D ISCUSSION

In this study, we examined the relations between plasma carotenoid and

tocopherol levels, and serum PSA levels among men with biochemical recurrence of PCa who were enrolled in a 6-month diet and lifestyle intervention trial in South Carolina. In an analysis of baseline data, no significant differences in mean PSA levels were observed between participants with high versus low carotenoid or tocopherol levels. We further

explored whether carotenoid and tocopherol levels at 3 months (during the study period) were associated with PSA levels at 3 months and at 6 months, adjusting for baseline PSA values. Results from this analysis showed that participants with higher cis-

lutein/zeaxanthin level at 3 months had statistically lower mean PSA level at 3 months. Additionally, participants with higher plasma levels of α-tocopherol, β-cryptoxanthin, all-trans-lycopene, and higher antioxidant score at 3 months, had significantly lower mean PSA level at 6 months. Finally, we examined whether percent change in plasma carotenoid and tocopherol levels from baseline to month 3 were inversely related to PSA levels at 3 months and at 6 months, independent of baseline PSA values. These results showed significantly lower mean PSA values at 3 months and at 6 months for participants with an increase in α-tocopherol and trans-β-carotene levels compared to who had a decrease in the levels of these nutrients. In addition, those with an increase in β- cryptoxanthin, cis-lutein/zeaxanthin, trans-lycopene and antioxidant score had significantly lower mean PSA values at 6 months. Overall, higher plasma levels of certain carotenoids and tocopherols paralleled with lower PSA level at various time points, with stronger findings for associations with the 6-month PSA values. This

suggests that it may take a few months before a clinical benefit on PSA is observed from a dietary intervention.

The idea of using dietary agents as an alternate therapy or as a neoadjuvant to delay the use of more traditional therapy such as androgen ablation is a prospect that would be appealing to most patients because of the severe side effects associated with traditional therapy [349, 350]. While it is plausible that intake of certain carotenoids and tocopherols may influence serum PSA levels, it is possible that these nutrients could alter

PSA levels without affecting cancer progression. Interestingly, declines in PSA have been found to correlate with inhibition of the androgen-sensitive LNCaP prostate tumor cell growth in animal and human studies [357, 367, 368]. Secretion of PSA and hormone- dependent LNCaP activity are both modulated by androgens [369, 370]. Higher blood levels of antioxidants such as lycopene and α-tocopherol have been found to down- regulate serum androgen levels [371-373]. Thus, the suppression of androgens may be an underlying mechanism for the potential effect of carotenoids and tocopherols on PSA, and possibly, PCa progression. Other mechanisms involving antioxidative and anti- inflammatory activities have also been proposed [374, 375].

Prior studies on men with biochemically recurrent PCa have focused primarily on multiple interventions involving diet, exercise, and stress reduction [11, 13, 357-361]. There is very little published literature on associations of carotenoids and tocopherols intake in relation to PSA levels among men with PCa relapse (reviewed in [355, 362, 363]). Data on carotenoids and tocopherols in relation to PSA progression among men with PCa relapse are lacking. The vast majority of the available data are from studies examining the potential benefits of supplemental or dietary lycopene. In a study

involving 71 men with biochemical recurrence who were randomized to intervention with supplemental lycopene alone (15 mg) or together with soy isoflavones capsule (40 mg) taken twice daily for 6 months, no decline in serum PSA level was observed in either group [376]. In that same study, however, the rate of PSA rise decreased in 95% of patients in the lycopene group and 67% of those in the lycopene and soy isoflavones group [376]. In another study where 36 men with biochemical recurrence of PCa were

given varying doses of lycopene (15, 30, 45, 60, 90 and 120 mg/day) for one year, no change in serum PSA was observed across all the six dose groups [377].

In a related study, Chen et al. [374] investigated the effect of lycopene on cancer progression among 32 patients with incident PCa treated tomato sauce-based diet

containing 30 mg of lycopene per day for 3 weeks before their scheduled prostatectomy. The results showed significant reduction in serum PSA levels as well as declines in markers of oxidative DNA damage measured in leukocytes and prostate tissue, when comparing pre- and post-intervention measurements [374]. Ansari and Gupta [378] evaluated the effect of lycopene and orchiectomy versus lycopene alone in 54 patients with metastatic PCa, and found significantly lower PSA levels in the lycopene group after 6 months of follow-up. Others have reported that supplemental lycopene intake decreases PSA velocity and may prolong PSA doubling time [379]. Among studies conducted in disease-free men, one found an inverse association between serum α-carotene levels and percent free PSA level (OR = 0.49, 95% CI = 0.32–0.76), but not total PSA, and no inverse association was found for other carotenoids [380]. Another found no association between tocopherol intake and serum PSA level or PSA velocity [381]. The variability is these findings may be related to the source of the nutrients (e.g., supplement versus diet for lycopene) or the possibility that these nutrients may have varying effect on different disease states.

To our knowledge, this is the first study to examine biomarkers of carotenoids and tocopherols in relation to PSA levels among men with biochemical recurrence of PCa. The results show that after controlling for baseline PSA values, certain plasma

timepoints. Despite these findings, it is conceivable that these nutrients may have served as surrogates for higher consumption of fruits and vegetables which contain other beneficial dietary factors. Of note, the original EASE intervention study did not find a beneficial effect of the diet and lifestyle intervention on PSA [13]. Challenges associated with conducting clinical trials of lifestyle interventions, such as lack of large enough contrast between the intervention and control group due to contamination or suboptimal compliance [382], may partially explain this finding. The current study results suggest that higher exposure to certain dietary antioxidants may have a beneficial effect on PSA rise following prostatectomy and should be confirmed in other larger studies.

Both strengths and limitation of the study deserve mention. Given the small sample size and the multiple comparisons made, there is a possibility that some of the findings could be due to chance. Because humans consume foods containing multiple nutrients, there is also the possibility that the study results may be reflecting interactions between plasma nutrients, rather than the effect of a specific nutrient per se [383]. The short duration of the study and lack of carotenoid and tocopherol data at 6 months prohibited evaluation of temporal trends over long periods. Restricting the study to a subgroup of PCa patients with strictly defined disease attributes precludes

generalizability of the findings to the larger population of men with PCa. However, since the study participants had already undergone radical prostatectomy and/or radical

radiation for the treatment of organ-confined disease, continuous rise in serum PSA level as defined in this study most likely reflect progressive disease (which was the intent of the study), rather than residual normal tissue left from radiation or spared during prostatectomy. Other strengths of the study include the use of biomarkers of nutrient

intake, which are more reliable measures of nutritional status relative to self-reported intake [384]. Several potential confounders including BMI, smoking, physical activity, tumor grade and race were controlled for in the analysis. The study findings add to the limited data on potentially beneficial dietary factors for men with biochemically recurrent PCa.