Selenium for preventing cancer

 

Characteristics of included studies [ordered by study ID]

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Methods	Cohort/sub-cohort controlled cohort study Country: France
Participants	Name of parent cohort: Etude du Vieillissement Antériel Study (EVA study) Participants: 1389 participants (41% male, 59% female) Inclusion criteria: 59 to 71 years of age; residents of Nantes; able to undergo examination at study centre Recruitment: 1991 to 1993 Outcome assessment: December 2001 Number of cases:  Any cancer: 45 (male/female: n.r.) Case definition: mortality Years of follow-up: 9.0 years Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Statistical methods: Cox proportional hazard model Variables controlled in analysis: gender, smoking, alcohol intake, medication use, obesity, diabetes mellitus, hypertension, CVD, age, education, dyslipidaemia, low cognitive function
Notes

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Methods	Matched, nested case-control study Countries: Denmark, Germany, Greece, Italy, the Netherlands, Spain, Sweden, the UK
Participants	Participants: approximately 130,000 men Inclusion criteria: male participants of the EPIC study Name of parent cohort: European Prospective Investigation into Cancer and Nutrition (EPIC) Recruitment: 1992 to 2000 Outcome assessment: at each country's study closure date (between June 1999 and January 2003) Number of cases: Prostate cancer: 959 (male/female: 959/0)  Case definition: incidence Years of follow-up: median 2.6 years (Greece) to 9.2 years (Sweden) Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled in analysis: BMI, smoking, alcohol consumption, physical activity, marital status, education Variables controlled by matching: age, study centre, time of day of blood collection, time between blood collection and last meal, sex
Notes

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Methods	Cohort Study Country: US
Participants	Participants: 13,887 men and women Inclusion criteria: male and female adults, aged 20 to 90 years, participating in the NHANES III: "stratified, multistage probability cluster to provide data representing the noninstitutionalized US population" (Bleys 2008, p. 404) Name of parent cohort: Third National Health and Nutrition Examination Survey (NHANES III) Recruitment: 1988 to 1994 Outcome assessment: 15 December 2000 Number of cases: Cancer deaths: 457 (male/female: n.r.) Case definition: mortality Years of follow-up: 6 to 12 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: Cox proportional hazard regression Variables controlled in analysis: age, sex, race, education, annual family income, post-menopausal status (women), cigarette smoking, serum cotinine level, alcohol consumption
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Name of parent cohort: Baltimore Longitudinal Study of Aging Participants: 1555 men Inclusion criteria: n.r. Recruitment: n.r. Outcome assessment: n.r. Number of cases: prostate cancer: 52 (male/female: 52/0) Case definition: incidence Years of follow-up: n.r. Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Analysed cases: analysis for 52 of 133 cases (reason for non-inclusion: plasma and/or histological confirmation of diagnosis not available) Statistical methods: logistic regression Variables controlled in analysis: years between blood donation and diagnosis/follow-up, age, age by years before diagnosis interaction, BMI, smoking history, alcohol use Variables controlled by matching: age
Notes

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Methods	Cohort/sub-cohort-controlled cohort study Country: US
Participants	Participants: 177 participants; no information on gender Inclusion criteria: persons at high risk of non-melanoma skin cancer Recruitment: n.r. Outcome assessment: n.r. Number of cases: skin (non-melanoma): 19 (male/female: n.r.)  Case definition: incidence Years of follow-up: mean: 3.0 years Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Statistical methods: Cox proportional hazard model
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: number of participants n.r.; both genders Inclusion criteria: employees of two Seattle companies Recruitment: 1972 to 1973 and 1976 Outcome assessment: not stated Number of cases: Any cancer: 154 (male/female: n.r.) Gastrointestinal cancer: 28 (male/female: n.r.) Breast cancer: 20 (male/female: 0/20) Prostate cancer: 13 (male/female: 13/0) Haematological cancers: 12 (male/female: n.r.) Cervical cancer: 12 (male/female: 0/12) Lung cancer: 11 (male/female: n.r.) Other: 58 (male/female: n.r.) Case definition: incidence Years of follow-up: n.r. Type of selenium marker: serum and plasma
Interventions	d.n.a.
Outcomes	Analysed cases: 154 (133 serum, 21 plasma) of 195 cases analysed (reason for non-inclusion: no sample available for analysis or no control available) Statistical methods: conditional logistic regression Variables controlled by matching: age, gender, race/ethnicity, year/month of sample collection, employer, plasma or serum sample
Notes	Primary publication: Coates 1988 Secondary publication: Coates 1987

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Methods	Cohort/sub-cohort-controlled cohort study Country: US
Participants	Participants: 1239 men and women Inclusion criteria: participants of the NPCT with valid selenium measurement at baseline Name of parent cohort: Nutritional Prevention of Cancer Trial (NPCT) Recruitment: see: Nutritional Prevention of Cancer Trial Outcome assessment: not stated Number of cases: Squamous cell cancer: 204 (male/female: n.r.) Case definition: incidence Years of follow-up: 2.0 years Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Statistical methods: Cox proportional hazard model Variables controlled in analysis: age, gender, current smoking, alcohol drinking
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: number of participants n.r.; both genders Inclusion criteria: residents of Washington County Name of parent cohort: CLUE I and II Cohort Recruitment: 1974/75 or 1989 Outcome assessment: n.r. Number of cases: Lung cancer: 258 (male/female: 157/101) Case definition: incidence Years of follow-up: n.r. Type of selenium marker: serum/plasma
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled by matching: age, gender, race/ethnicity, year and month of sample collection, participant of Clue I or Clue II cohort
Notes

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Methods	Cohort study Country: US
Participants	Participants: 339 participants (275 men; 64 women) Inclusion criteria: participants of a surveillance programme for men and women with Barrett's oesophagus, no prior history of oesophageal cancer or diagnosis of cancer within first three months of baseline Name of parent cohort: Seattle Barrett's Esophagus Program Recruitment: 1983 to 2004, baseline assessment for this study: 1 February 1995 to 1 July 2004 Outcome assessment: n.r. Number of cases: oesophageal adenocarcinoma: 37 (32 men, 5 women) Case definition: incidence Years of follow-up: mean: 5 years Type of selenium marker: intake of selenium supplements (self administered food frequency questionnaire)
Interventions	d.n.a.
Outcomes	Statistical methods: Cox proportional hazards regression Variables controlled in analysis: age, sex, fruit and vegetable consumption, percent energy from fat, waist-hip ratio, cigarette smoking, non-steroidal anti-inflammatory drug use
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 6426 women Inclusion criteria: female volunteers with serum available at the Breast Cancer Serum Bank in Columbia (Missouri)/U.S.A; no history of cancer at baseline; missing serum sample for analysis excluded Recruitment: 1987 to 1997 Outcome assessment: 1982 to 1983, 1989 Number of cases: Breast cancer: 105 (male/female: 0/105) Case definition: incidence Years of follow-up: median: 2.7 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled in analysis: serum cholesterol, packs of cigarettes / day, BMI Variables controlled by matching: age, year and month of sample collection, diagnosis of benign breast disease within two years prior to study enrolment, "sequence number of blood draw" for women who donate blood more than one time
Notes

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Methods	Matched, nested case-control study (Epplein 2009, Gill 2009) Country: US
Participants	Inclusion criteria: participants of the Multiethnic Cohort, aged 45 to 75 years (native Hawaiians: aged 42 years and older), blood sample provided before cancer diagnosis between 1997 and 2006 Name of parent cohort: Multiethnic Cohort Recruitment: 1993 to 1996 Case definition: incidence Type of selenium marker: serum Epplein 2009: Participants: 67,594 (male: 29,009 / female: 38,585) men and women Outcome assessment: 2006 Number of cases: Lung cancer: 207 (male/female: 136/71) Years of follow-up: 0 to 10 years Gill 2009: Participants: 29,009 men Outcome assessment: n.r. Number of cases: Prostate cancer: 467 (male/female: 467/0) Years of follow-up: n.r.
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Epplein 2009: Variables controlled in analysis: age, fasting hours, pack-years, pack-years squared, years of schooling, family history of lung cancer Variables controlled by matching: age, sex, race/ethnicity, date of sample collection, time of day of sample collection, fasting status, smoking Gill 2009: Analysed cases: 450 of 467 cases analysed Variables controlled in analysis: age, fasting hours, BMI, family history of prostate cancer, education Variables controlled by matching: age, race/ethnicity, date of sample collection, geographic site (California, Hawaii), time of day of sample collection, fasting status
Notes	Primary publication: Epplein 2009         Other publications: Gill 2009

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Methods	Matched, nested case-control study Country: Sweden
Participants	Participants: 7935 men Inclusion criteria: 46 to 48 years of age; residents of Malmo/Sweden; no restriction regarding malignant disease at baseline (11 of 35 cases were diagnosed with cancer at baseline screening examination and/or died during first year of follow-up) Name of parent cohort: Malmo Preventive Programme Recruitment: 1975 to 1979 Outcome assessment: June 1981 Number of cases: Any cancer: 35 (male/female: 35/0) Case definition: mortality Years of follow-up: 3.5 to 8.0 years Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Analysed cases: 35 of 61 cases analysed (reason for non-inclusion: no plasma sample available) Statistical methods: logistic regression, Mantel-Haenszel Variables controlled by matching: age, month of sample collection
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 62,641 women Inclusion criteria: female registered nurses in 11 U.S. states; aged 30 to 55 years at baseline; completed questionnaire in 1976 and provision of toenail sample in 1982; no history of cancer at baseline Name of parent cohort: Nurses' Health Study (NHS) Recruitment: 1976 (toenail sample collection in 1982) Outcome assessment: 1 June 1986 Garland 1995: Number of cases: Any cancer (without breast): 503 (male/female: 0/503) Colon and rectal cancer: 89 (male/female: 0/89) Melanoma: 63 (male/female: 0/63) Ovarian cancer: 58 (male/female: 0/58) Lung cancer: 47 (male/female: 0/47) Other: 155 (male/female: 0/155) Uterine cancer: 91 (male/female: 0/91) Hunter 1990: Number of cases: Breast cancer: 434 (0/434) Case definition: incidence Years of follow-up: 2.0 to 4.4 years Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	Statistical methods: logistic regression, conditional logistic regression Variables controlled in analysis: smoking status Variables controlled by matching: age, year and month of sample collection Hunter 1990 additionally controlled in analysis for: age at first birth, age at menarche, alcohol use, history of benign breast disease, menopausal status, maternal breast cancer, breast cancer in sister(s), oral contraceptive use, parity, relative weight
Notes	Primary publication: Garland 1995         Other publications: Hunter 1990

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Methods	Matched, nested case-control study Country: Norway
Participants	Participants: 100,000 men and women Inclusion criteria: serum available at Janus serum bank (Norwegian serum bank which is consolidated from several sources and maintained by the Norwegian Cancer Society for research purposes) Recruitment: 1972 to 1985 Outcome assessment: end of 1985 Number of cases: thyroid cancer: 43 (male/female: 12/31) Case definition: incidence Years of follow-up: 0.0 to 14.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled by matching: age, gender, year of sample collection, county of residence
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 18,314 men and women Inclusion criteria: asbestos workers: 45 to 74 years of age; smokers > 20 pack-years: 50 to 69 years of age; cohort of a RCT for lung cancer prevention in high risk populations Name of parent cohort: Caret (Carotene and Retinol Efficacy Trial) Recruitment: 1988 to 1994 Outcome assessment: April 1999 Number of cases: Lung cancer: 235 (male/female: n.r.) Prostate cancer: 356 (male/female: 356/0) Case definition: incidence Years of follow-up: 6.0 to 12.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: 235 of 236 prostate cancer cases analysed (reason for non-inclusion: no sample available for analysis or no control available); 356 of 385 lung cancer cases analysed (reason for non-inclusion: missing selenium values for case-control pairs) Statistical methods: conditional logistic regression Variables controlled by matching: age, smoking status at randomisation, year of randomisation, year of sample collection, treatment arm, exposure population
Notes

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Methods	Cohort/sub-cohort-controlled cohort study Country: Finland
Participants	Participants: 29,133 men Inclusion criteria: 50 to 69 years of age; smokers; no history of cancer (other than non-melanoma skin cancer) at baseline; no severe physical or psychiatric illness; intake of vitamin E/A/beta-carotene supplements in excess of defined amounts Name of parent cohort: Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study Recruitment: 1985 to 1988 Outcome assessment: 30 April 1993 Number of cases: Prostate cancer: 302 (male/female: 302/0) Case definition: incidence Years of follow-up: 5.0 to 8.0 years Type of selenium marker: intake (food use questionnaire)
Interventions	d.n.a.
Outcomes	Analysed cases: 302 of 317 cases included in analysis (reason for non-inclusion: no dietary information available) analysis stratified by randomisation status according to active interventions or placebo interventions in the RCT results reported separately for total selenium intake and non-supplemental selenium intake Statistical methods: Cox regression Variables controlled in analysis: age, living in urban area, beta-carotene intervention, total energy, BPH
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 10,456 men Inclusion criteria: residents of Washington county; cases with second malignancy or missing pathologic confirmation excluded Name of parent cohort: CLUE II Cohort Recruitment: 1989 Outcome assessment: September 1996 Number of cases: prostate cancer: 117 (male/female: 117/0) Case definition: incidence Years of follow-up: 6.8 to 7.8 years Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	Analysed cases: 117 of 145 cases analysed (reason for non-inclusion: no toenail clipping available) Statistical methods: conditional logistic regression Variables controlled in analysis: BMI at age 21, education, hours since last meal Variables controlled by matching: age, race/ethnicity, year and month of sample collection, size of toenail clipping
Notes

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Methods	Matched, nested case-control study Country: Japan
Participants	Participants: 20,000 men and women Inclusion criteria: survivors of the atomic bomb in Hiroshima or Nagasaki; serum available for analysis Name of parent cohort: Adult Health Study Hiroshima and Nagasaki Recruitment: 1960 (blood samples drawn in 1970 to 1972) Outcome assessment: 1983 Number of cases: Stomach cancer: 201 (male/female: 113/88) Lung cancer: 77 (male/female: 43/34) Case definition: incidence Years of follow-up: 12.0 to 14.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled in analysis: radiation dose, smoking, age, gender Variables controlled by matching: age, gender, year/month of sample collection, city
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 1805 men and women Inclusion criteria: at least one basal cell or squamous cell cancer before study entry; participants of an RCT for non-melanoma skin cancer prevention with oral beta-carotene supplementation Name of parent cohort: Skin Cancer Prevention Study Recruitment: February 1983 to February 1986 Outcome assessment: 30 September 1989 Number of cases: Squamous cell cancer: 131 (89% male/11% female) Case definition: incidence Years of follow-up: 3.0 to 5.0 years Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled in analysis: cigarette smoking Variables controlled by matching: age, gender, study centre of RCT, time in study (diagnosis date)
Notes

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Methods	Matched, nested case-control study (Knekt 1990, Hakama 1990, Knekt 1988, Knekt 1996) Cohort study (Knekt 1991) Country: Finland
Participants	Inclusion criteria: no history of cancer at baseline Name of parent cohort: Social Insurance Institution's Mobile Clinic Health Examination Survey Recruitment: 1968 to 1972 Knekt 1990: Participants: 39,268: 21,172 men and 18,096 women Outcome assessment: 31 December 1980 Number of cases: Any cancer: 1096 (male/female: 597/499) Stomach cancer: 95 (male/female: 58/37) Colon and rectal cancer: 91 (male/female: 32/59) Lung cancer: 198 (male/female: 189/9) Prostate cancer: 51 (male/female: 51/0) Urinary tract cancer: 47 (male/female: 34/13) Pancreatic cancer: 45 (male/female: 22/23) Breast cancer: 90 (male/female: 0/90) Gynaecological cancer (without breast): 86 (male/female: 0/86) Basal cell carcinoma (skin): 126 (male/female: 64/62) Other: 267 (male/female: 147/120) Hakama 1990: Participants: number of participants n.r.; both genders Inclusion criteria: aged 15 years and older Outcome assessment: 1977 Number of cases: Any cancer: 766 (male/female: n.r.) Lung cancer: 151 (male/female: 151/0) Breast cancer: 67 (male/female: 0/67) Stomach cancer: 76 (male/female: n.r.) Prostate cancer: 37 (male/female: 37/0) Knekt 1988: Participants: 36,265: 21,172 men and 15,093 women Outcome assessment: 31 December 1977 Number of cases: Oesophageal and stomach cancer: 86 (male/female: 51/35) Colon and rectal cancer: 57 (male/female: 21/36) Knekt 1991: Participants: 4538 men Inclusion criteria: aged 20 to 69 years, with dietary history taken Outcome assessment: 1986 Number of cases: Lung cancer: 117 (male/female: 117/0) Knekt 1996: Participants: 1896 women Outcome assessment: 1980 Number of cases:      Ovarian cancer: 24 (male/female: 0/24) Case definition: incidence Years of follow-up: 9 to 20 years Type of selenium marker: serum (Knekt 1990, Hakama 1990, Knekt 1988, Knekt 1996), intake (Knekt 1991: dietary history)
Interventions	d.n.a.
Outcomes	Knekt 1990: Statistical methods: conditional logistic regression Variables controlled in analysis: smoking Variables additionally controlled in analysis of highest four quintiles versus lowest quintile: occupation, BMI, parity, cholesterol, haematocrit Variables controlled by matching: age, gender, municipality, time of baseline examination, duration of storage of sample Hakama 1990: Analysed cases: 766 of 864 cases analysed (reason for non-inclusion: no serum sample) Statistical methods: conditional logistic regression Variables controlled in analysis: smoking Variables additionally controlled in analysis of highest four quintiles versus lowest quintile: retinol level, alpha-tocopherol level Variables controlled by matching: age, gender, municipality, time of baseline examination, duration of storage of sample Knekt 1988: Statistical methods: n.r. Variables controlled in analysis: smoking, serum cholesterol Variables controlled by matching: age, gender, municipality, time of baseline examination, duration of storage of sample Knekt 1991: Statistical methods: Cox-proportional hazards model Variables controlled in analysis: age, smoking (data stratified according to smoking status) Knekt 1996: Statistical methods: conditional logistic regression Variables controlled by matching: age, gender, municipality, time of baseline examination, duration of storage of sample
Notes	Primary publication: Knekt 1990 Other publications: Hakama 1990, Knekt 1988, Knekt 1991, Knekt 1996

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Methods	Matched, nested case-control study Country: Finland
Participants	Participants: 9101 men and women Inclusion criteria: 19 years or older; no history of cancer at baseline; serum sample available for analysis Name of parent cohort: Social Insurance Institution's Mobile Clinic Health Examination Survey Recruitment: 1973 to 1976 Outcome assessment: end of 1991 Number of cases: Lung cancer: 91 (male/female: approximately 95%/5%) Case definition: incidence Years of follow-up: 16.0 to 19.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: 91 of 95 (male/female: 90/5) cases analysed Statistical methods: conditional logistic regression Variables controlled in analysis: smoking, alpha-tocopherol, serum cholesterol, copper, orosomucoid, BMI Variables controlled by matching: age, gender, municipality, season of sample collection, length of storage of sample
Notes

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Methods	Matched, nested case-control study Country: the Netherlands
Participants	Participants: 10,532 men and women Inclusion criteria: inhabitants of Zoetermeer; 5 years or older Name of parent cohort: EPOZ Cohort (Epidemiologisch onderzoek naar risico-indicatoren voor hart- en vaatziekten) Recruitment: 1975 to 1978 Outcome assessment: 31 December 1983 Number of cases: Any cancer: 69 (male/female: 40/29) Case definition: mortality Years of follow-up: 6.0 to 9.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: 69 of 114 cases analysed (reason for non-inclusion: serum or baseline data not available, deaths in first year of follow-up excluded) Statistical methods: not specified Variables controlled in analysis: age, smoking, serum cholesterol, serum vitamin A and E, systolic and diastolic blood pressure, BMI, week of blood collection, years of education, gender (in group of both genders) Variables controlled by matching: age, gender, smoking status
Notes	Primary publication: Kok 1987b Other publication: Kok 1987a

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Methods	Matched, nested case-control study Country: Belgium
Participants	Participants: cohort size not reported; men and women Inclusion criteria: 25 to 74 years of age Name of parent cohort: Belgian Interuniversity Study on Nutrition and Health Recruitment: 1980 to 1984 Outcome assessment: n.r. Number of cases: Any cancer: 193 (male/female: 143/50) Case definition: mortality Years of follow-up: 10.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: 143 male/50 female cases analysed from 252 male/91 female cases (reason for non-inclusion: no selenium measurement available) Statistical methods: not specified Variables controlled in analysis: BMI, total energy, total fat, saturated fat, alcohol intake, fibre, retinol, vitamin C, smoking, beta-carotene Variables controlled by matching: age, gender
Notes

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Methods	Cohort/sub-cohort-controlled cohort study Country: the Netherlands
Participants	Participants: 878 men Inclusion criteria: 40 to 59 years of age; random sample of general male population at specific age in Zutphen Name of parent cohort: Zutphen Study Recruitment: 1960 Outcome assessment: 1985 Number of cases: lung cancer: 63 (male/female: 63/0) Case definition: mortality Years of follow-up: 25.0 years Type of selenium marker: intake (interview)
Interventions	d.n.a.
Outcomes	Statistical methods: Cox proportional hazard model Variables controlled in analysis: age, pack years of smoking
Notes

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Methods	Randomised controlled trial Allocation: randomised, "based on their residence area" Sequence generation: unclear, not described Concealment: unclear, not described Blinding: of participants: adequate (placebo), of investigators and doctors: unclear, not described Dropouts/withdrawals: no significant difference between percentage of drop-outs in intervention and control group (absolute numbers not reported) Intention-to-treat-analysis: unclear Recruitment period: unclear, not described Observation period: 3 years, started in 1996 Study period: unclear, not described Detection of cases: unclear, the study followed the diagnostic menu published by the National Cancer Control and Prevention Center, follow-up procedures not described Informed consent: unclear, not described
Participants	Country: China Number of participants: 2065 (selenium group: 1112; placebo group: 953) Condition: HBsAg carriers with negative AFP and normal ALT living in Qidong, Jiangsu province Demographics: men only; aged 20 to 65 years (screening group) Recruitment and setting: recruitment of 2065 HBsAg carriers from 17 villages out of a screening group of 18,000 men
Interventions	Intervention: 0.5 mg sodium selenite p.o. daily for 3 years Control: placebo
Outcomes	Primary outcome measure: incidence of primary liver cancer Other: blood selenium levels, activity of glutathione peroxidase Results: person-year incidence rate (number of cases/total number of persons) in intervention and control group: 1st year of follow-up: selenium group 899.25/100,000 (10/1112); placebo group: 1,888.77/100,000 (18/953) 2nd year of follow-up: selenium group 1,708.60/100,000 (19/1112); placebo group: 4,302.20/100,000 (41/953) 3rd year of follow-up: selenium group 3,057.55/100,000 (34/1112); placebo group: 5,981.11/100,000 (57/953)
Notes	adverse effects were not mentioned

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 14,916 men Inclusion criteria: participants of Physicians' Health Study who provided blood sample (healthy male physicians); no history of cancer at baseline; several physical conditions excluded at baseline: chronic renal failure, unstable angina pectoris, liver disease, peptic ulcer, history of TIA/stroke/myocardial infarction/gout; no use of vitamin A or beta-carotene supplements Name of parent cohort: Physicians' Health Study Recruitment: 1982 Outcome assessment:  1995 Number of cases: Prostate cancer: 586 (male/female: 586/0) Case definition: incidence Years of follow-up: 13.0 years Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Statistical methods: logistic regression Variables controlled in analysis: age at baseline, smoking status, duration of follow-up Variables controlled by matching: age, smoking status
Notes

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Methods	Matched, nested case-control study (McNaughton 2005b) Cohort study (Heinen 2007, van der Pols 2009) Country: Australia
Participants	Name of parent cohort: Nambour Skin Cancer Study Recruitment: 1992 to 1996 Case definition: incidence McNaughton 2005b: Participants: approximately 1000 men and women Inclusion criteria: randomly selected adults, aged 20 to 69 years; recruited for participation in a randomised controlled trial for skin cancer prevention with beta-carotene supplements and sunscreen application in 1992; living in the Nambour community; free of SCC at baseline; with blood sample and FFQ provided in 1996; participants with extreme energy intakes in FFQ excluded Outcome assessment: December 2001 Number of cases: Basal cell carcinoma of the skin: 90 (male/female: 39/51) Years of follow-up: 5.5 years Type of selenium marker: serum and nutritional intake (FFQ) Heinen 2007: Participants: 1001 men and women Inclusion criteria: randomly selected adults, aged 20 to 69 years; recruited for participation in randomised controlled trial for skin cancer prevention with beta-carotene supplements and sunscreen application in 1992; living in the Nambour community; with blood sample and FFQ provided in 1996; participants with extreme energy intakes in FFQ and missing consumption frequencies for more than 10% of food items excluded Outcome assessment: 31 December 2004 Number of cases: Basal cell carcinoma of the skin: 149 (male/female: 87/62) participants with 321 BCC tumours Squamous cell carcinoma of the skin: 116 (male/female: 70/46) participants with 221 SCC tumours, Case definition: incidence (tumour-based incidence and person-based incidence) Years of follow-up: 8 years Type of selenium marker: nutritional intake (FFQ) van der Pols 2009: Participants: 485 (male/female: 223/262) men and women Inclusion criteria: randomly selected adults, aged 20 to 69 years; recruited for participation in randomised controlled trial for skin cancer prevention with beta-carotene supplements and sunscreen application in 1992; randomised to placebo in the intervention trial; living in the Nambour community; free of SCC at baseline; with blood sample and FFQ provided in 1996; participants with extreme energy intakes in FFQ excluded Outcome assessment: 31 December 2004 Number of cases: Basal cell carcinoma of the skin: 77 (male/female: 46/31) participants with 173 BCC tumours Squamous cell carcinoma of the skin: 59 (male/female: 38/21) participants with 124 SCC tumours, Years of follow-up: 8 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	McNaughton 2005b: Statistical methods: conditional logistic regression Variables controlled in analysis: age, gender Variables controlled by matching: age, gender Heinen 2007: Statistical methods: generalised linear models Variables controlled in analysis: age, sex, intervention arm in RCT, energy intake, skin colour, elastosis of the neck, smoking, use of dietary supplements, history of skin cancer van der Pols 2009: Statistical methods: generalised linear models Variables controlled in analysis: age, sex, pack-years of smoking, alcohol intake, time spent outdoors on weekdays, history of skin cancer before 1996
Notes	Primary publication: McNaughton 2005b Other publication: Heinen 2007, van der Pols 2009 tumour-based incidence: number of newly developed histologically confirmed BCC or SCC divided by the person-years of follow-up accumulated over follow-up period person-based incidence: number of persons newly affected by BCC or SCC during the same person-years of follow-up time as calculated for the tumour-based analysis

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 25,804 men and women Inclusion criteria: female and male inhabitants of Washington county/Maryland; history of cancer at baseline excluded Name of parent cohort: CLUE I Cohort Recruitment: September to November 1974 Menkes 1986b: Outcome assessment: 1983 Number of cases: Lung cancer: 99 (69% male/31% female) Helzlsour 1996: Inclusion criteria: women only; women who used hormones at baseline excluded Outcome assessment: 1989 Number of cases: Ovarian cancer: 35 (male/female: 0/35) Breslow 1995: Outcome assessment: 1994 Number of cases: Melanoma: 23 (male/female: n.r.) Basal cell carcinoma (skin): 17 (male/female: n.r.) Squamous cell cancer: 37 (male/female: n.r.) Zheng 1993: Outcome assessment: 1990 Number of cases: Oral and pharyngeal: 28 (male/female: n.r.) Batieha 1993: Inclusion criteria: 15,161 women Outcome assessment: 31 May 1990 Number of cases: Cervical cancer: 50 (male/female: 0/50) Helzlsour 1989: Inclusion criteria: 20,305 men and women Outcome assessment: 1986 Number of cases: Bladder cancer: 35 (male/female: n.r.) Burney 1989: Outcome assessment: 1986 Number of cases: Pancreatic cancer: 22 (male/female: 9/13) Ko 1994: Outcome assessment: 25 September 1991 Number of cases: Colon cancer: 121 (male/female: 50/71) Case definition: incidence Years of follow-up: 8.0 to 16.8 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Menkes 1986b: Statistical methods: conditional logistic regression Variables controlled by matching: age, gender, race/ethnicity, smoking status, year and month of sample collection Helzlsour 1986: Statistical methods: conditional logistic regression Variables controlled by matching: Age, race/ethnicity, day time of blood sample collection, hours since last meal, time since last menstrual period (post-menopausal: years, pre-menopausal: days) Breslow 1995: Statistical methods: conditional logistic regression Analysed cases: 17 of 98 basal cell carcinoma cases, and 23 of 30 melanoma cases (and all squamous cell carcinoma cases) included in analysis Variables controlled by matching: age, gender, race/ethnicity Zheng 1993: Statistical methods: n.r. Variables controlled in analysis: smoking Variables controlled by matching: age, gender, race/ethnicity, year and month of sample collection, hours between previous meal and blood collection Batieha 1993: Statistical methods: conditional logistic regression Analysed cases: 50 of 60 cases (CIS and invasive cervical cancer) analysed (reason for non-inclusion: no matched control available) Variables controlled by matching: age, race/ethnicity, year and month of blood collection, hours since last meal, time since last menstrual period Helzlsour 1989: Statistical methods: n.r. Variables controlled in analysis: cigarette smoking, use of vitamin supplements Variables controlled by matching: age, gender, race/ethnicity, hours since last meal (all samples collected in same year) Burney 1989: Statistical methods: n.r. Variables controlled by matching: age, gender, race/ethnicity, hours since last meal Ko 1994: Analysed cases: 121 of 154 cases analysed (reason for non-inclusion: no serum sample available, tumour pathology or localisation unclear) Statistical methods: conditional logistic regression Variables controlled by matching: age, gender, race/ethnicity, year and month of sample collection, hours since last meal, women: time since last menstrual period, women: use of hormones/hormonal contraceptives
Notes	Primary publication: Menkes 1986b Other publications: Helzlsour 1996, Breslow 1995, Zheng 1993, Batieha 1993, Helzlsour 1989, Burney 1989, Ko 1994, Schober 1987 (cases included in Ko 1994), Menkes 1986a (cases included in Menkes 1986b)

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Methods	Matched, nested case-control study Country: Finland
Participants	Participants: 29,133 men Inclusion criteria: 50 to 69 years of age; smokers; no history of cancer (other than non-melanoma skin cancer) at baseline; no severe physical or psychiatric illness; intake of vitamin E/A/beta-carotene supplements in excess of defined amounts Name of parent cohort: Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study Recruitment: 1985 to 1988 Outcome assessment: 30 April 1993 Number of cases: Bladder cancer: 133 (male/female: 133/0) Case definition: incidence Years of follow-up: 5.0 to 8.0 years Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled in analysis: smoking dose and duration Variables controlled by matching: age, year/month of sample collection, intervention group status in RCT (only male smokers included in cohort)
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 101,950: 33,737 men, 68,213 women Inclusion criteria: cohort of HPFS (men) and NHS (women); no history of cancer at baseline Name of parent cohort: Health Professional Follow-Up Study (HPFS) and Nurses' Health Study (NHS) Recruitment: 1987 (HPFS), 1983 (NHS) Outcome assessment: 2000 Number of cases: Bladder cancer: 337 (male/female: 221/116) Case definition: incidence Years of follow-up: 13.0 to 17.0 years Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled in analysis: pack-years of smoking, heavy smoking at baseline Variables controlled by matching: age, gender, smoking status, month of sample collection
Notes

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Methods	Unmatched, nested case-control study Country: US
Participants	Participants: 6860 men Inclusion criteria: born 1900 to 1919; Japanese ancestry; inhabitants of Oahu/Hawaii; participants in the Honolulu Heart Program (1965 to 68) Name of parent cohort: Honolulu Heart Program Recruitment: 1971 to 1975 Outcome assessment: n.r. Number of cases: Any cancer: 280 (male/female: 280/0) Stomach cancer: 66 (male/female: 66/0)     Rectal cancer: 32 (male/female: 32/0) Lung cancer: 71 (male/female: 71/0) Colon cancer: 82 (male/female: 82/0) Bladder cancer: 29 (male/female: 29/0) Case definition: incidence Years of follow-up: 11.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: proportional hazards regression/Cox regression Variables controlled in analysis: age at examination, cigarettes/day (any cancer, lung cancer, bladder cancer) age at examination (stomach, rectum, colon)
Notes	N.B.: "Any cancer" in this study comprises all cancer cases for stomach, rectal, lung, colon and bladder cancer.

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 9345 men Inclusion criteria: no cancer diagnosis at baseline, blood sample available for analysis, men from two cohorts: sub-cohort one: participants of Nomura 1987; sub-cohort 2: brothers of participants in Nomura 1987 Recruitment: 1971 to 1977 Outcome assessment: 1995 Number of cases: Prostate cancer: 249 (male/female: 249/0)  Case definition: incidence Years of follow-up: 19.0 to 25.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: random sample of 249 (out of 360) cases analysed because of limited resources Statistical methods: generalised linear model Variables controlled in analysis: cigarette smoking history, age Variables controlled by matching: age, year/month of sample collection, recruitment in sub-cohort 1 or 2
Notes

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Methods	Randomised controlled trial Nutritional Prevention of Cancer Trial (NPCT) Allocation: random, block/stratified by clinic Sequence generation: computer generated random numbers Concealment: central assignment (sealed pill bottles) Blinding: participant blinded, doctor blinded, outcome assessor/pathologist unclear, review/coding of medical records blinded Dropouts/withdrawals: “9 patients (5 in the selenium group and 4 in the placebo group) declined to provide additional illness information” (Clark 1996, p. 1959)  - 0 participants lost to vital follow-up Intention-to-treat-analysis: yes Recruitment period: 1983 to 1991 End of predefined study period: 31 December 1993 Blinded intervention continued until the end of the blinded period: 31 January 1996 Intervention duration: 31 December 1993 (end of study period): mean = 4.5 years 31 January 1996 (end of blinded period): mean = 7.9 years Observation period/dermatologic follow-up: 31 December 1993 (end of study period): mean = 6.4 years 31 January 1996 (end of blinded period): mean = 7.4 years Detection of cases: dermatologic examination and interview every 6 months during follow-up; incident BCC and SCC were diagnosed by biopsy and confirmed by another dermatopathologist Informed consent: written informed consent forms, approval by institutional review board of participating institutions
Participants	Country: US Number of participants: 1312 (randomised to selenium group: 653, to placebo group: 659) Condition: male and female participants with history of 2 or more squamous cell or basal cell skin cancers Demographics: mean age 63.4 years (selenium)/63.0 years (placebo); 73.8% men (selenium). 75.6% men (placebo) Recruitment and setting: seven dermatological clinics (three academic units, four private practices) in the US
Interventions	Intervention: 200 µg selenium supplied as 500 mg selenium yeast tablets p.o./daily. Control: placebo
Outcomes	Primary outcome measure: incidence of basal and squamous cell carcinoma of the skin: all analyses were based on 1250 participants with initial blood collection within four days after randomisation (621 in the selenium group and 629 in the placebo group) Other reported outcomes and secondary outcome measures: Reported in Clark 1996: Incidence of lung cancer, prostate cancer, colorectal cancer, any cancer, head and neck cancer, bladder cancer, oesophageal cancer, breast cancer, melanoma, haematologic cancer, Reported in Duffield-Lillico 2002: Overall cancer mortality
Notes	Adverse effects: Clark 1996: 35 participants (21 in selenium and 14 in control group) complained of adverse effects, mostly involving gastrointestinal upset, and withdrew treatment. Post-hoc introduced secondary outcomes were: all-cause mortality, total cancer mortality, total cancer incidence and incidence of lung / prostate / colorectal cancers HR: adjusted for sex, age, smoking status, clinic site, plasma selenium concentration, clinical sun damage, sunscreen use at baseline and number of BCCs/SCCs/NMSCs in the 12 months before randomisation

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Methods	Cohort/sub-cohort-controlled cohort study Country: Channel Islands
Participants	Participants: 5162 women Inclusion criteria: ≥ 35 years of age; ostensibly healthy inhabitants of Guernsey Name of parent cohort: Channel Island Cohort Recruitment: 1967 to 1976 Outcome assessment: end of 1985 Number of cases: Breast cancer: 46 (male/female: 0/46) Case definition: incidence Years of follow-up: mean: 11 years for cases Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Analysed cases: 46 of 88 cases analysed (reason for non-inclusion: no plasma available) Statistical methods: logistic regression Variables controlled in analysis: age, age at menarche, age at first baby, parity, BMI
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 2530 men and women Inclusion criteria: 15 years of age and older; residents of Evans county; cases within first two years of follow-up excluded Name of parent cohort: Evans County Study Recruitment: 1967 to 1969 Outcome assessment: January 1981 Number of cases: Any cancer: 130 (male/female: 78/52) Case definition: incidence Years of follow-up: 11.0 to 14.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: n.r. Variables controlled by matching: age, gender, race/ethnicity, year/month of sample collection
Notes

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Methods	Matched, nested case-control study Country: Sweden
Participants	Participants: approximately 9500 men (exact figure not reported) Inclusion criteria: 46 to 48 years; residents of Malmo/Sweden Name of parent cohort: Malmö Preventive Programme Recruitment: 1974 to 1982 Outcome assessment: end of 1988 Number of cases: Any cancer: 302 (male/female: 302/0) Gastrointestinal cancer: 115 (male/female: 115/0) Respiratory tract cancer: 69 (male/female: 69/0) Other: 61 (male/female: 61/0) Urinary tract cancer: 57 (male/female: 57/0) Case definition: incidence Years of follow-up: 6.0 to 15.0 years Type of selenium marker: plasma selenium P
Interventions	d.n.a.
Outcomes	Analysed cases: 302 of 400 cases analysed (reason for non-inclusion: no sample available) Statistical methods: logistic regression, Mantel-Haenszel Variables controlled in analysis: smoking Variables controlled by matching: age, year/month/date of sample collection
Notes	Arbitrary unit: Concentration of selenoprotein P was expressed in arbitrary units (AU) relative to a standard of pooled plasma. 0.3 AU equal one standard deviation.

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 26,975 white non-Hispanic men Inclusion criteria: 55 to 74 years of age; excluded: no baseline questionnaire/informed consent/blood sample, no further contact after screening Name of parent cohort: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Recruitment: September 1993 to June 2001 Outcome assessment: 1 October 2001 Number of cases: Prostate cancer: 724 (male/female: 724/0) Case definition: incidence Years of follow-up: 0.3 to 8.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: 724 of 803 cases included in analysis (reason for non-inclusion: no selenium measurement available) Statistical methods: n.r. Variables controlled in analysis: age, time since initial screening, year of blood collection, study centre Variables controlled by matching: age, month of sample collection, time since initial screening
Notes

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Methods	Cohort study Country: US
Participants	Inclusion criteria: aged 50 to 76 years, participants recruited from subscribers of commercial mailing list, residents of western Washington state, non-whites excluded, no malignant disease at baseline Name of parent cohort: Vitamins and lifestyle (VITAL) study Recruitment: 1 October 2000 to 31 December 2002 Type of selenium marker: supplemental intake (questionnaire: use of supplements over the last 10 years, mean supplemental intake / day calculated) Case definition: incidence Peters 2008: Participants: 35,242 men Outcome assessment: 31 December 2004 Number of cases: Prostate cancer: 818 (male/female: 818/0)  Years of follow-up: 2 to 4 years Asgari 2009: Participants: 69,671 men and women Outcome assessment: 31 December 2006 Number of cases: Melanoma: 461 (male/female: n.r.) Years of follow-up: 4 to 5 years
Interventions	d.n.a.
Outcomes	Peters 2008: Analysed cases: 818 of 830 cases analysed (reason for non-inclusion: not reported) Statistical methods: Cox proportional hazard regression analysis Variables controlled in analysis: age, family history of prostate cancer, BPH, income, multivitamin use Asgari 2009: Analysed cases: one case not analysed (reason for non-inclusion: not reported) Statistical methods: Cox proportional hazard regression Variables controlled in analysis: age, sex, education, family history of melanoma, personal history of non-melanoma skin cancer, mole removal, freckles, sunburns, hair colour, reaction to sunlight exposure
Notes

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Methods	Matched, nested case-control study Country: China
Participants	Participants: 9143 men Inclusion criteria: 35 years or older; tin miners employed by the Yunnan Tin Corporation; 10 or more years of underground mining / smelting; no history of cancer at baseline Recruitment: 1992 to 1997 Outcome assessment: 1997 Number of cases: Lung cancer: 108 (male/female: 108/0) Case definition: incidence Years of follow-up: ≈ 3 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: plasma was available for 108 of a total of 339 identified cases Statistical methods: logistic regression, conditional logistic regression, Wilcoxon rank sum test  Variables controlled in analysis: radon exposure, smoking Variables controlled by matching: age, year and month of sample collection
Notes

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Methods	Randomised controlled trial Sub-study of the Nutritional Prevention of Cancer Trial (NPCT 1996) Allocation: random Sequence generation: computer generated random numbers Concealment: central assignment (sealed pill bottles) Blinding: participant blinded, doctor blinded, outcome assessor/pathologist unclear, review/coding of medical records blinded Dropouts/withdrawals: two participants declined to provide additional illness information, no participant lost to vital follow -up Intention-to-treat-analysis: yes Recruitment period: 1989-1992 Treatment duration: Blinded intervention continued until the end of the blinded period; 1 February 1996. Observation period/dermatologic follow-up: 1 February 1996 Detection of cases: dermatological examination and interview every 6 months during follow-up; incident BCC and SCC were diagnosed by biopsy and confirmed by another dermatopathologist Informed consent: written informed consent forms, approval by institutional review board of participating institutions
Participants	423 male and female participants with prior non-melanoma skin cancer Country: US Number of patients: 423 (randomised to selenium group: 210, to placebo group: 213) Condition: male and female patients with history of 2 or more squamous cell or basal cell skin cancers Demographics: mean age 63.8 years (selenium)/63.8 years (placebo); 66.2% men (selenium). 68.2% men (placebo) Recruitment and setting: dermatologic clinic in Macon, Georgia
Interventions	Intervention: 400 µg selenium supplied as selenium yeast tablets p.o./daily. Control: placebo 400 µg/day of selenium yeast or identical-appearing low selenium yeast placebo Recruitment: 12 September 1989 to 3 April 1992 End of the blinded treatment period: 2 February 1996
Outcomes	Primary outcome measure: incidence of basal and squamous cell carcinoma of the skin: all analyses were based on n = 423 participants with initial blood collection within 4 days after randomizations Other reported outcomes: total internal cancer incidence
Notes	Information on study design, which was not reported in Reid 2008, was taken from the information available on the Nutritional Prevention of Cancer Trial. Adverse effects: not reported HR: adjusted for: age (continuous), smoking status (never, former, current), gender

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Methods	Matched, nested case-control study Country: Norway
Participants	Participants: 9364 men and women Inclusion criteria: 20 to 54 years of age (men), 20 to 49 years of age (women); inhabitants of Tromso; blood sample provided in 1979; no history of cancer at baseline Name of parent cohort: Tromso Heart Study II Recruitment: 1979 to 1980 Outcome assessment: 1985 Number of cases: Any cancer: 60 (male/female: 26/34) Case definition: incidence Years of follow-up: 5.0 to 7.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: 60 of 72 cases analysed (reason for non-inclusion: no sample available) Statistical methods: n.r. Variables controlled by matching: age, gender, smoking status, month of sample collection, place of residence (district of Tromso)
Notes

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Methods	Matched, nested case-control study  Country: China
Participants	Participants: 41,563 men and women Inclusion criteria: inhabitants of Haiman city of Chinese origin; written consent; toenail clipping available Recruitment: January 1993 to December 1993 Outcome assessment: 30 September 2000 Number of cases:  Primary liver cancer: 166 (male/female: 154/12) Case definition: mortality Years of follow-up: 6.8 to 7.8 years Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	Analysed cases: 166 of 455 observed cases included in analysis (only cases with questionnaire, blood sample and toenail specimen analysed after 2000 due to different methods of selenium analysis) Statistical methods: not specified Variables controlled in analysis: both genders: age, gender, HBsAg-status, alcohol intake, history of acute hepatitis, occupation men: age, HBsAg-status, alcohol intake, history of acute hepatitis, family history of HCC, occupation women: HBsAg-status, age, history of acute hepatitis Variables controlled by matching: age, gender, township of residence
Notes

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Methods	Matched, nested case-control study Country: Finland
Participants	Participants: 8113 men and women Inclusion criteria: 31 to 59 years of age; random sample of inhabitants of two Finnish provinces; initially free of cancer Name of parent cohort: North Karelia Project Recruitment: February to April 1972 Outcome assessment: 31 December 1978 Number of cases: Any cancer: 128 (male/female: n.r.) Case definition: incidence Years of follow-up: 8.5 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: logistic regression / paired-sample OR Variables controlled in analysis: tobacco consumption, serum cholesterol, beer consumption, dietary saturated fats, years of education, study area Variables controlled by matching: age, gender, smoking (tobacco use/day), total serum cholesterol
Notes

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Methods	Matched, nested case-control study Country: Finland
Participants	Participants: 12,155 men and women Inclusion criteria: 30 to 64 years of age; random sample of residents of two Finnish provinces; initially free of cancer Name of parent cohort: North Karelia Project Recruitment: January to March 1977 Outcome assessment: 31 December 1980 Number of cases: Any cancer: 51 (male/female: 30/21) Case definition: mortality Years of follow-up: 3.7 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Analysed cases: 51 out of 56 cases (reason for non-inclusion: no serum sample available) Statistical methods: logistic regression Variables controlled by matching: age, gender, smoking (tobacco use/day)
Notes

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Methods	Randomised controlled trial SELECT (Selenium and Vitamin E Cancer Prevention Trial) Allocation: random, block/stratified by clinic Sequence generation: computer-generated random numbers Concealment: central assignment (pill bottles) Blinding: participant blinded, doctor blinded, outcome assessor/pathologist blinded, review/coding of medical records blinded Dropouts/withdrawals: of 35,533 randomised participants, 645 were excluded from analysis because they had prior prostate cancer, did not give informed consent or participated at two study sites, which were excluded due to management and regulatory issues Intention-to-treat-analysis: yes Recruitment period: 22 August 2001 to 24 June 2004 End of study period: 1 August 2009 Blinded intervention was discontinued on 23 October 2008 following the recommendation of the data safety and monitoring committee after the second formal interim analysis in September 2008 Detection of cases: Participants had clinic visits once every 6 months and reported prostate cancers to the study staff. Study staff obtained medical records to verify the diagnosis. Tissue and the corresponding pathology report were sent to the central pathology laboratory for confirmation. Informed consent: yes
Participants	Countries: US, Canada, Puerto Rico Number of participants: 34,888 men, randomised to four groups: placebo (8696), vitamin E (8737), selenium (8752), selenium + vitamin E (8703) Condition: healthy men, aged 50 years or older (African American) or 55 years or older (all other), no prior diagnosis of prostate cancer, 4 ng/ml or less of PSA in serum, a digital rectal examination not suspicious for cancer, no current use of anticoagulant therapy other than 175 mg/day or less of acetylsalicylic acid or 81 mg/day or less of acetylsalicylic acid with clopidogrel bisulphate, no history of haemorrhagic stroke, normal blood pressure. Demographics: median age: 62.3-62.6 years in all four intervention groups, 79% white in all four intervention groups Recruitment and setting: 427 participating sites
Interventions	Group 1: placebo + placebo Group 2: 400 IU/day all rac-alpha-tocopheryl acetate + placebo Group 3: 200 µg/day L-selenomethionine + placebo Group 4: 400 IU/day all rac-alpha-tocopheryl acetate + 200 µg/day L-selenomethionine
Outcomes	Primary outcome: incidence of prostate cancer as determined by routine clinical management Secondary outcomes: incidence of any cancer / lung cancer / colorectal cancer, diabetes mellitus, cardiovascular events, death from any cause
Notes	Adverse effects: alopecia RR 1.28, (99% CI 1.01 to 1.62) dermatitis grade 1-2 RR 1.17, (99% CI 1.00 to 1.35) dermatitis grade 3-4 RR 1.74, (99% CI 0.56 to 5.44) halitosis RR 1.17, (99% CI 0.99 to 1.38) nail changes RR 1.04, (99% CI 0.94 to 1.16) fatigue grade 1-2 RR 1.09, (99% CI 0.95 to 1.26) fatigue grade 3-4 RR 0.87, (99% CI 0.40 to 1.88) nausea grade 1-2 RR 1.19, (99% CI 0.94 to 1.52) nausea grade 3 RR 0.99, (99% CI 0.30 to 3.34)

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Methods	Cohort Study Country: US
Participants	Participants: 133,614 women Inclusion criteria: post-menopausal participants (aged 50 to 79 years) of the WHI clinical trial and observational study Name of parent cohort: Women's Health Initiative (WHI) Recruitment: n.r. Outcome assessment: December 2004 Number of cases: ovarian cancer: 451 (0/451) Case definition: incidence Years of follow-up: mean: 7 years Type of selenium marker: supplemental selenium intake (food frequency questionnaire)
Interventions	d.n.a.
Outcomes	Statistical methods: Cox logistic regression Variables controlled in analysis: participation in observational or intervention study, age, log calories, number of relatives with breast/ovarian cancer, dietary modification randomisation arm, hysterectomy, minority race, pack-years of smoking, physical activity, NSAID use, parity, infertility, duration of oral contraceptive use, number of lifetime ovulatory cycles, partial oophorectomy, age at menopause, hormone therapy at study entry
Notes

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Methods	Matched, nested case-control study Country: the Netherlands
Participants	Participants: 8760 women Inclusion criteria: 42 to 52 years of age; pre-menopausal; inhabitants of Utrecht Name of parent cohort: DOM (Diagnostic onderzoek mammacarcinoom) Study Recruitment: n.r. Outcome assessment: 1 February 1986 Number of cases: Breast cancer (pre-menopausal): 27 (male/female: 0/27) Case definition: incidence Years of follow-up: 0.6 to 3.5 years, mean: 2.1 years Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	Analysed cases: 7 cases were detected in the initial mammography screening in this study and not included in the analysis of incident cases Statistical methods: n.r. Variables controlled by matching: age, date of birth, pre-menopausal status
Notes

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Methods	Cohort/sub-cohort-controlled cohort study Country: the Netherlands
Participants	Name of parent cohort: Netherlands Cohort Study (NLCS) Recruitment: 1986 van den Brandt 1993b: Participants: 120,852: 58,279 men and 62,573 women; aged 55 to 69 years; returned baseline questionnaire; no history of cancer at baseline Outcome assessment: n.r. Number of cases: Stomach cancer: 104 (male/female: 84/20) Colon cancer: 234 (male/female: 121/113) Rectal cancer: 113 (male/female: 77/36) van den Brandt 1993a: Participants: 120,852: 58,279 men and 62,573 women; age 55 to 69 years; returned baseline questionnaire; no history of cancer at baseline Outcome assessment: n.r. Number of cases: Lung cancer: 370 (male/female: 335/35) van den Brandt 1994: Participants: 62,573 post-menopausal women Outcome assessment: 1989 Number of cases: Breast cancer (post-menopausal): 355 (male/female: 0/355) Breast cancer (post-menopausal), multivariate analysis: 270 (male/female: 0/270) Zeegers 2002: Participants: 120,852: 58,279 men and 62,573 women Outcome assessment: December 1992 Number of cases: Bladder cancer: 431 (male/female: 372/59) van den Brandt 2003: Participants: 58,279 men Outcome assessment: n.r. (probably December 1992) Number of cases: Prostate cancer: 540 (male/female: 540/0) Case definition: incidence Years of follow-up: 3.3 years (Brandt 1993a; Brandt 1993b; Brandt 1994), 6.3 years (Zeegers 2002; Brandt 2003) Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	van den Brandt 1993b: Analysed cases: 234 of 351 colon cancer cases / 104 of 176 stomach cancer cases / 113 of 185 rectal cancer cases analysed (reasons for non-inclusion: history of cancer at baseline not available, no pathological confirmation or CIS, no toenail clipping available) Statistical methods: Mantel-Haenszel Variables controlled in analysis: age, gender van den Brandt 1993a: Analysed cases: 370 of 617 cases analysed (reasons for non-inclusion: history of cancer at baseline not available, no toenail clipping, no pathological confirmation, problems with selenium measurement) Statistical methods: Statistical methods: Mantel-Haenszel Variables controlled in analysis: age, gender van den Brandt 1994: Analysed cases: 355 of 553 cases analysed (reasons for non-inclusion: history of cancer at baseline not available, CIS, no toenail sample or problems with selenium detection) Statistical methods: multivariate case-cohort analysis Variables controlled in analysis: age, history of benign breast disease, maternal breast cancer, breast cancer in sister(s), age at menarche, age at menopause, oral contraceptive use, parity, age at first birth, body mass index, education, current cigarette smoking, alcohol intake, energy intake Zeegers 2002: Analysed cases: 431 of 619 cases analysed (reason for non-inclusion: no toenails available) Statistical methods: exponentially distributed failure time regression models Variables controlled in analysis: age, gender, number of cigarettes/day, years of cigarette smoking van den Brandt 2003: Analysed cases: 540 of 704 cases analysed (reason for non-inclusion: no toenail samples or selenium detection not possible) Statistical methods: exponentially distributed failure time regression models Variables controlled in analysis: age, family history of prostate cancer, number of cigarettes/day, years of cigarette smoking, level of education
Notes	Primary publication: van den Brandt 1993b Other publications: Zeegers 2002, van den Brandt 1993a, van den Brandt 1994, van den Brandt 2003

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Methods	Cohort/sub-cohort-controlled cohort study Country: Finland
Participants	Participants: 1110 men Inclusion criteria: 55 to 74 years of age; inhabitants of Finnish rural areas; participants of prior study on CHD; serum sample available: cases within first year of follow-up excluded Name of parent cohort: Men in rural East and West Finland Recruitment: 1974 Outcome assessment: 31 December 1983 Number of cases: Any cancer: 109 (male/female: 109/0) Case definition: incidence Years of follow-up: 10.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: conditional logistic regression Variables controlled in analysis: age, area of residence, smoking, serum cholesterol, alcohol intake
Notes

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Methods	Frequency-matched cohort controlled study Country: China
Participants	Participants: Mark 2000: 29,584 men and women; Wei 2004: 1103 people who were originally selected as disease-free controls in Mark 2000 Inclusion criteria: 40 to 69 years of age; healthy inhabitants of 4 Linxian communities; participants of a randomised controlled trial Name of parent cohort: General Population Trial Linxian Recruitment: 1985 Outcome assessment: May 1991 (Mark 2000); n.r. (Wei 2004) Number of cases: Wei 2004: oesophageal cancer: 75 (male/female: 49/26) mortality stomach, cardia cancer: 36 (male/female: 22/14) mortality stomach, non-cardia cancer: 24 (male/female: 20/4) mortality other: 32 (male/female: 22/10) mortality Mark 2000: oesophageal cancer: 590 (male/female: 286/304) incidence oesophageal cancer: 332 (male/female: n.r.) mortality stomach, cardia cancer: 402 (male/female: 239/163) incidence stomach, cardia cancer: 232 (male/female: n.r.) mortality stomach, non-cardia cancer: 87 (male/female: 66/21) incidence stomach, non-cardia cancer: 68 (male/female: n.r.) mortality  Case definition: mortality, incidence Years of follow-up: unclear/approximately 9 years (Wei 2004), 6 years (Mark 2000) Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: cox-proportional hazard model Variables controlled in analysis: Wei 2004: age, cholesterol, smoking, alcohol intake, BMI; Mark 2000: age Variables controlled by matching: age category, gender
Notes	Primary publication: Wei 2004 Other publication: Mark 2000 Remark: Wei 2004 measured serum selenium in a sub-cohort derived from 29,584 male and female participants of the Linxian Population Trial. The earlier publication of this study, Mark 2000 reported 332 fatal cases and 590 incident cases. The later publication, Wei 2004 reported deaths from oesophageal cancer in the disease-free controls of Mark 2000 and analysed 75 fatal cases.

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 10,940 men and women Inclusion criteria: 30 to 69 years of age; serum sample available (only 4480 samples of cohort were available because of freezer breakdown); participants of an RCT on hypertension; institutionalised and bedfast people were excluded Name of parent cohort: Hypertension Detection Follow-Up Programme (HDFP) Recruitment: 1973 to 1974 Outcome assessment: n.r. Number of cases: Any cancer: 111 (male/female: 60/51)  Case definition: incidence Years of follow-up: 5.0 years Type of selenium marker: serum
Interventions	d.n.a.
Outcomes	Statistical methods: logistic regression of unmatched data Variables controlled by matching: age, gender, race/ethnicity, smoking status, year/month of sample collection, initial blood pressure, use of antihypertensive medication, randomisation group in women: parity, menopausal status
Notes

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Methods	Matched, nested case-control study Country: US
Participants	Participants: 33,737 men Inclusion criteria: 40 to 75 years of age; physicians from all 50 U.S. states; provision of toenails in 1987 and completed baseline questionnaire in 1986; exclusion of histologically confirmed prostate cancer at baseline and cases within first 2 years of follow-up Name of parent cohort: Health Professionals Follow-Up Study (HPFS) Recruitment: 1986 to 1987 Outcome assessment: 1994 Number of cases: Prostate cancer: 181 (male/female: 181/0) Case definition: incidence Years of follow-up: 8.0 to 9.0 years Type of selenium marker: toenail
Interventions	d.n.a.
Outcomes	Statistical methods: logistic regression, conditional logistic regression Variables controlled in analysis: quintiles of lycopene, saturated fat, calcium, family history of prostate cancer, BMI, vasectomy Variables controlled by matching: age, smoking status, year/month of sample collection
Notes

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---

Methods	Randomised controlled trial Allocation: random Sequence generation: unclear, not described Concealment: unclear, not described Blinding: described as double-blind; blinding of participants: adequate, placebo tablets; blinding of investigators and doctors: unclear Dropouts/withdrawals: unclear, not described Intention-to-treat-analysis: unclear, not described Recruitment period: unclear, not described Observation period: 2 years Study period: 2 years Detection of cases: unclear, use of "national standards" for the diagnosis of liver cancer Informed consent: unclear, not described
Participants	Country: China Number of participants: 2,474 Condition: first-degree relatives within three generations of families with 2 or more cases of liver cancer during the period 1972 to 1985 Demographics: gender distribution not reported; age: 15 to 75 years Recruitment and setting: participants were residents in Qidong province
Interventions	Intervention: 200 µg selenium as selenised yeast p.o. daily, intervention period unclear Control: placebo
Outcomes	Primary outcome measure: incidence of primary liver cancer within 2 years after start of intervention Results: 13 cases in 1030 placebo subjects 10 cases in 1444 selenium subjects
Notes	Data were extracted from Yu 1991. We identified two later publications (Li 2002, Yu 1993), which we assumed to report on the same trial as Yu 1991. However, total number of participants differed from the initial report (N = 3849 in the later publications with 1485 receiving placebo and 2364 receiving selenium). The total number of cases was not reported in either Li 1992 or Yu 1993. The reported results were: Li 1992: person-year incidence rate in intervention and control group: within one year of follow-up: selenium group 175.36/100,000; placebo group: 414.65/100,000 within two years of follow-up: selenium group 219.37/100,000; placebo group: 553.15/100,000 Yu 1993: cumulated incidence: after one year: selenium group 1.75/1000; placebo group: 4.15/1000 after two years: selenium group 2.19/1000; placebo group: 5.53/1000 We could not make contact with the study investigators to clarify these discrepancies. As we could not clarify the actual number of liver cancer cases in the later publications, we decided to use the data of Yu 1991 for this review. Adverse effects were not mentioned in Yu 1991 or Li 1992. Yu 1993 stated that no cases of selenosis were observed in the trial.

---

---

Methods	Randomised controlled trial Allocation: random Sequence generation: unclear, not described Concealment: unclear, not described Blinding: of participants: adequate (placebo), of investigators and doctors: unclear, not described Dropouts/withdrawals: unclear, not described Recruitment period: unclear, not described Intention-to-treat-analysis: unclear, not described Observation period: 1987 to 1994 Intervention period: 1987 to 1990 Detection of cases: unclear, monthly blood sample during follow-up for liver enzymes (SGPT, ZnTT), use of "national standards" for the diagnosis of liver cancer Informed consent: unclear, not described
Participants	Country: China Number of participants: 226 (selenium group: 113; placebo group 113) Condition: HBs-antigen carriers with normal liver function Demographics: 95 men, 131 women; age: 21 to 63 years Recruitment and setting: recruitment “through screening in a village in the city Qidong” (Li 1992)
Interventions	Intervention: 200 µg selenium as selenised yeast p.o. daily for 4 years Control: placebo
Outcomes	Primary outcome measure: incidence of primary liver cancer (defined as increase of SGPT and ZnTT) Results: at the end of the intervention period: 0 cases in the selenium group; 7 cases in the placebo group in a total of 445 person years of observation (person-time incidence rate: 1,573.03/100,000)
Notes	Adverse effects: "No side effects have been found in these trials." (Yu 1997, p124) further data reported in: Li 1992 (Chinese, translated); Yu 1991 In Yu 1991 a different incidence in the selenium group was reported (5 cases). We could not clarify this discrepancy to the later papers Li 1992 and Yu 1997.

---

---

Methods	Matched, nested case-control study Country: China (Taiwan)
Participants	Participants: 4841 men Inclusion criteria: 30 to 65 years of age; HBsAg-positive or/and HCV-positive; recruited at two centres: Government Employee Central Clinics or Liver Unit of Chang-Gung Memorial Hospital Recruitment: August 1988 to June 1992 Outcome assessment: 31 December 1996 Number of cases: Primary liver cancer: 69 (male/female: 69/0) Case definition: incidence Years of follow-up: 4.5 to 8.3 years Type of selenium marker: plasma
Interventions	d.n.a.
Outcomes	Analysed cases: 69 of 73 cases analysed (reason for non-inclusion: no sample available) Statistical methods: conditional logistic regression Variables controlled in analysis: age, cigarette smoking, alcohol intake, plasma levels of retinol/alpha-tocopherol/alpha-carotene/beta-carotene/lycopene Variables controlled by matching: age, year and season of sample collection, recruitment clinic
Notes

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Bostick 1993	Cohort study: Iowa Women's Health Study Cohort. Selenium exposure not assessed according to eligibility: only intake of selenium supplements yes/no in questionnaire assessed
Brock 1991	Case-control study with pre-cancerous condition (carcinoma in situ of the cervix)
Chen 1988	Case-control study
Chen 2003	Case-control study
Connelly-Frost 2009	Case-control study
Costello 2001	APPOSE (Australian Prostate Cancer Prevention Trial Using Selenium): publication describes study design, trial was not started
Criqui 1991	Population-based prospective case-control study: Lipid Research Clinic Prevalence and Follow-Up Study Results not reported according to inclusion criteria: differences in mean selenium levels were reported
Cui 2007	Nested case-control study Selenium exposure not assessed according to eligibility: selenium measurement was conducted in tissue of benign breast diseases
Davies 2002	Nested case-control study: EPIC Norfolk Study Cohort Results not reported according to inclusion criteria: RR estimate per unit increase in selenium level reported
Fleshner 2003	Randomised Study of Vitamin E, Selenium, and Soy Protein Isolate in Patients with High-Grade Prostatic Intraepithelial Neoplasia: Multicomponent intervention
Hagmar 1992	Historical cohort study
Hartman 2002	Nested case-control study: ATBC Cohort Results not reported according to inclusion criteria: differences in mean selenium levels reported; OR reported as graph and could not be calculated from reported data
Huzarski 2006	Interventional study without control group with 1489 female participants with BRCA1 mutation who received a selenium-containing nutritional supplement
Joniau 2007	Intervention study without control group with male participants with high-grade intraepithelial neoplasia of the prostate who received a selenium-containing nutritional supplement
Kellen 2008	Case-control study
Kilander 2001	Cohort study in Uppsala/Sweden Results not reported according to inclusion criteria: RR estimate per unit increase in selenium level reported
Knekt 1988a	Nested case-control study: Mobile Health Clinic Cohort Results not reported according to inclusion criteria: differences in mean selenium levels reported
Knekt 1988c	Nested case-control study: Mobile Health Clinic Cohort Results not reported according to inclusion criteria: differences in mean selenium levels reported
Knekt 1991b	Nested case-control study: Mobile Health Clinic Cohort Results not reported according to inclusion criteria: differences in mean selenium levels reported
Kok 1987c	Nested case-control study: Zoetermeer Cohort Results not reported according to inclusion criteria: differences in mean selenium levels reported
Kune 2006	Case-control study
Kuroda 1988	Case-control study
Lawson 2007	Cohort study on multivitamin use and risk of prostate cancer
Le Marchand 2006	Case-control study
Li 2004b	RCT for gastric cancer prevention with multi component intervention (200 mg synthetic allitridum and 100 μg selenium per day)
Limburg 2005	Randomised controlled trial: primary endpoint in this 2 by 2 factorial design trial with selenomethionine 200 µg daily and/or celecoxib 200 mg twice daily was the per-subject change (regression, stable, progression) of pre-existing oesophageal dysplasia - cancer incidence or mortality were not endpoints in this study
Linxian Pilot 2000	Randomised controlled trial with selenium supplements and celecoxib in participants with oesophageal squamous dysplasia in Linxian, China Endpoint was "regression of disease", cancer was not an endpoint in this investigation
Neuhouser 2009	Cohort study (Women's Health Initiative) on multivitamin use and risk of cancer and cardiovascular disease. No data for selenium and cancer risk reported.
Ray 2006	Cohort study (Women's Health and Aging Studies I and II) on selenium and carotenoid serum levels and mortality. No data for selenium and cancer mortality reported
Rayman 2001	PRECISE trial (Prevention of Cancer by Intervention with Selenium): trial has been stopped
Rendon	Randomised controlled trial: Vitamin E, Selenium, and Soy Protein in Preventing Cancer in Patients with High-Grade Prostate Neoplasia. Multicomponent intervention
Thompson 2009	Cohort study: Iowa Women's Health Study Cohort. Selenium exposure not assessed according to eligibility: only intake of selenium supplements yes/no in questionnaire assessed
Tsugane 1996	Case-control and cross-sectional studies
Ujiie 2002	A part of this study is a prospective cohort study in Miyagi/Japan Results not reported according to inclusion criteria: differences in mean selenium levels reported
van Noord 1992	Nested case-control study: DOM Cohort Results not reported according to inclusion criteria: differences in mean selenium levels reported
van Noord 1993	Nested case-control study: DOM II Cohort Results not reported according to inclusion criteria: RR estimate per unit increase of selenium level reported
van't Veer 1996	Case-control study
Wallace 2009	Case-control study
Watters 2009	Cohort study on smoking and prostate cancer risk. Selenium not reported as independent variable.
Wright 2004	Cohort study: ATBC Cohort Exposure to antioxidants was assessed using a self-developed index
You 2005	Randomised controlled trial to test retardation of the progression of pre-cancerous gastric lesions among 3400 adults in Shandong, China. Intervention: vitamin C, vitamin E, selenium, garlic preparation. Multicomponent intervention.
Yuan 2006	Nested case-control study: Shanghai Cohort Study No data on selenium and cancer risk reported
Zeegers 2009	Cohort study on factors influencing recurrence or progression of bladder cancer: West Midlands Bladder Cancer Prognosis Programme

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Characteristics of studies awaiting assessment [ordered by study ID]

 

Characteristics of ongoing studies [ordered by study ID]

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Trial name or title	Cancer Sero Epidemiology Among the Japanese in Hawaii
Methods	This is a sero-epidemiologic prospective study to identify biochemical markers related to common cancers. Among the aims are: (a) to see if low serum selenium levels increase prostate cancer risk (b) to determine whether low serum selenium levels increase urinary bladder cancer risk in men
Participants	9,345 male American Japanese subjects, examined in Hawaii
Interventions	d.n.a.
Outcomes	risk of prostate and urinary bladder cancer
Starting date	Project Start: 15 September 1983, Project End planned for: 30 June 2004
Contact information	Abraham M. Nomura Kuakini Medical Center 347 N Kuakini St Honolulu, HI 96817
Notes

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---

Trial name or title	Selenium supplementation for the prevention of hepatocellular carcinomas in HBsAg positive patients (pilot study)
Methods	Randomised controlled trial
Participants	Men aged 45 to 64 years with positive HBsAg test, negative AFP test and normal ALT values
Interventions	Placebo or 200 mg (sic!)/day selenium as selenised yeast
Outcomes	Primary liver cancer
Starting date	2003
Contact information	Prof Kar Keung Cheng, University of Birmingham, UK
Notes	Author contacted for further information, but no reply received. Should probably say 200 µg/day selenium yeast as intervention in the publication.

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Trial name or title
Methods	Double-blinded, placebo-controlled, 2 by 2 factorial, randomised controlled trial (SELENIB), nested within a prospective observational cohort study (Bladder Cancer Prognosis Programme BCPP)
Participants	1200 participants of the Bladder Cancer Prognosis Programme in the United Kingdom Inclusion criteria: Histopathologically confirmed non-muscle invasive transitional cell carcinoma. Solitary grade 1 pTa larger than 3 cm and all other stage pTa, pT1 or pTcis Exclusion criteria: 1. Disease characteristics - solitary grade 1 pTa < 3 cm or stage pT2 and above 2. Patients that are pregnant or breastfeeding 3. Patients diagnosed with human immunodeficiency virus (HIV) infection 4. Patients who are on immunosuppressive therapy following organ transplantation 5. Patients taking cyclosporin 6. Any condition, which, in the opinion of the local investigator, might interfere with the safety of the patient or evaluation of the trial objectives
Interventions	Four study arms: 1) selenium 2) alpha-tocopherol 3) selenium and alpha-tocopherol 4) placebo
Outcomes	Primary outcomes: recurrence-free survival, progression-free survival SELENIB trial - secondary outcomes 1. All cause mortality 2. Incidence of transitional cell carcinoma (TCC) outside the bladder 3. Incidence of all other malignancies clinically diagnosed 4. Incidence of cardiovascular events: myocardial infarction,. stroke, death from cardiovascular causes, 5. Quality of life - as assessed by the quality of life instruments: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-BLS24 and QLQ-BLM30
Starting date
Contact information
Notes	Ongoing trial Contact details: Prof K. K. Cheng The Public Health Building University of Birmingham Edgbaston Birmingham United Kingdom B15 2TT http://www.bcpp.bham.ac.uk

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Trial name or title	Phase III Randomised Chemoprevention Study of Selenium in Participants With Previously Resected Stage I Non-Small Cell Lung Cancer
Methods	Randomised controlled trial
Participants	Disease Characteristics: Histologically confirmed, completely resected stage IA (pT1, N0) or IB (pT2, N0) non-small lung cancer (except carcinoid) Completion of treatment for stage I lung cancer within the past 6 to 36 months and currently disease free At least one mediastinal lymph node sampled at resection Age: 18 years and over Performance status: ECOG 0-1 A total of 1,960 participants (980 per arm) will be accrued for this study within 4 years.
Interventions	Arm I: Participants receive oral selenium yeast daily for 6 months. Treatment repeats every 6 months for 8 courses for a total of 4 years in the absence of unacceptable toxicity Arm II: Participants receive an oral yeast placebo as in arm I Participants are followed annually
Outcomes	Second incidence/recurrence of primary lung tumours Toxicity Incidence of specific cancers, mortality from cancer, and overall survival
Starting date	October 2000
Contact information	Eastern Cooperative Oncology Group Daniel Karp, MD, Protocol chair Phone: [phone] Southwest Oncology Group Omer Kucuk, MD, Protocol chair Phone: [phone] Email: [e-mail]
Notes	Recruiting

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Trial name or title	L-selenium-based chemoprevention of prostate cancer among men with high-grade prostatic intraepithelial neoplasia (HGPIN)
Methods	Randomised controlled trial
Participants	Country: US 465 men, age 40 years and over with diagnosis of HGPIN with no evidence of cancer
Interventions	Placebo or 200 µg/day selenium
Outcomes	Incidence of prostate cancer
Starting date	February 2000
Contact information	James R. Marshall, Roswell Park Cancer Institute, Buffalo, New York, US
Notes	No longer recruiting

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Trial name or title	Negative Biopsy Trial (NBT)
Methods	The study is a Phase III cancer chemoprevention study among men at high risk of prostate cancer because of a persistent elevation in PSA above 4 ng/ml and a negative initial biopsy.
Participants	The trial will randomise at least 700 patients with persistently elevated PSA levels (greater 4 ng/ml) and at least one negative biopsy for prostate cancer. The principal purpose of this trial is to assess the potential for treatment with the essential trace element selenium (Se) to prevent prostate cancer (PCa).
Interventions	The trial will randomise patients to either placebo or one of two selenium dosages, 200 µg/day or 400 µg/day.
Outcomes	The primary endpoints for the trial are the incidence of PCa and the velocity of the primary serum marker of prostate cancer progression, prostate specific antigen (PSA). Safety endpoints for the trial include onset of mild symptoms of selenium toxicity as well as significant changes in liver and kidney enzyme levels.
Starting date	30 September 1999
Contact information	M. Suzanne Stratton, Ph.D. Research Assistant Professor Arizona Cancer Center Prostate Cancer Prevention Program 2504 E Elm Street. Tucson, AZ 85716 http://www.selenium.arizona.edu
Notes

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Comparison 1. Highest versus lowest selenium exposure

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Breast cancer risk (women)

7

Odds Ratio (Random, 95% CI)

1.00 [0.77, 1.29]

---

1.1 Breast cancer (all)

6

Odds Ratio (Random, 95% CI)

1.01 [0.74, 1.36]

---

1.2 Breast cancer (premenopausal)

1

Odds Ratio (Random, 95% CI)

1.10 [0.46, 2.65]

---

 2 Bladder cancer risk

5

Odds Ratio (Random, 95% CI)

0.67 [0.46, 0.97]

---

2.1 all (male + female)

2

Odds Ratio (Random, 95% CI)

0.65 [0.46, 0.92]

---

2.2 male

3

Odds Ratio (Random, 95% CI)

0.82 [0.41, 1.62]

---

2.3 female

1

Odds Ratio (Random, 95% CI)

0.36 [0.14, 0.92]

---

 3 Lung cancer risk (gender-aggregated data)

11

Odds Ratio (Random, 95% CI)

0.76 [0.57, 1.03]

---

3.1 incidence

10

Odds Ratio (Random, 95% CI)

0.75 [0.54, 1.03]

---

3.2 mortality

1

Odds Ratio (Random, 95% CI)

0.98 [0.41, 2.35]

---

 4 Lung cancer risk (gender-disaggregated data)

11

Odds Ratio (Random, 95% CI)

0.77 [0.60, 0.98]

---

4.1 all (female + male)

4

Odds Ratio (Random, 95% CI)

0.58 [0.39, 0.86]

---

4.2 female

4

Odds Ratio (Random, 95% CI)

0.83 [0.43, 1.61]

---

4.3 male

6

Odds Ratio (Random, 95% CI)

0.88 [0.61, 1.28]

---

 5 Lung cancer risk (ascending order of selenium levels)

7

1756

Odds Ratio (Random, 95% CI)

0.90 [0.69, 1.16]

---

 6 Lung cancer risk

11

Odds Ratio (Random, 95% CI)

0.76 [0.57, 1.03]

---

6.1 intake

1

Odds Ratio (Random, 95% CI)

0.98 [0.41, 2.35]

---

6.2 serum or plasma

8

Odds Ratio (Random, 95% CI)

0.84 [0.66, 1.06]

---

6.3 toenail

2

Odds Ratio (Random, 95% CI)

1.05 [0.11, 10.36]

---

 7 Prostate cancer risk

14

Odds Ratio (Random, 95% CI)

0.78 [0.66, 0.92]

---

 8 Prostate cancer risk (by selenium measurement)

14

Odds Ratio (Random, 95% CI)

0.78 [0.66, 0.92]

---

8.1 biochemical selenium level

12

Odds Ratio (Random, 95% CI)

0.74 [0.61, 0.88]

---

8.2 estimated selenium intake

2

Odds Ratio (Random, 95% CI)

1.00 [0.73, 1.36]

---

 9 Prostate cancer risk (by exposure assessment)

14

Odds Ratio (Random, 95% CI)

0.78 [0.66, 0.92]

---

9.1 intake

2

Odds Ratio (Random, 95% CI)

1.00 [0.73, 1.36]

---

9.2 serum or plasma

9

Odds Ratio (Random, 95% CI)

0.81 [0.68, 0.97]

---

9.3 toenail

3

Odds Ratio (Random, 95% CI)

0.53 [0.35, 0.81]

---

 10 Prostate cancer risk (by continent)

14

Odds Ratio (Random, 95% CI)

0.78 [0.66, 0.92]

---

10.1 Europe

4

Odds Ratio (Random, 95% CI)

0.91 [0.70, 1.17]

---

10.2 North America

10

Odds Ratio (Random, 95% CI)

0.71 [0.58, 0.88]

---

 11 Prostate cancer risk (by country)

14

Odds Ratio (Random, 95% CI)

0.78 [0.66, 0.92]

---

11.1 Several European countries

1

Odds Ratio (Random, 95% CI)

0.96 [0.70, 1.31]

---

11.2 Finland

2

Odds Ratio (Random, 95% CI)

1.24 [0.75, 2.05]

---

11.3 The Netherlands

1

Odds Ratio (Random, 95% CI)

0.69 [0.48, 0.99]

---

11.4 U.S.A.

10

Odds Ratio (Random, 95% CI)

0.71 [0.58, 0.88]

---

 12 Prostate cancer risk (ascending order of selenium levels)

9

2112

Odds Ratio (Random, 95% CI)

0.81 [0.68, 0.97]

---

 13 Stomach cancer risk

5

Odds Ratio (Random, 95% CI)

0.66 [0.43, 1.01]

---

13.1 stomach

4

Odds Ratio (Random, 95% CI)

0.65 [0.35, 1.19]

---

13.2 stomach: cardia cancer

1

Odds Ratio (Random, 95% CI)

0.47 [0.33, 0.66]

---

13.3 stomach: non-cardia cancer

1

Odds Ratio (Random, 95% CI)

1.07 [0.55, 2.08]

---

 14 Stomach cancer risk (by gender)

5

Odds Ratio (Random, 95% CI)

0.66 [0.42, 1.04]

---

14.1 all (female + male)

2

Odds Ratio (Random, 95% CI)

0.75 [0.41, 1.36]

---

14.2 female

2

Odds Ratio (Random, 95% CI)

0.73 [0.12, 4.35]

---

14.3 male

3

Odds Ratio (Random, 95% CI)

0.43 [0.14, 1.32]

---

 15 Colorectal cancer risk

5

Odds Ratio (Random, 95% CI)

0.89 [0.65, 1.23]

---

15.1 colon and rectal cancer

2

Odds Ratio (Random, 95% CI)

1.11 [0.50, 2.46]

---

15.2 colon cancer

3

Odds Ratio (Random, 95% CI)

0.80 [0.56, 1.15]

---

 16 Colorectal cancer risk (by gender)

5

Odds Ratio (Random, 95% CI)

0.89 [0.65, 1.23]

---

16.1 all (female + male)

1

Odds Ratio (Random, 95% CI)

1.22 [0.52, 2.86]

---

16.2 female

3

Odds Ratio (Random, 95% CI)

1.06 [0.57, 2.00]

---

16.3 male

3

Odds Ratio (Random, 95% CI)

0.69 [0.42, 1.12]

---

 17 Total cancer incidence and mortality

13

Odds Ratio (Random, 95% CI)

Subtotals only

---

17.1 incidence

8

Odds Ratio (Random, 95% CI)

0.69 [0.53, 0.91]

---

17.2 mortality

5

Odds Ratio (Random, 95% CI)

0.55 [0.36, 0.83]

---

 18 Total cancer incidence and mortality (ascending order of selenium levels)

11

Odds Ratio (Random, 95% CI)

Subtotals only

---

18.1 incidence

6

1297

Odds Ratio (Random, 95% CI)

0.69 [0.52, 0.91]

---

18.2 mortality

5

1032

Odds Ratio (Random, 95% CI)

0.55 [0.36, 0.83]

---

 19 Total cancer incidence and mortality (women)

5

Odds Ratio (Random, 95% CI)

Subtotals only

---

19.1 incidence

2

Odds Ratio (Random, 95% CI)

0.90 [0.45, 1.77]

---

19.2 mortality

3

Odds Ratio (Random, 95% CI)

0.92 [0.79, 1.07]

---

 20 Total cancer incidence and mortality (men)

8

Odds Ratio (Random, 95% CI)

Subtotals only

---

20.1 incidence

5

Odds Ratio (Random, 95% CI)

0.66 [0.42, 1.05]

---

20.2 mortality

3

Odds Ratio (Random, 95% CI)

0.56 [0.38, 0.81]

---

 

Table 1. Included observational studies by outcome

---

Organ System	Outcome	Number of studies/case definition	Meta- analysis	Countries	Number of participants	Number of cases	Selenium assessment	Reporting study
Any cancer	Any cancer	Total: 15 incidence: 8 mortality: 6 incidence & mortality combined: 1	✓ yes	US Finland Netherlands Sweden Norway Belgium France	total: ˜ 151,000	total: 3220 male: 1700 female: 736	serum: 11 plasma: 2 serum + plasma: 1 plasma selenium P: 1	Knekt 1990 Coates 1988 Kok 1987 Salonen 1984 Nomura 1987 Virtamo 1987 Willett 1983 Fex 1987 Ringstad 1988 Persson 2000 Salonen 1985 Peleg 1985 Kornitzer 2004 Akbaraly 2005 Bleys 2008
Gynecological cancer	Female breast cancer	Total: 7 incidence: 7 mortality: 0 incidence & mortality combined: 0	✓ yes	US Finland Netherlands Channel Islands	total / female: > 155,000 (one study did not report cohort size)	total / female: 992	serum: 2 plasma: 1 serum + plasma: 1 toenail: 3	Dorgan 1998 vd Brandt 1993 Coates 1988 Overvad 1991 Knekt 1990 Garland 1995 van Noord 1987
	Cervical cancer	Total: 2 incidence: 2 mortality: 0 incidence & mortality combined: 0	✗no	US	total / female: > 15,161 (one study did not report cohort size)	total / female: 62	serum: 2	Menkes 1986 Coates 1988
	Uterine cancer	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	US	total / female: 62,641	total / female: 91	toenail: 1	Garland 1995
	Ovarian cancer	Total: 4 incidence: 4 mortality: 0 incidence & mortality combined: 0	✗no	US Finland	total / female: ˜ 214,000	total / female: 568	serum: 2 toenail: 1 supplemental intake: 1	Knekt 1990 Garland 1995 Menkes 1986 Thomson 2008
	Gynecological cancer (without breast cancer)	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	Finland	total / female: ˜ 18,000	total / female: 86	serum: 1	Knekt 1990
Urological cancers	Urinary bladder cancer	Total: 5 incidence: 5 mortality: 0 incidence & mortality combined: 0	✓ yes	US/Hawaii Finland Netherlands	total: 279,100 female: 130,786 male: 128,009	total 965 female: 175 male 755	serum: 2 toenail: 3	Menkes 1986 Nomura 1987 Michaud 2002 vd Brandt 1993 Michaud 2005
	Urinary tract cancer	Total: 2 incidence: 2 mortality: 0 incidence & mortality combined: 0	✗no	Netherlands Finland	total: 48,000	total: 104 male: 91 female: 13	serum: 1 plasma: 1	Knekt 1990 Persson 2000
Respiratory tract cancers	Lung cancer	Total: 13 incidence: 12 mortality: 1 incidence & mortality combined: 0	✓ yes	China Japan US Finland Netherlands	total: ˜ 333,000 male: 125,341 female: 181,895	total: 1835 male: 1256 female: 333	serum: 8 serum + plasma: 2 toenail: 2 dietary intake: 1 (one study reported both serum levels and food intake)	Knekt 1990 Knekt 1998 Garland 1995 Coates 1988 Nomura 1987 vd Brandt 1993 Kabuto 1994 Menkes 1986 Goodman 2001 Comstock 1997 Kromhout 1987 Ratnasinghe 2000 Epplein 2009
	Oral / pharyngeal cancer	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	US	total: 25,804	total: 28	serum: 1	Menkes 1986
	Any cancer of the respiratory tract	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	Sweden	total / male: ˜ 9500	total / male: 69	Plasma selenium P: 1	Persson 2000
Andrological cancers	Prostate cancer	Total: 14 incidence: 14 mortality: 0 incidence & mortality combined: 0	✓ yes	US Europe	total / male: > 416,500 (one study did not report cohort size)	total / male: 5249	serum: 6 plasma: 3 toenail: 3 dietary intake: 2	Hartman 1998Helzlsouer 2000 Coates 1988 Brooks 2001 vd Brandt 1993 Nomura 2000 Goodman 2001 Yoshizawa 1998 Li 2004a Peters 2007 Peters 2008 Allen 2008 Epplein 2009
Gastrointestinal cancers	Oesophageal cancer	Total: 2 incidence: 2 mortality: 1 incidence & mortality combined: 0	✗no	China US	total: 29,923	total: > 959	serum: 1 supplemental intake: 1	Wei 2004 Dong 2008
	Oesophageal / stomach cancer	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	Netherlands	total: 36,265	total: 86 male: 51 female: 35	serum: 1	Knekt 1998
	Stomach cancer	Total: 5 incidence: 5 mortality: 1 incidence & mortality combined: 0	✓ yes	China Japan US/Hawaii Finland Netherlands	total: ˜ 197,000 male: 86,311 female: 80,669	total: 955 male: 626 female: 329	serum: 4 toenail: 1	Knekt 1990 vd Brandt 1993 Nomura 1987 Kabuto 1994 Wei 2004
	Primary liver cancer	Total: 2 incidence: 1 mortality: 1 incidence & mortality combined: 0	✗no	Taiwan	total: 46,404	total: 235 male: 223 female: 12	plasma: 1 toenail: 1	Yu 1999 Sakoda 2005
	Pancreatic cancer	Total: 2 incidence: 2 mortality: 0 incidence & mortality combined: 0	✗no	US Finland	total: 65,072	total: 67 male: 31 female: 36	serum: 2	Menkes 1986 Knekt 1990).
	Colon/colorectal cancer	Total: colon 2, colorectum 3 incidence: 5 mortality: 0 incidence & mortality combined: 0	✓ yes	US Netherlands Finland	total: 255,425 male: 86,311 female: 143,310	total: 617 male: 285 female: 332	serum: 3 toenail: 2	vd Brandt 1993 Nomura 1987 Menkes 1986 Garland 1995 Knekt 1990
	Rectal cancer	Total: 2 incidence: 2 mortality: 0 incidence & mortality combined: 0	✗no	US/Hawaii Netherlands	total: 127,712	total: 145 male: 109 female: 36	serum: 1 toenail: 1	vd Brandt 1993 Nomura 1987
	All gastrointestinal cancers	Total: 2 incidence: 2 mortality: 0 incidence & mortality combined: 0	✗no	US Sweden	total: > 9500 (one study did not report cohort size)	total: 143	plasma + serum: 1 plasma selenium P: 1	Coates 1988 Persson 2000
Skin cancer	Melanoma	Total: 3 incidence: 3 mortality: 0 incidence & mortality combined: 0	✗no	US	total: ˜ 158,000	total: 547	serum: 1 toenail: 1 supplemental intake: 1	Garland 1995 Menkes 1986 Peters 2008
	Basal cell carcinoma	Total: 3 incidence: 3 mortality: 0 incidence & mortality combined: 0	✗no	Australia US Finland	total: > 66,000	total: 292	serum: 3 dietary intake: 1	Knekt 1990 Menkes 1986 McNaughton 2005
	Squamous cell carcinoma	Total: 4 incidence: 4 mortality: 0 incidence & mortality combined: 0	✗no	Australia US	total: ˜ 30,000	total: 488	serum: 2 plasma: 1 dietary intake: 1	Combs 1993 Karagas 1997 Menkes 1986 McNaughton 2005
	Total non-melanoma skin cancer	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	US	total: 117	total: 19	plasma: 1	Clark 1985
Rare and other cancers	Haematological cancers	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	US	total: ˜ 6,200	total: 12	serum + plasma: 12	Coates 1988
	Thyroid cancer	Total: 1 incidence: 1 mortality: 0 incidence & mortality combined: 0	✗no	Norway	total: 100,000	total: 43 male: 12 female: 31	serum: 1	Glattre 1989
	Other cancers	Total: 5 incidence: 4 mortality: 1 incidence & mortality combined: 0	✗no	China US Finland Sweden		total: 573 male: 230 female: 285		Garland 1995 Coates 1988 Knekt 1990 Wei 2004 Persson 2000

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 Some studies did not report the gender of participants or cancer cases; consequently, figures for women and men not always sum up to the total number of participants or cancer cases.

 

Table 2. Risk of bias: observational studies

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Study	Publication	Newcastle Ottawa Scale (Cohort)				Newcastle Ottawa Scale (Case-Control)
		Selection	Comparability	Outcome	Total	Selection	Comparability	Exposure	Total
Kabuto 1994	Kabuto 1994	0-1-1-1	2	1-1-0	7	0-1-1-1	2	1-1-1	8
Ratnasinghe 2000	Ratnasinghe 2000	1-1-1-1	2	1-0-0	7	0-0-1-1	2	1-1-1	7
Sakoda 2005	Sakoda 2005	0-1-1-0	1	1-1-0	5	1-1-1-1	1	1-1-1	8
Wei 2004	Wei 2004	1-1-1-1	1	1-1-1	8	.-.-.-.		.-.-.
	Mark 2000	1-1-1-1	1	1-1-1	8	.-.-.-.		.-.-.
Yu 1999	Yu 1999	0-1-1-1	2	1-1-0	7	1-1-1-1	2	1-1-1	9
McNaughton 2005	McNaughton 2005	1-1-1-1	1	1-1-0	7	1-1-1-1	1	1-1-1	8
	Heinen 2007	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
	van der Pols 2009	1-1-1-1	2	1-1-0	8	.-.-.-.		.-.-.
Akbaraly 2005	Akbaraly 2005	0-1-1-1	2	0-1-0	6	.-.-.-.		.-.-.
Allen 2008	Allen 2008	1-1-1-1	2	1-1-0	8	1-1-1-1	2	1-1-1	9
Fex 1987	Fex 1987	1-1-1-0	2	1-1-1	8	1-0-1-1	2	1-1-1	8
Glattre 1989	Glattre 1989	0-1-1-0	1	1-1-1	6	1-1-1-1	1	1-1-1	8
Hartman 1998	Hartman 1998	1-1-0-1	2	1-1-0	7	.-.-.-.		.-.-.
Knekt 1990	Knekt 1990	1-1-1-1	2	1-1-1	9	0-1-1-1	2	1-1-1	8
	Hakama 1990	1-1-1-1	2	1-1-1	9	0-1-1-1	2	1-1-1	8
	Knekt 1988	1-1-1-1	2	1-1-1	9	0-0-1-1	2	1-1-1	7
	Knekt 1996	1-1-1-1	1	1-1-1	8	0-1-1-1	1	1-1-1	7
	Knekt 1991	1-1-1-1	2	1-1-1	9	0-1-1-1	2	1-1-1	8
Knekt 1998	Knekt 1998	1-1-1-1	2	1-1-1	9	0-1-1-1	2	1-1-1	8
Kok 1987	Kok 1987b	1-1-1-1	2	1-1-1	9	1-0-1-1	2	1-1-1	8
	Kok 1987a	.-.-.-.		.-.-.		.-.-.-.		.-.-.
Kornitzer 2004	Kornitzer 2004	1-1-1-0	1	1-1-1	7	1-1-1-1	1	1-1-1	8
Kromhout 1987	Kromhout 1987	1-1-1-0	2	1-1-1	8	.-.-.-.		.-.-.
Michaud 2002	Michaud 2002	1-1-1-1	2	1-1-0	8	0-1-1-1	2	1-1-1	8
Overvad 1991	Overvad 1991	1-1-1-0	1	1-1-0	6	.-.-.-.		.-.-.
Persson 2000	Persson-Moschos 2000	1-1-1-0	2	1-1-1	8	1-0-1-1	2	1-1-1	8
Ringstad 1988	Ringstad 1988	1-1-1-1	2	1-1-0	8	1-1-1-1	2	1-1-1	9
Salonen 1984	Salonen 1984	1-1-1-1	2	1-1-1	9	0-1-1-1	2	1-1-1	8
Salonen 1985	Salonen 1985	1-1-1-1	2	1-1-1	9	1-1-1-1	2	1-1-1	9
van Noord 1987	van Noord 1987	1-1-1-0	1	1-0-1	6	1-1-1-0	1	1-1-1	7
vd Brandt 1993	van den Brandt 1993	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
	van den Brandt 1994	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
	van den Brandt 1993	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
	van den Brandt 2003	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
	Zeegers 2002	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
Virtamo 1987	Virtamo 1987	0-1-1-1	2	1-1-1	8	.-.-.-.		.-.-.
Bleys 2008	Bleys 2008	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
Brooks 2001	Brooks 2001	0-1-1-0	2	1-0-0	5	1-0-1-1	2	1-1-0	7
Clark 1985	Clark 1985	0-1-1-0	0	0-0-0	2	.-.-.-.		.-.-.
Coates 1988	Coates 1988	0-1-1-0	1	1-1-0	5	1-0-1-0	1	1-1-1	6
	Coates 1987	.-.-.-.		.-.-.		.-.-.-.		.-.-.
Combs 1993	Combs jr 1993	0-1-1-0	2	1-0-0	5	.-.-.-.		.-.-.
Comstock 1997	Comstock 1997	0-1-1-0	2	1-1-0	6	1-1-1-1	2	1-1-1	9
Dong 2008	Dong 2008	1-1-1-1	2	1-1-1	9	.-.-.-.		.-.-.
Dorgan 1998	Dorgan 1998	0-1-1-1	2	0-1-0	6	1-1-1-1	2	1-1-1	9
Epplein 2009	Epplein 2009	0-1-1-1	2	1-1-0	7	0-1-1-1	2	1-1-1	8
	Gill 2009	0-1-1-1	1	1-1-0	6	0-1-1-1	1	1-1-1	7
Garland 1995	Garland 1995	0-1-1-1	2	1-1-1	8	1-1-1-1	2	1-1-1	9
	Hunter 1990	0-1-1-1	2	1-1-1	8	1-1-1-1	2	1-1-1	9
Goodman 2001	Goodman 2001	0-1-1-0	2	1-1-0	6	1-1-1-1	2	1-1-1	9
Helzlsouer 2000	Helzlsouer 2000	0-1-1-1	1	1-1-0	6	1-1-1-1	1	1-1-1	8
Karagas 1997	Karagas 1997	0-1-1-1	2	1-1-1	8	1-1-1-1	2	1-1-1	9
Li 2004a	Li 2004	0-1-1-1	2	0-1-1	7	1-1-1-1	2	1-1-1	9
Menkes 1986	Menkes 1986	0-1-1-1	2	1-1-0	7	1-1-1-1	2	1-1-1	9
	Batieha 1993	0-1-1-1	2	1-1-0	7	1-1-1-1	2	1-1-1	9
	Breslow 1995	0-1-1-1	2	1-1-0	7	1-0-1-1	2	1-1-1	8
	Burney 1989	0-1-1-1	2	1-1-0	7	0-1-1-1	2	1-1-1	8
	Helzlsouer 1996	0-1-1-1	2	1-1-0	7	0-1-1-1	2	1-1-1	8
	Helzlsouer 1989	0-1-1-1	2	1-1-0	7	1-1-1-1	2	1-1-1	9
	Ko 1994	0-1-1-0	2	1-1-0	6	1-1-1-1	2	1-1-1	9
	Menkes 1986	.-.-.-.		.-.-.		.-.-.-.		.-.-.
	Schober 1987	0-1-1-1	1	1-1-0	6	0-1-1-1	1	1-1-1	7
	Schober 1986	.-.-.-.		.-.-.		.-.-.-.		.-.-.
	Zheng 1993	0-1-1-1	2	1-1-0	7	0-1-1-1	2	1-1-1	8
Michaud 2005	Michaud 2005	0-1-1-1	2	0-1-0	6	1-1-1-1	2	1-1-1	9
Nomura 1987	Nomura 1987	1-1-1-1	2	1-1-1	9	1-1-1-1	2	1-1-1	9
Nomura 2000	Nomura 2000	1-1-1-1	2	1-1-1	9	1-1-1-1	2	1-1-1	9
Peleg 1985	Peleg 1985	1-1-1-1	1	1-1-0	7	1-1-1-1	1	1-1-1	8
Peters 2007	Peters 2007	0-1-1-1	2	1-1-0	7	1-1-1-1	2	1-1-1	9
Peters 2008	Peters 2008	0-1-1-1	1	1-1-1	7	.-.-.-.		.-.-.
	Asgari 2009	0-1-1-1	1	1-1-0	6	.-.-.-.		.-.-.
Thomson 2008	Thomson 2008	0-1-1-1	2	0-1-0	6	.-.-.-.		.-.-.
Willett 1983	Willett 1983	1-1-1-0	2	1-1-0	7	1-1-1-1	2	1-1-1	9
Yoshizawa 1998	Yoshizawa 1998	0-1-1-1	2	1-1-1	8	1-0-1-1	2	1-1-1	8

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Table 3. Risk of bias: randomised controlled trials

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Study	Sequence generation	Allocation concealment	Blinding	Completeness of outcome data	Risk of bias
NPCT 1996	adequate	adequate	adequate	adequate	low
Reid 2008	adequate	adequate	adequate	adequate	low
Li 2000	unclear	unclear	adequate	adequate	unclear
Yu 1997	unclear	unclear	adequate	unclear	unclear
Yu 1991	unclear	unclear	adequate	unclear	unclear
SELECT 2009	adequate	adequate	adequate	adequate	low

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Table 4. Results of observational studies not included in meta-analysis

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Organ system	Cancer	Case definition	Relative risk estimate (highest versus lowest exposure category)	95% CI	Selenium marker	Gender	Study
Gynecologic	Cervix	Incidence	0.89	0.40 to 2.00	serum	women	Menkes 1986 (Batieha 1993)
			1.10	n.r.	serum	Coates 1988
	Gynaecologic (without breast)	Incidence	0.96	n.r.	serum	Knekt 1990
	Ovary	Incidence	0.87	0.25 to 5.26	serum	Knekt 1990 (Knekt 1996)
			1.22	0.44 to 3.38	toenail	Garland 1995
			0.58	0.2 to 1.7	serum	Menkes 1986 (Helzlsour 1996)
			1.00 (HR)	0.73 to 1.37	suppl. intake	Thomson 2008
	Uterus	Incidence	1.38	0.62 to 3.08	toenail	Garland 1995
Gastrointestinal	Gastrointestinal tract (all)	Incidence	1.00	n.r.	serum/plasma	both	Coates 1988
			0.29	0.10 to 0.91	plasma	men	Persson 2000
	Oesophagus	Incidence	0.56	0.44 to 0.71	serum	both	Wei 2004 (Mark 2000)
		Mortality	0.62	0.44 to 0.89	serum
		Mortality	0.35	0.16 to 0.81	serum	both	Wei 2004 (Wei 2004)
		Incidence	0.27	0.03 to 2.21	suppl. intake	both	Dong 2008
	Oesophages and stomach	Incidence	0.45	n.r.	serum	men	Knekt 1990 (Knekt 1988)
		Incidence	0.67	n.r.	serum	women
	Liver	Incidence	0.62	0.21 to 1.86	plasma	men	Yu 1999
		Incidence	0.50	0.28 to 0.90	toenail	both	Sakoda 2005
		Mortality	0.50	0.28 to 0.90	both
			0.57	0.31 to 1.05	men
			0.18	0.03 to 1.13	women
	Pancreas	Incidence	0.08	0.01 to 0.56)	serum	men	Menkes 1986 (Burney 1989)
			0.83	0.4 to 1.67	women
			0.58	n.r.	serum	men	Knekt 1990
			3.49	n.r.	women
	Rectum	Incidence	0.625	n.r.	serum	men	Nomura 1987
			1.05	0.54 to 2.03	toenail	both	vd Brandt 1993
			0.91	0.41 to 2.00	men
			1.58	0.59 to 4.22	women
Urinary tract	Urinary tract (all)	Incidence	5.0	0.71 to ∞	plasma	men	Persson 2000
			0.81	n.r.	serum	men	Knekt 1990
			4.12	n.r.	women
Respiratory tract	Cavum oris/pharynx	Incidence	5.43	n.r.	serum	both	Menkes 1986 (Zheng 1993)
	Respiratory tract (all)	Incidence	6.0	1.5 to 24.2	plasma	men	Persson 2000
Skin	Melanoma	Incidence	1.66	0.71 to 3.85	toenail	women	Garland 1995
			0.90	0.30 to 2.50	serum	both	Menkes 1986 (Breslow 1995)
			0.98	0.69 to 1.41	suppl. intake	both	Peters 2008 (Asgari 2009)
	Any non-melanoma cancer	Incidence	0.77	n.r.	plasma	both	Clark 1985
	Basal cell carcinoma	Incidence	0.54	n.r.	serum	men	Knekt 1990
			1.55	n.r.	women
			0.80	0.10 to 4.5	serum	both	Menkes 1986 (Breslow 1995)
			0.86	0.38 to 1.96	serum	both	McNaughton 2005
			0.95	0.59 to 1.50	nutritional intake
	Squamous cell carcinoma	Incidence	0.69	0.51 to 0.92	plasma	both	Combs 1993
			0.60	0.20 to 1.50	serum	both	Menkes 1986 (Breslow 1995)
			0.86	0.47 to 1.58	plasma	both	Karagas 1997
			1.30	0.77 to 2.3	nutritional intake	both	McNaughton 2005
			0.49	0.24 to 0.99	serum
Other	Hematologic	Incidence	0.60	n.r.	serum/plasma	both	Coates 1988
	Thyroid	Incidence	0.15	0.0 to 5.0	serum	men	Glattre 1989
			0.12	0.01 to 1.11	women
			0.13	0.02 to 0.77	both

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 n.r.                  not reported