Abstract
In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study among 29,133 Finnish male smokers aged 50–69 years, daily α-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the post-intervention effects of α-tocopherol and β-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n=2,881) was 1.04 (95% confidence interval [CI], 0.96–1.11) among β-carotene recipients compared with nonrecipients. For prostate cancer (n=2,321) RR was 0.97 (95% CI, 0.89–1.05) among α-tocopherol recipients compared with nonrecipients with the preventive effect of α-tocopherol continuing approximately 8 years post-intervention. Body mass index significantly modified the effect of α-tocopherol on prostate cancer (P for interaction=0.01): RR 1.00 (95% CI, 0.88–1.14) in normal-weight men, 0.87 (95% CI, 0.77–0.98) in overweight men, and 1.25 (95% CI, 1.01–1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98–1.05) for α-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99–1.05) for β-carotene recipients compared with nonrecipients. α-Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70–0.99), whereas β-carotene increased it (RR, 1.20; 95% CI, 1.01–1.42). In conclusion, supplementation with α-tocopherol and β-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose α-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality.
Keywords: α-tocopherol, β-carotene, cancer, mortality, post-trial
In the early 1980s, evidence from laboratory and epidemiological studies suggested that antioxidants and other micronutrients might have preventive roles in carcinogenesis.1,2 This led to the initiation of large randomized, placebo-controlled trials that tested the effects of supplementation with various micronutrients against cancer. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study examined the impact of supplemental α-tocopherol and β-carotene on cancer incidence in male smokers.3 After a median of 6.1 years of intervention, lung cancer incidence was 17% higher, and overall mortality 8% higher, among participants who received β-carotene compared to those who did not receive it.4 These effects disappeared post-intervention approximately within the number of years that they became evident; i.e., 4 to 6 years.4 α-Tocopherol had no impact on lung cancer but decreased prostate cancer incidence by 34%.4 We report herein cancer incidence and mortality for the extended post-intervention follow-up of 18 years.
Material and methods
The ATBC Study was a randomized, double-blinded, placebo-controlled trial testing the effect of α-tocopherol and β-carotene supplementation on the incidence of lung cancer and other cancers in male smokers.3 The participants (n = 29,133) were recruited from the total male population aged 50–69 years living in southwestern Finland (n = 290,406) from April 1985 through June 1988. Subjects who were eligible and willing to participate in the trial were randomly assigned to one of the four intervention regimens: α-tocopherol (dl-α-tocopheryl acetate 50 mg daily) alone, β-carotene (20 mg daily) alone, both α-tocopherol and β-carotene, or placebo. All participants gave written informed consent prior to randomization. The trial period continued through April 30, 1993, and the study cohort was followed through national registries thereafter. This report includes the follow-up of those 25,563 participants alive at the beginning of the post-trial follow-up, and covers incident cancers and deaths through April 30, 2011 (i.e., an 18-year period). The ATBC Study was approved by the institutional review boards of the National Public Health Institute of Finland and the US National Cancer Institute.
At baseline the participants completed questionnaires on general background, medical and smoking histories, and alcohol intake.3 Height and weight were measured. Participants had three follow-up visits annually during which data on health and smoking were collected, compliance assessed, and a new capsule supply provided. In all, 20,166 men (79% of the randomized) entered the last scheduled trial follow-up visit in the winter 1992–1993.
Incident cancer cases were identified through the Finnish Cancer Registry which provides almost 100% case coverage.5 Medical records of all cases diagnosed through April 1999 were collected from the hospitals and pathology laboratories and reviewed centrally for cancer confirmation by one or two study physicians. Of the 6098 cases diagnosed after April 1999, 25% were selected for various sub-studies and had their medical records reviewed by one study physician. For the remaining 75%, information was based solely on Finnish Cancer Registry data.
We report herein results for cancers of lung, prostate, urinary tract (renal pelvis, ureter, and bladder), kidney, stomach, colon and rectum (excluding cancers of anal canal), and pancreas (excluding endocrine tumors). With the exception of non-melanoma skin cancer, all other cancers are combined. In situ carcinomas are excluded except for the urinary tract.
Deaths were identified from the national Register of Causes of Death. Cause-specific mortality was derived from the official underlying cause of death and categorized as death from lung cancer, prostate cancer, other cancer, and non-cancer causes.
Statistical analysis
In the analysis of cancer incidence, follow-up time accrued from the start of post-trial follow-up (i.e., May 1, 1993) until the first occurrence of a specific cancer, death, or the end of follow-up (i.e., April 30, 2011). In the analysis of mortality, follow-up continued until death or the same end of follow-up.
Crude cancer incidence rates per 10 000 person-years in each of the four intervention groups were calculated. Crude relative risk (RR) point estimates and their 95% confidence intervals (CI) were obtained from Poisson regression models.6 Differences in the RRs between the four groups were tested using the likelihood ratio test. We similarly estimated the RR and 95% CIs according to the 2 × 2 factorial design; i.e., participants who either received α-tocopherol supplementation (α-tocopherol plus β-carotene and α-tocopherol only groups) or did not receive α-tocopherol supplementation (placebo and β-carotene only groups), and similarly for the groups who either received or did not receive β-carotene supplementation. Effect modification by trial baseline age (<60 and ≥60 years), smoking (<20 and ≥20 cigarettes daily), alcohol consumption (ethanol ≤11 and >11 g/day), and body mass index (BMI of <25, ≥25–<30, and ≥30 kg/m2) was tested using the likelihood ratio test.
Generalized additive models7 were used to estimate the calendar time-specific RRs for lung and prostate cancer incidence and mortality. Calendar time was divided into monthly intervals with the exception of the first interval which combined the first 12 months of the trial because of the small monthly risk sets during this period. The monthly rates were treated as Poisson responses. For each target month, 25% of the nearest months defined a neighborhood where a weighted linear curve was used to estimate the smoothed RR and its 95% CIs at the target month. The weights for the monthly observations were calculated from a tricube kernel smoother.
Statistical analyses were performed using R version 2.15.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
The average age of the 25,563 men observed for cancer incidence and cause-specific mortality was 63.5 years at the start of the post-trial follow-up. Among the men with data at the last scheduled trial follow-up visit, 75% reported still being current smokers with an average intensity of 18 cigarettes daily.
Cancer incidence
Incidence and RR of site-specific cancers in the four intervention groups for the post-trial period are shown in Table 1. The post-trial risks did not significantly differ among the intervention groups for any of the cancers.
Table 1.
Incidence and relative risk of site-specific cancer and total mortality during 18-year post-trial follow-up by regimen in the ATBC Study.
Placebo | α-Tocopherol | α-Tocopherol and β-Carotene | β-Carotene | P for differencea | ||
---|---|---|---|---|---|---|
Lung | No. at risk | 6375 | 6349 | 6278 | 6281 | |
No. of incident cancers | 725 | 711 | 736 | 709 | ||
Rate per 10 000 person-years | 92.4 | 91.8 | 97.1 | 93.7 | ||
RR (95% CI) | Referent | 0.99 (0.90–1.10) | 1.05 (0.95–1.16) | 1.01 (0.91–1.13) | .72 | |
Prostate | No. at risk | 6388 | 6388 | 6308 | 6305 | |
No. of incident cancers | 605 | 553 | 587 | 576 | ||
Rate per 10 000 person-years | 79.6 | 73.3 | 79.8 | 78.3 | ||
RR (95% CI) | Referent | 0.92 (0.82–1.03) | 1.00 (0.89–1.12) | 0.98 (0.88–1.10) | .44 | |
Urinary Tractb | No. at risk | 6408 | 6386 | 6315 | 6328 | |
No. of incident cancers | 169 | 164 | 167 | 147 | ||
Rate per 10 000 person-years | 21.6 | 21.2 | 22.1 | 19.4 | ||
RR (95% CI) | Referent | 0.98 (0.79–1.22) | 1.02 (0.83–1.27) | 0.90 (0.72–1.12) | .68 | |
Kidneyc | No. at risk | 6427 | 6406 | 6333 | 6351 | |
No. of incident cancers | 63 | 65 | 60 | 67 | ||
Rate per 10 000 person-years | 8.0 | 8.3 | 7.8 | 8.7 | ||
RR (95% CI) | Referent | 1.04 (0.74–1.48) | 0.98 (0.69–1.40) | 1.10 (0.78–1.55) | .93 | |
Stomach | No. at risk | 6421 | 6408 | 6331 | 6345 | |
No. of incident cancers | 80 | 82 | 76 | 75 | ||
Rate per 10 000 person-years | 10.1 | 10.5 | 9.9 | 9.8 | ||
RR (95% CI) | Referent | 1.04 (0.76–1.41) | 0.98 (0.72–1.34) | 0.97 (0.71–1.33) | .98 | |
Colorectal | No. at risk | 6416 | 6403 | 6330 | 6340 | |
No. of incident cancers | 172 | 175 | 165 | 164 | ||
Rate per 10 000 person-years | 21.9 | 22.5 | 21.6 | 21.5 | ||
RR (95% CI) | Referent | 1.03 (0.83–1.27) | 0.99 (0.80–1.23) | 0.98 (0.80–1.22) | .98 | |
Pancreas | No. at risk | 6435 | 6416 | 6346 | 6360 | |
No. of incident cancers | 84 | 89 | 84 | 89 | ||
Rate per 10 000 person-years | 10.6 | 11.3 | 10.9 | 11.6 | ||
RR (95% CI) | Referent | 1.07 (0.79–1.44) | 1.03 (0.76–1.40) | 1.09 (0.81–1.47) | .94 | |
Other | No. at risk | 6376 | 6360 | 6296 | 6313 | |
No. of incident cancers | 455 | 404 | 442 | 425 | ||
Rate per 10 000 person-years | 58.5 | 52.3 | 58.5 | 56.3 | ||
RR (95% CI) | Referent | 0.89 (0.78–1.02) | 1.00 (0.88–1.14) | 0.96 (0.84–1.10) | .32 | |
Mortality | No. at risk | 6436 | 6418 | 6346 | 6363 | |
No. of deaths | 4171 | 4197 | 4185 | 4133 | ||
Rate per 10 000 person-years | 524.8 | 533.8 | 543.7 | 536.7 | ||
RR (95% CI) | Referent | 1.02 (0.97–1.06) | 1.04 (0.99–1.08) | 1.02 (0.98–1.07) | .44 |
Abbreviations: ATBC Study, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; RR, relative risk; CI, confidence interval
Differences in the RRs between the groups were tested using the likelihood ratio test.
Includes cancers of renal pelvis, ureter, and bladder
Includes renal cell carcinoma
During the 18-year post-trial follow-up, 2,881 incident lung cancers were ascertained among the 25,283 participants who had no lung cancer diagnosed through the end of the intervention period. The 18-year post-trial lung cancer incidence did not differ between α-tocopherol recipients and nonrecipients (RR, 1.01; 95% CI, 0.94–1.09) or between β-carotene recipients and nonrecipients (RR, 1.04; 95% CI, 0.96–1.11) (Table 2). The smoothed calendar time-specific RR of lung cancer for the α-tocopherol recipients compared with the nonrecipients was significantly below 1.0 for the first post-intervention year but varied non-significantly around 1.0 thereafter (Fig. 1a). For the β-carotene recipients compared with the nonrecipients, the RR was significantly elevated at the end of the intervention but declined below 1.0 approximately 4 years post-trial and varied non-significantly around 1.0 thereafter (Fig. 1b). Baseline age, BMI, smoking, and alcohol consumption did not modify the effect of α-tocopherol or β-carotene on lung cancer risk during the post-trial period (P>0.05 for interaction for each factor).
Table 2.
Site-specific cancer incidence during the 18-year post-trial follow-up by α-tocopherol or β-carotene supplementation in the ATBC Studya
Site of cancer | Number of menb | α-Tocopherol vs No α-Tocopherol | β-Carotene vs No β-Carotene | ||||
---|---|---|---|---|---|---|---|
Number of incident cancers | RR (95% CI)c | Number of incident cancers | RR (95% CI)c | ||||
α-Tocopherol | No α-Tocopherol | β-Carotene | No β-Carotene | ||||
Lung | 25 283 | 1447 | 1434 | 1.01 (0.94–1.09) | 1445 | 1436 | 1.04 (0.96–1.11) |
Prostate | 25 389 | 1140 | 1181 | 0.97 (0.89–1.05) | 1163 | 1158 | 1.03 (0.95–1.12) |
Urinary tractd | 25 437 | 331 | 316 | 1.05 (0.90–1.23) | 314 | 333 | 0.97 (0.83–1.13) |
Kidneye | 25 517 | 125 | 130 | 0.97 (0.76–1.24) | 127 | 128 | 1.02 (0.80–1.30) |
Stomach | 25 505 | 158 | 155 | 1.02 (0.82–1.28) | 151 | 162 | 0.96 (0.77–1.19) |
Colorectal | 25 489 | 340 | 336 | 1.02 (0.87–1.18) | 329 | 347 | 0.97 (0.84–1.13) |
Pancreas | 25 557 | 173 | 173 | 1.01 (0.81–1.24) | 173 | 173 | 1.03 (0.83–1.27) |
Other | 25 345 | 846 | 880 | 0.96 (0.88–1.06) | 867 | 859 | 1.04 (0.94–1.14) |
Abbreviations: ATBC Study, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; RR, relative risk; CI, confidence interval
Follow-up through April 30, 2011
Men without the site-specific cancer at start of the post-trial follow-up
Relative risk estimate from a Poisson regression model and 95% CI is approximate.
Includes cancers of renal pelvis, ureter, and bladder
Includes renal cell carcinoma
Figure 1.
Lung (a and b) and prostate (c and d) cancer incidence: smoothed relative risk curves and their 95% point-wise confidence intervals in calendar time for the α-tocopherol (AT) vs no α-tocopherol (no AT) and β-carotene (BC) vs no β-carotene (no BC) comparisons in the ATBC Study.
There were 2,321 incident prostate cancers during the 18-year post-trial follow-up among the 25,389 participants who had no prostate cancer diagnosed by the end of the intervention. No difference in incidence was observed between α-tocopherol recipients and nonrecipients (RR, 0.97; 95% CI, 0.89–1.05) or between β-carotene recipients and nonrecipients (RR, 1.03; 95% CI, 0.95–1.12) (Table 2). The smoothed calendar time-specific RR of prostate cancer for the α-tocopherol recipients compared with the nonrecipients was significantly below 1.0 for the last 5 years of the intervention period and reached 1.0 within about 8 years post-intervention (Fig. 1c). For the β-carotene recipients compared with the nonrecipients, the RR was nonsignificantly elevated for the last 5 years of the intervention period but decreased below 1.0 approximately 5 years post-trial and varied nonsignificantly around 1.0 thereafter (Fig. 1d).
BMI significantly modified the effect of α-tocopherol (P for interaction=0.01), but not that of β-carotene, on prostate cancer risk during the post-trial follow-up. Among recipients of α-tocopherol, compared to nonrecipients, the RR of prostate cancer was 1.00 (95% CI, 0.87–1.14) in normal-weight men (BMI of <25 kg/m2), 0.87 (95% CI, 0.78–0.98) in overweight men (BMI of ≥25–<30), and 1.25 (95% CI, 1.01–1.55) in obese men (BMI of ≥30). BMI also modified the effect of α-tocopherol on prostate cancer incidence during the intervention period during which the risks for the same BMI categories were 0.69 (95% CI, 0.45–1.06), 0.49 (95% CI, 0.33–0.72), and 1.23 (95% CI, 0.67–2.26), respectively (P for interaction=0.04). Baseline age, smoking, and alcohol consumption did not modify the effect of α-tocopherol or β-carotene on prostate cancer risk during post-trial follow-up (P>0.05 for interaction for each factor).
The incidence and RR of cancers other than lung and prostate did not differ by α-tocopherol or β-carotene intervention (Table 2).
Mortality
Of the 25,563 participants alive at the beginning of the post-intervention period, 16,686 (65%) died during the 18-year post-trial follow-up. The relative mortality was 1.02 (95% CI, 0.98–1.05) among α-tocopherol recipients compared with the nonrecipients, and 1.02 (95% CI, 0.99–1.05) among β-carotene recipients compared with the nonrecipients (Table 3).
Table 3.
Cause-specific mortality during the 18-year post-trial follow-up by α-tocopherol or β-carotene supplementation in the ATBC Studya
Cause of death | α-Tocopherol vs No α-Tocopherol | β-Carotene vs No β-Carotene | ||||
---|---|---|---|---|---|---|
Number of deaths | RR (95% CI)b | Number of deaths | RR (95% CI)b | |||
α-Tocopherol | No α-Tocopherol | β-Carotene | No β-Carotene | |||
Lung cancer | 1325 | 1346 | 0.99 (0.92–1.07) | 1349 | 1322 | 1.05 (0.97–1.13) |
Prostate cancer | 240 | 289 | 0.84 (0.70–0.99) | 285 | 244 | 1.20 (1.01–1.42) |
Other cancer | 1192 | 1163 | 1.03 (0.95–1.12) | 1170 | 1185 | 1.01 (0.94–1.10) |
Non-cancer | 5625 | 5506 | 1.03 (0.99–1.07) | 5514 | 5617 | 1.01 (0.97–1.05) |
Total | 8382 | 8304 | 1.02 (0.98–1.05) | 8318 | 8369 | 1.02 (0.99–1.05) |
Abbreviations: ATBC Study, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; RR, relative risk; CI, confidence interval
Follow-up of 25 563 men through April 30, 2011
Relative risk estimate from a Poisson regression model and 95% CI is approximate.
Of the post-trial deaths, 16.0% were due to lung cancer, 3.2% to prostate cancer, 14.1% to other cancers, and 66.7% to non-cancer causes. Neither supplementation had a significant effect on overall post-trial lung cancer mortality (Table 3). The smoothed calendar time-specific relative lung cancer mortality of the α-tocopherol recipients was similar to that of the nonrecipients throughout the post-intervention follow-up (Fig. 2a). The higher mortality of the β-carotene recipients compared with the nonrecipients evident by the end of intervention disappeared within approximately 3 years post-trial after which the mortality was similar in both groups (Fig. 2b).
Figure 2.
Lung (a and b) and prostate (c and d) cancer mortality: smoothed relative risk curves and their 95% point-wise confidence intervals in calendar time for the α-tocopherol (AT) vs no α-tocopherol (no AT) and β-carotene (BC) vs no β-carotene (no BC) comparisons in the ATBC Study.
Relative prostate cancer mortality was significantly lower among recipients of α-tocopherol than among nonrecipients (RR, 0.84; 95% CI, 0.70–0.99), whereas it was significantly higher among recipients of β-carotene than among nonrecipients (RR, 1.20; 95% CI, 1.01–1.42) (Table 3). The smoothed calendar time-specific relative prostate cancer mortality of the α-tocopherol recipients compared to the nonrecipients remained lower about 8 years post-trial (Fig. 2c). Prostate cancer mortality appeared slightly higher among β-carotene recipients compared with the nonrecipients during the entire post-trial follow-up (Fig. 2d).
Discussion
The primary aim of the ATBC Study was to determine whether supplementation with α-tocopherol or β-carotene would reduce the incidence of lung cancer in male smokers. By the end of the intervention period, α-tocopherol had no overall effect, whereas β-carotene increased the incidence by 17%.4 This difference disappeared within approximately 4 years after the start of the post-intervention follow-up without any remarkable difference thereafter. The Beta-Carotene and Retinol Efficacy Trial (CARET), another study that tested a combination of β-carotene and retinyl palmitate (vitamin A) in smokers and asbestos-exposed workers, reported a 28% increase in incidence of lung cancer in the active supplementation group,8 which remained elevated 4 years post-intervention.9 These temporal effects in both the ATBC Study and CARET suggest that β-carotene in some way accelerated the growth of preclinical tumors, and argue against an effect on earlier phases of lung carcinogenesis. The findings of the ATBC Study and CARET are inconsistent with the protective associations for β-carotene intake or circulating β-carotene observed in prospective epidemiological studies. A recent systematic review concluded, however, that the lower lung cancer risks are generally small and statistically nonsignificant in persons of higher β-carotene status.10 Furthermore, other plausible explanations for the inverse associations cannot be ruled out, such as residual confounding by cigarette smoking and the possibility that β-carotene serves as a marker of other beneficial components of fruits and vegetables or healthier lifestyles in general.10
In the ATBC Study, β-carotene supplements increased the risk of lung cancer among those who at baseline reported smoking 20 cigarettes or more per day (RR, 1.25; 95% CI, 1.07–1.46) compared with smokers of fewer cigarettes (RR, 0.97; 95% CI, 0.76–1.23).11 The higher risk related to heavier smoking disappeared within about 4 years after stopping β-carotene supplementation and no late effects were observed during the 18-year follow-up. In the CARET, the combination of β-carotene and retinyl palmitate increased the risk of lung cancer among current heavy smokers (RR,1.42; 95% CI, 1.07–1.87) whereas it had no effect among former heavy smokers (RR, 0.80; 95% CI, 0.48–1.31).8 In controlled trials with low prevalence of smokers, β-carotene supplementation did not impact lung cancer incidence.12–14 The mechanisms through which β-carotene affects the development of lung cancer in smokers have yet to be determined but a prevailing hypothesis involves a pro-oxidant effect from the oxidation of β-carotene that results from components of cigarette smoke in the presence of the relatively high oxygen tension in the lung.15 Alternative mechanistic hypotheses have also been presented.16 β-Carotene might improve lung function and lead to deeper inhalation of the carcinogens and other oxidants in smoke resulting in the larger increase in lung cancer risk among heaviest smokers.
β-Carotene supplementation also increased lung cancer incidence during the intervention period in men who had higher than average alcohol consumption (i.e., 11 g or more of ethanol daily), whereas it had no effect in men drinking less: RRs 1.35 (95% CI, 1.01–1.81) and 1.03 (95% CI, 0.85–1.24), respectively.11 This synergy disappeared shortly after the end of supplementation with no modifying effect of alcohol thereafter. In the CARET as well, the combination of β-carotene and retinyl palmitate led to increased lung cancer rates among subjects in the highest quartile of alcohol intake compared to non-drinkers (P=0.02) but due to lack of a consistent dose-response association and the multiple tests performed, the investigators considered the finding to be only suggestive.17 Alcohol could promote lung cancer in β-carotene supplemented subjects through several mechanisms, such as increasing circulating β-carotene concentration, accelerating the breakdown of retinol in the liver, or exacerbating the carcinogenicity of other xenobiotics, especially those contained in tobacco smoke.18 As adipose tissue is a major site of carotenoid deposition,19 it could also be hypothesized that the effect of β-carotene is prolonged in obese, compared with normal-weight, persons, but there was no indication of this during the post-trial follow-up reported here.
α-Tocopherol supplementation reduced the incidence of prostate cancer by 34%,4 with the preventive effect observed approximately 18 months after randomization.20 The preventive effect of α-tocopherol continued approximately 8 years post-intervention. Although laboratory experiments point to several potential mechanisms for a cancer preventive effect of α-tocopherol,21 its role in prostate carcinogenesis remains unclear. A sub-study within the ATBC Study suggested that α-tocopherol supplementation decreased serum concentrations of androstenedione and testosterone,22 sex hormones thought to be involved in the etiology of prostate cancer.
In contrasts to the ATBC Study findings, however, other placebo-controlled trials supplementing vitamin E as 400 IU daily or every other day have found no beneficial effect on prostate cancer incidence.23,24 The Selenium and Vitamin E Cancer Prevention Trial (SELECT) tested the effect of vitamin E (400 IU/d) and selenium (200 μg/d) on prostate cancer incidence in 35,533 men and was terminated ahead of schedule due to lack of efficacy after a median follow-up of 5.5 years when the hazard ratio for prostate cancer in the vitamin E-alone group (versus placebo) was 1.13 (99% CI, 0.95–1.35).25 With an extended follow-up of 2.8 years, the increased risk in the vitamin E-alone arm reached statistical significance: hazard ratio 1.17 (99% CI, 1.004–1.36).26 Use of vitamin E supplements has not been consistently associated with prostate cancer in observational studies, although some studies have found that among smokers, use of supplemental vitamin E was associated with reduced risk of advanced prostate cancer compared with non-use of supplemental vitamin E.27,28 Some serum studies have suggested reduced risk of prostate cancer among men with higher circulating α-tocopherol,29,30 but others have found no association.31–33
An intriguing finding was that BMI modified the effect of α-tocopherol on prostate cancer risk both during the intervention and the post-trial follow-up. The preventive effect was observed especially in over-weight men whereas there appeared to be higher risk among obese men. One trial that reported on vitamin E supplementation, BMI, and prostate cancer risk, found no such interaction.24 In cohort studies, the association between serum α-tocopherol and risk of prostate cancer has been similar among normal and overweight subjects, based on BMI divided at 25 or 26 kg/m2.29, 33 There is no obvious biologic mechanism to explain how α-tocopherol might decrease risk in over-weight men but increase risk in obese men, and this finding could be due to chance.
Overall mortality during the ATBC intervention period was 8% higher among men who received β-carotene compared with those who did not, and the excess mortality continued for 6 years post-intervention, roughly the equivalent time it took for the increased risk to become evident following the initiation of the trial supplementation.4 Thereafter, mortality was similar through 18 years of post-trial follow-up among both recipients and nonrecipients of β-carotene. In the CARET, the all-cause mortality was similar throughout the 6-year post-intervention follow-up in men who had received β-carotene plus retinyl palmitate and those who received placebo.9 Of the specific causes herein, mortality from prostate cancer was significantly higher among β-carotene recipients than among nonrecipients during the post-trial period. The relevance of this finding remains, however, unclear since β-carotene had no impact on post-trial prostate cancer incidence or overall mortality.
α-Tocopherol supplementation had no significant effect on overall mortality during the post-trial period. Of the specific causes, mortality from prostate cancer was 16% lower among α-tocopherol recipients than among nonrecipients, and the lower mortality was evident about 8 years post-trial. This observation provides additional support to the conclusion that the α-tocopherol supplementation, 50 mg daily, had preventive effect on clinically significant prostate cancers.20
In conclusion, α-tocopherol or β-carotene supplementation had no novel or late effects on cancer incidence in the post-trial analysis. The preventive effect of α-tocopherol on prostate cancer, however, continued several years post-trial resulting also in lower prostate cancer mortality. Further trials are warranted to confirm whether moderate-dose α-tocopherol prevents prostate cancer in smokers and whether BMI modifies the effect, i.e., α-tocopherol prevents prostate cancer in non-obese smokers and increases the risk in obese smokers. There is consistent evidence that β-carotene supplementation increases the risk of lung cancer and overall mortality in smokers, and thus, should be avoided by smokers.
What’s new?
In the ATBC Study, daily α-tocopherol supplementation decreased the risk of prostate cancer whereas β-carotene increased the risk of lung cancer. During post-trial follow-up these effects disappeared without novel impacts on other cancers. The reduced risk of prostate cancer lasted about 8 years post-trial and was accompanied by decreased 18-year post-trial mortality from prostate cancer. BMI may modify the effect of α-tocopherol on prostate cancer: overweight men have decreased risk but obese men increased risk.
Acknowledgments
The ATBC Study was supported by Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the U.S. National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and the Intramural Program of the U.S. National Cancer Institute. We acknowledge the long-term, exemplary contributions of Heikki Kilpeläinen for data managing and Anne Söderqvist for data collection in the ATBC Study at the National Institute for Health and Welfare.
Abbreviations
- ATBC
Alpha-Tocopherol, Beta-Carotene Cancer Prevention
- RR
relative risk
- CI
confidence interval
- BMI
body mass index
- CARET
Beta-Carotene and Retinol Efficacy Trial
Footnotes
Trial Registration clinicaltrials.gov Identifier: NCT00342992
References
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