Feasibility of dietary folic acid reduction intervention for men on active surveillance for prostate cancer.

BACKGROUND & AIMS: Fortification of the US food supply has increased folic acid intake and resulted in a concomitant decrease in neural tube defects in women. However, a body evidence supports the hypothesis that increased circulating folate levels due to excessive dietary or supplemental folic acid may be harmful for men with prostate cancer. Therefore, this pilot study aimed to investigate the feasibility of a reduced folic acid dietary intervention in men on an active surveillance monitoring program for prostate cancer. METHODS: Men with low-grade prostate cancer enrolled into a 12-week dietary folic acid reduction diet. Primary outcome was red blood cell (RBC) folate reduction at 12 weeks. Other outcomes include serum folate, homocysteine, and vitamin B12 levels. The number of patients who complete the trial and reasons for disenrollment or dropout were also assessed. RESULTS: Twenty-eight participants were enrolled into the dietary intervention study. Six participants withdrew from the study and a total of 21 participants completed all baseline and week 12 biochemical assessments. Only 18 participants completed all dietary questionnaires. Participants withdrew from the study due to difficulty with the diet or personal reasons. A substantial reduction was noted in serum folate (p < 0.007), RBC folate (p < 0.001) and dietary consumption of folic acid from foods (p = 0.003) and supplements (p = 0.003) without reduction in serum homocysteine or vitamin B12. Although an overall decrease in PSA from baseline to twelve weeks was found, the reduction was not significant (-3.55 ng/mL, p = 0.197). CONCLUSIONS: This phase 1 feasibility study reduced dietary folic acid intake from food and supplements and successfully lowered serum and RBC folate without resulting harmful effects. Data from this study supports future intervention trials with a larger prostate cancer active surveillance population and has the potential to reduce prostate cancer progression. There are no interventions to reduce progression of prostate cancer in man on active surveillance.

Divergence between dietary folate intake and concentrations in the serum and red blood cells of aging males in the United States.

BACKGROUND & AIMS: As part of a broader study examining the relationship between serum folate concentrations and prostate cancer progression, we determined if there are age related changes in serum folate concentration compared to folate intake in the U.S. male population. METHODS: Weighted data from the 2007-2008 and 2009-2010 NHANES databases was analyzed. A subpopulation of male participants was selected who were older than one year of age, had completed two days of dietary recall including supplement usage, and had fasted for at least 4 h prior to having their serum folate measured. Total dietary folate equivalent (DFE) intake (mcg) represented the combination of all natural food folate and folic acid from fortification and dietary supplements. Geometric means of serum folate (nM), red blood cell (RBC) folate (nM), and DFE intake were calculated for nine consecutive age groups, with each group generally representing a 10 year span. Analysis was then focused on males older than 20 years of age. RESULTS: A total of 19,142 subjects were in the initial NHANES population, which represented over 294 million people within the United States. Applying our inclusion criteria created a final subpopulation size of 3775. Subsequent analysis of the age groups for all males older than 20 years found the following: The mean serum folate (nM) with 95% CI levels ranged from 28.2 (26.6, 29.9) to 55.1 (47.5, 63.9). RBC folate (nM) concentrations with 95% CI levels without any fasting exclusions ranged from 795.6 (741.5, 853.7) to 1038.4 (910.7, 1184.2). Serum and RBC folate concentrations were significantly higher with age across these age groups (p < 0.001). However, the mean total daily DFE intake did not significantly differ ranging from 640.4 (574.7, 713.7) to 720.2 (665, 780) mcg, (p = 0.373). Serum folate concentrations in men with total daily DFE intake of at least 1000 mcg increased more significantly with increasing age than serum folate concentrations in men with less than 400 mcg of total daily DFE intake (p < 0.001). There was a similar trend with the RBC folate concentrations (p = 0.054). CONCLUSIONS: We observed higher serum and RBC folate concentrations and a divergence between dietary folate intake and these folate concentrations in older males. This phenomenon was evident at total DFE intakes that were significantly less than the 1000 mcg tolerable upper intake level currently recommended by the Institute of Medicine.

Impact of folate intake on prostate cancer recurrence following definitive therapy: data from CaPSURE™.

PURPOSE: A randomized, placebo controlled clinical trial of folic acid supplementation for the chemoprevention of colorectal adenoma revealed an increased incidence of prostate cancer in the treatment group. Limited data exist on postdiagnostic folate/folic acid intake and the risk of prostate cancer progression. We prospectively examined the association between postdiagnostic folate consumption and the risk of prostate cancer recurrence after radical prostatectomy, external beam radiation therapy and brachytherapy. MATERIALS AND METHODS: This study was done in 1,153 men treated with radical prostatectomy, external beam radiation therapy and brachytherapy who had clinical stage T1-T2c prostate adenocarcinoma and participated in the CaPSURE Diet and Lifestyle substudy by completing the semiquantitative Food Frequency Questionnaire in 2004 to 2005. We used Cox proportional hazards regression to analyze the association between folate intake and prostate cancer progression. RESULTS: Prostate cancer progressed in 101 men (8.76%) during a mean 34-month followup. After multivariate adjustment we observed no evidence of an association of the intake of total folate, dietary folate or dietary folate equivalents with prostate cancer recurrence. On secondary analysis by treatment after radical prostatectomy patients in the lowest decile of dietary folate intake had a 2.6-fold increase in the risk of recurrence (HR 2.56, 95% CI 1.23-5.29, p = 0.01). In patients treated with external beam radiation and brachytherapy we observed no evidence of an association between prostate cancer progression and increased folate intake. CONCLUSIONS: Results suggest that the consumption of foods and multivitamins that contain folate is not associated with prostate cancer progression after definitive treatment.

Opposing roles of folate in prostate cancer.

The US diet has been fortified with folic acid to prevent neural tube defects since 1998. The Physician Data Queries from the National Cancer Institute describe folate as protective against prostate cancer, whereas its synthetic analog, folic acid, is considered to increase prostate cancer risk when taken at levels easily achievable by eating fortified food or taking over-the-counter supplements. We review the present literature to examine the effects of folate and folic acid on prostate cancer, help interpret previous epidemiologic data, and provide clarification regarding the apparently opposing roles of folate for patients with prostate cancer. A literature search was conducted in Medline to identify studies investigating the effect of nutrition and specifically folate and folic acid on prostate carcinogenesis and progression. In addition, the National Health and Nutrition Examination Survey database was analyzed for trends in serum folate levels before and after mandatory fortification. Folate likely plays a dual role in prostate carcinogenesis. There remains conflicting epidemiologic evidence regarding folate and prostate cancer risk; however, there is growing experimental evidence that higher circulating folate levels can contribute to prostate cancer progression. Further research is needed to clarify these complex relationships.

Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate.

BACKGROUND: A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer (Figueiredo et al., J Natl Cancer Inst 2009; 101(6): 432-435). As tumor cells in culture proliferate directly in response to available folic acid, the goal of our study was to determine if there is a similar relationship between patient folate status, and the proliferative capacity of tumors in men with prostate cancer. METHODS: Serum folate and/or prostate tissue folate was determined in 87 randomly selected patients undergoing surgery for prostate cancer, and compared to tumor proliferation in a subset. RESULTS: Fasting serum folate levels were positively correlated with prostate tumor tissue folate content (n = 15; r = 0.577, P < 0.03). Mean serum folate was 62.6 nM (7.5-145.2 nM), 39.5% of patients used supplements containing folic acid (n = 86). The top quartile of patients had serum folates above 82 nM, six times the level considered adequate. Of these, 48% reported no supplement use. Among 50 patients with Gleason 7 disease, the mean proliferation index as determined by Ki67 staining was 6.17 ± 3.2% and 0.86 ± 0.92% in the tumors from patients in the highest (117 ± 15 nM) and lowest (18 ± 9 nM) quintiles for serum folate, respectively (P < 0.0001). CONCLUSIONS: Increased cancer cell proliferation in men with higher serum folate concentrations is consistent with an increase in prostate cancer incidence observed with folate supplementation. Unexpectedly, more than 25% of patients had serum folate levels greater than sixfold adequate. Nearly half of these men reported no supplement use, suggesting either altered folate metabolism and/or sustained consumption of folic acid from fortified foods.