Prior to the 1980s, ESCC constituted the large majority of esophageal cancer cases in the United States. But, in the past few decades rates of EAC have sharply increased while ESCC rates have decreased.10
Therefore, earlier epidemiologic studies of esophageal cancer were mostly focused on ESCC, but the rising numbers of cases now allow investigation of EAC risk factors as well. Likewise, GCA was uncommon in the past, but rates may have increased and more research is being conducted to identify specific risk factors for this cancer.10
Availability of relatively large numbers of cases in the NIH-AARP study made it possible to examine the associations between vitamin E intake and each of these cancers separately. The results of this study suggest that vitamin E may have different effects on different subtypes of esophageal and gastric cancer. Dietary α-tocopherol had a significant inverse association with ESCC and GCA risk in age- and sex-adjusted models but this was substantially attenuated in our fully adjusted models. Therefore, these apparent associations may be due to residual confounding. In contrast, we found that supplementary vitamin E use significantly increased the risk of GCA among the users of ≥360 mg/day, but there was no apparent trend across categories of supplement dose, so this result should be interpreted with caution. Fully adjusted models for supplementary vitamin E use suggested reduced risk of GNCA with higher doses of supplements, although only about 5% of the cohort took doses in the top category.
Previous case-control studies have consistently shown a strong association between vitamin E intake and reduced ESCC risk11–16
, but case-control design is not the preferred design for testing nutritional associations. Our results showed reduced risk of ESCC in age-and sex-adjusted models, but this was substantially attenuated in fully adjusted models and our adjustments may not have fully accounted for confounding. So, we found little evidence for the association in our study.
The results of a meta-analysis of retrospective case-control studies suggested an inverse association between vitamin E intake and EAC risk17
, but we found no evidence for this in our prospective study. In fact, our continuous model showed significantly elevated risk associated with higher intake of dietary α-tocopherol, but no association with vitamin E supplement use even at high doses.
Results from case-control studies for GCA have been mixed, showing marginally significantly protective associations 14,18
or no association15
with dietary intake of vitamin E. Results from a previous cohort in Finland reported an increased risk of GCA with higher intake of α-tocopherol.19
Results of our study showed no clear pattern of association, with no effect of dietary α-tocopherol, but a suggestion of increased risk with high dose supplementary vitamin E intake. Separation of adenocarcinomas at the esophagogastric junction into EAC versus GCA is difficult. 20
Combining these two cancer sites into a single entity would produce null results throughout this study (data not shown).
A number of studies have specifically addressed the associations between either dietary or supplemental vitamin E intake and future risk of GNCA using observational designs. Others, however, have not distinguished between GCA and GNCA and have reported only combined results. As GNCA tumors constitute the large majority of gastric cancers in most studies, we believe that the results of studies that have not distinguished between GCA and GNCA are best grouped with other GNCA studies. Results for case-control studies have been mixed,18,21–28
whereas most prospective studies have found no association between baseline dietary intake of vitamin E,29
or supplemental intake of vitamin E 30
and future risk of GNCA. Our results showed no statistically significant association between dietary intake of α-tocopherol and GNCA, except for an increased risk among cases diagnosed in the first few years. This may reflect a real change in risk or could be due to chance. In contrast, we found an inverse association between use of higher-doses of vitamin E supplements and risk of GNCA.
Several randomized trials have examined the association between supplemental vitamin E intake and the risk of gastric cancer. A chemoprevention trial in Finland 31
found no association between five years of daily supplementation with 50 mg α-tocopherol and GCA or GNCA risk. Another trial in Linxian, China,32
where people are deficient for several vitamins and minerals, showed no effect of daily supplementation for 5.25 years with a combination of 30 mg α-tocopherol, 50 μg selenium and 15 mg β-carotene on ESCC, but this same combination did significantly reduce the risk of gastric cancer mortality. In a UK study, daily supplementation with 600 mg vitamin E, 250 mg vitamin C, and 20 mg β-carotene for five years had no significant effect on GNCA mortality.33
Other studies have examined the association between serum α-tocopherol concentration and the risk of upper gastrointestinal cancers.19,34,35
and some have shown that higher serum concentrations were associated with higher risk of GNCA. The correlation between estimated dietary intake of vitamin E and concentrations measured in the blood varies widely in different studies. Because blood concentrations reflect intake and interpersonal variation in uptake and metabolism, studies using serum concentrations as a biomarker of vitamin E status should be examined separately from those using dietary intake and we could not measure serum concentrations in our study.
The strengths of this study include its prospective design, a large sample size, the use of a validated questionnaire, and the ability to adjust for potential confounders. One major limitation of this study is the potential misclassification of intake associated with the use of food frequency questionnaires.36
Also, the lack of H. pylori
data is a potential limitation and this may be important because a previous study reported non-significantly different greater protection from higher vitamin E intake for gastric cancer in subjects positive for H. pylori
In conclusion, the results of our study showed little evidence for associations between dietary α-tocopherol and risk of ESCC, EAC, or GCA, but higher intake was positively associated with GNCA risk in analyses restricted to the first few years of follow-up. We found no association between dietary γ-tocopherol intake and risk of any of these cancers. For supplemental vitamin E, the results were also mainly null, with the exception of an inverse association between high doses of supplemental vitamin E and GNCA risk. Overall, the association of vitamin E with risk of upper gastrointestinal tract cancers is unclear. Results from this and other observational studies of intake have been mixed as are results from intervention trials, using multiple agent interventions which included vitamin E. For these reasons, future work is needed to delineate the association between vitamin E intake and risk of upper gastrointestinal tract cancers.