14 Articles | JNCI Vol. 101, Issue 1 | January 7, 2009
A large number of epidemiologic studies have suggested that a diet
high in fruits, vegetables, and other foods derived from plants is
associated with a lower risk of cancer ( 1 – 8 ). Antioxidant nutrients
such as ascorbic acid, ? -tocopherol, and the carotenoids (eg, beta
carotene) that are present in plant-derived foods may have a major
preventive role against carcinogenesis ( 9 ), and it has been sug-
gested that they may suppress tumor cell growth and induce tumor
cell apoptosis ( 10 – 12 ). Antioxidants also counterbalance the pro-
duction of reactive oxygen species (ROS), which may cause oxida-
tive damage to cells and modify cell growth regulatory pathways,
leading to enhanced risk for carcinogenesis ( 13 – 15 ).
Over the past three decades, numerous clinical trials ( 16 – 30 )
have evaluated the effi cacy of antioxidants and minerals, used sin-
gly or in various combinations, in the prevention of cancers and
other chronic diseases. However, their fi ndings have been incon-
sistent, and results of most of them ( 16 – 27 ) did not support a
benefi t of vitamin or mineral supplements in primary cancer
prevention. Several recent meta-analyses also showed no reduction
in risk for cancer development with antioxidant vitamins or beta
carotene, with the exception of a possible reduction in cancer
Affiliations of authors: Division of Preventive Medicine, Department of
Medicine, Brigham and Women ’ s Hospital and Harvard Medical School,
Boston, MA (JL, NRC, CA, EZ, JMG, MVD, JEB, JAEM); Department of
Epidemiology, Harvard School of Public Health, Boston, MA (NRC, JEB,
JAEM); Cardiovascular Division (CA), Division of Aging (JMG), Department
of Medicine, Brigham and Women’s Hospital; Department of Ambulatory
Care and Prevention, Harvard Medical School, Boston, MA (JEB) .
Correspondence to: Jennifer Lin, PhD, Division of Preventive Medicine,
Department of Medicine, Brigham and Women’s Hospital and Harvard
Medical School, 900 Commonwealth Ave East, Boston, MA 02215 (e-mail:
See “Funding” and “Notes” following “References.”
© The Author 2008. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: email@example.com.
Vitamins C and E and Beta Carotene
Supplementation and Cancer Risk: A Randomized
Jennifer Lin , Nancy R. Cook , Christine Albert , Elaine Zaharris , J. Michael Gaziano , Martin Van Denburgh ,
Julie E. Buring , JoAnn E. Manson
Background Observational studies suggested that a diet high in fruits and vegetables, both of which are rich with anti-
oxidants, may prevent cancer development. However, findings from randomized trials of the association
between antioxidant use and cancer risk have been mostly negative.
Methods From 8171 women who were randomly assigned in the Women’s Antioxidant Cardiovascular Study, a
double-blind, placebo-controlled 2 × 2 × 2 factorial trial of vitamin C (500 mg of ascorbic acid daily),
natural-source vitamin E (600 IU of ? -tocopherol every other day), and beta carotene (50 mg every other
day), 7627 women who were free of cancer before random assignment were selected for this study.
Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the
National Death Index. Cox proportional hazards regression models were used to assess hazard ratios (rep-
resented as relative risks [RRs]) of common cancers associated with use of antioxidants, either individually
or in combination. Subgroup analyses were conducted to determine if duration of use modified the asso-
ciation of supplement use with cancer risk. All statistical tests were two-sided.
Results During an average 9.4 years of treatment, 624 women developed incident invasive cancer and 176 women
died from cancer. There were no statistically significant effects of use of any antioxidant on total cancer inci-
dence. Compared with the placebo group, the RRs were 1.11 (95% confidence interval [CI] = 0.95 to 1.30) in
the vitamin C group, 0.93 (95% CI = 0.79 to 1.09) in the vitamin E group, and 1.00 (95% CI = 0.85 to 1.17) in
the beta carotene group. Similarly, no effects of these antioxidants were observed on cancer mortality.
Compared with the placebo group, the RRs were 1.28 (95% CI = 0.95 to 1.73) in the vitamin C group, 0.87 (95%
CI = 0.65 to 1.17) in the vitamin E group, and 0.84 (95% CI = 0.62 to 1.13) in the beta carotene group. Duration
and combined use of the three antioxidants also had no effect on cancer incidence and cancer death.
Conclusions Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary pre-
vention of total cancer incidence or cancer mortality.
J Natl Cancer Inst 2009;101: 14 – 23
JNCI | Articles 15
mortality with selenium supplementation ( 31 – 35 ). The negative
fi ndings may be attributable to the short exposure to interventions,
with most trials lasting only 4 – 6 years ( 36 ): because malignant
cancer cells can take decades to develop, many trials may have been
too short to demonstrate any benefi t ( 36 ). Another possible expla-
nation is that most trials have evaluated the effects of high doses of
only one or two antioxidants ( 36 – 39 ), although experimental data
have suggested that antioxidants act not only individually but also
cooperatively to achieve optimal effects on cancer prevention.
Moreover, heterogeneity of the study populations may have con-
tributed to the divergence of the fi ndings, with the possibility that
antioxidants could be benefi cial among populations more likely to
experience oxidative stress ( 40 ).
In this randomized factorial trial of an average 9 years of sup-
plementation and follow-up among women at high risk of cardio-
vascular disease, we systematically evaluated the individual and
combined effects of three antioxidant supplements, ascorbic acid,
vitamin E, and beta carotene, in the primary prevention of cancer
incidence and mortality.
Subjects and Methods
Study Design and Population
The Women’s Antioxidant Cardiovascular Study (WACS)
(ClinicalTrials.gov identifier NCT00000541) is a randomized,
double-blind, placebo-controlled, 2 × 2 × 2 factorial trial evaluat-
ing the benefits and risks of synthetic vitamin C (500 mg of ascor-
bic acid daily), natural-source vitamin E (600 IU of ? -tocopherol
every other day), and beta carotene (50 mg of Lurotin every other
day) among women at high risk for cardiovascular disease (CVD).
Vitamin C and beta carotene were supplied by BASF Corp
(Wyandotte, MI) and vitamin E was supplied by (Cognis Corp,
LaGrange, Il). Approximately 2 – 3 years after random assignment
to the antioxidant arms, a folic acid – vitamins B6 and B12 compo-
nent was added to the trial, yielding a four-arm factorial trial. The
WACS trial was approved by the Institutional Review Board of
the Brigham and Women’s Hospital (Boston, MA). The trial’s
independent Data and Safety Monitoring Board met annually to
review the results. Written informed consent was obtained from
The design of the trial has been described in detail ( 41 , 42 ).
Briefl y, between September 1992 and May 1995, 53 788 women
from a pool of more than 450 000 respondents to an invitation
packet of the Women’s Health Study ( 25 , 43 , 44 ) were considered
likely to be eligible for the study and were sent the WACS invita-
tional mailing. Women were considered to be eligible to partici-
pate in the WACS if they were at least 40 years of age; were
postmenopausal or not intending to become pregnant; and had
known CVD or at least three of the following cardiac risk factors:
hypertension, high cholesterol level, diabetes, parental history of
myocardial infarction, or obesity (ie, body mass index ≥ 30 kg/m 2 ).
Women were excluded if they had a self-reported history of cancer
(except nonmelanoma skin cancer) within the past 10 years, had
active liver disease or cirrhosis, had chronic kidney failure, were
current users of anticoagulants, or were unwilling to avoid out-of-
study use of vitamins A, C, and E and beta carotene at intakes
exceeding the recommended daily allowance during the trial.
Between June 1995 and October 1996, a total of 8171 women
were randomly assigned according to a 2 × 2 × 2 factorial design.
Results for the trial’s primary endpoints of major cardiovascular
events have been reported previously ( 42 ). We excluded women
from this analysis who reported having had a diagnosis of cancer
(n = 544) more than 10 years ago because the etiologic factors for
primary and recurrent cancer incidence are likely different ( 45 – 47 ).
As a result, 7627 women (93.3%) free of cancer at enrollment were
included in this analysis for the primary prevention of cancer inci-
dence and mortality ( Figure 1 ). We had more than 90% power,
with a two-sided test ( ? = .05), to detect the individual effect of
vitamins C and E and beta carotene with a 30% reduction in the
risk for total cancer incidence. Power to detect the individual effect
of vitamins C and E and beta carotene with a 40% reduction in the
risk for cancer death was more than 80%.
Study Treatment and Follow-up
After random assignment, participants received a supply of
monthly calendar packs containing antioxidant supplements or
placebo as well as follow-up questionnaires on compliance, poten-
tial adverse effects, occurrence of endpoints, and risk factors that
were sent every 6 months for the first year and annually thereafter.
Study treatment and endpoint ascertainment were continued in a
blinded fashion through January 31, 2005, the scheduled end of
the trial. In July 2006, follow-up and validation of reported end-
points were complete and morbidity and mortality follow-up
were completed for 93% and more than 99% of subjects,
respectively ( 42 ).
Compliance for use of the three antioxidants has been reported
elsewhere ( 42 ). Compliance, defi ned as having taken at least two
CONTEXT AND CAVEATS
Although some observational studies suggest that a diet high in
fruits and vegetables and thus antioxidants may be associated with
a reduced risk of cancer, randomized trials have not supported this
Randomized controlled trial using a factorial design with hazard
ratios from Cox regression models to compare intervention
This study, which was designed to have 80% power to detect a 30%
reduction in the overall risk of cancer, suggests that long-term
dietary supplementation with any combination of the antioxidants
vitamin C, vitamin E, or beta carotene does not reduce the risk of
cancer or the risk of dying from cancer.
There is no basis for a recommendation that individuals increase
dietary levels of antioxidants as a means of reducing cancer risk.
This study had very limited statistical power to investigate any
effect of dietary antioxidants on the risk of specific cancers.
From the Editors
16 Articles | JNCI Vol. 101, Issue 1 | January 7, 2009
thirds of the study capsules, was 76% at 4 years and 68% at 8 years
for each antioxidant. The average compliance throughout the trial
was 73%. Outside use of the three antioxidant supplements for at
least 4 d/mo was ranged from 2% to 13% at both 4 and 8 years and
was not different between supplement and placebo groups. No
statistically signifi cant difference in side effects between the sup-
plement and placebo groups was observed ( 42 ).
Women reported the occurrence of cancer through follow-up ques-
tionnaires, letters, or telephone calls. Deaths were reported by fam-
ily members or postal authorities or through the National Death
Index. For women who reported a diagnosis of cancer and for those
who had died, we sought permission from participants or the next
of kin if deceased to acquire medical records and pathology reports,
which were then reviewed by the WACS Endpoints Committee of
physicians blinded to the treatment assignment. Reports of cancer
were confirmed with pathology or cytology reports (94%) or, when
a pathology or cytology review was not conducted, cancer was con-
firmed by clinical and radiological or laboratory marker evidence
(eg, elevated CA 125). The primary cancer outcome was any inva-
sive cancer, excluding nonmelanoma skin cancer. Only confirmed
cancer outcomes were included in the analysis.
Analyses were conducted for the primary endpoint of total invasive
as well as site-specific cancers. If a woman developed more than
one primary cancer (excluding nonmelanoma skin cancer), the first
following random assignment was used in these analyses.
We used Cox proportional hazards regression models to calcu-
late hazard ratios (that were presented as relative risks [RRs]) and
95% confi dence intervals (CIs). Models included main effect terms
of the three antioxidants and age. Tests of proportionality of the
relative risks over time were performed with an interaction term of
treatment with the logarithm of time in the Cox models. The pro-
portionality assumption was not violated for total invasive cancers
( P ≥ .11 for all three antioxidants) or cancer death ( P ≥ .26).
We additionally performed analyses of the multiplicative inter-
actions among the three antioxidants with cancer incidence and
mortality. We fi rst tested interactions between pairs of the three
antioxidants in the models with adjustment for age and main effect
terms of the three antioxidants. We also tested interactions among
all three antioxidants in the model with adjustment for age, main
effect terms of the three antioxidants, and interaction terms
between any pairs of the three antioxidants. To evaluate whether
duration of supplement use may affect the risk of cancer develop-
ment, we also conducted subgroup analysis according to duration
of supplementation (1 – 5 and >5 years after random assignment).
Moreover, we assessed the effect modifi cation by variables that
may induce oxidative stress, including smoking status (never, past,
and current), alcohol consumption (<15 g/d or <1 drink/d vs ≥ 15
g/d or ≥ 1 drink/d), and body mass index (BMI; <25 or ≥ 25 kg/m 2 )
( 48 – 50 ), by use of multiplicative interaction terms between sub-
group indicators and supplement assignment and testing for trends
for ordinal subgroup categories.
To investigate the effect of compliance, we carried out a sensi-
tivity analysis that censored women at the time when they stopped
taking at least two thirds of their study medications, reported
Figure 1 . Flow diagram of participants in the
Women’s Antioxidant Cardiovascular Study.
Assessed for eligibility
Excluded (n=3,109) not meeting
inclusion criteria or unwillingness
Excluded from analysis (n=263)
with prior history of cancer before
Vitamin C treatment (n=4,087) Vitamin C placebo (n=4,084)
Excluded from analysis (n=281)
with prior history of cancer before
Vitamin E supplement (n=2,041)
Vitamin E placebo (n=2,046)
Beta carotene supplement (n=2,043)
Beta carotene placebo (n= 2,044)
Vitamin E supplement (n=2,042)
Vitamin E placebo (n=2,042)
Beta carotene supplement (n=2,041)
Beta carotene placebo (n=2,043)
JNCI | Articles 17
taking outside supplements containing study agents, or had miss-
ing compliance information. All statistical analyses were conducted
by SAS version 9 (SAS Institute, Cary, NC), with a two-sided test
with a threshold of .05 for statistical signifi cance.
Baseline characteristics were similar between the supplement and
placebo groups ( Table 1 ). The mean age (±SD) of all women (N =
7627) was 60.4 ± 8.8 years. Most of the participants were post-
menopausal (77% or 5909 women) and overweight or obese (77%
or 5848 women), and few (27% or 2067 women) reported having
taken multivitamins at baseline. The average baseline intakes of
antioxidants, assessed by a semiquantitative food frequency ques-
tionnaire in all women, including those of vitamins A, C, and E,
were greater than the amounts recommended by the recommended
daily allowance, according to the 2005 Dietary Guidelines ( 51 ).
However, no statistically significant difference in baseline intakes
of these antioxidants was observed between the supplement and
placebo groups. The distribution of risk factors for cancers assessed
at baseline including BMI, physical activity, current smoking, hor-
mone therapy use, use of screening tests, and family history of
cancer was similar in participants receiving supplements or placebo
( Table 1 ). Approximately half of the participants in the supplement
and placebo groups reported having used a nonsteroidal anti-in-
flammatory drug or aspirin during the past month (data not
shown). The average duration of follow-up from random assign-
ment to the end of the trial was 9.4 years (range = 8.3 – 10.1
Primary Cancer Incidence and Cancer Mortality
During the trial period, 624 women had a confirmed diagnosis of
invasive cancer, excluding nonmelanoma skin cancer. The major
sites of cancer were the breast (n = 257), lung (n = 74), and colorec-
tum (n = 44, 31 colon and 13 rectum). The total number of cancer
deaths was 176. There were no statistically significant effects of use
Table 1 . Baseline characteristics of women free of cancer according to the assignment groups in the Women’s Antioxidant
Cardiovascular Study *
Vitamin C Vitamin E Beta carotene
ActivePlacebo Active PlaceboActivePlacebo
No. of participants
Mean age, y (SD)
Other or unknown
Smoking status, %
Mean BMI, kg/m 2 (SD)
Mean physical activity, kcal/wk (SD)
History of diabetes, %
Family history of cancer, %
Hormone therapy use, %
Current E + P use
Current E-alone use
No. of mammogram screening, %
1 – 2
3 – 4
the past year, %
Current multivitamin use, %
Mean dietary intake/d (SD)
Total alcohol intake † , g
Total energy intake † , kcal
Total fat intake † , g
Total vitamin C intake † , mg
Total vitamin E intake † , IU
Total carotene intake † , IU
Total vitamin A intake † , IU
38243803 3791 383638073820
60.4 (9) 60.4 (9)60.4 (9) 60.4 (9)60.4 (9)60.4 (9)
26.727.9 27.427.127.0 27.5
10 762 (8542)
13 936 (9665)
10 579 (8559)
13 711 (9578)
10 754 (8520)
13 917 (9580)
10 591 (8580)
13 733 (9663)
10 675 (8357)
13 821 (9447)
10 667 (8738)
13 826 (9793)
* E + P = estrogen plus progestin; E-alone = estrogen alone.
† Included 7209 women who provided sufficient dietary information and had plausible total energy intake (600 – 3500 kcal/d).
18 Articles | JNCI Vol. 101, Issue 1 | January 7, 2009
of any antioxidant on total cancer incidence ( Table 2 ). Compared
with the placebo group, the RRs were 1.11 (95% CI = 0.95 to 1.30)
in the vitamin C supplement group, 0.93 (95% CI = 0.79 to 1.09)
in the vitamin E group, and 1.00 (95% CI = 0.85 to 1.17) in the
beta carotene group. Similarly, no effects of these antioxidants
were observed on cancer mortality ( Table 2 ). Compared with the
placebo group, the RRs were 1.28 (95% CI = 0.95 to 1.73) in the
vitamin C group, 0.87 (95% CI = 0.65 to 1.17) in the vitamin E
group, and 0.84 (95% CI = 0.62 to 1.13) in the beta carotene group.
When evaluating site-specifi c cancers, we found that the vita-
min E supplement group had a reduced (albeit not to a statistically
signifi cant extent) risk for colorectal cancer development com-
pared with the placebo group (RR = 0.63, 95% CI = 0.34 to 1.15,
P = .13), due largely to a reduced risk of colon cancer (RR = 0.41,
95% CI = 0.10 to 0.89, P = .02). However, there was no statistically
signifi cant association of vitamin E supplementation with rectal or
other cancers. Beta carotene supplementation was associated with
a reduced risk of incident non-Hodgkin lymphoma (RR = 0.46,
95% CI = 0.22 to 0.97, P = .04). There was no evidence that beta
carotene had statistically signifi cant associations with the risk of
other cancers. We also did not fi nd evidence for an association of
vitamin C supplementation with reduced risk of any cancers. The
vitamin C supplement group had a higher incidence rate for lung
cancer (RR = 1.84, 95% CI = 1.14 to 2.97, P = .01) compared with
the placebo group. The associations of the three antioxidants with
the risk of breast tumors in situ were also not statistically signifi -
cant (data not shown).
There were no statistically signifi cant interactions between
pairs of the antioxidants or among all three antioxidants for total
cancer incidence or death (see total years in Figure 2 ), and no sta-
tistically signifi cant interactions were observed for specifi c cancers
(data not shown). We conducted a sensitivity analysis by censoring
Table 2 . Total or site-specific cancer incidence and cancer mortality in the Women’s Antioxidant Cardiovascular Study *
Vitamin CVitamin E Beta carotene
No. of case
RR (95% CI) †
No. of case
RR (95% CI) †
No. of case
RR (95% CI) † ActivePlacebo ActivePlacebo Active Placebo
Other cancers ‡
1.11 (0.95 to 1.30)
1.11 (0.87 to 1.41)
1.84 (1.14 to 2.97)
0.76 (0.42 to 1.38)
2.32 (0.89 to 6.04)
0.85 (0.49 to 1.49)
0.84 (0.36 to 1.93)
0.99 (0.50 to 1.99)
0.93 (0.79 to 1.09)
0.98 (0.77 to 1.25)
1.25 (0.79 to 1.97)
0.63 (0.34 to 1.15)
1.00 (0.41 to 2.39)
0.67 (0.38 to 1.18)
0.58 (0.24 to 1.37)
0.77 (0.39 to 1.56)
1.00 (0.85 to 1.17)
1.01 (0.79 to 1.30)
1.26 (0.80 to 1.99)
1.32 (0.73 to 2.39)
1.24 (0.51 to 2.99)
1.27 (0.73 to 2.23)
1.20 (0.52 to 2.78)
0.46 (0.22 to 0.97)
1.24 (0.76 to 2.02)
1.28 (0.95 to 1.73)
1.03 (0.64 to 1.68)
0.87 (0.65 to 1.17)
0.81 (0.50 to 1.33)
0.84 (0.62 to 1.13)
* Hazard ratios are presented as relative risks (RRs) and 95% confidence intervals (CIs).
† RR is the rate in the treatment group compared with the rate in the placebo group for each agent.
‡ Included cancers of the thyroid, melanoma, leukemia, kidney, and bladder, with the number of cases ranging between 10 and 20.
012345012345678 9 10 11 12 13 14 15 16
Figure 2 . Hazard ratios and 95% confi dence intervals of total cancer incidence ( left ) and cancer mortality ( right ) according to duration of treatment
in the Women’s Antioxidant Cardiovascular Study. VC = vitamin C supplement; VE = vitamin E supplement; BC = ? -carotene supplement. Hazard
ratio is the rate in the treatment group compared with the rate in the placebo group for single and combined agents.
JNCI | Articles 19
women who did not meet our compliance criteria and found that
the results were not appreciably changed for total cancer incidence
or death (data not shown).
Duration of Antioxidant Supplementation
When separating the supplementation and follow-up time into two
periods, the early (year 1 to year 5) and later (year 6 to year 10)
periods of supplementation, we observed no statistically significant
associations of the three antioxidants (taken singly or combined)
with total cancer incidence or mortality for either period ( Figure 2 ).
However, there was a nonstatistically significant increase for either
period in cancer mortality in the vitamin C supplement group
( Figure 2 ).
We further evaluated whether the variables that may induce oxida-
tive stress modified associations of the three antioxidants with total
cancer incidence and cancer death. There was a modification by
cigarette smoking on vitamin E supplementation and cancer mor-
tality of borderline statistical significance ( P value for interaction =
.08). Women in the vitamin E supplement group who currently
smoked or had smoked in the past had lower rates of cancer death
(for current smokers, RR = 0.80, 95% CI = 0.45 to 1.41; and for
past smokers, RR = 0.62, 95% CI = 0.39 to 0.99), in contrast to
those who never smoked (RR = 1.50, 95% CI = 0.87 to 2.57). In
addition, women of normal BMI (<25 kg/m 2 ) in the vitamin
C supplement group had marginally higher rates of cancer death
(RR = 2.00, 95% CI = 1.12 to 3.58, P = .02) ( Table 3 ). However,
there was no statistically significant effect of vitamin C on the risk
of cancer death among women with high BMI ( ≥ 25 kg/m 2 ) ( Table 3 ).
The effects of the three antioxidants on cancer mortality were not
modified by alcohol consumption ( Table 3 ). The modification by
cigarette smoking, alcohol consumption, and BMI was also not
statistically significant for the effects of the three antioxidants on
total cancer incidence ( Table 3 ).
In this randomized trial of vitamins C and E and beta carotene
supplementation among women at high risk for cardiovascular
events, we observed no overall associations of the three antioxidant
supplements, taken singly or combined, with total cancer incidence
or mortality. Duration of supplementation also did not appear to
alter the associations of these supplements with risk of cancer or
mortality due to cancer.
In melanoma cells, vitamin C treatment effectively decreased the
expression of cyclooxygenase-2 and type I insulin-like growth factor
receptor, resulting in suppression of cell proliferation ( 10 ). Treatment
with antioxidants such as vitamin E and beta carotene was also
shown to induce cell apoptosis in breast cancer cells by restoring
transforming growth factor- ? and Fas (or CD95) signaling path-
ways ( 11 ) or increasing the expression of peroxisome proliferator –
activated receptor gamma ( 12 ). Antioxidants also counterbalance the
production of ROS and thus prevent the harmful effects of these
oxygen intermediates on cellular nucleic acids, lipids, and proteins
( 13 , 15 ). Growth regulatory pathways that are involved in cell prolif-
eration and apoptosis are sensitive to ROS, and these unavoidable
byproducts of aerobic respiration may in some circumstances lead to
inappropriate cell signaling and carcinogenesis ( 14 ).
Previous observational studies that assessed the relationship
between total intakes of antioxidant nutrients and cancer preven-
tion have yielded inconsistent results. Several case – control studies
have reported an inverse association between antioxidant intakes
and cancer risk, but cohort studies have generally observed little
association. A meta-analysis that reported risk reduction for
esophageal and gastric cardia adenocarcinoma with higher intakes
of vitamins E and C and beta carotene was based primarily on
case – control studies ( 52 ). Similarly, another meta-analysis con-
cluded that vitamin C or beta carotene intakes were inversely
associated with breast cancer risk, but the inverse association was
mainly driven by case – control studies ( 6 ). By contrast, other
pooled analyses of prospective studies have not shown an associa-
tion of vitamins E and C or beta carotene intakes with risk of
incident cancers of the breast ( 53 ), colorectum ( 54 ), lung ( 55 ), or
ovary ( 56 ). Therefore, the cumulative data from observational
studies offer limited, if any, support for an inverse association
between antioxidant intakes and risk for cancer development.
Numerous randomized trials have also been conducted to
investigate the effects of antioxidants in the prevention of cancers,
but the fi ndings have been mostly disappointing ( 16 – 27 ). A meta-
analysis that pooled data from 12 randomized trials of antioxidants
and primary cancer prevention showed no reduction in risk for
total cancer incidence with antioxidant supplementation (RR =
0.99, 95% CI = 0.94 to 1.04) ( 35 ). With respect to individual types
of antioxidants, the authors of this meta-analysis concluded that
vitamin E did not reduce overall cancer (RR = 0.99, 95% CI = 0.94
to 1.04), but beta carotene supplementation was associated with a
slight increase in cancer incidence (RR = 1.06, 95% CI = 1.00 to
1.12), with the increased risk mostly seen in smokers (RR = 1.10,
95% CI = 1.03 to 1.18) ( 35 ). Similarly, meta-analyses of the asso-
ciation of antioxidants and minerals with incidence of cancer at
specifi c sites indicated no benefi cial effects of antioxidants or min-
erals. Two meta-analyses ( 31 , 32 ) on incident gastrointestinal can-
cers found no statistically signifi cant effects of supplementation
with beta carotene; vitamins A, C, and E; and selenium (alone or
in combination) [from Bjelakovic et al. ( 31 ), pooled RRs = 0.90,
95% CI = 0.77 to 1.05; and from Bjelakovic et al. ( 32 ), pooled
RRs = 0.94, 95% CI = 0.83 to 1.06]. Another meta-analysis of
eight randomized trials also reported no statistically signifi cant
effects of beta carotene; vitamins A, C, or E; or selenium supple-
ments, alone or in combination, on the prevention of colorectal
adenoma (pooled RR = 0.82, 95% CI = 0.60 to 1.1) ( 33 ). Consistent
with these analyses, we also found no effects of vitamins C and E
and beta carotene supplementation in reducing the risk for total
Systematic reviews of antioxidant trials also found no reduction
in cancer mortality with antioxidant supplementation. The meta-
analysis of 12 randomized trials of vitamin or mineral supplements
described above reported no association between antioxidants and
cancer mortality (pooled RR = 1.03, 95% CI = 0.92 to 1.15) ( 35 ).
Specifi cally, no reduction in cancer mortality was found with vita-
min E (RR = 1.04, 95% CI = 0.94 to 1.04) or beta carotene (RR =
1.16, 95% CI = 0.98 to 1.37) supplementation ( 35 ). However, a
possible risk reduction in cancer mortality was observed for the
20 Articles | JNCI Vol. 101, Issue 1 | January 7, 2009
Table 3 . Total cancer incidence and cancer mortality according to randomization status in the Women’s Antioxidant Cardiovascular Study *
No. of case
RR (95% CI) †
P interaction ‡
No. of case
RR (95% CI) †
P interaction ‡
No. of case
RR (95% CI) †
P interaction ‡
1.08 (0.84 to 1.39)
1.04 (0.81 to 1.34)
1.00 (0.78 to 1.28)
1.13 (0.89 to 1.43)
0.85 (0.67 to 1.07)
0.99 (0.78 to 1.25)
1.19 (0.82 to 1.74)
0.93 (0.64 to 1.36)
1.08 (0.74 to 1.58)
Low ( ≤ 15 g/d or
≤ 1 drink per d)
1.11 (0.94 to 1.30)
0.92 (0.78 to 1.08)
0.98 (0.83 to 1.16)
High (>15 g/d or >1 drink per d)
1.28 (0.71 to 2.30)
1.04 (0.58 to 1.88)
1.25 (0.69 to 2.25)
Body mass index
<25 mg/m 2
1.29 (0.94 to 1.78)
0.75 (0.54 to 1.04)
1.05 (0.76 to 1.45)
≥ 25 mg/m 2
1.07 (0.89 to 1.28)
0.98 (0.82 to 1.18)
0.99 (0.83 to 1.19)
1.06 (0.62 to 1.80)
1.50 (0.87 to 2.57)
0.82 (0.48 to 1.39)
1.29 (0.81 to 2.05)
0.62 (0.39 to 0.99)
0.84 (0.53 to 1.33)
1.65 (0.93 to 2.95)
0.80 (0.45 to 1.41)
0.94 (0.53 to 1.65)
Low ( ≤ 15 g/d or
≤ 1 drink per d
1.29 (0.94 to 1.75)
0.84 (0.62 to 1.14)
0.83 (0.61 to 1.13)
High (>15 g/d or >1 drink per d)
1.22 (0.39 to 3.80)
1.46 (0.46 to 4.63)
0.99 (0.32 to 3.06)
Body mass index
<25 mg/m 2
2.00 (1.12 to 3.58)
0.74 (0.42 to 1.29)
0.93 (0.54 to 1.62)
≥ 25 mg/m 2
1.08 (0.76 to 1.54)
0.92 (0.65 to 1.31)
0.80 (0.56 to 1.14)
* Hazard ratios are presented as relative risks (RRs) and 95% confidence intervals (CIs). † RR is the rate in the treatment group compared with the rate in the placebo group for each agent.
‡ Two-sided, based on the chi-square test for interaction.
JNCI | Articles 21
mineral supplement selenium (RR = 0.78, 95% CI = 0.65 to 0.94)
( 35 ). A pooled analysis of fi ve studies from the two Linxian trials
(the Linxian General Population Trial and the Linxian Dysplasia
Trial) also did not present strong evidence that vitamin C com-
bined with molybdenum improves cancer survival (RR = 1.06, 95%
CI = 0.92 to 1.21) ( 34 ). Two recent meta-analyses have concluded
that there may be an increase in total mortality with increasing
antioxidant use ( 31 , 57 ). A review of 19 clinical trials reported a
dose – response relationship between vitamin E and risk for total
death ( 57 ). A later review comprising 47 low-bias risk (high meth-
odological quality) trials reported that supplementation with vita-
min E or beta carotene increased total mortality (RR = 1.04, 95%
CI = 1.01 to 1.07, and RR = 1.07, 95% CI = 1.02 to 1.11, respec-
tively), but a modifi cation of risk estimates by dosage was evident
only with beta carotene supplementation ( 58 ). By contrast, supple-
mentation with vitamin C did not infl uence total mortality ( 58 ). In
this population, we observed no association of supplementation
with vitamin C or E or beta carotene with fatal cancer events.
A recent meta-analysis of four large randomized trials sug-
gested that beta carotene supplementation may be associated with
elevated lung cancer risk among current smokers (RR = 1.24, 95%
CI = 1.10 to 1.39) but not among past smokers (RR = 1.10, 95%
CI = 0.84 to 1.45) ( 59 ). In our population with a low prevalence of
smoking, we observed no effect of beta carotene on lung cancer.
Nonetheless, we found that vitamin C was associated with an ele-
vated risk for lung cancer incidence. Two previous trials of vitamin
C combined with other antioxidants reported no effects on inci-
dence of respiratory cancers ( 16 , 24 ). The Linxian General
Population Trial also reported no statistically signifi cant effect of
vitamin C combined with molybdenum on lung cancer death
(RR = 1.01, 95% CI = 0.73 to 1.39) ( 60 ). In observational studies,
no association between total vitamin C intake and lung cancer risk
was reported in a pooled analysis of nine prospective studies (RR
comparing the highest vs lowest quintile = 0.97, 95% CI = 0.78 to
1.22, P for trend = .82) ( 55 ). It has been suggested that vitamin C
may act as a pro-oxidant and promote oxidative damage to DNA
when its local concentrations are high ( 61 , 62 ). However, the over-
all evidence thus far suggests that there is no substantial oxidative
DNA damage in humans who ingest high amounts of vitamin C
( 63 , 64 ). Our results that indicate an association between vitamin C
supplementation and lung cancer may be due to chance.
Nevertheless, a possible increase in lung cancer risk among women
with vitamin C supplementation warrants further investigation in
analyses of data from other completed randomized trials.
In our trial, neither duration of treatment nor combination of
the three antioxidant supplements had effects on overall fatal or
nonfatal cancer events. Thus, our results are in agreement with the
recent review of randomized trials indicating that total mortality
was not affected by duration of supplementation and single or
combined antioxidant regimens ( 58 ).
Several other factors besides duration and the combination of
supplements could affect the effi cacy of antioxidants. For instance,
lifestyle behaviors may modify an individual’s response, in terms of
cancer risk, to antioxidant supplementation. Findings from the
Linxian General Population Trial ( 65 ), which showed a possible
reduction in cancer incidence with vitamin and mineral supplemen-
tation in a poorly nourished population, suggest that antioxidant
supplementation is most likely benefi cial for individuals who are
low or defi cient for various nutrients. By contrast, most studies,
including ours, were conducted among well-nourished populations
that had suffi cient intakes of antioxidants ( 58 ). In addition, there
may be a sex-specifi c difference in the effect of antioxidants on
cancer risk. In the Supplémentation en Vitamines et Minéraux
Antioxydants (SUVIMAX) trial, antioxidant supplementation was
associated with a lower cancer incidence in men, but not in women
( 16 ). Although men in the SUVIMAX trial may have benefi ted
from antioxidant supplements due to their lower baseline levels of
antioxidants ( 16 ), subsequent fi ndings of an inverse association
between baseline serum antioxidant levels and total cancer inci-
dence in men but not in women suggest that factors other than
baseline antioxidant levels may play a role in mediating any effects
on carcinogenesis ( 66 ). Different antioxidant effects attributable to
gender also could have contributed to the null results in trials con-
ducted among female populations, including ours.
Limitations of the WACS trial include the lack of complete
follow-up and compliance. However, when we conducted sensitiv-
ity analyses that excluded women who did not meet the compliance
criteria, we observed no major changes in the results. Another
limitation of this study is that it may not be appropriate to apply
our results, obtained from a population at high risk for CVD, to
the general population. Nevertheless, our results are mostly con-
sistent with previous fi ndings from high-risk populations. We also
had limited power to evaluate the combined effects of the three
antioxidants on site-specifi c incident cancers. For example, there
was less than 40% power to detect a 30% reduction in the risk for
major site-specifi c cancers such as the breast, colorectum, or lung
with supplementation with the three antioxidants. However, we
have tested the combined effects on total cancer incidence with
nearly 80% power for detection of the same magnitude of risk
reduction and did not fi nd any statistically signifi cant effects result-
ing from the combined supplements. Finally, although this ran-
domized trial of antioxidants is one of the few trials with long
duration of treatment, it may still be of insuffi cient duration to
assess effects on cancer incidence, given the long latency for
In conclusion, fi ndings from the WACS trial suggest that there
are no overall benefi ts or risks of vitamins C and E and beta caro-
tene supplementation in the primary prevention of total cancer
incidence or cancer mortality.
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Grant HL46959 from the National Heart, Lung, and Blood Institute and
grants CA112529 and CA126846 from the National Cancer Institute.
The study sponsor had no role in the design of the study; the collection, analysis,
and interpretation of the data; the writing of the manuscript; or the decision to
publish. J. M. Gaziano has received pills and packaging for another study from
We acknowledge the invaluable contributions of the WACS staff, includ-
ing Jean MacFadyen, Eleanor Danielson, Marilyn Chown, Shamikhah Curry,
Margarette Haubourg, Felicia Zangi, Tony Laurinaitis, Geneva McNair,
Philomena Quinn, Harriet Samuelson, Ara Sarkissian, Natalya Gometskaya,
and M. V. Moorthy. We also thank the cancer endpoints reviewers including
Wendy Chen, I-Min Lee, and Shumin Zhang. Finally, we are indebted to the
dedicated WACS participants.
Manuscript received April 23 , 2008 ; revised October 3 , 2008 ; accepted
October 30 , 2008 .