Introduction: Bladder cancer patients are faced with significant morbidity and mortality due to tumor recurrence and progression and therefore would benefit from an effective chemopreventive strategy. Green tea consumption has been associated with a reduction in bladder cancer risk. Polyphenon E is a green tea polyphenol formulation primarily consisting of epigallocatechin gallate (EGCG) which has been shown in preclinical studies to inhibit growth of bladder cancer. We evaluated the tolerability, tissue accumulation, and biologic effects of polyphenon E in a randomized, double-blind, placebo-controlled phase II preoperative study in patients with bladder cancer.

Methods: Patients who had an initial diagnosis or recurring bladder tumor found on diagnostic cystoscopy were randomized in a 1:1:1 ratio to receive 800 mg, 1200 mg or placebo polyphenon E prior to undergoing TURBT or radical cystectomy. The primary objective of the study was to assess the nonmalignant bladder tissue levels of EGCG. Secondary objectives included comparison of EGCG levels in nonmalignant versus malignant tissue within treatment arms; examination of the dose-dependent modulation of surrogate endpoint biomarkers (PCNA, MMP2, Clusterin, VEGF, p27, IGF-1, IGFBP-3) in malignant and nonmalignant bladder tissue; correlation of plasma, urine and tissue levels of EGCG; examination of the levels of other catechins (epicatechin, epicatechin gallate, and epigallocatechin) in plasma, tissue, and urine; metabolism of EGCG in plasma, urine and tissue by COMT and UGT in relation to pharmacogenomic mutations.

Results: 31 patients (84% male, 16% female) were randomized with a mean age of 67.2 years. Four patients (13%) were non-compliant and drug administration was interrupted in one other patient (3%), whereas the remainder of patients for which we have reports completed study agent administration (n=24, 77%). The worst adverse event severity was severe (grade 3) for one (3%) patient, moderate for five patients (16%), and mild for eight (26%) patients, whereas no adverse event occurred in 17 (55%) of the patients. Although we found a low rate of detectability in tissue (4/25 with detectable values), tissue levels of EGCG were identified in a dose-dependent fashion in both normal (0.00, 0.50, 1.72 ng/ml, p=0.046) and malignant (0.00, 0.00, 2.54 ng/ml p=0.005) bladder tissue for the placebo, low dose and high dose polyphenon E arms respectively. Plasma EGCG levels (2.94, 78.09, 87.52 ng/ml, p=0.001) and urine EGCG levels (0.00, 2.60, 4.32 ng/ml, p<0.001) were also found to be dose-dependent. Statistically significant dose-dependent downregulation of tissue biomarkers PCNA (0.41, 0.38, 0.35 OD, p=0.016) and clusterin (0.074, 0.061, 0.046 OD, p=0.008) was observed, also accompanied by a nonsignificant reduction in p27 expression (0.36, 0.35, 0.31 OD, p=0.15). No consistent relationship between COMT and UGT pharmogenomic mutational status and EGCG metabolism was observed.

Conclusions: We demonstrate in a phase II pilot study tissue accumulation of EGCG in benign and malignant bladder urothelium which follows both plasma and urine levels in a dose-dependent fashion. Furthermore, tissue endpoint biomarkers of proliferation (PCNA) and apoptosis (clusterin) were reduced in a statistically significant dose-dependent fashion. Acknowledging the limitations of this pilot study, we feel these findings indicate polyphenon E administration results in definable tissue accumulation and more importantly desirable biologic activity which warrant further clinical studies assessing the effect of polyphenon E on actual bladder tumor recurrence/progression.

Citation Format: Jason R. Gee, Daniel R. Saltzstein, KyungMann Kim, Jill Kolesar, Wei Huang, Tom Havighurst, Barbara W. Wollmer, Jeanne Stublaski, Tracy Downs, Hasan Mukhtar, Margaret House, Howard Parnes, Howard Bailey. A phase II randomized, presurgical placebo-controlled trial of polyphenon E in bladder cancer patients to evaluate bladder tissue levels of EGCG and biomarkers of growth and apoptosis. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A20.