Int. J.
Cancer: 119, 2221–2224 (2006)
' 2006 Wiley-Liss, Inc.
SHORT REPORT
Antioxidant vitamins supplementation and mortality: A randomized trial in head
and neck cancer patients
Isabelle Bairati1, François Meyer1*, Edith Jobin1, Michel Gelinas2, Andre Fortin3, Abdenour Nabid4,
François Brochet5 and Bernard Têtu1
1
Laval University Cancer Research Center, Quebec City, Quebec, Canada
2
Centre Hospitalier de l’Universit
e de Montreal, Montreal, Quebec, Canada
3
Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada
4
Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
5
Complexe Hospitalier de la Sagamie, Saguenay, Quebec, Canada
There has been concern that long-term supplementation with high-
dose antioxidant vitamins, especially vitamin E (a-tocopherol), may
increase all-cause mortality. We conducted a randomized controlled
trial with a-tocopherol (400 IU/day) and b-carotene (30 mg/day)
supplements among 540 head and neck cancer patients treated by
radiation therapy. Supplementation with b-carotene was discontin-
ued during the trial. The supplements were given during radiation
therapy and for 3 additional years. During the follow-up (median
6.5 years), 179 deaths were recorded. All death certificates were
obtained. All-cause and cause-specific mortality rates were com-
pared between the 2 arms of the trial by Cox regression. All-cause
mortality was significantly increased in the supplement arm: hazard
ratio: 1.38, 95% confidence interval 1.03–1.85. Cause-specific mor-
tality rates tended to be higher in the supplement arm than in the
placebo arm. Our results concur with previous reports to suggest
that high-dose vitamin E could be harmful.
' 2006 Wiley-Liss, Inc.
Key words: randomized trial; cancer; mortality; antioxidant vitamins;
a-tocopherol; b-carotene
Recently published metaanalyses of randomized trials testing
antioxidant vitamins and minerals supplementation have provided
evidence for their lack of efficacy, and raised concern about
increased mortality thus questioning the perceived benefits of
these supplements.1–3 We conducted a multicenter, double-blind,
placebo-controlled, randomized chemoprevention trial with a-to-
copherol and b-carotene supplements among patients treated by
radiation therapy for head and neck cancer.4,5 Here, we report the
trial results for all-cause and cause-specific mortality.
Methods
Between October 1, 1994 and June 6, 2000, 540 patients with
stage I or II head and neck cancer were recruited in 5 radiation
therapy centers in the province of Quebec, Canada, to take part in
a double-blind, placebo-controlled, randomized chemoprevention
trial with a-tocopherol and b-carotene supplements. The primary
objective of the trial was the prevention of second primary
cancers. On the basis of an expected 50% reduction of the rate of
second primary cancers in the supplement arm, 555 patients had to
be randomized to provide a statistical power of 80% to the trial.
The institutional review board of each participating center ap-
proved the study protocol. All patients gave written informed con-
sent prior to randomization. Patients with any of the following
conditions were ineligible for the study: Karnofsky performance
score of less than 60; multiple primary head and neck cancers or a
history of cancer; severe cardiovascular disease; inadequate renal,
hepatic or hematologic function; anticoagulant therapy; pregnancy
or average daily supplement intake of b-carotene or vitamin E
in the preceding year greater than 6.0 mg and 50 IU, respectively.
A computer-generated randomization list was prepared in advance
for each collaborating center using an allocation ratio of 1:1 and
random permuted blocks. Patients were randomly assigned to
receive a daily supplementation consisting of vitamin E (1 capsule
of 400 IU DL-a-tocopherol) and b-carotene (1 capsule of 30 mg)
Publication of the International Union Against Cancer
or placebos during radiation therapy and for 3 years after radiation
therapy ended. Concerns about adverse effects of b-carotene
supplementation prompted the investigators to halt the use of b-
carotene after the first 156 patients had been enrolled. The trial
was continued with a-tocopherol alone.
Follow-up information was obtained by the collaborating radia-
tion oncologists and the study nurses every 6 months during the
3 years following the end of radiation therapy and then once a year
until the end of the study. At each follow-up visit during the sup-
plementation period, the study nurse assessed compliance sepa-
rately for each supplement or placebo by dividing the total number
of unreturned capsules by the number of days between visits. As
per protocol, follow-up was continued beyond the supplementa-
tion period because a prolonged residual effect of antioxidant sup-
plementation was anticipated. Copies of medical notes, pathology
reports and hospital records were requested for all important
health events and hospitalizations during follow-up. In most in-
stances, deaths were identified by the study staff in the collaborat-
ing hospitals. In addition, to ensure complete ascertainment, re-
cord linkage with the Quebec mortality files was performed using
the unique Quebec health insurance identifier from enrollment
until December 31, 2004, for all but 10 participants who did not
consent to this record linkage. Death certificates were obtained for
all participants who died either from the hospital where the patient
had died or from the Institut de la statistique du Quebec. The cause
of death was taken as indicated on the death certificate except
when evidence from medical and hospital data clearly indicated
another cause. In all cases, the cause of death was assigned with-
out knowledge of the patient intervention arm assignment.
Follow-up time was calculated from the time of randomization
until the date of last visit (for the 10 participants who had not con-
sented to record linkage), the date of death or December 31, 2004.
Distribution of time until failure in the 2 treatment arms was
described using Kaplan-Meier survival curves. The analysis, per-
formed under the intention-to-treat principle, compared the mortal-
ity rates in the 2 study arms in Cox proportional hazards models.6
For each hazard ratio (HR), the 95% confidence interval (CI) was
calculated. The Cox models were used to adjust for covariates; how-
ever, none of the observed effects was confounded by patient base-
line characteristics. The proportionality assumption of the models
was always satisfied. All analyses were performed using SAS, ver-
sion 8.2 (SAS Institute, Cary, NC). All statistical tests are 2-sided.
Results
During the recruitment period, 1,151 new patients with stage I
or II squamous cell carcinoma of the head and neck were treated
Grant sponsor: National Cancer Institute of Canada with funds from the
Canadian Cancer Society; Grant numbers: 4738, 8176, 13211.
*Correspondence to: E-mail: francois.meyer@chuq.qc.ca
Received 13 December 2005; Accepted 15 February 2006
DOI 10.1002/ijc.22042
Published online 13 July 2006 in Wiley InterScience (www.interscience.
wiley.com).
2222 BAIRATI ET AL.

FIGURE 1 – Flow diagram of subjects’ progress through the trial.

TABLE I – BASELINE CHARACTERISTICS OF THE 540 TRIAL PARTICIPANTS

BY TREATMENT ARM
Supplement arm Placebo arm p-value

Total number of 273 267

patients randomized
Patients randomized to 79 77
a-tocopherol and
b-carotene or placebos
Patients randomized 194 190
to a-tocopherol
alone or placebo
Age (years) [mean (SD)] 63 (10) 62 (9) 0.30
Male sex [no. (%)] 223 (82) 203 (76) 0.11
Smokers in preceding 178 (65) 165 (62) 0.41
year [no. (%)]
Laryngeal cancer 225 (82) 225 (84) 0.56
[no. (%)]
Stage II [no. (%)] 101 (37) 107 (40) 0.46
Plasma a-tocopherol 33 (10) 34 (14) 0.27
(lmol/l) [mean (SD)] FIGURE 2 – Kaplan-Meier curves of survival until death from any cause
Plasma b-carotene 0.23 (0.18) 0.23 (0.24) 0.79 among participants randomly assigned to the supplement arm (solid line) or
(lmol/l) [mean (SD)] to the placebo arm (dotted line). Data are only shown up to 10 years of fol-
low-up because of the small numbers of participants beyond that time.

in the participating radiation oncology centers. Of these 1,151, (Fig. 1). The baseline characteristics of the 273 and 267 patients
15% refused to participate and 38% were ineligible. The remain- randomly assigned to the supplement and placebo arms, respec-
ing 47% (n 5 540) were eligible and consented to be enrolled tively, were similar in the 2 groups (Table I). The compliance with
 ANTIOXIDANT VITAMINS SUPPLEMENTATION AND MORTALITY 2223
TABLE II – NUMBER OF DEATHS, MORTALITY RATE (PER 1,000 PERSON-YEARS (PY)) FOR DEATHS OF ANY CAUSE AND FOR DEATHS ATTRIBUTED
TO THE INITIAL HEAD AND NECK CANCER, TO A SECOND PRIMARY CANCER, TO ANY CANCER, OR TO NONCANCER RELATED CAUSES, CRUDE HAZ-
ARD RATIOS (HR) AND 95% CONFIDENCE INTERVALS (CIS) ASSOCIATED WITH THE INTERVENTION ACCORDING TO THE TYPE OF SUPPLEMENTATION1
Supplement arm Placebo arm
Cause of death Supplementation HR (95% CI)
No. deaths Mortality rate No. deaths Mortality rate
per N at risk (per 1,000 py) per N at risk (per 1,000 py)

Any cause Any supplementation 102/273 62.63 77/267 45.52 1.38 (1.03–1.85)
Any cause a-Tocopherol 1 b-carotene 37/79 66.58 30/77 50.99 1.31 (0.81–2.11)
Any cause a-Tocopherol alone 65/194 60.58 47/190 42.61 1.43 (0.98–2.07)
Initial cancer Any supplementation 32/273 19.65 23/267 13.60 1.42 (0.83–2.43)
Second primary Any supplementation 39/273 23.95 31/267 18.33 1.32 (0.83–2.12)
cancer
Any cancer Any supplementation 71/273 43.60 54/267 31.93 1.36 (0.96–1.94)
Noncancer causes Any supplementation 35/273 21.49 27/267 15.96 1.36 (0.82–2.24)
1
Any supplementation: a-tocopherol 1 b-carotene or a-tocopherol alone; a-tocopherol 1 b-carotene; a-tocopherol alone.

the prescribed supplementation was excellent throughout the trial.
During the prescribed supplementation period, 36 patients in the
intervention arm and 34 patients in the placebo arm stopped taking
the capsules and were assigned zero compliance for the rest of the
supplementation period. In the supplement arm, the average com-
pliance, assessed by capsule count, was 90% during radiation ther-
apy and 88, 84 and 80% during the 1st, 2nd and 3rd years after the
end of radiation therapy, respectively. In the placebo arm, these
figures were 89, 86, 83 and 80%, respectively.
The median duration of radiation therapy was 43 days and the
median duration of the supplementation was 3.1 years. These
durations were identical in the 2 arms of the trial. The median du-
ration of follow-up was 6.4 years in the supplement arm and
6.6 years in the placebo arm of the trial. A total of 179 deaths, 102
in the supplement arm and 77 in the placebo arm, were recorded
during the follow-up. Figure 2 presents the distribution of survival
time until death in the 2 treatment arms. Overall survival was con-
sistently lower among participants randomized to the supplement
arm (p 5 0.033). Table II presents the crude hazard ratios associ-
ated with supplementation for death of any cause, death attributed
to the initial head and neck cancer, to the second primary cancer,
to cancer (either the initial head and neck cancer or the second pri-
mary cancer), and to noncancer causes. When compared with par-
ticipants in the placebo arm, those randomized to the supplement
arm had a statistically significant increased all-cause mortality
rate: HR 5 1.38 (95% CI 5 1.03–1.85). The hazard ratios for spe-
cific causes of death were consistently increased and of similar
magnitude (HR ranging from 1.31 to 1.43). Higher all-cause mor-
tality rates were observed in patients who had received a-tocoph-
erol alone (HR 5 1.43, 95% CI 5 0.98–2.07) and in those who
had also received b-carotene supplements in addition to a-tocoph-
erol for some time at the beginning of the trial (HR 5 1.31, 95%
CI 5 0.81–2.11).
mortality. All patients in the supplement arm of the trial were
exposed to a-tocopherol during the entire supplementation period.
Some have also been exposed to b-carotene for a short period of
time at the beginning of the trial. Our results suggest that, in our
trial, the addition of b-carotene to a-tocopherol did not markedly
affect the mortality rates.
Three trials testing specifically b-carotene supplementation
showed moderate (relative risk (RR) ranging from 1.07 to 1.18),
often not statistically significant, increases in all-cause and cancer
mortality7–9 while another10 has not (RR 5 1.02). Nine trials test-
ing specifically a-tocopherol supplementation have assessed its
effect on all cause mortality; 5 of them7,11–14 showed no effect
(RR 0.85–1.04) while 4 others15–18 indicated moderate, not statis-
tically significant, increases in all-cause mortality (RR 1.07–1.22).
Four of these trials have examined the effect of a-tocopherol sup-
plementation on cancer specific mortality, 3 of them7,14,16 showed
a moderate, not statistically significant increase (RR 1.08–1.12)
while the other13 indicated no association. The interpretation of
the results is less straightforward for the several trials in which the
supplementation combined a-tocopherol with other antioxidant
vitamins (often b-carotene and vitamin C) and minerals.3
Although vitamin E is considered relatively safe, long term use
of high-dose could be associated with adverse effects.19 At high
dose, vitamin E may have prooxidant effects and displace other
antioxidants thus increasing vulnerability to oxidative dam-
age.20,21 Despite the absence of proven benefits, antioxidant vita-
min supplements are taken at high doses for prolonged periods of
time by many healthy adults, by people at high risk of cardiovas-
cular disease or cancer and by cancer patients.22,23 Approximately
11% of the U.S. adult population consumes at least 400 IU of vita-
min E per day.22 Our results concur with previous reports3 to sug-
gest that high-dose vitamin E could be harmful.

Discussion Acknowledgements
Our results add to the growing evidence that long-term supple- Dr. Bairati is the recipient of a senior scientist award from the
mentation with high-dose antioxidant vitamins could increase Fonds de Recherche en Sante du Quebec.

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