title: Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions.
abstract: Epidemiologic and preclinical data support the oral cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPL) to receive GTE at 500, 750, or 1,000 mg/m(2) or placebo thrice daily for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n = 28; 50%) versus placebo (n = 11; 18.2%; P = 0.09) but did not reach statistical significance. However, the two higher-dose GTE arms [58.8% (750 and 1,000 mg/m(2)), 36.4% (500 mg/m(2)), and 18.2% (placebo); P = 0.03] had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%; P = 0.65), although not statistically significant. GTE was well tolerated, although higher doses increased insomnia/nervousness but produced no grade 4 toxicity. Higher mean baseline stromal vascular endothelial growth factor (VEGF) correlated with a clinical (P = 0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n = 5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in nonresponsive patients at 12 weeks (versus at baseline). An extended (median, 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12-week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Tsao
authors.forename: Diane
authors.initials: D
authors.lastname: Liu
authors.forename: Jack
authors.initials: J
authors.lastname: Martin
authors.forename: Xi-ming
authors.initials: XM
authors.lastname: Tang
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.forename: Kirk S
authors.initials: KS
authors.lastname: Culotta
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.forename: Ann
authors.initials: A
authors.lastname: Gillenwater
authors.forename: Yuko M
authors.initials: YM
authors.lastname: Sagesaka
authors.forename: Waun K
authors.initials: WK
authors.lastname: Hong
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papadimitrakopoulou
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000517:prevention & control*; D008517:Phytotherapy; D010919:Placebos; D010936:Plant Extracts / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011230:Precancerous Conditions / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013662:Tea; D014018:Tissue Distribution; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D010919:Placebos; D010936:Plant Extracts; D012333:RNA, Messenger; D013662:Tea; D042461:Vascular Endothelial Growth Factor A