Higher serum and supplemental α-tocopherol appeared to improve overall prostate cancer survival in this investigation. Overall, estimates were similar for the baseline and 3 year serum α-tocopherol determinations, suggesting both dietary and supplemental vitamin E may contribute to improved prostate cancer survival. Baseline serum values reflect dietary intake as men who reported taking supplements above minimum limits upon enrollment were not eligible to participate in the trial, whereas 3 year serum concentrations resulted from dietary intake and the intervention supplementation. The strongest survival associations were seen for men who received α-tocopherol supplementation and had high serum α-tocopherol concentrations at baseline or 3 years, as well as during the first six years following the trial supplementation. Neither serum nor supplemental β-carotene or serum retinol had apparent effects on survival. These findings build upon previous research showing a 41% reduction of prostate cancer mortality in response to α-tocopherol supplementation in the controlled trial component of the ATBC Study from 1985–1993 (20
). The data presented here included an additional 12 years of follow-up. Our findings stand in contrast to those recently reported for two large, randomized controlled studies, the Physicians’ Health Study (PHS) II and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). PHS II tested vitamins C and E and found no effect of vitamin E supplementation on prostate cancer mortality (HR=1.01, 95% CI 0.64, 1.58) or incidence (HR=0.97, 95% CI 0.85, 1.09) following up to 10 years of intervention (26
). Similarly, SELECT tested selenium and vitamin E in over 35,000 healthy men and resulted in a non-significant increased rate of prostate cancer among the men receiving the supplemental vitamin E (HR=1.13, 99% CI 0.95, 1.35) compared to those receiving the vitamin E placebo (27
). The dose of vitamin E used in the PHS II was 400 IU synthetic α-tocopherol every other day, half the effective daily dosage of 400 IU daily all rac-α-tocopheryl acetate used in SELECT. Several factors could account for these differing results. First, our analysis was based on measured serum alpha-tocopherol, whereas PHS II and SELECT tested and reported on their supplementation groups. The intervention dose in the ATBC Study was 50 IU dl-α-tocopherol acetate/day, 4 to 8 times lower than the other trials and also had a longer period of follow-up (up to 20 years). PHS II and SELECT evaluated much higher dosages for shorter periods and have not yet reported on prospectively measured vitamin E blood levels which could reveal a different association compared to the high-dose supplementation. Second, PHS II and SELECT were conducted in the U.S. where PSA testing is common and those enrolled in SELECT were required to undergo prostate cancer screening prior to study entry in contrast to the ATBC Study. If vitamin E affects advanced prostate cancer in particular, as has been observed (8
), then an unscreened population would likely show a stronger beneficial relationship. Third, both recently reported trials were comprised of more diverse study populations with relatively few smokers compared to the ATBC Study participants. It is possible that the survival benefit of vitamin E is only experienced by smokers.
There are few other studies investigating vitamin E and prostate cancer survival. Two studies included daily vitamin E supplements within their interventions; one found improved survival in combination with ω-3 polyunsaturated fatty acids (27
) and another concluded that a vegan diet with soy, fish oil, and several micronutrient supplements delayed disease progression (29
). Although each study demonstrated sizeable effects, it is not possible to distinguish the contribution of supplemental vitamin E from the other dietary intervention components. However, dietary agents have been shown to impact prostate cancer survival. An investigation within the Health Professionals Follow-up Study examined pre- and post- diagnostic diet and found high intake of tomato sauce (HR=0.56, 95% CI 0.38, 0.82) and fish (HR=0.73, 95% CI 0.52, 1.02) were protective against disease progression (14
). As prostate cancer is a disease with relatively good survival, there is interest in other causes of death in men diagnosed with prostate cancer. We found a trend toward protection for all-cause mortality (including prostate cancer) (HR=0.67, 95% CI 0.52, 0.87 for highest versus lowest quintile; Ptrend
= 0.01) which was slightly attenuated when those who died of prostate cancer were excluded (HR=0.70, 95% CI 0.46, 0.98 for highest versus lowest quintile; Ptrend
= 0.11), suggesting a possible effect for α-tocopherol on other causes of death in men with prostate cancer. Although meta-analyses suggest vitamin E has no effect on all-cause mortality (30
), lower mortality rates were observed for men with higher serum vitamin E at baseline in another analysis within the ATBC data (31
There is considerably more evidence available for the relationship between vitamin E and prostate cancer risk than for survival. Several, but not all, observational and intervention studies have shown a strong inverse association between α-tocopherol and the risk of developing prostate cancer, particularly for advanced cancers or among smokers (32
). For example, analysis from the PLCO trial found no association with risk in the general population, but vitamin E was strongly protective in smokers (RR=0.29, 95% CI 0.12, 0.68) (10
). Similar work using the ATBC Study with 19 years of follow-up found that serum α-tocopherol was associated with reduced risk of prostate cancer (RR=0.80, 95% CI 0.66, 0.96 for highest versus lowest quintile), especially advanced disease (RR=0.56, 95% CI 0.36, 0.85) (8
), whereas the original effect seen in the trial period of the study was a 32% reduction in prostate cancer risk with α-tocopherol supplementation (20
). New observational studies are needed to tease apart the relationship between prostate cancer risk and α-tocopherol from supplementation versus serum levels as well as the possible interactions with smoking. Similar investigations are needed to determine the role of nutritional factors in prostate cancer survival.
The mechanisms through which vitamin E might affect the development and progression of prostate cancer are not fully understood; however, a number of biologically plausible pathways have been suggested. α-Tocopherol is thought to affect carcinogenesis by detoxifying oxidizing radicals via its antioxidant properties, inducing cell cycle arrest in prostate cancer cells (33
), decreasing cell growth by down-regulating the phosphoinositide 3-kinase pathway (34
), enhancing cell-mediated immunity (16
), targeting transcription factors, such as NF-κB, that contribute to malignant transformation and cell growth (35
), and decreasing serum androgen concentrations (36
). Many of these biological actions are likely to be involved in prostate cancer survival.
Prostate cancer survival was greater for men with baseline serum α-tocopherol ≥ 11 mg/L, regardless of supplementation status, but there was slightly better survival for those receiving the vitamin E supplementation (HR= 0.51, 95% CI 0.27, 0.96). Similar results were seen after 3 years among those in the highest α-tocopherol quintiles who received supplementation had considerably better survival (HR= 0.29, 95% CI 0.10, 0.82). Vitamin E supplementation has been associated with decreased prostate cancer risk in several cohort studies, which reflects self-selected supplement use rather than randomized assignment in an intervention trial. Long-term (10 years average) supplement use of vitamin E (≥ 400 IU) was associated with the reduced risk of advanced prostate cancers (HR= 0.43, 95% CI 0.19, 1.00) in the VITamins And Lifestyle (VITAL) cohort study (37
). A similar non-significant trend was seen for advanced cases in nonsmokers, but not current or former smokers in the NIH-AARP Diet and Health Study, a large cohort study of men 50 to 71 years; however, supplemental vitamin E intake was unrelated to prostate cancer risk in the total population (7
). Other recent analyses suggest possible harm from such supplements (38
). Our analyses suggest that both dietary vitamin E, as evidenced by baseline levels, and supplemental vitamin E as reflected in on-study serum concentrations at 3 years, impacted survival favorably.
When all categories of serum α-tocopherol at 3 years and supplementation were compared to men in the lowest quintile without supplementation, there appeared to be a non-significant trend with better survival in the highest quintiles. Unexpectedly, however, the poorest survival was seen for men in the lowest quintile of serum α-tocopherol who had received supplementation, and not all men who received supplements were in the higher α-tocopherol quintiles at 3 years even though supplemental vitamin E contributes much more to biochemical status than do dietary sources (40
). It is important to note that there were very few participants (n=27, including 5 cases) in this category, however, and the finding could be due to chance. It is also foreseeable that less healthy men may be less likely to take supplements, yet compliance, as measured by capsule adherence and number of visits, was no different for these 27 participants than the general study population. Finally, it is possible that these men may be more likely to have a genetic polymorphism that is related to both survival and vitamin E metabolism. Vitamin E levels have been shown to modify prostate cancer risk for polymorphisms in magnanese-superoxide dismutase (MnSOD) and XRCC1, for example, with stronger associations seen for aggressive cancers (41
). At present, genotyping data to test this hypothesis are not available for all cases.
Our findings that serum β-carotene and retinol were unrelated to prostate cancer survival mirror other observational and intervention studies that generally found no association with either nutrient and prostate cancer risk (9
). Results for β-carotene and prostate cancer risk have been inconsistent. There was no association detected in the Physicians Health Study (RR= 1.0, 95% CI 0.9, 1.1) (45
), a randomized trial of aspirin and 50 mg β-carotene on alternate days, but β-carotene was associated with an increased risk of aggressive prostate cancer in a nested case-control study using data from the PLCO Trial (RR= 1.67, 95% CI 1.03, 2.72) (46
There are several notable strengths of this study. The availability of a large number of prostate cancer cases with considerable post-diagnosis follow-up provided substantial power to detect potential associations with survival that may have been obscured in smaller studies. The use of serum nutrient biomarkers reduces the measurement error associated with self-reported data for dietary and supplement intake. Participants were exceptionally adherent during the trial period, with 96% of supplement capsules taken as scheduled and there was no off-trial supplement use reported. Finally, because PSA screening was not widely employed at the time of the ATBC trial, the potential for lead-time bias caused by overdiagnosis of cancers that are not clinically relevant was low.
Limitations of the study include its being conducted in a relatively homogeneous cohort of male Finnish smokers, which limits the generalizability of our findings to nonsmokers and other races and ethnicities. We did not have comprehensive data concerning prostate cancer treatment; however, surgery was distributed equally across categories of serum α-tocopherol (baseline and 3 years) and supplementation status among those who died of prostate cancer. Another limitation was lack of detailed data on stage and grade of prostate cancer in those diagnosed after September 2001. However, cross-tabulations of α-tocopherol levels by stage in those diagnosed at or before September 2001 failed to reveal a correlation of α-tocopherol levels with stage. Thus, stage is unlikely to confound our results. Moreover we adjusted stage and period of diagnosis in three categories (1
) before September, 2001 and stage I or II, 2) before September, 2001 and stage III or IV, and 3) after September, 2001 or missing). Gleason score, a strong predictor of survival, was available only for cases diagnosed before May 1, 1993 (<10% of cases) and thus, not included in these analyses. An examination of available data showed that Gleason score was strongly associated with survival as expected, but was not associated with serum α-tocopherol or β-carotene at either baseline or 3 years reducing concerns about potential confounding. We did not have information on serum levels or diet after 3 years on-study or post-trial supplement use, thus changes in diet or supplement use could have resulted in misclassification that would have biased our results to toward the null. This was an observational study of prostate cancer cases, even though it was conducted within the ATBC cohort for a randomized trial. Thus, we cannot exclude the possibility of residual confounding by unmeasured or unknown characteristics, especially clinico-pathological factors that may be related to survival, even though we adjusted for a number of potential confounders.
In summary, our results suggest dietary and supplemental α-tocopherol may improve prostate cancer survival. Data from similar studies in other populations would be useful. Considering the large number of men diagnosed with prostate cancer, such nutritional modifications could have a significant impact if subsequent randomized trials in men with newly diagnosed prostate cancer prove a benefit.