?-Carotene Supplementation for Patients with Low
Baseline Levels and Decreased Risks of Total and
Nancy R. Cook, Sc.D.1
Meir J. Stampfer, M.D.2,3,4
Jing Ma, M.D.2
JoAnn E. Manson, M.D.1,2,3
Frank M. Sacks, M.D.2,4
Julie E. Buring, Sc.D.1,3
Charles H. Hennekens, M.D.1,3
1Division of Preventive Medicine, Department of
Medicine, Brigham and Women’s Hospital and
Harvard Medical School, Boston, Massachusetts.
2Channing Laboratory, Department of Medicine,
Brigham and Women’s Hospital and Harvard Med-
ical School, Boston, Massachusetts.
3Department of Epidemiology, Harvard School of
Public Health, Boston, Massachusetts.
4Department of Nutrition, Harvard School of Public
Health, Boston, Massachusetts.
Presented in part at the Annual Meeting of the
American Society of Clinical Oncology, Denver,
Colorado, May 17–20, 1997.
Source of financial support: Grants CA34944,
CA40360, CA42182, and CA58684 from the Na-
tional Institutes of Health.
The authors thank James Anderson, technical spe-
cialist at the vitamin analysis laboratory, for his
assistance with the laboratory assays.
Dr. Hennekens is currently Visiting Professor of
Epidemiology and Public Health at the University of
Miami, School of Medicine and his current address
is 1415 W. Camino Real, Boca Raton, FL 33486.
Address for reprints: Nancy R. Cook, Sc.D., Divi-
sion of Preventive Medicine, 900 Commonwealth
Avenue East, Boston, MA 02215-1204.
Received October 13, 1998; revisions received
January 6, 1999, and February 25, 1999; accepted
February 25, 1999.
BACKGROUND. The Physicians’ Health Study was a randomized, double-blind,
placebo-controlled trial using a 2 ? 2 factorial design including supplementation
with ?-carotene (50 mg every other day) in the primary prevention of cancer
among 22,071 U.S. male physicians ages 40–84 years at randomization. Before
randomization, the authors collected baseline blood specimens to determine
whether any benefit was greater among or confined to those with low baseline
levels of ?-carotene.
METHODS. Baseline blood samples were collected from 14,916 participants. These
samples were assayed, according to a nested case–control design, from 1439 men
subsequently diagnosed with cancer over 12 years of follow-up (631 with prostate
carcinoma) and 2204 controls matched by age and smoking habits.
RESULTS. Men in the lowest quartile for plasma ?-carotene at baseline had a
marginally significant (P ? 0.07) increased risk of cancer compared with those in
the highest quartile (relative risk [RR] ? 1.30, 95% confidence interval [CI], 0.98–
1.74). Men in the lowest quartile assigned at random to ?-carotene supplementa-
tion had a possible but nonsignificant decrease in overall cancer risk (RR ? 0.83,
95% CI, 0.63–1.09) compared with those assigned to placebo. This was primarily
due to a significant reduction in the risk of prostate carcinoma (RR ? 0.68, 95% CI,
0.46–0.99) in this group. After the first 2 years of follow-up were excluded, the
results were virtually unchanged.
CONCLUSIONS. These prespecified subgroup analyses appeared to support the idea
that ?-carotene supplementation may reduce risk of prostate carcinoma among
those with low baseline levels. Further follow-up of this population will help
determine whether these findings are valid. [See editorial on pages 1629–31, this
issue.] Cancer 1999;86:1783–92. © 1999 American Cancer Society.
KEYWORDS: ?-carotene, case–control studies, neoplasms, prostatic neoplasms.
larly those rich in ?-carotene, are at lower risk for cancer incidence,
suggesting a role for ?-carotene in the primary prevention of can-
cer.1,2Although these findings have been supported by plausible
biologic mechanisms,3case–control or cohort studies cannot distin-
guish the components of fruits and vegetables responsible for the
observed benefit.4Recent evidence from randomized trials have not
supported a protective effect of ?-carotene supplementation in can-
cer prevention. In the Alpha-Tocopherol, Beta-Carotene Cancer Pre-
vention Study (ATBC)5and the Beta-Carotene and Retinol Efficacy
Trial (CARET),6incidence of lung carcinoma was increased among
those assigned to active ?-carotene in populations of smokers or
bservational epidemiologic studies consistently have indicated
that individuals with diets high in fruits and vegetables, particu-
© 1999 American Cancer Society
asbestos workers. In contrast, the Physicians’ Health
Study (PHS) found no significant benefit or harm of
?-carotene supplementation with respect to total car-
cinoma or lung carcinoma incidence rates among U.S.
male physicians.7Although current smokers com-
prised 11% of PHS participants at baseline, there were
no significant differences in cancer incidence or mor-
tality rates with ?-carotene supplementation by base-
line smoking status.
Before randomization to the PHS, participants
were asked to provide a baseline blood specimen that
then was frozen and stored. The primary aim was to
assess whether any effect of ?-carotene supplementa-
tion was either larger or even limited to those with the
lowest levels of baseline plasma ?-carotene.8Evidence
supporting such effect modification was provided by
data from the Chinese Cancer Prevention Trial,9in
which supplementation with a combination of ?-car-
otene, vitamin E, and selenium led to a reduced risk of
gastric carcinoma and total mortality in a poorly nour-
ished population. Although data from both the ATBC10
and CARET11studies suggest no such modification for
lung carcinoma among those at high risk, the PHS is
the only trial to examine this issue in a population
comprised largely of nonsmokers, in which total can-
cer is influenced largely by prostate carcinoma. In this
report, we describe the observed effects of ?-carotene
supplementation in the PHS on total and prostate
carcinoma among those with low baseline plasma lev-
els of ?-carotene, using a prospective, nested, case–
PATIENTS AND METHODS
The PHS was a randomized, double-blind, placebo-
controlled trial with a 2 ? 2 factorial design testing the
effects of aspirin and ?-carotene in the primary pre-
vention of cardiovascular disease and cancer among
22,071 U.S. male physicians. The methods and main
study results have been described previously.7Partic-
ipants were ages 40–84 years in 1982 and had no
history of cancer (except nonmelanoma skin cancer),
myocardial infarction, stroke, or transient cerebral
ischemia; had no contraindications to aspirin use; and
were not currently taking aspirin, other platelet-active
medications, or supplements of vitamin A. Partici-
pants were asked to respond to a baseline question-
naire regarding medical history and health habits.
This included a limited semiquantitative food fre-
quency questionnaire containing food items high in
dietary ?-carotene. At baseline in 1982, 50% of partic-
ipants were never, 39% were past, and 11% were cur-
Physicians were randomly assigned to 1 of 4
groups including active aspirin (325 mg on alternate
days [Bufferin; Bristol-Myers, New York, NY]) plus
?-carotene placebo, active ?-carotene (50 mg on al-
ternate days [Lurotin; BASF Corporation, Mount Olive,
NJ]) plus aspirin placebo, both active agents, or both
placebos. Written informed consent was obtained
from all study participants, and the research protocol
was reviewed and approved by the institutional review
board at the Brigham and Women’s Hospital in Bos-
ton, Massachusetts. The randomized aspirin compo-
nent of the study was terminated early on January 25,
1988, primarily due to a statistically extreme (P ?
0.001) 44% reduction in the incidence rate of first
myocardial infarction among those patients assigned
to active aspirin.12The ?-carotene component contin-
ued until its scheduled end in December 1995 after an
average of 12 years of follow-up. At the end of 11 years
of follow-up, the last year completed by all partici-
pants, 99.2% of participants still were providing mor-
bidity information; follow-up for mortality was virtu-
ally 100% complete. At that time, 80% of participants
still were taking the study pills in both the active and
placebo ?-carotene groups.
Prior to randomization, study participants were
asked to provide baseline blood specimens for analy-
sis of plasma ?-carotene levels. Blood kits were mailed
to all enrolled physicians with instructions to have
their blood drawn into vacutainer tubes containing
ethylenediamine tetracetic acid. Participants were
asked to fractionate the blood by centrifugation and to
return (by overnight, prepaid courier) the plasma in
polypropylene cryopreservation vials. Each kit con-
tained a coldpack to keep the specimens cool until
they were received the following morning, when they
were divided into aliquots and stored at -82 °C. During
storage, precautions were taken so that no specimen
was thawed or warmed substantially. Specimens were
received from 14,916 of the randomized physicians
(68%), with 70% of samples received in the fall, be-
tween September and November 1982. Participants
who returned specimens were slightly older (age 53.4
years vs. 53.0 years; P ? 0.006), weighed less (24.9
kg/m2vs. 25.1 kg/m2; P ? 0.001), exercised more (2.4
times/week vs. 2.2 times/week; P ? 0.001), smoked
less (10.1% current smokers vs. 13.1% current smok-
ers; P ? 0.001), and drank slightly more alcohol (3.6
drinks/week vs. 3.5 drinks/week; P ? 0.04) than those
who did not return specimens. They were similar with
respect to ?-carotene assignment and dietary ?-caro-
Selection of Cases and Controls
On report of a diagnosis of cancer, medical records
were requested from hospitals and treating physicians
1784 CANCER November 1, 1999 / Volume 86 / Number 9
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