© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 20, 1738-1743,
October 20, 1999
© 1999 Oxford University Press
REPORTS |
Serum 
-Tocopherol and Subsequent Risk of Lung Cancer Among Male Smokers
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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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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BACKGROUND: Higher blood levels of
-tocopherol, the predominant form of vitamin E,
have been associated in some studies with a reduced risk of lung cancer, but other studies have
yielded conflicting results. To clarify this association, we examined the relationship between
prospectively collected serum -tocopherol and lung cancer in the Alpha-Tocopherol,
Beta-Carotene Cancer Prevention (ATBC) Study cohort. METHODS: The ATBC Study was a
randomized, clinical trial of 29 133 white male smokers from Finland who were 50-69
years old and who had received -tocopherol (50 mg), ß-carotene (20 mg), both, or
neither daily for 5-8 years. Data regarding medical histories, smoking, and dietary factors were
obtained at study entry, as was a serum specimen for baseline -tocopherol determination.
-Tocopherol measurements were available for 29 102 of the men, among whom
1144 incident cases of lung cancer were diagnosed during a median observation period of 7.7
years. The association between -tocopherol and lung cancer was evaluated with the use of
multivariate proportional hazards regression. RESULTS: A 19% reduction in lung cancer
incidence was observed in the highest versus lowest quintile of serum -tocopherol (relative
risk = 0.81; 95% confidence interval = 0.67-0.97). There was a stronger
inverse association among younger men (<60 years), among men with less cumulative tobacco
exposure (<40 years of smoking), and possibly among men receiving -tocopherol
supplementation. CONCLUSIONS: In the ATBC Study cohort, higher serum -tocopherol
status is associated with lower lung cancer risk; this relationship appears stronger among younger
persons and among those with less cumulative smoke exposure. These findings suggest that high
levels of -tocopherol, if present during the early critical stages of tumorigenesis, may inhibit
lung cancer development.
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INTRODUCTION |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Many carcinogens create free radicals that damage DNA and other cellular structures, both initiating and promoting tumor development (1). Antioxidants can neutralize free radicals, thereby preventing this cell damage and subsequent malignant transformation.
-Tocopherol (the predominant and most active form of vitamin E in
humans) is the major chain-breaking antioxidant in lipid phases, such
as within the hydrophobic regions of cellular membranes or low-density
lipoproteins (2), and it is thought to inhibit carcinogenesis
primarily through its antioxidant activity (3). In addition to
its antioxidant role, -tocopherol may also inhibit carcinogenesis
through various alternative mechanisms, including inhibition of cell
proliferation (4), induction of apoptosis (i.e., programmed
cell death) (4), inhibition of angiogenesis (5), and
enhancement of immune function (6).
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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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sample population. The sample population consisted of 29 133 white male smokers aged 50-69 years participating in the ATBC Study conducted in Finland. The ATBC Study was a randomized, placebo-controlled trial designed to determine whether
-tocopherol (50 mg/day), ß-carotene (20 mg/day), or both substances would reduce the
incidence of lung and other cancers. The overall design, rationale, and objectives of this study
have been published (15). Recruited during the period from 1985 through
1988, participants were followed during the active trial period until death or April 30, 1993
(median follow-up, 6.1 years). The trial results showed a 16% increase in lung cancer
incidence among men who received ß-carotene supplementation and no effect for vitamin E (14). Men continue to be followed after intervention. Excluded from the
study were men who were alcoholics, who had cirrhosis of the liver, who had severe angina with
exertion, who were diagnosed with chronic renal insufficiency, who were previously diagnosed
with cancer, or who were taking vitamin A or E or ß-carotene beyond specified doses (14). The ATBC Study was approved by the institutional review boards of
the National Cancer Institute (U.S.) and the National Public Health Institute of Finland, and
written informed consent was obtained from each participant prior to random assignment. 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
data—along with a fasting blood sample—were 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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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The analytical cohort comprised 29 102 men, including 1144 men diagnosed with incident cases of lung cancer ascertained during up to 10 years of follow-up (median, 7.7 years). Serum
-tocopherol
levels, after adjustment for serum cholesterol levels, ranged from 1.4
to 110.6 mg/L, with the median value being 11.6 mg/L. -Tocopherol
concentrations were statistically significantly correlated with dietary
-tocopherol intake (r = .36) but not with age, years of
cigarette smoking, number of cigarettes smoked daily, alcohol
consumption, or serum ß-carotene or retinol concentrations (range
of r values, -0.07 to 0.09). The demographic and smoking
characteristics, serum vitamins, and dietary intakes at baseline for
lung cancer case patients and noncase subjects are shown in Table
1.
Compared with noncase subjects, patients were—on
average—older; had smoked for a longer time; had lower serum
-tocopherol, ß-carotene, and retinol concentrations; and
consumed a diet lower in calories, vitamins, and other micronutrients.
Twelve percent of the case patients and 10% of the noncase subjects
reported using vitamin E supplements prior to random assignment to an
intervention.
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Baseline serum
-tocopherol, dietary -tocopherol, and dietary vitamin E were
inversely associated with lung cancer risk (Table 2). We observed
reductions in estimated relative risk of 19% (95% confidence interval
[CI] = 3%-33%), 20% (95% CI =
3%-34%), and 23% (95% CI = 7%-36%) for the
fifth compared with the first quintile of serum -tocopherol, dietary -tocopherol, and
dietary vitamin E, respectively. The risk estimates remained unchanged when intakes of
-tocopherol and vitamin E were evaluated by combining baseline dietary and supplemental
sources (data not shown). The associations between serum -tocopherol and lung cancer
mortality, based on 883 deaths, were essentially the same as for cancer risk (data not shown). To
avoid potential bias from the influence of preclinical cancer on baseline serum levels or dietary
intake, we did separate analyses that excluded case patients diagnosed early during follow-up (i.e.,
within the first, second, or third years) and observed no changes in the risk estimates (data not
shown).
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We evaluated the association between serum
-tocopherol and lung cancer according to
histologic subtypes (Table 3). We observed only modest differences. Only
the more smoking-related cancers (21)—i.e., squamous cell and
small-cell carcinomas—exhibited inverse associations with -tocopherol; only for
squamous cell carcinoma did the test for trend approach statistical significance (P
= .09).
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We evaluated modification of the association between baseline serum
-tocopherol and
lung cancer by age, education, number of cigarettes smoked daily, years of smoking, alcohol
consumption, dietary vitamin C intake, serum ß-carotene, serum retinol, and intervention
assignment. We observed material interactions only with age, years of smoking, and possibly
-tocopherol intervention assignment (Table 4, A). There were
statistically significant trends for men younger than 60 years and men who had smoked fewer than
40 years at study entry. The risk estimates regarding the fifth compared with the first quintile of
serum -tocopherol were reduced by 40% (among men <60 years old) and
50% among lighter smokers who smoked for fewer than 40 years. An inverse association
was also stronger and statistically significant among men who were in the -tocopherol
supplementation arm of the trial. The tests for interaction were statistically significant only for age
and for years of smoking. It should be borne in mind that, in this population of older smokers, age
and years of smoking are highly correlated (r = .66): The younger age and lower
smoke-years categories represent some of the same men (e.g., 47% of men <55 years
old smoked for <32 years).
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On the basis of these findings, we hypothesized that older subjects and/or those with a longer history of smoking probably had a greater cumulative carcinogenic exposure that required higher levels of
-tocopherol for protection against lung cancer. Therefore, we explored whether the
trial -tocopherol supplementation influenced the effect of age and years of smoking on the
relationship between baseline serum -tocopherol and lung cancer (Table 4,
B). An inverse association was apparent among the younger subjects given
supplements of -tocopherol but not among older subjects. The test for interaction between
the -tocopherol supplementation group and serum concentrations, however, was only
suggestive among men younger than 60 years, and the three-way interaction (group x
serum level x age) was not significant (P = .30).
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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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We found serum
-tocopherol to be inversely associated with lung
cancer risk in a trial-based cohort of 29 102 male smokers in
Finland. Similar inverse associations were observed for dietary
-tocopherol and vitamin E intake. These relationships persisted
after we controlled for several potential confounders, including age,
smoking, alcohol consumption, other dietary factors, and ß-carotene
and -tocopherol supplementation group. The inverse association
between serum -tocopherol and lung cancer was apparent only in
younger men, in men with less cumulative tobacco exposure, and possibly
in men who had received -tocopherol supplementation during the trial.
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 diurnal—but 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 years—presumably subgroups with less cumulative exposure to tobacco
carcinogens—is 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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 T. M. Penning and C. Lerman Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment Cancer Prevention Research, July 1, 2008; 1(2): 80 - 83. [Full Text] [PDF]
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S. Rohrmann, J. Linseisen, H. C. Boshuizen, J. Whittaker, A. Agudo, P. Vineis, P. Boffetta, M. K. Jensen, A. Olsen, K. Overvad, et al. Ethanol Intake and Risk of Lung Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Am. J. Epidemiol., December 1, 2006; 164(11): 1103 - 1114. [Abstract] [Full Text] [PDF]
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M. E. Wright, S. T. Mayne, R. Z. Stolzenberg-Solomon, Z. Li, P. Pietinen, P. R. Taylor, J. Virtamo, and D. Albanes Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers Am. J. Epidemiol., July 1, 2004; 160(1): 68 - 76. [Abstract] [Full Text] [PDF]
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J.-M. Yuan, D. O. Stram, K. Arakawa, H.-P. Lee, and M. C. Yu Dietary Cryptoxanthin and Reduced Risk of Lung Cancer: The Singapore Chinese Health Study Cancer Epidemiol. Biomarkers Prev., September 1, 2003; 12(9): 890 - 898. [Abstract] [Full Text] [PDF]
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G. E. Goodman, S. Schaffer, G. S. Omenn, C. Chen, and I. King The Association between Lung and Prostate Cancer Risk, and Serum Micronutrients: Results and Lessons Learned from {beta}-Carotene and Retinol Efficacy Trial Cancer Epidemiol. Biomarkers Prev., June 1, 2003; 12(6): 518 - 526. [Abstract] [Full Text] [PDF]
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L. Djousse, J. F. Dorgan, Y. Zhang, A. Schatzkin, M. Hood, R. B. D'Agostino, D. L. Copenhafer, B. E. Kreger, and R. C. Ellison Alcohol Consumption and Risk of Lung Cancer: The Framingham Study J Natl Cancer Inst, December 18, 2002; 94(24): 1877 - 1882. [Abstract] [Full Text] [PDF]
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J.-M. Yuan, R. K. Ross, X.-D. Chu, Y.-T. Gao, and M. C. Yu Prediagnostic Levels of Serum {beta}-Cryptoxanthin and Retinol Predict Smoking-related Lung Cancer Risk in Shanghai, China Cancer Epidemiol. Biomarkers Prev., July 1, 2001; 10(7): 767 - 773. [Abstract] [Full Text] [PDF]
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J. K. Sandhu, A. S. Haqqani, and H. C. Birnboim Effect of Dietary Vitamin E on Spontaneous or Nitric Oxide Donor-Induced Mutations in a Mouse Tumor Model J Natl Cancer Inst, September 6, 2000; 92(17): 1429 - 1433. [Abstract] [Full Text] [PDF]
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