Affiliations of authors: K. Woodson, J. A. Tangrea, P. R. Taylor, D. Albanes, Cancer Prevention Studies Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD; M. J. Barrett, Information Management Services, Inc., Silver Spring, MD; J. Virtamo, National Public Health Institute, Helsinki, Finland.
Correspondence to: Karen Woodson, Ph.D., M.P.H., National Institutes of Health, 6006 Executive Blvd. MSC 7058, Bethesda, MD 20892-7058.
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ABSTRACT |
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INTRODUCTION |
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Observational studies in humans of the association between -tocopherol and lung cancer
have yielded inconsistent results. Prediagnostic serum levels have been shown to be inversely
associated with lung cancer in some (7-9) but not all (10-12) cohort investigations, and case-control studies [reviewed in (13)] are generally supportive of reduced lung cancer risk among persons having
higher blood levels of
-tocopherol.
We investigated the relationship between prospectively collected serum -tocopherol and
lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.
Although this controlled trial did not provide evidence of lung cancer prevention from
-tocopherol supplementation overall (14), it was important in this
setting to evaluate whether prerandomization serum
-tocopherol concentrations, reflecting
usual dietary intake, absorption, and other aspects of the vitamin's metabolism, were
predictive of the subsequent development of lung cancer. The study's size and number of
events provided sufficient power to tightly control for confounding and to carefully evaluate effect
modification by several relevant study factors. Underlying our investigation was the hypothesis
that, because the ATBC Study was made up of older, chronic cigarette smokers, baseline serum
levels might better reflect their long-term exposure to antioxidants during earlier, critical periods
of tumorigenesis.
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SUBJECTS AND METHODS |
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Identification of lung cancer case patients. Participants in the trial who were diagnosed with incident primary cancer of the lung or bronchus [International Classification of Diseases, 9th revision, code No. 162 (15)] up to December 31, 1994, were identified through the Finnish Cancer Registry and the Register of Causes of Death, which provided close to 100% case ascertainment nationwide (16). The medical records of the case patients diagnosed during the intervention period (up to April 30, 1993; n = 874) were centrally reviewed independently by two study physicians, and those of the cases patients who were identified after intervention (up to December 31, 1994; n = 270) were reviewed by one study physician. Histologic or cytologic confirmation, with the use of the classification of the International Classification of Diseases for Oncology (17), was made for 93% of the cases. Histologic subtype information for the trial period case patients was obtained from central review of histopathologic and cytologic specimens by two pathologists and pulmonary cytologists, respectively. Thirty-four percent of the cases were of the squamous cell type, 18% were of the small-cell type, 13% were adenocarcinomas, and 35% were of other and indeterminant cell types. Locally reviewed pathology reports on postintervention cases were available but were not included in the histologic subtype analyses.
Data collection. General medical history, diet, smoking, and other background
dataalong with a fasting blood samplewere obtained from all subjects at
baseline. Blood samples were protected from light, divided into aliquots, and frozen and were
analyzed soon after collection (within 2 years), thus minimizing the risk of -tocopherol
degradation. Serum concentrations of
-tocopherol were determined by high-performance
liquid chromatography at one laboratory (18), and the between-run
coefficients of variability were 2.2%.
-Tocopherol was successfully measured for 29
102 (99.9%) participants. The dietary information was gathered with the use of a validated,
self-administered food-use questionnaire given to all participants before the randomization
process (19). Using a color picture booklet as an aid, participants were
asked to report their usual frequency of consumption and portion sizes during the previous year
for more than 270 common food items and beverages. Of the entire cohort, 27 111
(93.1%) men completed the questionnaire. Dietary nutrient intake (including
-tocopherol and all vitamin E compounds) was estimated through the use of food
composition data available from the National Public Health Institute of Finland. Because higher
dose vitamin E supplementation was one of the exclusion criteria of the main trial, we had only
2928 men reporting taking some form of supplemental vitamin E at baseline, with the usual daily
dose being 6.7 mg. A separate variable was created that combined baseline dietary intake and
self-reported supplemental intake of vitamin E.
Statistical analyses. Statistical analyses were performed with the use of software
developed by the SAS Institute, Inc. (Cary, NC). Cox regression models were used to estimate
the association between serum and dietary -tocopherol and the incidence of lung cancer. All
correlations were Spearman correlation coefficients. Dietary and serum variables were
log-transformed and evaluated both as continuous predictors and as indicator variables defined by
quintiles on the basis of their distribution among the entire cohort, with the lowest quintile serving
as the reference group. Dietary
-tocopherol and vitamin E (four tocopherols and four
tocotrienols, combined) were evaluated separately. An ordinal score value based on the median
value within each quintile was used to test for trend or dose-response relationship across quintiles.
Serum
-tocopherol was adjusted for serum cholesterol, and dietary
-tocopherol and
vitamin E were adjusted for calories. Calorie adjustment for the dietary factors was performed by
two separate methods: 1) the residual method described by Willett (20)
and 2) the inclusion of total energy intake as a continuous covariate in the hazard models.
Multivariate models were developed by including serum
-tocopherol in a model for lung
cancer as previously described (14). This model included age at random
assignment, body mass index (BMI) defined as the weight in kilograms divided by the square of
the height in meters, years of cigarette smoking, number of cigarettes smoked daily, and
intervention group. Other study factors were assessed as confounders by evaluating whether their
inclusion into the multivariate model changed the risk estimates by more than 15%.
Intervention group assignment was evaluated with indicator variables for supplementation with
-tocopherol, ß-carotene, both, or none (reference). Effect modification was assessed by
inclusion of factors and their cross-product terms in the model and by stratified analysis of study
factors by tertile or median split categories based on their distribution among the entire cohort.
The validity of the proportional hazards assumption was tested by evaluating the cross-product
term of log of follow-up time and the covariate of interest. All reported P values
(including tests for trend and interaction) are two-sided and were considered statistically
significant if less than .05.
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RESULTS |
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Similar effect modification by -tocopherol supplementation group was apparent for
years of smoking, with an inverse association for baseline serum
-tocopherol being observed
only among the shorter term smokers (i.e., <40 years) who received the trial
-tocopherol
supplementation (Table 4,
B). The baseline serum
-tocopherol
concentration was not significantly related to lung cancer risk among either the longer term
smokers who received
-tocopherol and men not given supplements of
-tocopherol
(regardless of years of smoking). The interaction between
-tocopherol group and serum
-tocopherol was significant among the men who smoked for fewer than 40 years, while the
three-way interaction was not (P = .35)
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DISCUSSION |
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Relatively few studies have examined the association between dietary intake or blood levels of
-tocopherol and lung cancer. In general, null or weak inverse associations have been
observed. Of six prospective studies evaluating serum levels of this substance (7-12), only three (7-9) showed statistically significant inverse
associations. Case-control studies have generally reported lower
-tocopherol levels among
case patients than among control subjects [reviewed in (13)].
Data regarding modification of this effect by smoking history are inconsistent. Comstock et al. (7) observed no differences in lung cancer risk associated with serum
-tocopherol concentrations across smoking categories (i.e., nonsmokers, former smokers, or
current smokers). Consistent with our findings, Knekt et al. (10,22) found
in another Finnish cohort that a higher serum
-tocopherol concentration was more
protective among male nonsmokers and younger subjects.
Our investigation is unique among these reports and is strengthened by having both
biochemical and dietary measurements of -tocopherol collected prospectively and evaluated
for nearly the entire cohort of more than 29 000 men. Although we observed similar
results for both indicators, it is not clear whether dietary and serum
-tocopherol values are
interchangeable. Serum assessment is generally considered more accurate and biologically
meaningful than dietary estimates of the vitamin, in that it reflects the aggregate effects of intake
(from both diet and supplemental sources), absorption, utilization, and other aspects of
metabolism, including depletion of serum and tissue sources by oxidative stressors such as
cigarette smoking (23). Furthermore, our use of prospectively collected
samples minimized the possibility that differences in
-tocopherol concentrations were an
artifactual consequence of cancer. On the other hand, given the one-time measurement of serum
concentration and possible diurnalbut not seasonal (24)variation, dietary estimate provides an alternative indicator of chronic exposure to the
vitamin.
We did not observe a sequential dose-response association of serum -tocopherol;
instead, a threshold was seen between the first and second quintile, suggesting that serum
-tocopherol concentrations greater than 10 mg/L were sufficient for reducing lung cancer
risk by about 20%. These results could be explained by the relatively narrow range of
serum
-tocopherol in our population, which might be accounted for, in part, by the
propensity of cigarette smoke to reduce
-tocopherol concentrations in blood, presumably
because of the high uptake and turnover of antioxidants in smokers (23).
Unfortunately, the serum values are not directly comparable to those from other similar cohort
studies because the methods of biochemical analysis, duration of storage, and adjustment for
serum cholesterol all varied substantially between studies.
-Tocopherol has been shown experimentally to inhibit carcinogen-induced DNA damage
(25), to modulate the redox potential of the cell (26), and to alter expression of metabolic enzymes such as glutathione-S-transferase (27). Aside from its antioxidant role in the prevention of
cancer, there is a growing body of evidence suggesting that
-tocopherol exerts other effects.
-Tocopherol has been shown to regulate cell growth and differentiation, probably through
its influence on several interconnected pathways. For example,
-tocopherol is thought to
block prostaglandin and arachidonic acid metabolism (28), it inhibits
protein kinase C activity (29), and it may affect expression of hormones
and growth factors (30,31). The multiple functions of
-tocopherol
may allow it to inhibit tumorigenesis at various stages, from initiation and promotion to
progression and tumor growth.
The stronger inverse association observed among younger men and men who smoked for
fewer yearspresumably subgroups with less cumulative exposure to tobacco
carcinogensis intriguing. Higher -tocopherol status might be protective only in such
a lower risk setting. It is also possible that high
-tocopherol levels slowed the progression or
growth of subclinical tumors among these subgroups, such that their clinical manifestation and
diagnosis were delayed beyond the period of observation. Alternatively, the interaction with age
could be explained by age-related changes in metabolism and transport of
-tocopherol; e.g.,
activity of lipoprotein lipase, an enzyme that during lipolysis releases
-tocopherol from the
chylomicrons and transfers it to tissues, has been shown to decrease with age (32-34). The limited age range of our population (50-69 years old), however, and the
possibly stronger association for the tumors with more smoking-related histology make a
compelling argument for smoking-related effects. These findings also highlight the need for
further studies to evaluate broader populations that include nonsmokers and younger and older
adults and test whether similar associations exist among women.
Our study is unique in its ability to evaluate prospectively within the same cohort the
potential impact of both chronic vitamin E status, as assessed by serum -tocopherol, dietary
-tocopherol, and vitamin E, and a randomized, placebo-controlled test of daily
-tocopherol supplementation. We have previously reported (14) that
the latter demonstrated no effect on lung cancer incidence overall, although secondary analyses
suggested that participants having longer exposure to
-tocopherol supplementation may
have accrued some marginal benefit (i.e., a 10%-15% reduction in incidence). The
present findings reinforce the importance of adequate vitamin E status to lung cancer risk,
particularly among smokers. The fact that this beneficial relationship for higher pretrial
-tocopherol status was observed primarily among those given supplements of
-tocopherol (50 mg daily) suggests synergism between usual intake and the controlled
intervention. Such a finding could be explained by higher pretrial levels representing those
subjects with more efficient absorption, metabolism, and ultimate bioavailability of
-tocopherol. Alternatively, in the presence of higher background vitamin E status,
supplementation may have provided the higher dosages possibly required for inhibition of
carcinogenesis. While it is tempting, based on the present data, to speculate that the
administration of greater quantities of
-tocopherol (i.e., >50 mg daily) might have
produced a substantial reduction in lung cancer incidence in the ATBC Study, only future studies,
and controlled trials in particular, can shed light on this question.
Our data are compatible with a beneficial influence of higher vitamin E status on lung cancer development and indicate a possibly stronger effect among persons who have accumulated lower levels of lung carcinogens from chronic cigarette smoking. Additional prospective studies of vitamin E status and lung cancer that include women and nonsmokers and that assess the association across a spectrum of lung cancer risk (e.g., especially age and smoking exposures) will be particularly informative.
Supported by Public Health Service contract N01CN45165 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
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Manuscript received January 19, 1999; revised July 16, 1999; accepted August 18, 1999.
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