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 (OPLs) to receive GTE at 500 mg/m2, 750 mg/m2, or 1000 mg/m2 or placebo TID 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 2 higher-dose GTE arms (58.8% [750, 1000 mg/m2], 36.4% [500 mg/m2], 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), though not statistically significant. GTE was well-tolerated although higher doses increased insomnia/nervousness but produced no grade-4 toxicity. Higher mean baseline stromal 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 non-responsive 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.

Treatment of oral leukoplakia with a low‐dose of beta‐carotene and vitamin C supplements: A randomized controlled trial

“…The lack of uniformity of treatment choices in these studies makes it difficult to perform a meta-analysis to examine the outcome of chemopreventive agents. 3 The best outcome so far is with lycopene-a carotenoid-which has shown a significant improvement at 5-month followup (Table 4), in a study using 4 or 8 mg. 28 A recent study 37 used a green tea extract and reported a significant clinical response (59%) compared with placebo (18%). A dose-response was also reported.…”

Chemoprevention and Novel Treatments of Non-Muscle Invasive Bladder Cancer

“…Another ingredient, catechins, may exhibit anti-tumor activity through inhibition of nitrosamine formations and decreased chromosomal damage (Kamori et al, 1993). Additional research on green tea suggests other possible mechanisms for a variety of its ingredients including caspase mediation (Oz & Ebersole, 2010), inhibition of angiogenesis (Tsao et al, 2009), and others. Evidence for green tea in prevention of bladder cancer is variable.…”

Chemoprevention of Squamous Cell Carcinoma of the Head and Neck: No Time to Lose Momentum

“…Since the landmark study of 13-cis-retinoic acid, published in 1986 by Hong and colleagues, which showed that high-dose 13-cis-retinoic acid works for SCCHN prevention in patients with oral leukoplakia, but tolerability was problematic and lesions recurred shortly after the drug was stopped, numerous studies have been performed (6). Included in agents studied are low-dose retinoids and caretenoids, other antioxidant vitamins, epigallocatechin gallate (EGCG) and Bowman-Birk inhibitor compound and other nutritional organic compounds, and nonsteroidal antiinflammatory drugs, such as ketorolac and celecoxib (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…Unfortunately, we are not there yet. Some studies to date have shown a pharmacodynamic effect in biomarker studies (12)(13)(14)(15)38). Markers of proliferation, such as Ki-67 by immunohistochemistry, are doable and appealing as surrogate endpoints, but showing a decline in premalignant proliferation does not equal eradication of cancer risk.…”