Affiliations of authors: P. R. Taylor, C. C. Abnet, S. M. Dawsey (Center for Cancer Research), S. D. Mark (Division of Cancer Epidemiology and Genetics), National Cancer Institute, Bethesda, MD; Y.-L. Qiao, W. Wang, Z.-W. Dong, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, Peoples Republic of China; C. S. Yang, Rutgers State University of New Jersey, Piscataway, NJ; E. W. Gunter, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA; W. J. Blot, International Epidemiology Institute, Rockville, MD.
Correspondence to: Philip R. Taylor, MD, ScD, Cancer Prevention Studies Branch, Center for Cancer Research, National Cancer Institute, 6116 Executive Blvd., Rm. 705, Bethesda, MD 208928314 (e-mail: ptaylor{at}mail.nih.gov).
ABSTRACT
Participants in the General Population Trial, a randomized nutrition intervention trial in Linxian, China, who received a combination of selenium, -carotene, and vitamin E supplements, had statistically significantly lower cancer mortality rates than those who did not receive the supplements. In the current study, we used a casecohort design to examine the association between pre-trial serum vitamin E levels and the risks of developing esophageal and gastric cancers during the trial. We measured serum
- and
-tocopherol and cholesterol levels in 1072 case patients with incident esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), or gastric noncardia cancer (GNCC) and in 1053 control subjects. The relative risks for comparisons of the highest to the lowest quartiles of serum
-tocopherol were 0.63 (95% confidence interval [CI] = 0.44 to 0.91) for ESCC, 0.84 (95% CI = 0.55 to 1.26) for GCC, and 2.05 (95% CI = 0.89 to 4.75) for GNCC. Serum
-tocopherol level was not associated with the incidence of any of these cancers. Our findings provide support for the role of
-tocopherol in the etiology of upper gastrointestinal cancers.
The design (14) and results (11) of the General Population Trial have been previously described in detail. Participants included 29 584 men and women aged 4069 years from Linxian, an area of China with extraordinarily high esophageal and gastric cardia cancer rates whose residents have numerous well-documented vitamin and mineral deficiencies. All participants provided written informed consent, and the trials were conducted in accordance with the U.S. Department of Health and Human Services Office for Protection from Research Risks guidelines. In the spring of 1985, each participant was interviewed, given a brief physical examination, and had blood drawn. The intervention began in March 1986 and continued through May 1991. The stratified casecohort design, subject selection, quality-control procedures, and statistical analytic methods used in the current study were the same as those used and described in a previous publication on pre-diagnostic serum selenium levels and upper gastrointestinal cancer (15). In the current study, we evaluated all case patients identified during the intervention (i.e., 590 patients diagnosed with ESCC, 395 patients diagnosed with GCC, and 87 patients diagnosed with GNCC) and 1053 control subjects for whom adequate serum was available. We used a modified simultaneous isocratic high-performance liquid chromatography assay, which was performed in the Rutgers University laboratory of Dr. C. S. Yang and was based on a previously described method (16,17), to determine serum - and
-tocopherol concentrations. Serum cholesterol levels were measured by the National Health and Nutrition Examination Survey laboratory at the Centers for Disease Control and Prevention (Atlanta, GA) with the use of an Ektachem 250 Dry Chemistry Analyzer and a single-slide two-point enzymatic cholesterol test (Eastman Kodak, Rochester, NY).
We estimated relative risks (RRs) and 95% confidence intervals (CIs) by using the casecohort estimator for the stratified Cox proportional hazards model (1821). (The data conformed to proportional hazards assumptions.) We estimated relative risks by using measures of serum - and
-tocopherol on three scales: continuous, quartile, and ordinal. All reported relative risks were adjusted for sex, age, serum cholesterol level, body mass index, smoking status, and alcohol status. Treatment group assignment did not affect relative risk estimates and therefore was not included in the models. We also estimated the relative risks for baseline serum
-tocopherol levels separately for those randomly assigned to the selenium/
-carotene/vitamin E supplement group and those who did not receive this supplement, and found that there was no interaction between pre-trial serum levels and treatment group assignment (data not shown).
Our analyses considered two different endpoints: all incident cancers, both fatal and nonfatal, and the more restricted endpoint of fatal cancers. Because the results of analyses that used the two endpoints were similar, we present only the data for the incident cancer endpoint. In addition to the site-specific relative risk estimates, we estimated the relative risk of the combined endpoint of ESCC and GCC. This combined category was the primary cancer endpoint of the General Population Trial. In this and two other analyses of pre-trial nutrient levels (15,22), we found that the exposurecancer associations were similar at these two sites.
Table 1 shows the number of subjects studied according to casecontrol status as well as median age and serum levels of
- and
-tocopherol and cholesterol at the start of the trial. For comparison, the median serum
-tocopherol level in the latest (i.e., the third) National Health and Nutrition Examination Survey in the United States was 969 µg/dL (23), which is 17% higher than the median value reported here from the General Population Trial cohort in Linxian. Neither the geometric mean (data not shown) nor the median values for
- or
-tocopherol differed statistically significantly between case patients and control subjects. Table 2
shows the relative risks and 95% confidence intervals for regression models of the associations between cancer risk and serum
- and
-tocopherol levels, which were considered to be continuous variables (where all values were standardized so that a change of one unit corresponds to a change of approximately 25% of the distribution) as well as by quartiles (15). As shown, each standardized unit increase in serum
-tocopherol was associated with a 10% decreased risk of ESCC incidence (P = .016), a 2% decreased risk of GCC (P = .644), a 19% increased risk of GNCC (P = .047), and a 7% decreased risk of the combined ESCC and GCC endpoint (P = .049). Compared with subjects in the lowest quartile of serum
-tocopherol, those in the highest quartile of serum
-tocopherol had a 37% lower risk of ESCC (P = .015), a 16% lower risk of GCC risk (P = .40), a 105% higher risk of GNCC (P = .093), and a 29% lower risk of ESCC and GCC combined (P = .030). Serum
-tocopherol levels were not associated with cancer risk at any of the cancer sites studied in any of the models evaluated. The relative risks for
-tocopherol were unchanged when we included both
- and
-tocopherol in the same model, and no differences in the relative risks were seen when we excluded cases that occurred in the first 2 years of follow-up or between subgroups defined by sex, smoking status, alcohol status, or intervention assignment (data not shown).
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In the General Population Trial itself, the participants were randomly assigned to receive a combination of 50 µg of selenium, 15 mg of -carotene, and 30 mg of
-tocopherol or no such supplements. Although reductions in cancer mortality and incidence were observed in the supplemented group, the simultaneous administration of three supplements prevented assessment of potentially differential effects of selenium versus
-carotene versus
-tocopherol. Our observational analyses of the association between cancer risks and pre-trial serum levels of these compounds do not overcome this non-separability problem. However, our findings suggest that
-tocopherol and selenium are more likely than
-carotene to be involved in the reduced cancer rates observed with supplementation during the trial. Assuming that
-tocopherol is an inhibitor of esophageal and gastric cardia cancers, we have no ready explanation for our finding that higher blood levels of
-tocopherol were associated with an elevated relative risk of GNCC, particularly when considering that trial subjects who took the supplements had lower risks for each type of stomach cancer individually. Taken together with the findings of the General Population Trial, the results reported here provide support for a role of
-tocopherol in the etiology and prevention of upper gastrointestinal cancers.
REFERENCES
1 Ricciarelli R, Zingg JM, Azzi A. Vitamin E: protective role of a Janus molecule. FASEB J 2001;15:231425.
2 Knekt P. Role of vitamin E in the prophylaxis of cancer. Ann Med 1991;23:312.[ISI][Medline]
3 Stahelin HB, Rosel F, Buess E, Brubacher G. Cancer, vitamins, and plasma lipids: prospective Basel study. J Natl Cancer Inst 1984;73:14638.[ISI][Medline]
4 Stahelin HB, Gey KF, Eichholzer M, Ludin E, Bernasconi F, Thurneysen J, et al. Plasma antioxidant vitamins and subsequent cancer mortality in the 12-year follow-up of the prospective Basel Study. Am J Epidemiol 1991;133:76675.[Abstract]
5 Nomura AM, Stemmermann GN, Heilbrun LK, Salkeld RM, Vuilleumier JP. Serum vitamin levels and the risk of cancer of specific sites in men of Japanese ancestry in Hawaii. Cancer Res 1985;45:236972.[Abstract]
6 Nomura AM, Ziegler RG, Stemmermann GN, Chyou PH, Craft NE. Serum micronutrients and upper aerodigestive tract cancer. Cancer Epidemiol Biomarkers Prev 1997;6:40712.[Abstract]
7 Knekt P, Aromaa A, Maatela J, Aaran RK, Nikkari T, Hakama M, et al. Serum vitamin E and risk of cancer among Finnish men during a 10-year follow-up. Am J Epidemiol 1988;127:2841.[Abstract]
8 Knekt P, Aromaa A, Maatela J, Aaran RK, Nikkari T, Hakama M, et al. Vitamin E and cancer prevention. Am J Clin Nutr 1991;53:283S286S.[Abstract]
9 Knekt P, Aromaa A, Maatela J, Alfthan G, Aaran RK, Teppo L, et al. Serum vitamin E, serum selenium and the risk of gastrointestinal cancer. Int J Cancer 1988;42:84650.[ISI][Medline]
10 Knekt P, Aromaa A, Maatela J, Alfthan G, Aaran RK, Nikkari T, et al. Serum micronutrients and risk of cancers of low incidence in Finland. Am J Epidemiol 1991;134:35661.[Abstract]
11 Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85:148392.[Abstract]
12 Li JY, Taylor PR, Li B, Dawsey S, Wang GQ, Ershow AG, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst1993;85:14928.[Abstract]
13 Malila N, Taylor PR, Virtanen MJ, Korhonen P, Huttunen JK, Albanes D, et al. Effects of alpha-tocopherol and beta-carotene supplementation on gastric cancer incidence in male smokers (ATBC Study, Finland). Cancer Causes Control 2002;13:61723.[CrossRef][ISI][Medline]
14 Li B, Taylor PR, Li JY, Dawsey SM, Wang W, Tangrea JA, et al. Linxian nutrition intervention trials. Design, methods, participant characteristics, and compliance. Ann Epidemiol 1993;3:57785.[Medline]
15 Mark SD, Qiao YL, Dawsey SM, Wu YP, Katki H, Gunter EW, et al. Prospective study of serum selenium levels and incident esophageal and gastric cancers. J Natl Cancer Inst 2000;92:175363.
16 Miller KW, Yang CS. An isocratic high-performance liquid chromatography method for the simultaneous analysis of plasma retinol, alpha-tocopherol, and various carotenoids. Anal Biochem 1985;145:216.[ISI][Medline]
17 Sowell AL, Huff DL, Yeager PR, Caudill SP, Gunter EW. Retinol, alpha-tocopherol, lutein/zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, trans-beta-carotene, and four retinyl esters in serum determined simultaneously by reversed-phase HPLC with multiwavelength detection. Clin Chem 1994;40:4116.
18 Prentice RL. A case cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 1986;73:111.[ISI]
19 Self SF, Prentice RL. Asymptotic distribution theory and efficiency results for case-cohort studies. Ann Stat 1988;16:6481.[ISI]
20 Epicure. Seattle (WA): Hirosoft International Corp.; 1998.
21 Mark SD, Katki H. Influence function based variance estimation and missing data issues in case-cohort studies. Lifetime Data Anal 2001;7:33144.[CrossRef][ISI][Medline]
22 Abnet CC, Qiao Y, Dawsey SM, Buckman DW, Yang CS, Blot WJ, et al. Prospective study of serum retinol, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin and esophageal and gastric cancers in China. Cancer Causes Control. In press 2003.
23 Institute of Medicine. Panel on dietary antioxidants and related compounds. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington (DC): National Academy Press; 2000. p. 4445.
Manuscript received February 19, 2003; revised June 30, 2003; accepted July 10, 2003.
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