A Phase II Randomized, Double-blind, Presurgical Trial of Polyphenon E in Bladder Cancer Patients to Evaluate Pharmacodynamics and Bladder Tissue Biomarkers.
We performed a phase II pharmacodynamic prevention trial of Polyphenon E [a green tea polyphenol formulation primarily consisting of epigallocatechin gallate (EGCG)] in patients prior to bladder cancer surgery. Patients with a bladder tumor were randomized to receive Polyphenon E containing either 800 or 1,200 mg of EGCG or placebo for 14 to 28 days prior to transurethral resection of bladder tumor or cystectomy. The primary objective was to compare the postintervention EGCG tissue levels in patients receiving Polyphenon E as compared with placebo. Secondary objectives included assessments of tissue expression of PCNA, MMP2, clusterin, VEGF, p27, IGF-1, IGFBP-3; correlation of tissue, plasma, and urine levels of EGCG; and EGCG metabolism by catechol-O-methyltransferase and UDP-glucuronosyltransferase pharmacogenomic mutations. Thirty-one patients (male:female, 26:5; mean age, 67.2 years) were randomized and 29 (94%) completed the study. There was not an observed significant difference (P= 0.12) in EGCG tissue levels between two Polyphenon E dosage groups combined versus placebo. However, a dose-response relationship for EGCG levels was observed in both normal (P= 0.046) and malignant bladder tissue (P= 0.005) across the three study arms. In addition, EGCG levels in plasma (P< 0.001) and urine (P< 0.001) increased and PCNA (P= 0.016) and clusterin (P= 0.008) were downregulated in a dose-dependent fashion. No pharmacogenomic relationship was observed. EGCG levels in plasma, urine, and bladder tissue followed a dose-response relationship, as did modulation of tissue biomarkers of proliferation and apoptosis. Despite the limitations of this pilot study, the observed pharmacodynamics and desirable biologic activity warrant further clinical studies of this agent in bladder cancer prevention.Cancer Prev Res; 10(5); 298-307. ©2017 AACR.
Institute of Urology, Lahey Hospital and Medical Center, Burlington, Massachusetts. Jason.R.Gee@Lahey.org.
Jason R
JR
Gee
Urology San Antonio Research, University of Wisconsin-Madison, Madison, Wisconsin.
Daniel R
DR
Saltzstein
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.|Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
KyungMann
K
Kim
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Jill
J
Kolesar
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Wei
W
Huang
Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
Thomas C
TC
Havighurst
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Barbara W
BW
Wollmer
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Jeanne
J
Stublaski
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Tracy
T
Downs
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Hasan
H
Mukhtar
Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD.
Margaret G
MG
House
Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD.
Howard L
HL
Parnes
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Howard H
HH
Bailey
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D014018:Tissue Distribution; D001743:Urinary Bladder / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms
D014408:Biomarkers, Tumor; D002392:Catechin; C472086:polyphenon E