suburban Gastroenterology, South Wey-mouth, Mass; Joseph S. Rice, MD, Columbia Gastrointestinal Endoscopy Center Ine, Columbia, SC;Arvey I. Rogers, MD, University of Miami VeteransAffairs Medical Center, Miami, Fla; Bernard
Schuman, MD, Medical College of Georgia, Augusta;Edward H. Smith Jr, MD, Medical College of Georgia, Augusta; and Jerry C. Woodard, MD, WilsonGastroenterology, Wilson, NC.
The Safety Monitoring and Advisory Committee: Tim E. Byers, MD, MPH; Harvey Cohen, MD,PhD; Stephen L. George, PhD; E. Robert Green-berg, MD; and Philip R. Taylor, MD, DSc.
The Executive Committee: Gerald F. Combs Jr,PhD, and Bruce W. Turnbull, PhD.
This study was funded in part by grants from theAmerican Institute of Cancer Research (84B01R87A),the American Cancer Society (PDT-298B), the National Institutes of Health (R01-CA42334 and R01-CA49764), and Nutrition 21, La Jolla, Calif.
The authors gratefully acknowledge the important contributions of the following people: Doug Al-breski, DPM,
Margery Bates,Maria
Bishop,MD,
Teresa Bogue, John Bray, PhD, Lynne Deuschle,Lisa Higgins, MPH, Anne Hodgson, Margie Knox,Thomas Kramer, Frances Lee-Lin, MSN, ChemaineMcCray, Tamara Montano, Ann Pursley, JeanShelton, Regina Spivey, Donna Sugerman, CynthiaTie, MD, Edward Wittke, and Rebecca Williams.
We especially thank the Nutritional Prevention ofCancer project participants for their years of dedication and perseverance.
References
1. Shamberger RJ, Frost DV. Possible protectiveeffect of selenium against human cancer. Can MedAssoc J. 1969;100:682.2. Shamberger RJ, Willis CE. Selenium distributionof human cancer mortality. Crit Rev Clin Lab Sci.1971;2:211-221.
3. Schrauzer GN, Thead WJ. Interpretation of themethylene blue reduction test of human plasma andthe possible cancer protecting effect of selenium. Ex-perientia. 1971;27:1069-1071.4. Combs GF Jr, Combs S. The Role of Selenium inNutrition. New York, NY: Academic Press; 1986.5. Burk RF, Hill KE. Regulation of selenoproteins.Annu Rev Nutr. 1993;13:65-81.6. Combs GF Jr. Essentiality and toxicity of sele-nium: a critique of the recommended dietary allow-ance and the reference dose. In: Mertz W, AbernathyCO, Olin SS, eds. Risk Assessment ofEssential El-ements. Washington, DC: ILSI Press; 1994:167-183.7. Subcommittee on the Tenth Edition of the RDAs,Food and Nutrition Board, Commission on Life Sci-ences, National Research Council. Recommended Di-etary Allowances, Tenth Edition. Washington, DC:
National Academy Press; 1989.
8. Combs GF Jr. Selenium and cancer. In: Wang Z,ed. Biochemistryand Molecular Biology ofSelenium.Beijing, China: Chinese Academy of Science; 1995.9. Milner JA. Effect of selenium on virally inducedand transplantable tumor models. Fed Proc. 1985;44:2568-2572.10. Ip C. The chemopreventive role of selenium incarcinogenesis. J Am Coll Toxicol. 1986;5:7-2011. Ip C, Medina D. Current concept of selenium andmammary tumorigenesis. In: Medina D, Kidwell W,Heppner G, Anderson EP, eds. Cellular and Mo-lecular Biology of Breast Cancer. New York, NY:Plenum Press; 1987:479.12. El-Bayoumy K. The role of selenium in cancer
prevention. In: DeVita VT, Hellman S, RosenbergSS, eds. Practice of Oncology. 4th ed. Philadelphia,Pa: JB Lippincott; 1991:1-15.13. Schrauzer GN, White DA, Schneider CJ. Cancermortality correlation studies, III. Bioinorganic Chem.1977;7:23-34.14. Clark LC, Cantor KP, AllawayWH. Selenium inforage crops and cancer mortality in US counties.Arch Environ Health. 1991;46:37-42.15. Clark LC. The epidemiology of selenium and can-cer. Fed Proc. 1985;44:2584-2590.16. Salonen JT, Alfthan G, Huttunen JK, Puska P.Association between serum selenium and the risk ofcancer. Am J Epidemiol. 1984;120:342-349.17. Salonen JT, Salonen R, Lappetel\l=a"\inenR, M\l=a"\en-p\l=a"\\l=a"\PH, AlfthanG, Puska P. Risk of cancer in rela-tion to serum concentrations of selenium and vita-
mins A and E. BMJ. 1985;290:417-420.18. Willett W, Polk B, Morris S, et al. Prediagnosticserum selenium and risk of cancer. Lancet. 1983;2:130-134.19. Kok FJ, De Bruijn AM, Hofman A, Vermeeren R,Valkenburg HA. Is serum selenium a risk factor forcancer in men only? Am J Epidemiol. 1987;125:12-16.20. Virtamo J, Valkeila E, Alfthan G, Punsar S,Huttunen JK, Karvonen MJ. Serum selenium andrisk of cancer. Cancer. 1987;60:145-148.21. van den Brandt P, Goldbohm R, van't Veer P, etal. A prospective cohort study of toenail seleniumlevels and risk of gastrointestinal cancer. J NatlCan-cer Inst. 1993;85:224-229.22. Peleg I, Morris S, Hames CG. Is serum seleniuma risk factor for cancer? Med Oncol Tumor Phar-macother. 1985;2:157-163.23. Knekt
P,Aromaa
A,Maatela
J,et al. Serum se-
lenium and subsequent risk of cancer among Finnishmen and women. J Natl Cancer Inst. 1990;82:864-868.24. Glattre E, Thomassen Y, Thoresen SO, et al.Prediagnosticserum selenium in a case-control studyof thyroid cancer. Int J Epidemiol. 1989;18:45-49.25. Fex G, Pettersson B, Akesson B. Low plasmaselenium as a risk factor for cancer death in middle-aged men. Nutr Cancer. 1987;10:221-229.26. Menkes MS, Comstock GW, Vuilleumier JP,HelsingKJ, Rider AA, Brookmeyer RP. Serum beta-carotene, vitamins A and E, selenium, and the risk oflung cancer. N Engl J Med. 1986;315:1250-1254.27. Garland M, Morris JS, Stampfer MJ, et al. Pro-spective study of toenail selenium and cancer amongwomen. J Natl Cancer Inst. 1995;87:497-505.28. Schober SE, Comstock GW, Helsing KJ, et al.Serologic precursors of cancer. Am J Epidemiol.1987;126:1033-1041.29. Nomura A, Heilbrun LK, Morris JS, Stemmer-mann GN. Serum selenium and the risk of cancer, byspecific sites. J Natl Cancer Inst. 1987;79:103-108.30. Knekt P, Aromaa A, Maatela J, et al. Serumvitamin E, serum selenium and the risk of gastro-intestinal cancer. Int J Cancer. 1988;42:846-850.31. Ringstad J, Jacobsen BK,Tretli S, Thomassen Y.Serum selenium concentration associated with riskof cancer. J Clin Pathol. 1988;41:454-457.32. Coates RJ, Weiss NS, Daling JR, Morris JS,Labbe RF. Serum levels of selenium and retinol andthe subsequent risk of cancer. Am J Epidemiol. 1988;128:515-523.33. Clark LC, Graham GF, Crouse RG, Grimson R,Hulka B, Shy CM. Plasma selenium and skin neo-plasms. Nutr Cancer. 1984;6:13-21.
34. Clark LC, Graham GF, Turnbull BW, Bray J,
Hulka B, Shy CM. Non-melanoma skin cancer andplasma selenium: a prospective cohort study. In:Combs GF Jr, Spallholz JE, Levander OA, OldfieldJE, eds. The Third International Symposium onSelenium in Biology and Medicine. Westport, Conn:AVI Publishing Co; 1986:1122-1135.35. Blot WJ, Li JY, Taylor PR, et al. Nutrition in-tervention trials in Linxian, China. J Natl CancerInst. 1993;85:1483-1492.36. Li JY, Taylor PR, Li B. Nutrition interventiontrials in Linxian, China. J Natl Cancer Inst. 1993;85:1492-1498.37. Olson OE, Palmer IS, Cary EE. Modification ofthe official fluorometric method for selenium in plants.J Assoc OffAnal Chem. 1975;58:117-126.38. McShane LM, Clark LC, Combs GF Jr, TurnbullBW. Reporting the accuracy of biochemical mea-surements for epidemiologic and nutrition studies.Am J Clin Nutr. 1991;53:1354-1360.39. Abu-Libdeh H, Turnbull BW, Clark LC. Analy-sis of multi-type recurrent events in longitudinal stud-ies. Biometrics. 1990;46:1017-1023.40. Luo X, Turnbull BW, Cai H, Clark LC. Regres-sion for censored survival data with lag effects. Com-mun Stat. 1994;23:3417-3438.41. Allaway WH, Kubota J, Losee F, Roth M. Se-lenium, molybdenum and vanadium in human blood.Arch Environ Health. 1968;16:342-348.42. National Cancer Institute, State Cancer Controland DataProgram. CancerMortalityby Pentad 1953\x=req-\1957 to 1983-1987. Bethesda, Md: National Institutes
of Health; 1992.43. Nelson MA, EinspahrJG, Alberts DS, et al. Analy-sis of the p53 gene in human precancerous actinickeratosis lesions and squamous cell cancers. CancerLett. 1994;85:23-29.44. Gailani MR, Leffell DJ, Ziegler A, Gross EG,Brash DE, Bale AE. Relationship between sunlightexposure and a key genetic alteration in basal cellcarcinoma. J Natl Cancer Inst. 1996;88:349-354.45. Lanfear J, Fleming J, Wu L, Webster G, Har-rison PR. The selenium metabolite selenodiglutathi-one induces p53 and apoptosis. Carcinogenesis. 1994;15:1378-1392.46. Yang GQ, Yin S, Zhou R. Studies of safe maximaldaily dietary Se-intake in a seleniferous area of China.J Trace Elem Electrolytes Health Dis. 1989;3:123\x=req-\130.47.
Thompson JH,Wilson
A,Lu
J,et al.
Comparisonof the effects of an organic and inorganic form ofselenium on a mammary carcinoma cell line. Carci-
nogenesis. 1994;15:183-186.48. Pahor M, Gurainik JM, FerrucciL,etal.Calcium-channel blockade and incidence of cancer in agedpopulations. Lancet. 1996;348:493-497.49. The LRC Study Group. The Lipid Research Clin-ics Coronary Primary Prevention Trial results.JAMA. 1984;251:351-364.50. Frick MH, Elo O, Haapa K, et al. Helsinki HeartStudy: primary-prevention trial with gemfibrozil inmiddle-aged men with dyslipidemia.N Engl J Med.1987;317:1237-1245.51. Comstock GW, Bush TL, Helzlsouer K. Serumretinol, beta-carotene, vitamin E and selenium asrelated to subsequent cancer of specific sites. Am JEpidemiol. 1992;135:115-121.52. Pocock SJ, Geller NL, Tsiatis AA. The analysisof multiple endpoints in clinical trials. Biometrics.1987;43:487-498.53. Rothman KJ. No adjustments are needed formultiple comparisons. Epidemiology. 1990;1:43-46.54. Tannock IF. False-positive results in clinical tri-als. J Natl Cancer Inst. 1996;88:206-207.55. Cook RJ, Farewell VT. Multiplicityconsiderationsin the design and analysis of clinical trials. J R StatSoc A. 1996;159:93-110.56. Peto R, Pike MC, Armitage P, et al. Design andanalysis of randomized clinical trials requiring pro-longed observation of each patient, I: introductionand design. Br J Cancer. 1976;34:585-612.57. Cox DR. In Discussion: Jennison C, TurnbullBW. Interim analyses. J R Stat Soc B. 1989;51:338.58. Jennison C, Turnbull BW. Interim analyses.
J R Stat Soc B. 1989;51:305-361.
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