The prognosis for advanced stage oral squamous cell carcinomas (oral SCCs) remains among the lowest of solid tumors. Clearly, early detection of the precursor lesion for oral SCC i.e. oral epithelial dysplasia combined with local intervention strategies, such as chemoprevention, could dramatically improve clinical outcomes. While oral cancer chemopreventive is an attractive concept, the treatments attempted to date, which relied primarily on systemic agent administration, have proven to be largely ineffective. We have demonstrated that freeze dried black raspberries (FBR) possess cancer preventing properties at both the in vitro and in vivo levels. Further, our laboratories recently completed a pilot Phase I/II clinical trial that entailed topical application of a bioadhesive gel that contained 10% FBR to oral dysplastic lesions (0.5 gm 4-times per day for 6 weeks). Trial data show that gel application significantly reduced loss of heterozygosity indices (LOH) at loci associated with tumor suppressor genes, decreased histologic grades of lesional epithelium, reduced expression of genes associated with RNA processing, growth factor recycling and inhibition of apoptosis, decreased lesional angiogenesis and significantly reduced lesional epithelial cyclooxygenase 2 (COX-2) levels. Furthermore, consistent with the use of a natural product, no deleterious effects were observed in either the 10 normal control participants or the 20 participants with premalignant oral lesions. While these data are promising, this was a pilot study which entailed short treatment duration (6 weeks) and only evaluated the active gel formulation. A longer duration, placebo-controlled, multicenter study is the logical and necessary step to move this chemopreventive project forward. Approximately 30% of oral dysplastic lesions recur despite excision with microscopically clear surgical margins. Further, although approximately 33% of premalignant oral lesions will progress to oral SCC, we are unable at this time to predict which lesions will undergo malignant transformation. Identification of nontoxic, effective chemopreventive compounds delivered in formulations that provide therapeutically relevant levels to oral dysplastic lesions, has the potential to positively impact clinical outcomes. Based on our in vitro, in vivo and clinical data we propose that longer treatment duration (3 months) will augment the chemopreventive efficacy of the 10% FBR gel. Accordingly, we propose the following Specific Aims:
Specific Aim 1 : Assess chemopreventive efficacy of topical application of a10% FBR gel (0.5 gm, four times a day, for 3 months) on microscopically documented oral epithelial dysplastic lesions by evaluating effects on selected clinically relevant, readily quantifiable, evaluative parameters.
Specific Aim 2 : Determine the effects of topical application of a placebo gel (identical gel base, absence of FBR, same application schedule) on microscopically confirmed oral epithelial dysplastic lesions. Identical evaluative parameters will be assessed.
Squamous cell carcinoma, which is the primary cancer that develops in the head and neck region, will affect over 35,000 Americans in 2009, resulting in approximately 7,600 American deaths. Further, despite marked treatment advances for many cancers, the overall prognosis for individuals diagnosed with head and neck cancer remains among the lowest of all solid tumors. To help address this concern, we propose to conduct a placebo-controlled clinical trial to test the oral cancer preventing effects of a natural product based bioadhesive gel that demonstrated promising results in our previous pilot study.
