In this randomized controlled trial of β-carotene + retinyl palmitate, men who used the CARET study vitamins plus another dietary supplement had a 52% increased risk of aggressive prostate cancer compared to all men in the placebo arm or those who used only the CARET vitamins. This risk diminished upon discontinuation of study vitamins. Any suggestion of increased risk due to supplement use was for aggressive disease only and was only observed during the active CARET intervention. Conversely, a modest protective association for non-aggressive disease was observed among men using only the CARET vitamins during the active intervention. Because aggressive disease has a poor prognosis, whereas the clinical relevance of non-aggressive disease is less certain, the results for increased risk of aggressive disease have potential clinical relevance.
The observed differences in risk between the CARET intervention phase (when risk of aggressive disease was increased) and the post-intervention phase (when risk of aggressive disease was decreased) are consistent with the growing evidence that the effects of antioxidants on cellular processes may vary depending upon the oxidative milieu of the tissues (16
). Similar effects were noted in a randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer, wherein there was an increased risk of recurrence or second primary cancer during the supplementation period (HR= 2.88, 95%CI 1.56-5.31), but a lower risk after supplementation was discontinued (HR= 0.41, 95%CI 0.16-1.03) (17
). Under this proposed mechanism, we are unclear, though, why the use of CARET vitamins resulted in a 35% reduced risk for non-aggressive prostate cancer. Clearly, much remains to be learned regarding the effects of antioxidant supplements on normal and neoplastic cells. Taken together, our results add to the growing body of evidence that dietary supplements, particularly multiple supplements or those used in large, pharmacologic doses should be used with caution.
Our results are consistent with some, but not all, previously published reports. Two cohort studies have reported a finding of increased risk of fatal or aggressive prostate cancer among dietary supplement users, compared to non-users (7
). One of these studies, the AARP cohort, reported the greatest risk among men using excessive multivitamins, or more than one preparation per day. From reports of randomized, controlled trials, the Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Prevention Study reported a lower risk of prostate cancer in men randomized to the alpha-tocopherol arm of the trial, no effect for the alpha-tocopherol plus beta-carotene arm and a slight non-significant increase in prostate cancer risk for the β-carotene only arm (RR=1.23, 95%CI 0.89-1.70)(18
). Consistent with the findings we present from CARET, any β-carotene-related excess risk disappeared in the post-ATBC follow-up period (19
There are strengths to this study. CARET was a randomized controlled trial where participants came to annual clinic visits with additional contacts by phone. At these visits, health status and personal lifestyle habits were updated using a uniform protocol across all CARET clinical centers to ensure standardized data collection. Another strength is that there was excellent follow-up of all CARET participants during and after the trial with careful adjudication of 92% of all prostate cancer cases. There are also limitations. Since our data only captured information on whether or not participants used dietary supplements, we are unable to investigate which particular nutrients or combinations of nutrients (especially in high doses) may place persons at risk. Additionally, we have no data on duration of supplement use, which at least one study has suggested a decrease in prostate cancer risk when supplement use is ten years or more in duration (7
). Another limitation is that we were underpowered to examine prostate cancer deaths, an endpoint which was associated with dietary supplement use in other cohorts (7
). While our classification of “aggressive disease” included Gleason ≥ 7 or stage III/IV at diagnosis (both highly predictive of poor outcome), most future cohorts will have few cases diagnosed at later stages due to PSA screening and early detection programs (20
). For comparisons across studies, use of Gleason alone might be beneficial for newer studies. Further, despite CARET's design (randomized controlled trial), we are unable to completely rule out residual confounding, particularly for variables measured with imprecision or those not assessed at all in CARET. For example, diabetes has been shown to be inversely associated with prostate cancer risk, but diabetes data were not collected in CARET (21
). Other lifestyle variables, such as energy intake and physical activity, may increase and decrease prostate cancer risk, respectively, but these self-report data are well known to be subject to measurement error (22
). Finally, the CARET cohort was comprised of heavy smokers and former heavy smokers. While the results from this study may not be generalizeable to all U.S. males, our findings are applicable to the millions of men who are current or former smokers.
In summary, our results provide modest evidence that a high-dose of β-carotene (30 mg/day) and retinyl palmitate (25,000 IU/day) plus at least one other dietary supplement may increase risk of aggressive prostate cancer. These results are consistent with other recently published findings, including those using various high-dose supplements in relation to risk of other cancers or precancerous lesions (23
). Men may want to carefully consider whether or not they should use a supplement, especially if they have existing risk factors for prostate cancer.