Correspondence to: Edward Giovannucci, M.D., Sc.D., Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
In this issue of the Journal, Helzlsouer et al. (1) report findings from a nested casecontrol study that examines plasma levels of -tocopherol,
-tocopherol, and selenium in relation to incident prostate cancer. The study suggests protective associations for
-tocopherol and selenium, although these were not statistically significant, as well as a strong protective association with
-tocopherol. In a previous randomized intervention study designed to examine selenium supplementation in relation to recurrent skin cancer (2), a striking 65% reduction in prostate cancer risk was observed among men randomly assigned to receive selenium. In a subsequent nested casecontrol study (3) of 181 cases of advanced prostate cancer and 181 age-matched control pairs based on toenail selenium in the Health Professionals Follow-up Study, men in the highest quintile of selenium also had a 65% lower risk relative to those in the lowest quintile. A recent study by Nomura et al. (4) also suggests a benefit of selenium. Although the evidence for selenium as protective against prostate cancer appears to be quite promising, not all of the data are supportive. Finland began fortification of agricultural fertilizers with selenium in the fall of 1984. Although the average selenium intake subsequently increased twofold to threefold (5,6), national prostate cancer incidence and mortality rates did not appear to decrease appreciably, at least during the first decade. Perhaps a longer time period is required, although the randomized trial (2) demonstrated a reduction within several years.
In striking parallel to the selenium story, a randomized trial not specifically designed to examine prostate cancer as a primary end point found a potential benefit of -tocopherol on prostate cancer risk. Specifically, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC study) conducted in smokers in Finland found men randomly assigned to receive 50 mg of
-tocopherol to have a statistically significant 32% reduction in incidence of prostate cancer and a 41% reduction in mortality from prostate cancer (7). Epidemiologic studies of
-tocopherol are somewhat conflicting. A nested casecontrol study of 578 prostate cancer cases in the Physicians' Health Study by Gann et al. (8) did not show a relationship between plasma levels of
-tocopherol and total prostate cancer but did find a suggestive inverse association for "aggressive" prostate cancer [extraprostatic or Gleason grade
7 (9)] (relative risk [RR] = 0.64; 95% confidence interval [CI] = 0.381.07). In a small study conducted in Switzerland (10), male smokers with low prediagnostic serum levels of vitamin E were at an increased risk of fatal prostate cancer. No clear association was seen for serum
-tocopherol levels and prostate cancer risk in nested casecontrol studies among Japanese-American men (11) or in a U.S. cohort study (12). A recent study of male health professionals (13) examined vitamin E supplement use and risk of prostate cancer based on 1896 prostate cancer cases. No association was found for total prostate cancer (RR = 1.07; 95% CI = 0.951.20) for more than 100 IU of vitamin E supplements per day or for fatal or metastatic prostate cancer (RR = 1.14; 95% CI = 0.821.59).
An interesting pattern regarding the -tocopherolprostate cancer connection has been that an inverse association for more advanced forms of prostate cancer has been observed consistently among smokers. In a plasma-based study of U.S. physicians (8), the suggestive inverse association for aggressive cancer was stronger among current/ex-smokers (RR = 0.51; 95% CI = 0.260.98) than among never smokers (RR = 0.84; 95% CI = 0.361.94). A study in Switzerland by Eichholzer et al. (10) examined fatal prostate cancer and found that only men with low plasma levels of
-tocopherol and who smoked were at elevated risk. A study by Chan et al. (13) that was otherwise negative showed that, in the subgroup of current smokers or recent quitters, vitamin E supplement use appeared to be related to a lower risk of fatal and metastatic prostate cancer (RR = 0.47; 95% CI = 0.240.92 for >15 IU per day of vitamin E). Curiously, suggestive elevated risks were observed for greater than or equal to 100 IU per day of
-tocopherol for never smokers (RR = 1.42; 95% CI = 0.872.32) or for those who had quit smoking more than 10 years earlier (RR = 1.49; 95% CI = 0.822.69). Finally, the ATBC study (7) (discussed above), which generated much of the interest in vitamin E, was conducted exclusively in smokers and, in an additional analysis in that study, the reduction of prostate cancer was seen for longer term smokers (43% reduction) but not for shorter term smokers (3% reduction; P = .05 for statistical interaction) and was greater for heavier smokers (
20 cigarettes/day, 51% reduction; <20 cigarettes/day, 25% reduction). Thus, four studies indicated a benefit of
-tocopherol for smokers, whereas existing data, while limited, do not support a benefit for nonsmokers. Smoking, while not usually considered to be a risk factor for incidence of all prostate cancers, does appear to be a risk factor for fatal prostate cancer (14,15).
The most provocative finding by Helzlsouer et al. (1) is the fivefold reduction in risk comparing the top with the bottom quintile of -tocopherol. Few other data have examined this relationship. The considerably larger plasma-based study of U.S. physicians did not show an association with
-tocopherol (8). The study of Japanese-American men also was not consistent with such a strong protective effect of
-tocopherol (RR = 0.7; 95% CI = 0.31.5, between high and low quintiles) (11).
Although the -tocopherol finding requires confirmation, the possibility of the association raises some potentially important issues regarding the use of vitamin E supplementation, especially at high doses.
-Tocopherol is the primary form of vitamin E in supplements. The major dietary sources of
-tocopherol and
-tocopherol, as well as other tocopherols, are oils. The relative concentrations vary widely by source of oil; for example, safflower oil contains primarily
-tocopherol, whereas
-tocopherol is more abundant in soybean and corn oils. All tocopherols are absorbed in the intestine and transported to the liver via chylomicrons. Once in the liver,
-tocopherol appears preferentially in the plasma because of selection by the hepatic
-tocopherol transfer protein (16). In U.S. residents, levels of plasma
-tocopherol are about five times higher than those of
-tocopherol, but this ratio further increases to greater than 20-fold in people taking vitamin E supplements (17). Is the displacement of
-tocopherol by large supplementary doses of
-tocopherol a potential health concern? This question cannot be answered with currently available data. Of interest, in the study by Chan et al. (13), increasing intake of
-tocopherol supplements (especially >400 IU/day) was associated with increasing risk of advanced prostate cancer, particularly among nonsmokers. While it is premature to make firm conclusions about benefits of
-tocopherol, displacement of
-tocopherol by high doses of
-tocopherol is of concern. In the ATBC study (7), the dose of
-tocopherol was relatively low.
Until recently, most of the benefits of vitamin E have been attributed to the potent antioxidant properties of -tocopherol. However, more and more potential functions of various tocopherols are becoming apparent (16,18). Of possible interest for prostate carcinogenesis is recent evidence that
-tocopherol is a superior trapping agent for electrophilic species, like nitrogen oxides or NOx (19). Inflammation is typically the major source of exposure of cells to NOx. Chronic inflammationa definite cause of carcinomas of the liver, large bowel, urinary bladder, esophagus, and stomachhas recently been suggested to contribute to prostate carcinogenesis (20) as well. Specifically, De Marzo et al. (21) postulate that focal prostatic glandular atrophy, a common proliferative lesion hypothesized to be a precursor to prostatic adenocarcinoma (22,23), arises in the setting of increased oxidative stress, likely derived from proximate inflammatory cells. Of interest, lycopene, which is also found to have an inverse association with aggressive prostate cancer in some studies (8,24), is a potent trapper of NOx (19,25,26).
The results of the study by Helzlsouer et al. (1) provide further reason for optimism but also hint at complexity. There are now a number of compounds, known to trap highly reactive compounds, for which there are varying degrees of evidencenone definitivefor protection against prostate cancer. These include selenium, -tocopherol,
-tocopherol, and lycopene. Some of their benefits may be synergistic or complementary, and potential displacement effects, such as displacement of
-tocopherol by large doses of
-tocopherol, may be important. The balance of these agents, as well as potential modifiers of risk, such as smoking, should be considered in the design and interpretation of results of future observational and intervention studies.
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