Supplements prevent prostate cancer

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Supplements prevent prostate cancer

Hi All,

The below seem to suggest that taking supplements of vitamins and minerals help

reduce prostate cancer.

Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, Estaquio C,

Hercberg

S.

Antioxidant vitamin and mineral supplementation and prostate cancer prevention

in

the SU.VI.MAX trial.

Int J Cancer. 2005 Mar 30;116(2):182-186 [Epub ahead of print]

PMID: 15800922

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=15800922 & query_hl=6

Prevention of prostate cancer by antioxidant vitamins and minerals is an area of

intensive research since 2 randomized trials have shown, unexpectedly, that

supplementation with selenium or vitamin E was associated with a significant

reduction of prostate cancer risk.[1][2] These findings remain to be confirmed

by 2

large randomized trials specifically designed to assess the effect of

antioxidant

micronutrients supplementation on prostate cancer risk.[3][4] In these trials,

large

doses of antioxidant vitamins are brought by the supplementation. However, there

is

evidence to suggest that the preventative effect of supplementation is mainly

observed among men with low baseline status of antioxidant vitamins or

minerals.[1][5] Some studies,[5][6][7][8][9][10] but not others,[11][12][13]

have

shown that men with low levels of antioxidant vitamins or minerals are at

increased

risk of developing prostate cancer. It is therefore possible that the

normalization

of antioxidant status, by diet or supplementation at nutritional doses, is

sufficient to protect men with low antioxidant status from increased prostate

cancer

risk. The supplémentation en vitamines et minéraux antioxydants (SU.VI.MAX)

trial is

a primary prevention trial conducted in middle-aged men and women to determine

whether daily supplementation with nutritional doses of antioxidant vitamins

(vitamin C, vitamin E and ß-carotene) and minerals (selenium and zinc) could

decrease the incidence of cancer and ischemic heart disease.[14] ...

Material and methods

.... The SU.VI.MAX study is a large population-based, double-blind,

placebo-controlled, randomized trial ... 13,017 volunteers free of severe health

problems (7,876 women aged 35-60 and 5,141 men aged 45-60) were randomized to

take a

capsule containing either a placebo or a combination of 120 mg vitamin C, 30 mg

alpha-tocopherol, 6 mg ß-carotene, 100 g selenium and 20 mg zinc every day

during 8

years. ... Men taking the antioxidant supplements had a lower cancer (all sites)

incidence (hazard ratio = 0.69) and a lower all-cause mortality (hazard ratio =

0.63) than those taking the placebo, while no effect was observed in women.[15]

....

Study population

The population for the present study is based on the 5,141 men randomized in the

SU.VI.MAX trial. ... population for the analysis of the primary outcome is

formed by

2,522 men randomized to the supplementation arm and 2,512 men ... Total

prostate-specific antigen (PSA) ... insulin-like growth factor-I (IGF-I), and

insulin-like growth factor-II (IGF-II). ... hazard ratio (HR), the 95%

confidence

interval (CI) ... the following variables: age, smoking, body mass index,

baseline

plasma PSA and baseline serum levels of antioxidant vitamins and minerals. For

....

Results

The baseline characteristics of the participants were well balanced between the

2

arms of the trial (Table I). The median duration of follow-up was 8.8 years in

the

placebo arm and 9.0 years in the supplementation arm of the trial. Minor side

effects were attributed to the supplementation in fewer than 10 participants. No

withdrawal was due to supplementation side effects. During the follow-up, 103

new

cases of prostate cancer were diagnosed. There was a statistically significant

increase in the rate of prostate cancer with higher age, baseline PSA and body

mass

index (Table II). The hazard ratio of prostate cancer associated with the

supplementation was 0.88 with a 95% confidence interval ranging from 0.60 to

1.29

(Table III). Only 2 baseline characteristics did modify this association: total

PSA

(p-value for interaction = 0.009) and serum vitamin C (p-value for interaction =

0.02). In men with baseline PSA < 3 g/L, who represented over 90% of the trial

population, there was a statistically significant reduction in the rate of

prostate

cancer associated with the supplementation (HR = 0.52; 95% CI = 0.29-0.92). In

the

men with a baseline PSA >/=3 g/L, the HR was 1.54 (95% CI = 0.87-2.72). Among

participants with a baseline serum vitamin C below the median, the intervention

was

associated with a reduction in the rate of prostate cancer (HR = 0.52; 95% CI =

0.26-1.04) of borderline statistical significance, while the association was

inverse

among those with a baseline vitamin C above the median (HR = 1.48; 95% CI =

0.84-2.63). There was no marked variation in the association between

supplementation

and prostate cancer according to categories of the other baseline variables

considered.

Table I. Baseline Characteristics of Trial Participants by Intervention Arm

-------------------------------------------------

----Supplement arm Placebo arm

--------------------------------------------------

----Number Mean (SD) or % Number Mean (SD) or %

-------------------------------------------------

Body mass index >/=27 (%) 2,415 23.8 2,405 23.6

Table II. Hazard Ratios and Related 95% Confidence Intervals of Prostate Cancer

Associated with Known or Potential Risk Factors Measured at Baseline

-------------------------------------------------

----Number of prostate cancer/n Hazard ratio 95% confidence interval

---------------------------------------------------------

Age

< 55 years 40/3,615 1.00 2.61-5.78

55 years 63/1,419 3.89

Plasma PSA

< 3.0 g/L 51/4,563 1.00 11.1-24.3

3.0 g/L 50/292 16.5

Current smokers

No 86/4,076 1.00 0.56-1.74

Yes 14/742 0.99

Body mass index

< 27 kg/m2 68/3,679 1.00 1.00-2.36

>/=27 kg/m2 30/1,141 1.54

Serum ß-carotene

< 0.373 mol/L 43/2,153 1.00 0.63-1.45

0.373 mol/L 44/2,172 0.96

Serum alpha-tocopherol

< 31.3 mol/L 47/2,159 1.00 0.56-1.31

31.3 mol/L 40/2,169 0.86

Serum vitamin C

< 8.63 g/mL 35/1,844 1.00 0.87-2.07

8.63 g/mL 48/1,847 1.34

Serum selenium

< 1.11 mol/L 48/2,298 1.00 0.69-1.51

1.11 mol/L 54/2,522 1.02

Serum zinc

< 13.4 mol/L 44/2,311 1.00 0.81-1.78

13.4 mol/L 57/2,519 1.20

-----------------------------------------------------

Table III. Hazard Ratios and Related 95% Confidence Intervals of Prostate Cancer

Associated with Supplementation, Overall and According to Potentially Modifying

Variables

-------------------------------------------------------------

----Supplement arm, number of prostate cancer/n Placebo arm, number of prostate

cancer/n Hazard ratio 95% confidence interval p-value for inter action

-------------------------------------------------

All participants 49/2,522 54/2,512 0.88 0.60-1.29

Age < 55 years 20/1,815 20/1,800 0.97 0.52-1.80 0.73

Age 55 years 29/707 34/712 0.83 0.51-1.37

Initial PSA < 3.0 g/L 18/2,293 33/2,270 0.52 0.29-0.92 0.009

Initial PSA >/=3.0 g/L 31/149 19/143 1.54 0.87-2.72

Nonsmokers 39/2,040 47/2,036 0.81 0.53-1.23 0.43

Smokers 8/372 6/370 1.27 0.44-3.67

Body mass index < 27 kg/m2 29/1,841 39/1,838 0.72 0.45-1.17 0.21

Body mass index </=27 kg/m2 17/574 13/567 1.25 0.61-2.57

ß-carotene < 0.373 mol/L 24/1,081 19/1,072 1.20 0.66-2.20 0.30

ß-carotene 0.373 mol/L 20/1,113 24/1,059 0.78 0.43-1.40

alpha-tocopherol < 31.3 mol/L 25/1,078 22/1,081 1.11 0.62-1.96 0.48

alpha-tocopherol 31.3 mol/L 19/1,118 21/1,051 0.82 0.44-1.53

Vitamin C < 8.63 g/mL 13/968 22/876 0.52 0.26-1.04 0.02

Vitamin C 8.63 g/mL 28/887 20/960 1.48 0.84-2.63

Selenium < 1.11 mol/L 23/1,132 25/1,166 0.93 0.53-1.63 0.86

Selenium >/=1.11 mol/L 26/1,290 28/1,232 0.85 0.50-1.46

Zinc < 13.4 mol/L 21/1,149 23/1,162 0.90 0.50-1.63 0.99

Zinc 13.4 mol/L 28/1,274 29/1,245 0.91 0.54-1.52

-----------------------------------------------------------

The changes that occurred during the follow-up in 5 markers of prostate cancer

risk

were compared between the 2 arms of the trial. The baseline characteristics were

well balanced between the 1,857 men randomized to the supplement arm and the

1,759

men randomized to the placebo arm of the trial. Similarly, there was no

difference

in the baseline levels of plasma PSA, free PSA, percentage of free PSA, IGF-I

and

IGF-II between the 2 arms of the trial (Table IV). The median time elapsed

between

the initial and the final plasma sample collection was identical in the 2 arms

of

the trial: 6.6 years. There was no statistical difference in the 2 arms of the

trial

in the changes that occurred over time in the level of the 5 markers (Table IV).

None of the baseline characteristics modified these associations or lack

thereof. In

particular, the supplementation did not affect the level of any of the 5 markers

in

men with plasma PSA < 3 g/L or among those with low-serum vitamin C at baseline.

Table IV. Baseline and Final Values for 5 Potential Determinants of Prostate

Cancer

Risk Among 1,857 Men Randomized in the Supplement ARM and 1,759 Men Randomized

in

the Placebo Arm of the Trial

---------------------------------------------------

----Supplement arm Placebo arm

----Baseline level, mean (SD) Final level, mean (SD) Baseline level, mean (SD)

Final

level, mean (SD) p-value for the difference of changes between arms

-------------------------------------------------

PSA (g/L) 1.22 (1.23) 1.64 (2.14) 1.28 (1.53) 1.66 (2.44) 0.55

Free PSA (g/L) 0.30 (0.20) 0.33 (0.26) 0.30 (0.19) 0.33 (0.26) 0.70

% free PSA 30 (14) 27 (12) 30 (14) 27 (12) 0.90

IGF-I (g/L) 157 (48) 139 (45) 159 (50) 142 (42) 0.84

IGF-II (g/L) 1,083 (202) 1,041 (197) 1,083 (194) 1,041 (192) 0.95

-----------------------------------------------

The p-values presented are those associated with the differences in the changes

that

occurred during the follow-up between the 2 arms of the trial.

Discussion

In this randomized trial, middle-aged men free of severe health condition took

either a placebo or a combination of antioxidant vitamins and minerals at

low-nutrition-like doses daily for 8 years. As in the Linxian trials,[22] the

supplementation consisted of a combination of several vitamins and minerals.

Thus,

the supplementation effect cannot be ascribed to any particular component of the

supplementation. Overall, there was a tendency for lower incidence of prostate

cancer among men in the supplement arm of the trial, but the supplementation had

opposite effects in men with total PSA below 3 g/L and in those with a higher

PSA

presumably because of yet undiagnosed prostate pathologies. In men with elevated

PSA

at baseline, the supplementation was associated with an increased incidence of

prostate cancer of borderline statistical significance. This result raises

concern

that antioxidant supplementation, even at low doses, could have adverse effects

on

subjects at high risk or with yet undiagnosed cancer as previously observed

among

smokers in the ATBC and CARET trials.[2][23] In men with normal PSA, the vitamin

and

mineral supplementation was associated with a statistically significant 48%

reduction in the incidence of prostate cancer in the present study. This effect

should be compared with what has been reported in previous prostate cancer

chemoprevention trials: a 63% reduction for selenium supplements,[1] a 32%

reduction

for alpha-tocopherol supplements,[2] either no effect or a 23% increase for

ß-carotene supplements[2][24] and no effect for a combination of ß-carotene and

vitamin A.[25] The doses of specific vitamins and minerals used in

supplementation

were 40-80% lower in the SU.VI.MAX trial than in these previous studies. The

median

duration of the supplementation was 8 years, the second longest duration among

all

antioxidant supplementation trials after the Physicians' Health Study I. In the

SU.VI.MAX trial, the baseline serum levels were, for selenium, 20% lower than in

the

study published by et al.[1]; for alpha-tocopherol, 20% higher than in the

ATBC trial[2]; for ß-carotene, 47% higher than in the ATBC trial[2] and

comparable

to that of men in the Physicians' Health Study.[5] No trial has yet evaluated

the

potential effect of vitamin C or zinc supplementation on prostate cancer, 2

micronutrients that were part of the supplementation used in the SU.VI.MAX

trial. It

is interesting to note that, in addition to high doses of single antioxidant

vitamins, the ongoing Physicians Health Study II will also assess the effect of

a

multivitamin and mineral supplement.[4]

The investigators of previously published trials have examined whether the

association between supplementation and prostate cancer was modified by a

variety of

factors: age,[2][24] education,[2] body mass index,[2][24] physical

activity,[24]

alcohol intake,[24] smoking,[2][24] baseline plasma antioxidant

level[1][2][5][11]

and dietary intake.[2][11][24] Unfortunately, the SU.VI.MAX investigators did

not

collect information on family history of prostate cancer. However, since the

intervention was randomly allocated, family history could not confound the

results.

It is possible that the intervention had a different effect among men with

family

history and among those without, but there are no data to suggest this modifying

effect in the literature. In our study, the effect of intervention on prostate

cancer incidence differed according to baseline vitamin C level, with a tendency

for

a protective effect among men with low vitamin C status. Overall, our results

and

those of previous studies do not provide sufficient evidence in favor of or

against

the hypothesis that the effect of the supplementation on prostate cancer

prevention

is greater among those with low baseline vitamin or mineral status. In the ATBC

trial, alpha-tocopherol supplementation had similar effects in men with low or

high

alpha-tocopherol serum levels.[2] Selenium supplementation appeared to have more

pronounced effects in men with lower plasma selenium than among those with

higher

levels in the trial conducted by et al.[1] In the Physicians' Health

Study,

there was no effect of ß-carotene supplementation overall, but a protective

effect

was observed for men in the lower quartile of baseline plasma ß-carotene.[5] It

should be noted that most studies, including ours, did not have sufficient

statistical power to address properly other than strong effect modification.

A particular feature of our study was the assessment of vitamin and mineral

supplementation on intermediary markers of prostate cancer risk: PSA and

IGF.[26][27] Prostate-specific antigen is a serine protease produced by the

epithelial cells of the prostate.[28] PSA, free PSA and percentage of free PSA

are

strongly associated with prostate cancer risk. The long-term predictive value of

total PSA has been established, even for low levels well within the normal

range.[29] The 2 insulin-like growth factors IGF-I and IGF-II are peptide

hormones

involved in regulation of cell proliferation, differentiation and apoptosis.[30]

High levels of IGF-I[31][32] and of IGF-II[33] and low levels of IGF binding

protein-3[32] have been associated with prostate cancer risk. However, a few

recent

studies have shown diverging results.[34][35] In our study, the reduction in the

rate of prostate cancer by the supplementation among men with normal baseline

PSA

was not accompanied by an effect on PSA or IGF levels. This suggests that

neither

the PSA nor the IGF axes are involved by the biologic mechanisms of prostate

cancer

chemoprevention by antioxidant vitamins and minerals.

The SU.VI.MAX trial followed a pragmatic approach in testing the effect of a

combination of 5 antioxidant vitamins or mineral at low doses. It is thus not

possible to identify which individual micronutrient or combination is

responsible

for the preventative effect observed. Nevertheless, our study results support

the

hypothesis that chemoprevention of prostate cancer can be achieved with

antioxidant

vitamins and minerals. In this respect, our findings are consistent with those

of

the 2 previous trials that have shown a reduction of prostate cancer risk with

either selenium or alpha-tocopherol supplementation.[1][2] Further studies

should be

conducted to identify the best preventative agent or combination of agents and

to

determine which dosages are both safe and effective.

Al Pater, PhD; email: old542000@...

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