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Heavy Multivitamin Use May Be Linked to Advanced Prostate Cancer
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Journal of the National Cancer Institute, May 16, 2007
"....In this large prospective study, we found that multivitamin use was unrelated to overall risk of total and organ-confined prostate cancer. However, we found an increased risk of advanced and fatal prostate cancer among those who took multivitamins more than seven times per week compared with never users. The risk of advanced prostate cancer and prostate cancer mortality associated with heavy multivitamin use was highest in men who reported concomitant use of selenium, beta-carotene, or zinc supplements, or who had a positive family history of prostate cancer. Although there was no main effect of multivitamin use on localized prostate cancer, we found an increased risk of localized prostate cancer among those who took multivitamins more than seven times per week versus never use, in men also taking vitamin E, selenium, or folate supplements..." see text from study below.
MEMO TO THE MEDIA
Press Release
Liz Savage
While regular multivitamin use is not linked with early or localized prostate cancer, taking too many multivitamins may be associated with an increased risk for advanced or fatal prostate cancers, according to a study in the May 16 issue of the Journal of the National Cancer Institute.
Millions of Americans take multivitamins because of a belief in their potential health benefits, even though there is limited scientific evidence that they prevent chronic disease. Researchers have wondered what impact multivitamin use might have on cancer risk.
Karla Lawson, Ph.D., of the National Cancer Institute in Bethesda, Md., and colleagues followed 295,344 men enrolled in the National Institutes of Health-AARP Diet and Health Study to determine the association between multivitamin use and prostate cancer risk. After five years of follow-up, 10,241 men were diagnosed with prostate cancer, including 8,765 with localized cancers and 1,476 with advanced cancers.
The researchers found no association between multivitamin use and the risk of localized prostate cancer. But they did find an increased risk of advanced and fatal prostate cancer among men who used multivitamins more than seven times a week, compared with men who did not use multivitamins. The association was strongest in men with a family history of prostate cancer and men who also took selenium, beta-carotene, or zinc supplements.
"Because multivitamin supplements consist of a combination of several vitamins and men using high levels of multivitamins were also more likely to take a variety of individual supplements, we were unable to identify or quantify individual components responsible for the associations that we observed," the authors write.
In an accompanying editorial, Goran Bjelakovic, M.D., of the University of Nis in Serbia, and Christian Gluud, M.D., of Copenhagen University Hospital in Denmark, discuss the positive and negative health effects of antioxidant supplements. "Lawson [and colleagues] add to the growing evidence that questions the beneficial value of antioxidant vitamin pills in generally well-nourished populations and underscore the possibility that antioxidant supplements could have unintended consequences for our health," the authors write.
EDITORIAL
Surviving Antioxidant Supplements
Goran Bjelakovic, Christian Gluud
Affiliations of authors: Department of Internal Medicine-Gastroenterology and Hepatology, Medical Faculty, University of Nis, Nis, Serbia (GB); The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (GB, CG)
Correspondence to: Goran Bjelakovic, MD, Dr Med Sci, Department of Internal Medicine-Gastroenterology and Hepatology, Medical Faculty, University of Nis, Blvd Dr Zorana Djindjica 81, 18000 Nis, Serbia (e-mail: goranb@junis.ni.ac.yu) or Christian Gluud, MD, Dr Med Sci, The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, Dept 33.44, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (e-mail: cgluud@ctu.rh.dk).
An association between healthy diet and good health has been noted since Hippocrates (460-377 BC)-and in fact long before (1). Our diet provides numerous vitamins and trace elements that are essential to good health. Observational studies have shown that there is a positive association between a healthy diet, especially high intake of fruits and vegetables, and delayed aging, reduced risk of cancer, and reduced risk of cardiovascular diseases (2,3). Fruits and vegetables contain numerous micronutrients, including beta-carotene (a precursor of vitamin A), vitamin C, vitamin E, and selenium. These organic components have antioxidant potential and are defined as essential micronutrients (4). Because our body cannot synthesize them, they must be consumed.
In spite of intensive research, it is still not clear exactly which specific dietary constituents of fruits and vegetables might be beneficial. Antioxidant vitamins and elements have attracted most attention in this regard. It is assumed that antioxidants may prevent oxidative damage to cellular components, a potentially important function given that oxidative stress might play a role in aging and the pathogenesis of number of diseases, including cardiovascular diseases and cancer, the leading causes of death in high-income countries (5).
Hypotheses as to the role played by oxidative stress in human disease have stimulated interest in the preventive potential of antioxidant supplements. Worldwide, institutions have been created to study antioxidants, and many resources have been allocated to this area. Consumption of antioxidant supplements in high-income countries has become widespread-it is estimated that about one-third of adults in high-income countries consume antioxidant supplements (6). A large number of primary or secondary prevention randomized trials have been conducted to assess the benefits and harms of antioxidant supplements versus placebo or no intervention. Systematic reviews and meta-analyses of these randomized trials have not demonstrated that beta-carotene, vitamin A, and vitamin E in the administered dosages lead to decreased mortality, and some analyses have suggested the possibility of increased mortality (7-11). As to vitamin C and selenium, the verdict is still out (11).
There are several possible explanations for the potential negative effect of antioxidant supplements. Reactive oxygen species in moderate concentrations are essential mediators of reactions by which the body gets rid of unwanted cells. Thus, if administration of antioxidant supplements decreases free radicals, it may interfere with essential defensive mechanisms for ridding the organism of damaged cells, including those that are precancerous and cancerous (12). Thus, antioxidant supplements may actually cause some harm (7-11,13). Our diets typically contain safe levels of vitamins, but high-level antioxidant supplements could potentially upset an important physiologic balance (7-11,13).
The amounts of antioxidants that may afford protection are not known and may differ among individuals. People exposed to increased oxidative stress may have elevated antioxidant requirements. Furthermore, antioxidants could be beneficial in people with innate or acquired high baseline levels of reactive oxygen species but be harmful in people with lower innate levels (12). It is important to keep in mind that antioxidant supplements are synthetic and possess prooxidant properties as well (14). These factors could explain a possible increase in the risk of cancer (8,9,13) and cardiovascular diseases (7). Meta-analyses of randomized clinical trials have not shown that antioxidant supplements reduce cancer incidence (8,9,13,15).
In this issue of the journal, Lawson et al. (16) report the results of a prospective observational study. They investigated the association between multivitamin use and prostate cancer risk in 295344 men enrolled in the National Institutes of Health (NIH)-AARP Diet and Health Study (16). The men were clinically cancer free at enrollment. The authors found that use of multivitamins more than seven times per week, when compared with never use, was associated with a doubling in the risk of fatal prostate cancer (relative risk = 1.98, 95% confidence interval = 1.07 to 3.66). The study of Lawson et al. (16) is observational, and therefore confounding by indication and other confounding cannot be excluded. But the sample studied is very large, which reduces random errors, and the study seems well conducted. The results are in accord with the results of systematic reviews and meta-analyses of randomized clinical trials (7-11,13). The findings lend further credence to the possibility of harm associated with increased use of supplements, including increased rates of cancer (8,9,13,15) and cardiovascular mortality (7).
Lawson et al. (16) add to the growing evidence that questions the beneficial value of antioxidant vitamin pills in generally well-nourished populations (16) and underscore the possibility that antioxidant supplements could have unintended consequences for our health. There are still many gaps in our knowledge of the mechanisms of bioavailability, biotransformation, and action of antioxidant supplements. How much fruit and vegetables do we have to eat to obtain an optimal amount of these nutrients? Why is it not possible to take a vitamin pill to obtain the same effect as a balanced diet? Antioxidant supplements in pills are synthetic, factory processed, and may not be safe compared with their naturally occurring counterparts (17-21). a possible explanation for the negative effects of antioxidant supplementation observed in trials is that the studies were conducted in middle- and high-income countries among populations already well saturated with vitamins and trace elements (11). The American diet provides 120% of the recommended dietary allowances for beta-carotene, vitamin A, and vitamin C, and dietary vitamin E deficiency has never been reported in the United States (17-21). Whether oxidative stress is a primary cause of chronic diseases and the aging process itself or merely a secondary phenomenon is another question that deserves debate and scrutiny (22).
Results of ongoing clinical trials and further studies will be required to extend our knowledge of the impact of antioxidant supplements on health. Is oxidative stress the cause of disease or rather a consequence? Is it wise to artificially modulate the delicate balance between oxidative stress and antioxidants in our cells? Ideally, we should have more data to address these questions.
One way to extend our knowledge about the effects of supplemental vitamins on health would be to test for benefits and harms of supplements before they come to the market. This would entail fair testing of all commercial ingested products with claimed health benefits, as we intend to do with pharmaceutical drugs (23,24). What happens in a petri dish or in preclinical assays may not happen in people (http://www.jameslindlibrary.org; http://www.cochrane.org). Public investment in independent clinical research will be needed to adequately test hypotheses generated in the laboratory.
ARTICLE
Multivitamin Use and Risk of Prostate Cancer in the National Institutes of Health-AARP Diet and Health Study
Karla A. Lawson, Margaret E. Wright, Amy Subar, Traci Mouw, Albert Hollenbeck, Arthur Schatzkin, Michael F. Leitzmann
Affiliations of authors: Divisions of Cancer Prevention (KAL), Cancer Epidemiology and Genetics (KAL, MEW, TM, A. Schatzkin, MFL), and Cancer Control and Population Sciences (A. Subar), National Cancer Institute, Bethesda, MD; AACR, Washington, DC (AH)
ABSTRACT
Background: Multivitamin supplements are used by millions of Americans because of their potential health benefits, but the relationship between multivitamin use and prostate cancer is unclear.
Methods: We prospectively investigated the association between multivitamin use and risk of prostate cancer (localized, advanced, and fatal) in 295344 men enrolled in the National Institutes of Health (NIH)-AARP Diet and Health Study who were cancer free at enrollment in 1995 and 1996. During 5 years of follow-up, 10241 participants were diagnosed with incident prostate cancer, including 8765 localized and 1476 advanced cancers. In a separate mortality analysis with 6 years of follow-up, 179 cases of fatal prostate cancer were ascertained. Multivitamin use was assessed at baseline as part of a self-administered, mailed food-frequency questionnaire. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated by use of Cox proportional hazards regression, adjusted for established or suspected prostate cancer risk factors.
Results:
No association was observed between multivitamin use and risk of localized prostate cancer. However, we found an increased risk of advanced and fatal prostate cancers (RR = 1.32, 95% CI = 1.04 to 1.67 and RR = 1.98, 95% CI = 1.07 to 3.66, respectively) among men reporting excessive use of multivitamins (more than seven times per week) when compared with never users. The incidence rates per 100000 person-years for advanced and fatal prostate cancers for those who took a multivitamin more than seven times per week were 143.8 and 18.9, respectively, compared with 113.4 and 11.4 in never users. The positive associations with excessive multivitamin use were strongest in men with a family history of prostate cancer or who took individual micronutrient supplements, including selenium, beta-carotene, or zinc.
Conclusion: These results suggest that regular multivitamin use is not associated with the risk of early or localized prostate cancer. The possibility that men taking high levels of multivitamins along with other supplements have increased risk of advanced and fatal prostate cancers is of concern and merits further evaluation.
Multivitamin supplements constitute a major portion of vitamin intake in the United States, with 35% of adults taking some type of multivitamin-multimineral supplement (1). Supplements are used largely because of their potential health benefits (2,3), although scientific support for their efficacy for prevention of chronic disease is limited (3,4). Prostate cancer is the most commonly diagnosed cancer in men in the United States, where it accounts for the third largest number of cancer-related deaths (5). Therefore, any association between intake of multivitamin supplements and the risk or severity of prostate cancer would have important consequences for public health.
Data on the relationship of multivitamins to prostate cancer risk are sparse (6) and are derived from two analytic epidemiologic studies (7,8) and a randomized clinical trial (9). A case-control study (7) found that, compared with non use, regular multivitamin use (seven or more times per week) was not associated with prostate cancer incidence (relative risk [RR] = 0.96, 95% confidence interval [CI] = 0.73 to 1.26). However, two consecutive reports (8,10) from the Cancer Prevention Study-II suggested that multivitamin use was associated with a higher risk of fatal prostate cancer. The first report (8) found that, compared with nonusers, men consuming multivitamins for 5 or more years were at increased risk of fatal prostate cancer (RR = 1.31, 95% CI = 1.04 to 1.66). An updated analysis (10) reported that multivitamin use for 15 or more times per month was associated with a marginally increased risk of fatal prostate cancer (RR = 1.07, 95% CI = 0.99 to 1.15) compared with non use. Neither analysis addressed the relationship between multivitamin use and the risk of early-stage, incident prostate cancer. Recently, the Supplementation en Vitamines et Mineraux Antioxydants trial (9) investigated the effect of nutritional doses of a mixture of antioxidant vitamins on the incidence of prostate cancer. It reported that among men with normal baseline prostate-specific antigen (PSA) levels (<3 mg/L), taking multivitamin-multimineral supplements containing a limited number of individual agents (vitamin C, beta-carotene, selenium, and zinc) markedly reduced prostate cancer risk compared with placebo (RR = 0.52, 95% CI = 0.29 to 0.92). However, a reduction in risk was not seen in men with elevated baseline PSA levels (RR = 1.54, 95% CI = 0.87 to 2.72).
Overall, the available data suggest that multivitamin use may protect against the initiation of prostate cancer but may be associated with more rapid progression. To further investigate the association of multivitamin supplements and the risk of prostate cancer and prostate cancer progression, we examined whether multivitamin use was differentially associated with organ-confined versus more advanced stages of prostate cancer, in a large, prospective cohort study of US men. We also evaluated whether the relationship between multivitamin use and prostate cancer risk was modified by concomitant use of individual vitamin and mineral supplements, screening for elevated PSA, abnormal digital rectal examination results, or a family history of prostate cancer.
Results
Among men in this analysis (n = 295344), 122111 (41%), 34828 (12%), and 16576 (6%) reported use of a one-a-day, theragran, and stress-tab type of multivitamin, respectively (some participants reported using more than one type); consistent daily (seven times per week) intake of some type of multivitamin was reported by 105978 men (36%; Table 1). Five percent of the men included in the analysis (n = 13854) were heavy users of multivitamins (intake more than seven times per week). Of the supplements queried, multivitamins were the most commonly used (51%), followed by vitamin C (40%), vitamin E (37%), and calcium (22%).
To assess the potential for confounding, we evaluated multivitamin use in relation to prostate cancer risk factors including age, body mass index, physical activity, smoking status, education, race, marital status, supplement use, history of diabetes, history of cancer screening, and dietary intakes of red meat, fish, tomato products, alcohol, a-linolenic acid, calcium, vitamin D, a-tocopherol, and zinc (Table 1). Frequency of multivitamin use was positively associated with elements of a healthy lifestyle, including less current smoking; greater physical activity; more frequent prostate cancer screening; increased dietary intakes of tomato products, fish, calcium, vitamin E, and zinc; and decreased consumption of red meat. Use of individual supplements of calcium, zinc, vitamin E, vitamin A, beta-carotene, vitamin C, iron, selenium, and folate were all associated with increased multivitamin use.
We next examined the association of multivitamin use with prostate cancer risk (Table 2) using never users of multivitamin supplements as the reference group. The age-adjusted relative risks of total, localized, advanced, and fatal prostate cancers for heavy use of multivitamin supplements (more than seven times per week) were 1.05 (95% CI = 0.96 to 1.16), 1.02 (95% CI = 0.92 to 1.13), 1.27 (95% CI = 1.02 to 1.59), and 1.65 (95% CI = 0.94 to 2.91), respectively. In multivariable analyses, controlling for dietary, anthropometric, and lifestyle factors potentially related to prostate cancer (listed in Table 2), the corresponding relative risks for total, organ-confined, advanced, and fatal prostate cancers were 1.06 (95% CI = 0.97 to 1.17), 1.02 (95% CI = 0.92 to 1.14), 1.32 (95% CI = 1.04 to 1.67), and 1.98 (95% CI = 1.07 to 3.66), respectively. The incidence rates per 100000 person-years for advanced prostate cancer for those who took more than seven multivitamins per week was 143.8 (95% CI = 113.2 to 174.4), compared with 113.4 (95% CI = 105.0 to 121.8) in never users. The incidence rates per 100000 person-years for fatal prostate cancer for those who took more than seven multivitamins per week was 18.9 (95% CI = 9.0 to 28.7), compared with 11.4 (95% CI = 9.0 to 13.8) in never users.
Because latent prostate cancer symptoms could have led to increased multivitamin use, thereby biasing our results, we repeated our analysis excluding men diagnosed with prostate cancer within the initial 2 years of follow-up. The relative risk of advanced prostate cancer with heavy multivitamin use was attenuated after excluding these individuals (RR = 1.06, 95% CI = 0.74 to 1.50), but the association with prostate cancer mortality was essentially the same as that observed with the total study population (RR = 1.96, 95% CI = 1.03 to 3.71), and it became stronger after excluding those diagnosed within the first 3 years of follow-up (RR = 2.42, 95% CI = 1.25 to 4.68).
We investigated whether the association of multivitamin use to prostate cancer risk varied according to individual supplement use (Table 3). Among men who reported using a selenium supplement, heavy multivitamin use (versus never use) was associated with a statistically significant 37% increased risk of localized prostate cancer, whereas no association was apparent among those who did not report using selenium (P value for test of interaction = .008). Similar effect modification was noted for use of supplemental folate and vitamin E (P values for tests of interaction = .012 and .028, respectively). There was also a statistically significant interaction between daily dose of supplemental vitamin E and multivitamin use for localized prostate cancer (P value for test of interaction = .019), with those reporting the highest daily dose of vitamin E supplement intake (>/=800 IU) having the highest risk of localized prostate cancer associated with multivitamin use (Table 4). Thus, despite the overall lack of association between multivitamin use and risk of localized prostate cancer, we found a statistically significant increased risk of localized prostate cancer among heavy multivitamin users who consumed a selenium, folate, or vitamin E supplement. Use of selenium, vitamin E, or folate as individual supplements was not associated with prostate cancer (data not shown).
The statistically significant positive association between heavy multivitamin use (more than seven times per week) and advanced prostate cancer was somewhat modified by beta-carotene supplement use (P value for test of interaction = .074), with an association apparent only among those concomitantly taking a beta-carotene supplement (RR for increasing categories of multivitamin use among beta-carotene users = 1.00 [referent], 1.21 [95% CI = 0.74 to 1.97], 1.29 [95% CI = 0.89 to 1.87], and 1.66 [95% CI = 1.06 to 2.61]; P value for test of trend = .036). Despite the small number of participants, heavy multivitamin users who were also taking a selenium supplement had a statistically significant 5.8-fold increased risk of fatal prostate cancer, whereas among nonusers of a selenium supplement, there was no association between fatal prostate cancer and multivitamin use (P value for test of interaction = .037). Heavy multivitamin use versus never use was associated with an increased risk of both advanced prostate cancer (RR = 2.48, 95% CI = 1.45 to 4.23) and fatal prostate cancer (RR = 16.41, 95% CI = 2.62 to 102.68) among men with a positive family history of prostate cancer, whereas no association was apparent among those without a family history (RR = 0.97, 95% CI = 0.70 to 1.34; RR = 1.07, 95% CI = 0.44 to 2.58) (Table 5).
Our main effects analysis had revealed a positive association of multivitamin use with advanced and fatal prostate cancers that was limited to heavy use of multivitamins (more than seven times per week) but was not seen for nonheavy use (less than or equal to seven times per week). Thus, we tested whether such a pattern, of increased risk seen only in one group of users, could be confirmed in subgroup analyses by conducting tests for interaction that were based on a two-level multivitamin variable (seven or fewer versus more than seven times per week). The subgroup-specific findings were consistent with those observed in the main analysis for the interaction between heavy multivitamin use and positive family history of prostate cancer. Multivitamin use at more than seven versus seven or fewer times per week was related to increased risk of advanced and fatal prostate cancers but only among men with a positive family history of prostate cancer, with P values for the tests of interaction for advanced and fatal prostate cancers of .002 and .043, respectively. Among men who reported taking a zinc supplement, multivitamin use at more than seven versus seven or fewer times per week was associated with an increased risk of fatal prostate cancer (RR = 4.36, 95% CI = 1.83 to 10.39), whereas no association with multivitamins was observed for men not taking a zinc supplement (RR = 1.13, 95%CI = 0.46 to 2.80; P value for test of interaction = .042). Thus, the apparent adverse effect of multivitamin use on prostate cancer seen among the subgroup of men defined by a positive family history of prostate cancer and zinc supplement use was stronger in heavy versus nonheavy use of multivitamins.
The level of specific dietary micronutrients or foods (with the exception of tomato products) consumed did not modify the association between multivitamin use and prostate cancer risk. An increased risk of advanced prostate cancer was observed for heavy multivitamin users with intakes of tomato products above the population mean (P value for test of interaction = .043). Age; smoking status; history of PSA screening or digital rectal examinations; use of supplements other than selenium, folate, vitamin E, beta-carotene, and zinc; and intake of dietary nutrients or foods other than tomato products did not substantially modify the associations between multivitamin use and total, localized, or advanced prostate cancer, or prostate cancer mortality (data not shown).
Discussion
In this large prospective study, we found that multivitamin use was unrelated to overall risk of total and organ-confined prostate cancer. However, we found an increased risk of advanced and fatal prostate cancer among those who took multivitamins more than seven times per week compared with never users. The risk of advanced prostate cancer and prostate cancer mortality associated with heavy multivitamin use was highest in men who reported concomitant use of selenium, beta-carotene, or zinc supplements, or who had a positive family history of prostate cancer. Although there was no main effect of multivitamin use on localized prostate cancer, we found an increased risk of localized prostate cancer among those who took multivitamins more than seven times per week versus never use, in men also taking vitamin E, selenium, or folate supplements.
We considered several possible biases that could be responsible for the observed associations. Early-stage or localized prostate cancers are particularly prone to detection bias with current PSA-screening practices (17). The increased risk of localized prostate cancer with heavy multivitamin use among men concomitantly using a vitamin E, selenium, or folate supplement could be due to detection bias if supplement users were more likely to undergo PSA screening. In our study, prostate cancer PSA screening was most frequent among heavy users of multivitamins, consistent with survey data (18) showing men who used supplements were more likely to have PSA examinations than nonusers. Thus, it is possible that the positive association with heavy use of multivitamins along with certain supplements was spurious because more intensive screening led to increased diagnosis of localized prostate cancer in groups that used the supplements. In support of this possibility, the risk of localized prostate cancer tended to increase with increasing supplemental vitamin E intake among smokers in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial study (19), despite the findings in the Alpha-Tocopherol, Beta-Carotene (ATBC) trial (20) of decreased prostate cancer incidence in male smokers who were given vitamin E supplements. Thus, there could be increased prostate cancer detection among a subpopulation of men who both smoke and use vitamin E and are more likely to seek health care. Indeed, this interpretation is supported by the Health Professionals Follow-up Study, which showed that current smokers were more likely to undergo screening for prostate cancer than nonsmokers (21,22). The increased risk of localized prostate cancer among men with heavy multivitamin use and concomitant use of a selenium or folate supplement in our study may be due to similar diagnostic bias, although potential toxicity with high selenium intake is also possible (23), and high plasma or dietary folate levels have been associated with increased risk of prostate cancer (24-26).
Although advanced prostate cancers are not typically prone to detection bias, the observed relationship between multivitamin use and advanced prostate cancer in our study may have been due to increased multivitamin use among men with early symptoms related to prostate cancer because the association with advanced prostate cancer disappeared when those diagnosed in the initial years of follow-up were excluded. However, increased multivitamin use due to early symptoms of prostate cancer cannot account for the increased risk of fatal prostate cancer among heavy multivitamin users because the association persisted and even strengthened when we disregarded those diagnosed in the initial years of follow-up.
Multivariable adjustment for use of individual supplements did not materially alter the association between multivitamin use and prostate cancer. However, we could not rule out the possibility that residual confounding due to inadequate control for individual supplements distorted the relation of multivitamin use to prostate cancer. Thus, to control more rigorously for supplement use, we conducted analyses stratified by individual supplements. The associations between multivitamin use and prostate cancer were strengthened substantially when we restricted our analyses to men additionally using certain individual supplements, and no associations were apparent among nonusers of individual supplements. Thus, excessive intake of certain individual micronutrients that are used in combination with multivitamins may be the underlying factor that is related to risk and not the multivitamins themselves. The possibility of excessive use of certain vitamins among men in our study is consistent with recent survey data (27) reporting that US supplement users had several fold greater intakes of vitamins A, C, and E and folate than the estimated average requirements for these micronutrients.
The increased risk of advanced prostate cancer and prostate cancer mortality with heavy use of multivitamins among men with a positive family history of prostate cancer could be due to men with a positive family history taking additional, unspecified supplements as part of a "prostate health" package to prevent the future development of prostate cancer. A recent survey (28) found that 50% of men at high risk for prostate cancer (defined by African American ethnicity, positive family history, or positive BRCA1 gene mutation) took one or more supplements to prevent prostate cancer, and more than 25% took three or more agents concomitantly. Of a total of 40 supplements reported, multivitamins were the most common, followed by supplemental vitamins E and C, zinc, calcium, selenium, saw palmetto, soy isoflavones, and flax seeds. Thus, confounding associations between individual agents that we were unable to assess and the risk of prostate cancer among men with a positive family history in our study were possible.
Our observation of an increase in advanced prostate cancer with heavy multivitamin use in combination with a beta-carotene supplement use is troubling, given results from the ATBC study showing that beta-carotene supplementation caused a 23% increase in total prostate cancer and a statistically significant 35% increase in the incidence of clinically relevant disease (stages II-IV) (20,29). The Beta-Carotene and Retinol Efficacy Trial (30) did not corroborate the results seen in the ATBC trial (20,29,30), and supplemental levels of -carotene were also not associated with prostate cancer in the PLCO study (19), but three separate studies (31-33) have found a statistically non-significant increased risk of prostate cancer with high serum levels of beta-carotene. The possibility of an adverse effect of beta-carotene on prostate cancer risk deserves further study.
We also found an increased risk of prostate cancer mortality among men with heavy multivitamin use who took a zinc supplement. Previous data linking supplemental zinc to increased risk of prostate cancer are sparse, but one study found that dosage of zinc at greater than 100 mg/day was related to an increased risk of advanced prostate cancer (34). The apparent adverse effect of multivitamin supplements in combination with supplemental zinc on prostate cancer risk could be due to nonessential, potentially harmful trace elements contained in zinc supplements, such as cadmium (35,36), a known carcinogen (37).
Strengths of our study include its prospective design and thorough investigation of distinct prostate cancer endpoints related to increasing disease aggressiveness. Previous data from one case-control study (7), two reports from a prospective cohort (8,10) and one clinical trial (9), suggest that multivitamin use may protect against the initiation of prostate cancer but adversely affect the progression of the disease. The only directed epidemiologic research on the effect of multivitamins on prostate cancer risk that will be available in the near future will come from the Physicians' Health Study II, a randomized controlled trial of several supplements, including multivitamins, that is scheduled to conclude in December 2007 (38).
Measurement error in our assessment of multivitamin use should not be a major concern, as the agreement (kappa) between multivitamin use as assessed by the National Cancer Institute/Block Health Habits Questionnaire (39) and that from a detailed in-person interview and transcription of the labels of supplement bottles was 0.68 for one-a-day multivitamins and 0.66 for stress-tab/B complex type multivitamins (40). These results support the validity of our instrument because the National Cancer Institute/Block Health Habits Questionnaire is similar to ours.
Limitations of this study include its lack of information regarding duration of multivitamin use, information which may have helped to determine whether associations were limited to long-time users. Residual confounding due to history of PSA and digital rectal examination screening may exist as this information was not available for all participants at baseline. Small case numbers limited our ability to investigate three-way interactions among multivitamin use, single supplement use, and family history of prostate cancer. Multiple comparisons could have produced chance findings in some subgroup analyses.
In summary, we found evidence to suggest that multivitamin use was not associated with a decreased risk of prostate cancer. In fact, excessive use of multivitamin supplements or a closely related behavior was associated with an increased risk of advanced and fatal prostate cancer. Because multivitamin supplements consist of a combination of several vitamins and men using high levels of multivitamins were also more likely to take a variety of individual supplements, we were unable to identify or quantify individual components responsible for the associations that we observed. Our findings of a markedly increased prostate cancer risk among men using multivitamin supplements is of concern and warrants further research.
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