Dietary antioxidants and melanoma: evidence from cohort and intervention studies

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Dietary antioxidants and melanoma: evidence from cohort and intervention studies

Journal name: Nutrition and Cancer

Kyoko Miura1§

, Adèle C Green1,2

1 QIMR Berghofer Medical Research Institute, Cancer and Population Studies Group, 300

Herston Road, Herston, Brisbane, Queensland, 4006 Australia.

2 Cancer Research UK Manchester Institute and University of Manchester, Manchester

Academic Health Science Centre, Oxford Road, Manchester M13 9PL, UK.

§ Corresponding author:

Kyoko Miura

Mailing address: QIMR Berghofer Medical Research Institute, Cancer and Population

Studies Group, 300 Herston Road, Herston, Brisbane,

Queensland, 4006 Australia

Phone: +61 (0)7 3845 3561

Fax: +61 (0)7 3845 3503

Email: [email protected]

Word count: 2817

Number of figures: 0

Number of tables: 4

Supplemental Material: Online supporting material 5

A running title: Dietary antioxidants and melanoma risk

Author disclosures: KM, ACG, No conflicts of interest.

mailto:[email protected]

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Dietary antioxidants and melanoma: evidence from cohort and intervention studies 1

Abstract 2

Melanoma is the most serious form of skin cancer affecting mostly people of Caucasian 3

origin and is associated with high exposure to solar ultraviolet (UV) radiation. Antioxidants 4

in the diet are thought to prevent UV-induced DNA damage and oxidative stress and 5

laboratory-based studies have shown that high antioxidant intakes inhibit melanoma 6

development. Corresponding epidemiological evidence is inconsistent, however. We 7

therefore reviewed results from prospective observational studies and randomized controlled 8

trials (RCTs) to clarify whether consumption of antioxidant vitamin C, E (tocopherol), A 9

(retinol), carotenoids and selenium, as food, supplements, or both, or high fruit and vegetable 10

intake, reduce the incidence of cutaneous melanoma. A total of nine studies (two cohort, one 11

nested case-control, six RCTs) were included. Neither antioxidant nutrients, individually or 12

combined, nor fruit and vegetable intake showed any strong and significant associations with 13

melanoma, though the number of relevant studies was limited and several had 14

methodological shortcomings. In particular, melanoma was not a primary disease outcome in 15

any of the RCTs and therefore, none adequately accounted for potential confounding by sun 16

exposure. In conclusion, available evidence is currently inadequate to assess possible 17

beneficial effects of antioxidant intake on melanoma risk. 18

19

Keywords: antioxidants, melanoma, skin cancer, review 20

21

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Introduction 22

The incidence of melanoma of the skin, the most serious form of skin cancer, has increased 23

steadily in the last 50 years (1) and it is now one of the more common cancers among white-24

skinned populations with an estimated 232,000 individuals diagnosed worldwide in 2012 (2). 25

The key environmental cause of melanoma is exposure to ultraviolet (UV) radiation which 26

causes oxidative damage to target-cell DNA as well as mutations (3). To protect against this 27

oxidative stress and damage, human skin has an antioxidant defence system (4) which 28

includes enzymatic and non-enzymatic antioxidants. Enzymatic antioxidants such as 29

glutathione peroxidises are generated by cells in the body. Non-enzymatic antioxidants such 30

as carotenoids can directly neutralize reactive oxygen species or indirectly induce enzymatic 31

antioxidant production in the body, and can be derived from dietary sources (5). 32

33

Antioxidant nutrients commonly assessed are vitamin C, vitamin E (tocopherols), β-carotene, 34

carotenoids and selenium (5) and these are mainly found in fruit and vegetables except 35

selenium, a trace mineral which occurs in meat and grains. Vitamin C is a water-soluble 36

vitamin that reduces reactive oxygen species and free radicals, and assists in oxidised vitamin 37

E (α-tocopheroxyl radical) regeneration to vitamin E (5). Vitamin E is a fat-soluble vitamin 38

that protects tissue lipids by preventing peroxidation and is able to terminate free radicals (6, 39

7). β-carotene and carotenoids are able to scavenge single oxygen and inhibit free radical 40

reactions (8) while selenium is necessary for some of the enzymatic antioxidant activities (9). 41

However, the antioxidant defence system may be depleted after excess or chronic UV-42

exposure. Dietary intakes of antioxidants, therefore, may be influential in protecting against 43

melanoma development by repairing damage from UV-induced free radicals (10). 44

45

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While animal and cell system studies have shown beneficial effects of antioxidant nutrients 46

on melanoma (11-14), findings from epidemiological studies to date have differed with none 47

of the antioxidant nutrients (e.g. β-carotene), other bioactive compounds (e.g. polyphenols), 48

or food groups high in antioxidant content (e.g. fruit and vegetables) consistently showing a 49

significant inverse association (15-21). A possible reason may be the uneven quality of the 50

available evidence because it has been derived from case-control studies that are liable to 51

selection bias especially in hospital-based studies and to reporting bias in regard to dietary 52

intake before melanoma diagnosis among cases (22, 23). Prospective studies are not prone to 53

these biases, and we therefore reviewed available prospective evidence to clarify whether 54

antioxidant vitamin and/or mineral intakes are associated with the incidence of cutaneous 55

melanoma, independent of the role of sun exposure. 56

57

Methods 58

We included published prospective cohort studies and randomized controlled trials (RCT); 59

published in English that assessed dietary antioxidant nutrients, namely vitamin C, vitamin E 60

(tocopherol), vitamin A (retinol) carotenoids, and selenium consumed as food or supplements 61

or both (6), or fruit and vegetable intake in relation to incident melanoma of the skin among 62

humans. Studies of melanoma mortality were excluded. Literature searches were conducted 63

via PubMed and Embase databases to August 2014 using following search terms to identify 64

published papers: (cutaneous melanoma OR skin neoplasms OR malignant melanoma OR 65

skin cancer) AND (antioxidant OR vitamin A OR retinol OR beta-carotene OR carotenoids 66

OR vitamin E OR alpha-tocopherol) AND (cohort studies OR prospective studies OR 67

randomized controlled trials OR randomized clinical trials). The reference lists of relevant 68

articles were cross-checked and any additional studies identified. If multiple publications 69

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evaluated the same or highly overlapped study populations, only the one with the most 70

relevant and comprehensive data was included. 71

72

Data were extracted and recorded according to study features: design, inclusion criteria, 73

recruitment, randomization (where applicable), demographic characteristics of participants 74

(age, sex, race/ethnicity), mode of melanoma case ascertainment, and aspects of the exposure 75

measurement such as the dietary assessment method, management of potential confounding 76

factors and results. Design weaknesses or potential sources of bias were noted. 77

78

Results 79

Between 1991 and 2014, nine studies (two prospective cohort studies, one nested case-80

control, six RCTs) conducted mostly in the USA and Europe were identified for inclusion. 81

Findings for observational studies and intervention studies were summarized separately 82

below. 83

84

Observational studies: cohort and nested case-control study characteristics 85

The two cohort studies were conducted in the USA (17, 19, 20) and one nested case-control 86

study was from Finland (24) (Table 1). Feskanich et al. (17) investigated dietary intakes and 87

melanoma in a large cohort of white-skinned women comprising two sub-cohorts of 73,525 88

women aged between 30–55 years (the Nurses’ Health Study (NHS)), and 88,553 women 89

aged between 25–42 years (NHS II) respectively, which yielded 414 melanoma cases. The 90

second cohort study comprised 69,671 white-skinned men and women aged between 50–76 91

years participating in the VITamins And Lifestyle (VITAL) study, among whom 461 cases of 92

melanoma (20) and 566 cases (19) were available for anti-oxidant intake analyses. The nested 93

case-control study was based on 10 new melanoma cases observed on follow-up of a general 94

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population of about 40,000 men and women aged 15 years and older and 18 age- and sex-95

matched controls (24). 96

97

Both the NHS-NHS II (17) and the VITAL (19) cohort studies assessed the antioxidant 98

intakes from food in the previous year using a food frequency questionnaire (FFQ) (17, 19). 99

However, their measures of supplement intake at baseline were different: NHS-NHS II 100

participants (17) were asked about supplement use during the past year whereas the VITAL 101

cohort members (19) were asked about their supplement use over the last 10 years. Although 102

both NHS-NHS II and the VITAL studies assessed “multivitamin supplement” intake, the 103

VITAL study (19, 20) defined “multivitamin supplement” as the combination of vitamin C, 104

vitamin E, β-carotene, selenium and zinc supplement use, while NHS-NHS II (17) did not 105

define “multivitamin supplement”. The nested case-control study used biomarkers of 106

antioxidant intake, namely serum concentrations of α-tocopherol, β-carotene, retinol, and 107

selenium (24). 108

109

Regarding melanoma ascertainment, NHS-NHS II (17) identified melanoma occurrence by 110

questionnaire and only about 53% of reported cases were confirmed against medical records, 111

while the VITAL and Finnish studies ascertained melanoma occurrence initially through 112

cancer registries (Table 1). A number of potential confounding factors such as phenotype and 113

sun exposure were considered and adjusted for in the NHS-NHS II (17) and the VITAL (19) 114

studies whereas the nested case-control study adjusted only for smoking due to the small 115

analytical sample (24). 116

117

Vitamin C 118

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Only one cohort study, the combined NHS-NHS II, has examined the association between 119

vitamin C intake (from food, supplements and in total) and melanoma (17) (Supplemental 120

Table 1). After adjustment for age, phenotype, sun exposure, and hormonal factors, higher 121

vitamin C intakes from food (≥175 mg/day) appeared to be positively associated with 122

melanoma compared with lower intakes (<90 mg/day) (p-trend=0.05) (Supplemental Table 123

1). However, neither total vitamin C intake from food and supplements nor vitamin C intake 124

from supplements only was associated with melanoma incidence. 125

126

Vitamin E (α-tocopherol) 127

The association between vitamin E and melanoma was examined in the NHS-NHS II cohort 128

(17) and the nested case-control study (24) (Supplemental Table 2) with mixed results. The 129

former showed no significant associations with vitamin E intake (17) while the latter (24) 130

found that serum α-tocopherol concentration was negatively associated with melanoma 131

incidence with a relative risk (RR) of 0.20 (no confidence interval provided; p-trend <0.01) 132

(Supplemental Table 2). 133

134

β-carotene, retinol and vitamin A 135

There was no association of β-carotene intake and melanoma reported by either of the cohort 136

studies (17, 19) (Table 2) whereas the nested case-control study found a significant negative 137

association, adjusted for smoking only, with serum β-carotene concentration (RR 0.03, no 138

confidence interval provided ; p-trend<0.01) (24) 139

140

Similarly in the NHS-NHS II cohort, retinol from food and total retinol intake were not 141

associated with melanoma overall (17), though stratified analyses showed a significant 142

negative association of melanoma with total retinol intake among women with several 143

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melanoma risk factors present at baseline (≥1800 µg/day vs. <400 µg/day RR 0.39; 0.22–144

0.71, p-trend=0.01). The VITAL study found a significant negative association between 145

retinol supplement use (current use vs. none: hazard ratio (HR) 0.60; 95% CI 0.41–0.89) and 146

high supplement dose (>1200 µg/day vs. none: HR 0.74; 95% CI 0.55–1.00) and melanoma 147

but there was no linear trend (p-trend=0.28) (19) (Table 2). The same study did not find 148

associations with retinol intake from food or total retinol intake and melanoma (19). 149

Similarly, the nested case-control study also reported no association between serum retinol 150

concentration and melanoma (24). 151

152

Only the VITAL study assessed vitamin A intake from a range of sources (from food, 153

supplement, and total) but no association with melanoma was seen (19) (Table 3). 154

155

Selenium 156

The VITAL cohort study (20) and the nested case-control study (24) investigated the 157

association of melanoma with selenium intake and serum selenium concentration respectively 158

(Supplemental Table 3) but no associations were found. 159

160

Antioxidant or multivitamin supplements 161

Assessment of multivitamin supplement use in the NHS-NHS II cohort revealed no 162

significant association with melanoma (17) (Table 3). Similarly, although the VITAL study 163

used multiple measures of multivitamin use, none of these measures were associated with 164

melanoma occurrence (Table 3), and sex-stratified analyses did not change the results (20) 165

(Supplemental Table 4). 166

167

Fruit and vegetables 168

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Only the NHS-NHS II cohort was examined for an association of melanoma with fruit and 169

vegetable intake (17) (Supplemental Table 5). A range of fruit and vegetable intake measures 170

were evaluated: total fruit and vegetable intake, fruit and vegetables high in vitamin C and in 171

carotenoids, and frequency of orange juice intake. Compared with low consumption, a high 172

consumption of vitamin C-rich fruit and vegetables was positively associated with melanoma 173

(0.5 servings/day vs. ≥2 servings/day RR 1.43, 95% CI 0.99–2.07; p-trend=0.01). Frequent 174

consumption of orange juice was also positively associated with melanoma (never vs. 175

≥once/day HR 1.61, 95% CI 0.92–2.84; p-trend=0.008) (Supplemental Table 5). 176

177

Randomized controlled trials 178

A total of six RCTs published between 1999 and 2012 were identified for inclusion: one 179

conducted in multiple countries (25), four conducted in the USA (26-29), and one in France 180

(30) (Table 4). All studies assessed effects of one or more types of antioxidant vitamin or 181

mineral supplementation and were placebo-controlled. Data from one RCT investigated 182

women only (26) and two RCTs, men only (27, 29). Melanoma incidence was not a primary 183

outcome in any of these intervention studies and only one took account of phenotype or sun 184

exposure (30). The antioxidant vitamin/mineral supplementations assessed were vitamin E 185

(25), β-carotene (26, 27), selenium (28), and a combination of antioxidant vitamins and 186

minerals (29, 30), and intervention durations ranged from 2 to 12.9 years (Table 4). Findings 187

for each antioxidant intervention in relation to melanoma outcome have been reviewed 188

separately below. 189

190

Vitamin E supplementation 191

One study combined the Heart Outcomes Prevention Evaluation (HOPE) (n=9,541) and 192

HOPE TOO (n=7,030) trials and assessed various outcomes of vitamin E supplementation 193

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among adults with histories of CVD or diabetes (25). After 7-years of follow-up, a total of 33 194

cases of melanoma were observed in these two trial populations combined, and the risk of 195

melanoma was no different in the supplement and the placebo groups (25) (Table 4). 196

197

β-carotene supplementation 198

Two RCTs investigated the effectiveness of β-carotene supplementation (both 50 mg 199

alternative days) in preventing cardiovascular disease (26, 27). Among male physicians in the 200

Physicians’ Health Study (n=22,071), β-carotene supplementation did not influence 201

melanoma risk after 12.9 years of follow-up (27) (Table 4). Similarly in the Women’s Health 202

Study (N=39,876), the number of melanoma cases did not differ between the intervention and 203

placebo groups after 2 years intervention and 2 years post intervention follow-up (26) though 204

melanoma risk factors were not taken into account (Table 4). 205

206

Selenium supplementation 207

One RCT, the Nutritional Prevention of Cancer Trial, among 1,250 men and women with a 208

history of basal cell or squamous cell skin cancers assessed the effectiveness of selenium 209

supplementation in relation to melanoma which was not an initially planned primary disease 210

outcome (28). After 7.4-years of intervention, risk of melanoma occurrence did not differ 211

between the intervention and placebo groups (28) (Table 4). 212

213

Antioxidant supplementation 214

Two RCTs assessed antioxidant supplementation and melanoma incidence (Table 4). In the 215

Physician’s Health Study II, the risk of melanoma did not differ between supplement and 216

placebo groups after 11 years of follow-up (29) (Table 4) and results did not change when the 217

analysis was stratified by history of other cancers (Supplemental Table 4). The Vitamins and 218

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Mineral Antioxidants (SU.VI.MAX) trial was conducted among middle-aged men and 219

women to prevent chronic diseases (30, 31). After the seven years of intervention, a 220

significantly increased risk of melanoma was observed for women in the supplement group 221

(HR 4.31; p=0.02) but not men (HR 0.49; p=0.32) after adjustment for age, treatment group, 222

latitude, and antioxidant status at baseline (31). Five years after cessation of the intervention, 223

however, the risks of melanoma for both men and women were not significantly different 224

between the supplement and placebo groups (30). 225

226

Discussion 227

This review assessed in detail the published evidence from prospective observational and 228

intervention studies regarding antioxidant nutrients and subsequent incidence of melanoma. 229

All antioxidant nutrients examined in this review had previously shown protective effects 230

against melanoma development in cell systems or animal studies (11-13), yet overall, we 231

found insufficient human evidence to determine whether associations exist between dietary 232

antioxidant nutrients (individually or combined) and melanoma. 233

234

There are a number of possible reasons for the lack of significant epidemiological 235

associations. First, there may be no association between antioxidant nutrients and melanoma, 236

or it may be too small to be detected in studies to date. If true associations do exist, the 237

duration of the intervention or the follow-up periods (ranging from 6–7 years for cohort 238

studies and 4–13 years for RCTs) may have been too short to observe any effects (32). 239

Regarding the six RCTs, none of these trials considered baseline antioxidant status yet it is 240

likely to be an important factor to take into account in assessing the relationship between 241

antioxidant supplementation and melanoma risk (e.g. only those with low baseline 242

antioxidant status may benefit from supplementation) (33). 243

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244

Another major limitation was the lack of accounting for known risk factors and potential 245

confounding factors in analyses: results that do not account for major melanoma risk factors 246

related to sun exposure should be interpreted with caution. While RCTs included in this 247

review collected information on melanoma occurrence, it was not an initially planned 248

primary disease outcome in any of these trials; and these trials thus did not collect or did not 249

sufficiently collect known risk factors for melanoma. Although randomization is expected to 250

allocate known and unknown confounding factors into experimental and control groups 251

equally, it is not always successful. Furthermore, potential interactions of phenotype and sun 252

exposure with antioxidant treatments should have been assessed by RCTs when melanoma is 253

the outcome. Accurate ascertainment of melanoma occurrence was also a potential problem 254

with many of the studies. A number relied on self-report (17, 26, 27, 31), a proportion of 255

which were verified using medical records, while the majority of studies relied on cancer 256

registries to ascertain melanoma (19, 20, 24, 28, 34). Without comprehensive cross-checking, 257

it is likely that either of these methods alone will have resulted in under-ascertainment of 258

melanomas and misclassification of disease status. 259

260

Combined nutrients are expected to synergistically benefit health (35) and thus high intakes 261

of fruit and vegetables which contain diverse antioxidants and other bioactive compounds 262

(such as polyphenols) would be expected to exert potent antioxidant activity in epidermal 263

tissue to protect against UV-induced oxidative damage associated with melanoma 264

development (7). However, only one cohort study among women examined high 265

consumption of fruit and vegetables and risk of melanoma (17) and various positive 266

associations were observed. These unexpected findings may be due to chance, confounding, 267

or perhaps to the effect of furocoumarin, mainly found in citrus fruit, which can increase 268

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photo-sensitivity (17). Further evidence is needed before the potential role of fruit and 269

vegetables in the development of melanoma can be properly assessed. 270

271

While a combination of vitamins and minerals in the form of supplements theoretically may 272

have beneficial effects (36), none of the studies reported a reduced risk of melanoma. 273

Although an RCT (29) and two cohort studies (17, 20) found no association with 274

multivitamin/antioxidant supplements, the French RCT (30, 31) reported a higher risk from 275

antioxidant supplementation among women but not men, that is, no consistent result was 276

evident in the studies to date. 277

278

In conclusion, the evidence regarding dietary antioxidants in relation to melanoma risk in 279

humans is severely limited and inconsistent. It is not possible to draw firm conclusions about 280

the likely benefits (or harms) of anti-oxidant nutrients from food or supplements or of fruit 281

and vegetable intake in relation to melanoma. Further prospective cohort studies and RCTs 282

that examine antioxidant intakes and melanoma risk should measure and account for known 283

melanoma risk factors. Studies should comprehensively ascertain and histologically verify 284

incident melanomas in participants and they should also be large enough to detect moderate 285

associations in order to clarify the role of antioxidant intake in melanoma development. 286

287

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Acknowledgements 288

KM was supported by a program grant from the National Health and Medical Research 289

Council of Australia (no. 552429). 290

291

Statement of Authors’ Contribution to Manuscript 292

KM searched for published literature and synthesized the manuscript. ACG assisted in 293

interpretation of the data and the revision of the manuscript. KM had primary responsibility 294

for the final content. All authors read and approved the final manuscript. 295

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Table 1: Characteristics of cohort and nested case-control studies

Study,

country

Participants,

ethnicity

Age (yrs),

sex (%)

Number of

participants

Follow-up (yrs) Melanoma ascertainment Primary

outcome

Exposure assessment

/exposure

Remarks

/limitations

Cohort

(Feskanich,

Willett et

al. 2003)

(17) USA

Registered

nurses

Participants of

the Nurses’

Health Study

(NHS) and

NHS II

Ethnicity: white

Ages [NHS

30–55,

NHS II

25–42]

W: 100%

NHS: 73,525

NHS II:

88,553

Cases: 414

NHS 1984

followed to

1991

Mailed questionnaire,

confirmed by medical

records

Major

Cancers

FFQ NHS 85%

medical record

reviewed, 52%

confirmed, NHS

II 76%

reviewed, 55%

confirmed.

Intake of: Vit C, Vit E,

retinol, β-carotene (from

food, supplements, and

total), total F, total V, F

& V high in carotenoids,

F & V high in Vit C,

orange juice during the

past year.

use of multi-vitamin

supplements during the

past year.

NHS II 1991

followed to

1999

Response rate

90%

(Asgari,

Brasky et

al. 2012)

(19) USA

(Asgari,

Maruti et

al. 2009)

(20)

Adults from

Western

Washington

State residents

VITamins And

Lifestyle

(VITAL) study

Ethnicity: white

Ages 50–

76 (mean

62)

M: 48%

N=69,635 Mean 5.8

Cancer registry Melanoma

and other 5

different

types of

cancer,

total

cancer

FFQ

Retinol, β-carotene, vit

A, lutein, lycopene: total,

from food, supplement,

and total, supplement

dose/use.

Vit C, Vit E, β-carotene,

selenium, zinc from

supplements.

Self-report of

supplement use

over the 10 yrs

before baseline.

Cases: 566

(M: 354, W:

212)

N= 69,671 Mean 5

Cases: 461

(M: 286, W:

165)

Nested case-control

(Knekt,

Aromaa et

al. 1991)

(24)

Finland

General healthy

population

Ethnicity: not

stated

Ages: ≥15

Sex not

stated

N=39,268 Follow-up:

1968–72 to

1997

Cancer registry Unplanned Serum concentration of:

α-tocopherol, β-carotene,

retinol, retinol-binding

protein, selenium

No information

on the

distribution: sex,

age, ethnicity.

Analyses

adjusted for

smoking. Small

number of cases.

Cases: 10

Controls: 18

(age, sex,

place of

residence

matched)

F: fruit; FFQ: food frequency questionnaire; M: men; NHS: Nurses’ Health Study; V: vegetables; Vit A: vitamin A; vit C: vitamin C; vit E: vitamin E; W: women.

Miura 20

Table 2: A summary of β-carotene, retinol, vitamin A intake and melanoma risk from cohort and nested case-control studies

Study Exposure Exposure level RR (95% CI) Adjustment

Cohort Phenotype Sun exposure Other

(Feskanich,

Willett et al.

2003) (17)

β-carotene intake total

(ųg/d)

Low: <2400 (cases 56)a 1.00 Skin reaction

after sun

exposure,

phototype, No of

moles, hair

colour.

No of sunburns,

sun exposure

during

childhood and

lifetime or

teenage years,

state of

residence.

Age, follow-up cycle,

Vitamin supplement use,

menopausal status, OC

use, postmenopausal

hormone use, parity,

height, BMI, family

history of melanoma (and

multivitamin supplement

use for retinol from food).

High: ≥ 6000 (cases 80) 1.22 (0.86–1.74) p-trend=0.96

Retinol from food (µg/d) Low: <300 (cases 79)a 1.00

High: ≥850 (cases 90) 1.07 (0.74–1.55) p-trend=0.99

Retinol total (µg/d) Low: <400 (cases 87)a 1.00

High: ≥1800 (cases 83) 0.85 (0.63–1.16) p-trend=0.52

(Asgari,

Brasky et al.

2012) (19)

β-carotene from food

(µg/d)

Low: ≤2138.8 (cases 103)a 1.00 Presence of

freckles, hair

colour,

phototype, family

history of

melanoma, mole

removed.

No. of sunburns Age, sex, education, BMI,

alcohol, macular

degeneration, history of

non-melanoma skin cancer

High: >5648.5 (cases 151) 1.15 (0.87–1.53) p-trend=0.46

β-carotene supplement

(µg/d)

None user (cases 237) a 1.00

Low: 6.4–600 (cases 200) 1.16 (0.95–1.41)

High: >600 (cases 119) 1.08 (0.86–1.36) p-trend=0.36

Total β-carotene (ųg/d) Low: ≤3515.0 (cases 101)

a 1.00


Retinol from food (µg/d) Low: ≤280.5 (cases 119)a 1.00


Retinol supplement

(µg/d)

Non-user (cases 213)a 1.00

Low: 19.3–1200 (cases

279)

1.13 (0.93–1.36)


Retinol total (µg/d) Low: ≤514.2 (cases 126)

a 1.00


Vit A from food (RAE/d

)

Low: ≤574.4 (cases 105)a 1.00

High: ≥1176.6 (cases 147) 1.16 (0.84–1.59) p-trend=0.67

Vit A supplement

(RAE/d)

None user (cases 211)a 1.00

Low: 19.3–1500 (cases

273)

1.06 (0.88–1.28)


Total Vit A (RAE/d) Low: ≤992.3 (cases 125)a 1.00


Nested case-controlb

Miura 21

(Knekt,

Aromaa et al.

1991) (24)

Serum β-carotene

(µg/L)c

cases 58.0 0.03, p-trend <0.01 — — Smoking

controls 121.5

Serum retinol (µg/L)c

cases 599 0.79, p-trend=0.60

controls 633 a Reference group.

b Relative risk is interpreted as the increase in risk of melanoma for every one standard unit increase (standard deviation) of the serum level of micronutrient in the

conditional logistic regression model. c Mean levels of serum micronutrients.

BMI: body mass index, No.: number, OC: oral contraceptive, RAE: retinol activity equivalents (1 RAE=1 µg all-trans retinol); Vit A: vitamin A

Miura 22

Table 3: A summary of multivitamin and mineral supplement use and melanoma risk from cohort studies

Study Exposure Exposure level RR (95% CI) Adjustment

Phenotype Sun exposure Others

(Feskanich,

Willett et al.

2003) (17)

Multivitamin supplement

use

Never (cases 143)a 1.00 skin type, No of

moles, hair

colour,

No of

sunburns, state

of residence

Age, follow-up

cycle, family history

of melanoma,

menopausal status,

OC use,

postmenopausal

hormone use, parity,

height, BMI.

Past (cases 83) 0.96 (0.51–1.83)

Current (cases 185) 1.02 (0.82–1.28)

(Asgari,

Maruti et al.

2009) (20)

Multivitamin supplements:

overall use

None (cases 152)a 1.00 Moles removed,

hair colour, skin

type.

Presence of

freckles, No. of

sunburns

Age, sex, education,

family history of

melanoma, history of

non-melanoma skin

cancer

Former (cases 24) 0.88 (0.57–1.36)

Current (cases 275) 1.04 (0.85–1.27) p-trend=0.065

Multivitamin supplements:

duration (yrs)

0 (cases 152)a 1.00

≥ 7 (cases 197) 1.05 (0.85–1.30) p-trend=0.55

BMI: body mass index; HR: hazard ratios; OC: oral contraceptive. a Reference group.

Miura 23

23

Table 4: Characteristics of randomised controlled trials and their results

Study,

country

Participants Age (yrs),

sex (%)

Intervention No. of

participants

Follow-up

(yrs)

Method of

melanoma

ascertainment

Primary

outcome

Results (HR, 95% CI) Risk

factors

accounted

(Lonn,

Bosch et

al. 2005)

(25)

multiple

countries

(Canada,

USA,

Mexico,

Europe

and South

America)

Adults with

history of

CVD/diabetes

Heart Outcomes

Prevention

Evaluation

(HOPE) and

HOPE TOO

participants

Ethnicity: 89%

white

Ages

[intervention

66, control

66]

M: 74%

PRR-α-

tocopheryl

acetate 400

IU/d or

placebo

HOPE:

intervention:

4,761

control:

4,780

HOPE: 4.5

HOPE

TOO: 2.6

Total

median: 7

Pathology (or

cytology) report,

discharge and other

clinical summaries,

results of imaging,

serum markers, and

other diagnostic

procedures.

HOPE:

CVD

HOPE

TOO: CVD,

cancer in

general

All participants No

Control (18 cases)a

1.00

Intervention (15 cases)

0.84 (0.42–1.66)

HOPE

TOO:

intervention:

3,520

control:

3,510

HOPE TOO only

Control (17 cases) 1.00


0.76 (0.37–1.57)

(Lee,

Cook et

al. 1999)

(26) USA

Female health

professionals,

Women’s’

Health Study

Ethnicity: not

stated

Ages:≥ 45

W: 100%

β-carotene 50

mg or placebo

on alternative

days.

intervention:

19,939

control:

19,937

Intervention:

2.1

Post-

intervention:

2

Self-report,

confirmed with

medical and

pathological

records

CVD,

cancer in

general

Control (21 cases) No


Not stated

(Cook,

Lee et al.

2000) (27)

USA

Male physicians,

Physicians’

Health Study

Ethnicity: not

stated

Ages: 40–84

(mean 53)

M: 100%

β-carotene 50

mg on

alternative

days or

placebos.

Total

N=22,071

12.9 (11.7–

14.4)

Self-report,

confirmed with

medical records

(93% confirmed)

CVD,

cancer in

general

Control (77 cases)a

1.00

No


0.9 (0.6–1.2)

(Duffield-

Lillico,

Reid et al.

2002) (28)

USA

Nutritional

Prevention of

Cancer Trial

participants.

Ethnicity: not

stated

Ages:

[intervention

mean 63.4

(SD 10.2);

control

mean 63.0

(SD 9.9)]

M: 75%

selenium

200µg daily

(0.5-g high

selenium

baker’s yeast

tablet) or

placebo

intervention:

621

control: 629

7.4 Periodical medical

records review, the

National Death

Index and

ChoicePoint

(database of

personal

information).

Keratinocyte

skin cancers

Control (9 cases)a 1.00 No


1.18 (0.49–2.85)

(Gaziano, Male physicians Ages synthetic α- intervention: 11.2 Medical record, CVD, Control (cases 96)a No

Miura 24

24

Sesso et

al. 2012)

(29)

USA

The Physicians’

Health Study II

(PHS II)

Ethnicity: not

stated

[intervention

64.2 (SD

9.1), control

64.3 (SD

9.2)]

M: 100%

tocopherol

400 IU

alternate days,

synthetic

ascorbic acid

500 mg daily,

lurotin (β-

carotene)

50mg

alternate days;

or placebos

7,317

control:

7,324

reviewed by the

PHS II Endpoints

Committee

(physicians

blinded)

cancer in

general

1.00

Intervention (cases

108) 1.12 (0.85–1.47)

p=0.42

(Hercberg,

Ezzedine

et al.

2007) (31)

General

population,

subsample of

Supplementation

in Vitamins and

Mineral

Antioxidants

(SU.VI.MAX)

study

Ethnicity: not

stated

Ages:

M 45–60,

W 35–60

M: 39%

Antioxidants

capsule (Vit C

120 mg; Vit E

30 mg; β-

carotene 6

mg; selenium

100 mg; zinc

20 mg) daily

or placebo

Total

N=13,017

12.5

(intervention

7.5 + post-

intervention

5)

6-monthly

questionnaires,

confirmed by

clinical records

(diagnostic tests,

procedure and

pathology report).

CVD,

cancer in

general

Men Yes

(sun

exposure

information

unavailable

for 29% of

participants)

Control (6 cases)a 1.00


0.49 (0.12, 1.97)

p=0.32

Women



4.31 (1.23, 15.13)

p=0.02

(Ezzedine,

Latreille

et al.

2010) (30)

France

5-yr post intervention

Men

Control (10 cases)a

1.00


1.15 (0.31–4.27)

p=0.83

Women



0.64 (0.18–2.27)

p=0.49

CVD: cardiovascular disease; M: men; vit C: vitamin C; vit E: vitamin E; W: women. a Reference group.

Dietary antioxidants and melanoma: evidence from cohort and intervention studies

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