Vitamins E and C in the Prevention of Prostate and Total Cancer in Men:  The Physicians' Health Study II Randomized Controlled Trial FREE

In some observational studies, intake or blood levels of vitamins E and C have been associated with reduced risk of certain cancers.¹ Basic research has provided plausible mechanisms by which antioxidant micronutrients such as vitamin E and vitamin C may delay various steps in carcinogenesis.^2- 4 However, definitive proof that vitamins E and C can reduce the risk of overall or site-specific cancers must rely on large-scale randomized trials.

A number of trials have addressed the potential role of vitamins in the prevention of cancer; however, the results from these trials have not been consistent. Some^5- 8 but not all^9- 16 have supported a role for various antioxidants in the prevention of total or site-specific cancers. The most compelling data supporting a role of vitamin E in the prevention of prostate cancer have come from the Finnish ATBC (α-Tocopherol, Beta Carotene) Cancer Prevention Trial.⁹ This trial was designed to test the effect of vitamin E and beta carotene on lung cancer risk among current and past smokers. Although there was no reduction in risk of lung cancer with either agent, men assigned to active α-tocopherol had a 34% reduction in the hazard of prostate cancer (HR, 0.66; 95% CI, 0.52-0.86).¹⁷ The HOPE-TOO (Heart Outcomes Prevention Evaluation–The Ongoing Outcomes) trial reported no reduction in prostate cancer among those treated with vitamin E compared with placebo for an average of 7 years (HR, 0.98; 95% CI, 0.76-1.26).¹⁶

Other trials of vitamin E were not designed specifically to address prostate cancer risk, and most of these trials were of just a few years’ duration, which may be too short to detect longer-term effects on cancer. Vitamin C alone has been less well studied in large-scale trials. One other recently completed study evaluated vitamin C (500 mg daily) supplementation and total and site-specific cancer risk among women.¹⁸

Despite uncertainty about the long-term health effects or benefits, more than half of US adults take vitamin supplements, and vitamins E and C are among the most popular individual supplements.¹⁹ Given this widespread use, the gaps in knowledge about the role of these agents in cancer prevention, and the uncertainties about other long-term health effects of vitamins E and C, we conducted the Physicians' Health Study (PHS) II, a randomized, double-blind, placebo-controlled factorial trial designed to provide clinically relevant information on the individual effects of vitamin E and vitamin C on total and prostate cancer among 14 641 male physicians treated and followed up for an average of 8.0 years. In this article, we present the findings on prostate, total, and other common cancers. The effects of these agents on cardiovascular events were recently published.²⁰

The PHS II is a randomized, double-blind, placebo-controlled, 2 × 2 × 2 × 2 factorial trial evaluating the balance of risks and benefits of vitamin E (400-IU synthetic α-tocopherol or its placebo on alternate days; BASF Corporation, Florham Park, New Jersey), vitamin C (500-mg synthetic ascorbic acid or its placebo daily; BASF Corporation), and a multivitamin (Centrum Silver or its placebo daily; Wyeth Pharmaceuticals, Madison, New Jersey) in the prevention of cancer and cardiovascular disease among 14 641 male physicians 50 years or older.²¹ A fourth randomized component, beta carotene (50-mg Lurotin or placebo on alternate days; BASF Corporation), was terminated on schedule in March 2003. The multivitamin component is continuing at the recommendation of the data and safety monitoring committee.

The PHS II study design has previously been described.^20- 21 In brief, recruitment, enrollment, and randomization of men into PHS II occurred in 2 phases (Figure 1). Starting in July 1997, 18 763 PHS I participants^10,22 were invited to participate in PHS II. Men were ineligible if they reported a history of cirrhosis or active liver disease, were receiving anticoagulants, or reported a serious illness that might preclude participation. Men with a history of cancer as well as myocardial infarction or stroke were eligible to enroll in PHS II. Participants also must have been willing to forgo during the course of PHS II any current use of multivitamins or individual supplements containing more than 100% of the recommended daily allowance of vitamin E, vitamin C, beta carotene, or vitamin A. A total of 7641 willing participants (41%) from PHS I were randomized into PHS II and retained their original beta carotene treatment assignment.

In 1999, invitational letters and baseline questionnaires were mailed to 254 597 US male physicians 50 years or older identified from a list provided by the American Medical Association, excluding PHS I participants. Between July 1999 and July 2001, 42 165 men completed a baseline questionnaire. Of these, 11 128 were willing and eligible following the same eligibility criteria as PHS I participants. A 12-week placebo run-in period excluded men who were nonadherent, an attribute that typically emerges during the first several months of participation.^21,23 Of 11 128 physicians who entered the run-in phase, 7000 willing and eligible men (63%) took at least two-thirds of their pills and were randomized into PHS II.

Thus, 14 641 men (7641 from PHS I and 7000 new physicians) were randomized into PHS II in blocks of 16 and stratified by age; prior diagnosis of cancer; prior diagnosis of cardiovascular disease; and, for the 7641 PHS I participants, their original beta carotene treatment assignment. Men were randomly assigned to receive vitamin E or its placebo, to receive vitamin C or its placebo, and to receive active or placebo beta carotene and multivitamin. With respect to vitamins E and C, randomization yielded 4 nearly equal-sized groups receiving active vitamin E alone, active vitamin C alone, both active agents, or both placebos. There were 1307 men (8.9%) with a history of cancer (excluding nonmelanoma skin cancer) prior to randomization into PHS II. All participants provided written informed consent, and the institutional review board at Brigham and Women's Hospital approved the research protocol.

Participants were sent monthly calendar packs containing vitamin E or placebo (taken every other day) and vitamin C or placebo (taken daily) every 6 months for the first year and annually thereafter. Participants were also sent annual questionnaires asking about adherence, potential adverse events, the occurrence of new end points, and updated risk factors. Treatment and follow-up continued in blinded fashion through August 31, 2007, the scheduled end of the vitamin E and C components of PHS II. Analyses include follow-up and validation through September 2008 of reported end points that occurred through the end of August 2007. Morbidity and mortality follow-up rates were extremely high, at 95.3% and 97.7%, respectively. Morbidity and mortality follow-up as a percentage of person-time each exceeded 99.9%, with only 1055 and 289 person-years of potential morbidity and mortality follow-up lost through August 31, 2007.

Adherence was defined from participant self-reports as taking at least two-thirds of the study agents. For active vitamin E and its placebo, adherence at 4 years was 78% and 77%, respectively (P = .12), and at the end of follow-up (mean, 8.0 years), 72% and 70% (P = .004). For active vitamin C and its placebo, adherence at 4 years was 78% and 78%, respectively (P = .99), and at the end of follow-up, 71% and 71% (P = .54). There were no differences between groups in average rates of individual nontrial vitamin E (3.2% active, 3.1% placebo) or vitamin C supplement use (3.8% active, 4.4% placebo) for 31 or more days per year (drop-ins) at the end of the trial (each P > .05).

For the vitamin E component, the primary cancer end point was total prostate cancer; total cancer (excluding nonmelanoma skin cancer) was the primary end point for the vitamin C component and a prespecified secondary end point for vitamin E. Incident colorectal cancer was another prespecified secondary end point for the vitamin E component. Other individual sites of cancer were assessed and validated, as well as total mortality and cancer mortality. For each end point reported by participants by follow-up questionnaire, letter, telephone call, and other correspondence, we requested permission from the participant to examine relevant medical records. Once consent was obtained, records were requested from the hospital or attending physician and reviewed by an end-points committee of physicians blinded to randomized treatment assignment.

The vast majority of cancers were confirmed with pathology or cytology reports. Rarely, the committee confirmed a reported case of cancer based on strong clinical and radiological or laboratory marker evidence when pathology or cytology review was not conducted. Total mortality was confirmed by the end-points committee or by obtaining a death certificate. A National Death Index search was performed for any participants with unknown vital status. Only confirmed end points are included in this report.

All primary analyses classified study participants based on the intention-to-treat principle, in which randomized participants were classified according to their randomized vitamin E or vitamin C treatment assignments and were followed up until the occurrence of a disease end point, death, loss to follow-up, or the end of the vitamin E and vitamin C components of PHS II on August 31, 2007, whichever came first. SAS version 9.1 (SAS Institute Inc, Cary, North Carolina) was used, with statistical significance set at P < .05 using 2-sided tests.

The PHS II was designed to have greater-than-80% power to detect a 13% reduction in the hazard of total cancer (excluding nonmelanoma skin cancer) and a 19% reduction in the hazard of prostate cancer. Estimates of study power relied on historical event rates observed in PHS physicians that predicted the trial would accrue 418 incident prostate cancer cases and 877 total cancer cases in the half of participants randomized to a placebo treatment. The actual number of cases of prostate cancer and total cancer accrued in the vitamin E placebo group exceeded the numbers predicted for power calculations by 23% and 9%, respectively.

We first compared baseline characteristics by vitamin E or C treatment assignment to evaluate whether randomization equally distributed baseline characteristics. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) comparing event rates in the vitamin E and placebo groups and the vitamin C and placebo groups. For each prespecified end point, models were stratified on the presence of cancer at randomization and adjusted for study design variables: age; PHS cohort (original PHS I participant, new PHS II participant); and randomized beta carotene, vitamin E or vitamin C, and multivitamin assignments. For total cancer analyses, all new cancers were included, regardless of whether the participant had a baseline history of cancer. For each site-specific cancer analysis, participants were excluded if they had a baseline history of cancer of the same site. Thus, these analyses included 13 983 men initially free of prostate cancer, 14 520 initially free of colorectal cancer, and 14 610 initially free of lung cancer.

For analyses of the secondary end points of total mortality, any cancer mortality, and site-specific cancer deaths, we included all participants. The association between vitamin E and prostate cancer mortality was also examined separately among the 13 334 men without and 1307 with a baseline history of cancer. We tested the proportional hazards assumption by modeling interaction terms separately for vitamin E or C with the logarithm of time, and these assumptions were not violated (P > .05). We then investigated whether vitamin E or C adherence affected our primary results through sensitivity analyses that censored follow-up when a participant reported taking less than two-thirds of either vitamin E or vitamin C over the previous year. To explore a possible late benefit associated with vitamin E or C, we analyzed separately the person-time and outcomes in the first 4 years of treatment and then after 4 years. Additional exploratory analyses considered estimated treatment effects within 2-year time intervals and also whether an effect was present if only events and person-time after 6 years of treatment were considered. Finally, we conducted subgroup analyses stratified by major cancer risk factors as well as previous cancer history and assessed effect modification by using interaction terms between subgroup indicators and either vitamin E or C assignment.

The PHS II randomized 14 641 men with a mean (SD) age of 64.3 (9.2) years. Randomization equally distributed all baseline characteristics between vitamin E or vitamin C and their placebo groups (all P > .05) (Table 1). During a mean follow-up of 8.0 years (median, 7.6 years; interquartile range, 7.1-9.6 years; maximum, 10.0 years), total follow-up was 117 711 person-years. There were 1943 confirmed total cancer cases and 1008 prostate cancer cases, with some men experiencing multiple events. A total of 1661 men died during follow-up.

The overall rates of prostate cancer were 9.1 and 9.5 per 1000 person-years in the active and placebo vitamin E groups, respectively. There was no effect of vitamin E on prostate cancer incidence (HR, 0.97; 95% CI, 0.85-1.09; P = .58) (Table 2). The cumulative incidence curves indicate that this lack of effect did not vary for up to 10 years of treatment and follow-up (log-rank P = .53) (Figure 2). For total cancer, the overall rates were 17.8 and 17.3 per 1000 person-years in the active and placebo vitamin E groups, respectively.

Compared with placebo, vitamin E also did not reduce the incidence of total cancer (HR, 1.04; 95% CI, 0.95-1.13; P = .41). We found no effect for any site-specific cancers, including colorectal (HR, 0.88; 95% CI, 0.64-1.19; P = .40), lung (HR, 0.89; 95% CI, 0.60-1.31; P = .55), bladder (HR, 1.21; 95% CI, 0.76-1.94; P = .43), and pancreatic (HR, 1.14; 95% CI, 0.67-1.93; P = .63). In addition, there was no significant effect of vitamin E on total mortality (HR, 1.08; 95% CI, 0.98-1.19; P = .13) or cancer mortality (HR, 1.13; 95% CI, 0.95-1.34; P = .16). Censoring participants at the time of vitamin E nonadherence did not impact the results for prostate cancer (HR, 0.95; 95% CI, 0.84-1.07; P = .38) or total cancer (HR, 1.02; 95% CI, 0.93-1.11; P = .68).

We next evaluated whether baseline history of cancer, risk factors, and other randomized interventions from PHS II modified the effect of vitamin E on prostate cancer or total cancer (Table 3). Among 13 334 men without a baseline history of cancer, vitamin E had no effect on the prevention of total cancer, nor was there any substantial effect of vitamin E on newly diagnosed cancer among 1307 men with cancer at baseline or on prostate cancer among men with another cancer at baseline. In addition, we found no other significant effect modification by baseline risk factors on prostate cancer. In addition, there was no effect modification by randomized beta carotene or vitamin C or the ongoing multivitamin treatment assignment. Analyses focused on the possibility that a number of years of treatment were required before emergence of an effect found no apparent relationship of vitamin E with either prostate or total cancer in data restricted to person-time and events after 4 years of treatment. Further restriction to events and time after 6 years of treatment similarly found no apparent relationships.

The overall rates of total cancer for the active and placebo vitamin C groups were 17.6 and 17.5 per 1000 person-years, respectively. There was no effect of vitamin C on the primary end point of total cancer (HR, 1.01; 95% CI, 0.92-1.10; P = .86) (Table 2). The cumulative incidence curves showed no difference between groups in the HRs over time (log-rank P = .92) (Figure 2). The rates of prostate cancer were 9.4 cases per 1000 person-years for the active vitamin C group and 9.2 cases per 1000 person-years for the placebo group (HR, 1.02; 95% CI, 0.90-1.15; P = .80). Vitamin C also had no effect on other site-specific cancers, including colorectal (HR, 0.86; 95% CI, 0.63-1.17; P = .35), lung (HR, 0.95; 95% CI, 0.64-1.39; P = .78), bladder (HR, 0.85; 95% CI, 0.53-1.36; P = .49), and pancreatic (HR, 0.97; 95% CI, 0.57-1.64; P = .91). In addition, no effect was found between vitamin C and either total mortality (HR, 1.07; 95% CI, 0.97-1.18; P = .17) or cancer mortality (HR, 1.06; 95% CI, 0.89-1.25; P = .53). Censoring for nonadherence with vitamin C did not appreciably affect our findings for total cancer (HR, 1.00; 95% CI, 0.92-1.09; P = .98).

We then evaluated whether baseline history of cancer, risk factors, and other randomized interventions from PHS II or follow-up time modified the effect of vitamin C on the primary end point total cancer (Table 4). There was no effect modification by any cancer risk factor on the effect of vitamin C on total cancer, including stratifying by previous history of cancer. In addition, there was no effect modification by randomized treatment assignments, including beta carotene, vitamin E, or the ongoing multivitamin component. To evaluate the effect of the latency period, the effect of vitamin C treatment assignment was examined by years of follow-up in 2-year increments. Further, analyses restricted to events and times after 4 years of treatment, or after 6 years, found no association of vitamin C with total cancer.

When we examined the 2-way interaction between randomized vitamin E and vitamin C assignments, we found no significant interactions for either total cancer (P for interaction = .87), prostate cancer (P for interaction = .55), colorectal cancer (P for interaction = .59), or lung cancer (P for interaction = .44) (Figure 3).

As previously published,²⁰ we assessed a number of potential adverse effects of vitamins E and C, and there were no significant effects of either agent on minor bleeding (including hematuria, easy bruising, and epistaxis) or gastrointestinal tract symptoms (peptic ulcer, constipation, diarrhea, gastritis, and nausea), fatigue, drowsiness, skin discoloration or rashes, or migraine. A greater number of hemorrhagic strokes was observed among those assigned to vitamin E compared with placebo (39 vs 23 events; HR, 1.74; 95% CI, 1.04-2.91), a finding that was observed in the ATBC Cancer Prevention Trial⁹ but not observed in other trials of vitamin E.

In this large-scale, randomized controlled trial among middle-aged and older men, neither long-term vitamin E nor vitamin C supplementation reduced the risk of prostate or total cancer. Neither vitamin reduced the risk of cancer death; major site-specific cancers, including colorectal, lung, bladder, pancreatic, lymphoma, leukemia, or melanoma; or total mortality. There was no suggestion of a latent effect for either vitamin.

The most compelling data suggesting that vitamin E may reduce the risk of prostate cancer come from the Finnish ATBC Cancer Prevention Trial. The ATBC trial was a randomized, double-blind, placebo-controlled trial of α-tocopherol (50 mg daily) and beta carotene (20 mg daily) among 29 133 male smokers. Among those assigned to 50 mg of α-tocopherol supplementation daily, there was no overall reduction in cancer risk; however, there was a 34% reduction in prostate cancer incidence during a median follow-up period of 6.1 years.⁹

This effect attenuated after several years of posttrial follow-up. The effect of vitamin E appeared to be stronger on more advanced tumors. A 41% reduction in prostate cancer mortality was also observed. Since prostate cancer was not a prespecified end point, it remains possible that this finding was due to chance. Other completed trials of vitamin E, including several among individuals at high risk for cardiovascular disease, were not powered to address the possible benefit of vitamin E on prostate cancer. The HOPE-TOO prostate cancer results demonstrated no clear harm or benefit of 400 IU daily of vitamin E.¹⁶

In response to the ATBC finding, we launched the PHS II trial to specifically test the hypothesis that vitamin E might prevent prostate cancer in middle-aged or older men. Because the effect in the ATBC trial appeared to be stronger in later-stage cancers, we chose not to screen for prostate cancer and even included a small number of participants with previously diagnosed cancers. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was also designed to assess the role of vitamin E in the prevention of incident prostate cancer.²⁴ In contrast to PHS II, SELECT enrolled men initially free of prostate cancer based on baseline prostate-specific antigen values and digital rectal examinations. Using a factorial design, SELECT also tested selenium in the prevention of prostate cancer.

One notable difference between the PHS II and ATBC trials was the prevalence of smoking in ATBC and the very low levels of smoking in PHS II. If the effect of vitamin E was confined to smokers, PHS II would likely miss this effect. Another notable difference between the 2 trials was the lower dose of vitamin E in ATBC (50 mg daily), compared with 400 IU on alternate days in PHS II. Alternatively, the results of PHS II suggest that the observed beneficial findings of vitamin E on the development of prostate cancer from the ATBC trial may have been due to the play of chance. This illustrates the importance of cautious interpretation of findings on secondary end points.

Mixed results have been obtained from trials of vitamin E supplementation and total cancer. In the ATBC trial, there was no reduction in risk of total cancer among those randomized to α-tocopherol (50 mg daily) and/or beta carotene (20 mg daily), and vitamin E alone had no effect on the primary end points of lung or total cancer.²⁵ In the Chinese Cancer Prevention Trial, conducted among 29 584 poorly nourished residents of Linxian, China, those assigned to a combined daily treatment of vitamin E (30 mg), beta carotene (15 mg), and selenium (50 μg) experienced statistically significant reductions of 9% in total mortality, 13% in cancer mortality, and 21% in gastric cancer mortality after nearly 6 years of treatment and follow-up.⁵ However, these results may not be generalizable to well-nourished populations. Moreover, because 3 agents were tested in combination, the specific benefit of vitamin E, beta carotene, or selenium cannot be determined. In the ATBC trial, those assigned to vitamin E had a nonsignificant 22% reduction (HR, 0.78; 95% CI, 0.55-1.09) in colorectal cancer incidence.^9,17 In the Women's Health Study, there was no reduction in the risk of colorectal cancer among middle-aged and older women (HR, 1.00; 95% CI, 0.77-1.31).¹⁵ Our findings do not support a role of vitamin E in the prevention of total cancer, colorectal cancer, or other common cancers.

In contrast to vitamin E, which is available in a limited number of foods, vitamin C is derived from many fruit and vegetable sources. In a review of data from more than 90 epidemiologic studies of dietary intake of vitamin C (or foods that supply vitamin C) and total cancer, Block²⁶ found that almost all showed a protective relationship, with a median 2-fold increased relative risk for low compared with high intake. The effects were statistically significant in three-fourths of the studies. Both dietary intake^27- 29 and blood-based studies have shown inverse relationships. Epidemiologic evidence suggests an inverse association between dietary intake of vitamin C and risk of a variety of specific cancers.²⁶ Published reports show significant protective effects of vitamin C on breast, oral, gastric, esophageal, pancreatic, lung, cervical, and rectal cancer, while none have reported elevated risk with increasing intake.^26,30- 31

A major gap in the evidence regarding a possible role of vitamin C in the prevention of cancer is lack of data from large-scale primary prevention trials. Secondary prevention trials focusing on vitamin C for the recurrence of colon cancer or polyps have also yielded mixed results, ranging from a nonsignificant reduction (relative risk, 0.86; 95% CI, 0.51-1.45) among individuals with colon polyps assigned to a combination of vitamin E and C, compared with placebo,³² to no evidence that either combined vitamins E and C or beta carotene alone reduced the incidence of subsequent colorectal adenomas among patients with previous adenoma.³³

The PHS II attempted to fill the gap in the vitamin C literature with a long-term trial of individual vitamin C supplements at a commonly used dose in a large group of men. Our findings of no reduction in risk of total cancer and no clear evidence of a reduction in site-specific cancers do not support the use of vitamin C supplementation in the prevention of cancer. It remains possible that vitamin C intake is a marker of other nutrients that are consumed with vitamin C in the diet.

Major strengths of this study were the high levels of adherence to the study agents over a long period of time and the high quality of reporting of health information. Further, the conduct of this trial entirely by mail greatly increased the efficiency and reduced the cost of this study. Recruitment costs were about $200 per participant and annual follow-up costs were about $100 per participant, a fraction of the cost of similar studies that require establishment of many study sites with dedicated research personnel.

The study was conducted in a well-nourished population, and thus, these results may not preclude potential benefits in less well-nourished populations. One concern is the choice of dose used. It is not feasible to test multiple doses in these large-scale trials. The doses of vitamin E and C in the PHS were chosen because they were in the range of those commonly in use, because they did not have known major adverse effects that would impact adherence, and because their safety data were sound—a critical issue when conducting a trial by mail. The form of vitamin E chosen for our study was synthetic α-tocopherol, the most abundant component of natural vitamin E. However, in nature, vitamin E is composed of both α- and γ-tocopherol. γ-Tocopherol has been postulated to possibly play a more important role in prostate cancer protection.³⁴

The duration of a large-scale trial is also an issue of concern. We had to balance the desire to extend treatment and follow-up as long as possible considering issues of cost and adherence; however, it remains possible that chemoprevention may require even longer durations of treatment and follow-up than is feasible in randomized trials. We will continue to follow the PHS II cohort for emergent latent effects. Adherence remains an issue of concern in any long-term study, but levels of adherence in the PHS II remained good after a mean follow-up of 8.0 years. It remains possible that these agents have a role in chemoprevention only when taken in the context of other micronutrients, a hypothesis we are testing in the continuation of the multivitamin component of PHS II.

In this long-term, large-scale, low-cost trial, after a mean of 8.0 years of treatment and follow-up in 14 641 men, neither vitamin E nor vitamin C supplementation reduced the risk of prostate or total cancer. There was also no clear effect of either agent on other site-specific cancers. It is reassuring that there was not a clear signal of harm for either agent. These data provide no support for the use of these supplements in the prevention of cancer in middle-aged and older men. Results of the multivitamin arm of the PHS II will be forthcoming in several years.