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| Date: 06-30-2015 | HC# 061531-523 |
Re: Green Tea Catechin Intake Does Not Reduce Prostate Cancer Diagnoses in At-risk Men
Kumar NB, Pow-Sang J, Egan KM, et al. Randomized, placebo-controlled trial of green tea catechins for prostate cancer prevention. Cancer Prev Res (Phila). April 14, 2015; [epub ahead of print]. doi: 10.1158/1940-6207.CAPR-14-0324.
Prostate cancer (PCa) is the most common noncutaneous cancer among American men. Green tea (Camellia sinensis, Theaceae) catechins (GTCs) have been shown to safely inhibit cancer cell proliferation and induce apoptosis of cancer cells. Among GTCs, epigallocatechin-3-gallate (EGCG) is the most potent modulator of molecular pathways thought to play a role in the development of PCa. This randomized, double-blind, placebo-controlled trial investigated the effect of a high-potency EGCG green tea extract in men with high-grade prostatic intraepithelial neoplasia (HGPIN), a premalignant lesion, and/or atypical small acinar proliferation (ASAP), a strong predictive factor associated with PCa.
Polyphenon E® (PolyE; Mitsui Norin Co., Ltd.; Shizuoka, Japan) is a purified tea fraction containing 80-98% total catechins by weight, the main component of which is EGCG (50-75%), as well as small amounts of caffeine (<1.0%), theobromine (<1.0%), and gallic acid (<0.5%). In this study, a hard gelatin formulation containing 200 mg EGCG per capsule was used. Placebo capsules were hard gelatin capsules with no difference in appearance, taste, or smell.
Eligibility criteria included men between the ages of 30 and 80, diagnosed with HGPIN and/or ASAP within 3 months prior to the study, no history of cancer or hepatic or renal disease, not taking steroids or other supplements, and not consuming more than 6-12 cups of green tea daily. Subjects were recruited at the Moffitt Cancer Center and the James A. Haley VA Hospital in Tampa, Florida, and at the University of Florida in Jacksonville, Florida, from September 2008 to March 2013.
Potential subjects participated in a 10-day run-in period during which multivitamin/mineral supplements were provided and food intake and symptom logs were used to assure compliance with supplement intake. Subjects with a diagnosis confirmed by central pathology review, ≥85% compliance to instructions during the run-in period, and normal laboratory results were selected to participate in the study. Ninety-seven subjects were enrolled and randomly assigned into the PolyE (n=49) or placebo (n=48) group. Subjects consumed 1 tablet twice daily of PolyE, totaling 400 mg a day, or placebo for 12 months. Baseline blood and urine samples and tissue from diagnostic biopsy were also collected.
Quality of life and nutritional intake, lower urinary tract symptoms (LUTS), plasma catechin levels, and prostate-specific antigen (PSA) levels were examined at baseline and 3, 6, and 12 months. The subjects were evaluated monthly for toxicity, concomitant medications, and organ function. At 6 months, biopsies were repeated for those with a PSA level >0.75 ng/mL or with a prostate nodule detected on rectal examination. All subjects without a biopsy-confirmed diagnosis of PCa at 6 months underwent another biopsy at 12 months. At baseline, the 2 groups had similar potential predictive markers, including age, race, PSA levels, number of positive core samples, and body mass index.
Of the 97 men enrolled, 70 completed the 12-month study, and 74 underwent at least 1 biopsy at 6 months. Subjects that developed PCa or a serious adverse side effect discontinued participation in the study. The primary endpoint, a between-group comparison of the number of PCa diagnoses at the end of the study, was not met, as significant differences in PCa rates were not observed. Of the 14 subjects diagnosed with PCa, 5 (10.2%) were in the PolyE group and 9 (18.8%) were in the placebo group. For a pre-certified secondary endpoint, the authors compared the combined rate of PCa plus ASAP at the end of the study among subjects with HGPIN without ASAP at baseline. They found a significantly lower rate of PCa plus ASAP in the PolyE group (3 of 26) compared with the placebo group (10 of 25) (P<0.024).
Fewer subjects with HGPIN without ASAP at baseline were subsequently diagnosed with ASAP in the PolyE (0 of 26) group than in the placebo (5 of 25) group. No one with HGPIN without ASAP at baseline met the criteria for biopsy at 6 months in either group. Among the subjects with ASAP at baseline, 2 of 17 in the PolyE group and 4 of 14 in the placebo group were subsequently diagnosed with PCa during the study.
Another secondary endpoint was a between-group comparison of the effect of PolyE on PSA values. A decrease of 0.87 ng/mL in PSA levels was observed in the PolyE group; however, PSA values did not change significantly in the 14 subjects diagnosed with PCa during the study. Acknowledging that the mechanism responsible for the reductions in PSA in the PolyE group is unclear, the authors speculate "that the reduction in serum PSA with GTCs could be due to reduced inflammation." Plasma catechin EGCG concentrations increased significantly in the PolyE group at 6 months (P<0.0001) and 12 months (P=0.0002). EGCG concentrations were nondetectable in most subjects in the placebo group throughout the study.
LUTS can greatly affect quality of life with prostate conditions, but because the subjects were asymptomatic at baseline, the authors could not evaluate the effect of PolyE on these symptoms. No significant between-group differences were found in the subjects' quality of life from baseline to study's end.
While the authors feel the strength of their study is its randomized, double-blind, placebo-controlled design, they also feel the rigorous design may have interfered with their ability to get accurate information, stating that U.S. Food and Drug Administration (FDA)-compliant eligibility criteria and frequent toxicity testing "adversely affected accrual and study completion rates." Additionally, the rate of PCa in the placebo group was less than expected and lead to the study being underpowered to detect small changes in PCa rates. The authors conclude that a standardized catechin mixture containing EGCG consumed daily for 1 year "accumulated in plasma and was well tolerated but did not reduce the likelihood of a subsequent PCa diagnosis in men with baseline HGPIN or ASAP." They suggest any "future PCa chemoprevention trials should ideally enroll larger cohorts of men at higher risk for this disease, perhaps with durations of interventions that continue beyond one year."
—Shari Henson
