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.

Figure 1

a) Photographic example of a high risk OPL patient at baseline; b) same patient after GTE treatment demonstrating a clinical response; c) baseline histologic example of a high-risk OPL patient at baseline demonstrating dysplasia; d) same patient demonstrating a histologic response after GTE treatment.

Figure 1

a) Photographic example of a high risk OPL patient at baseline; b) same patient after GTE treatment demonstrating a clinical response; c) baseline histologic example of a high-risk OPL patient at baseline demonstrating dysplasia; d) same patient demonstrating a histologic response after GTE treatment.

Figure 1

a) Photographic example of a high risk OPL patient at baseline; b) same patient after GTE treatment demonstrating a clinical response; c) baseline histologic example of a high-risk OPL patient at baseline demonstrating dysplasia; d) same patient demonstrating a histologic response after GTE treatment.

Figure 1

a) Photographic example of a high risk OPL patient at baseline; b) same patient after GTE treatment demonstrating a clinical response; c) baseline histologic example of a high-risk OPL patient at baseline demonstrating dysplasia; d) same patient demonstrating a histologic response after GTE treatment.

Figure 2

Dose-dependent increases in caffeine concentrations during TID administration on Day 84 of GTE. Time-dependent accumulation of caffeine over 12 weeks of GTE is revealed by the 8-fold greater mean trough concentration observed at the 1000 mg/m² dose. The average time elapsed between drug administration and predose or postdose blood collection was 3.3 hours. Each symbol represents arithmetic mean concentrations ± SD.

Figure 3

A trend toward a dose-dependent increase in plasma EGCG concentrations during TID administration of green tea extract (GTE). Each symbol represents arithmetic mean concentrations ± SD. The data shows some dose-dependent accumulation of EGCG over the sampling period of approximately 9–12 hours although variability in plasma concentrations at 1000 mg/m² is very high. Trough concentrations following the last dose from the previous day are similar for both arms and no significant accumulation of drug is observed.