Cancer Therapy: Clinical Topical Application of a Mucoadhesive Freeze-Dried Black Raspberry Gel Induces Clinical and Histologic Regression and Reduces Loss of Heterozygosity Events in Premalignant Oral Intraepithelial Lesions: Results from a Multicentered, Placebo-Controlled Clinical Trial

Purpose: Approximately 30% higher grade premalignant oral intraepithelial neoplasia (OIN) lesions will progress to oral cancer. Although surgery is theOIN treatmentmainstay,manyOIN lesions recur, which is highly problematic for both surgeons andpatients. This clinical trial assessed the chemopreventive efficacy of a natural product-based bioadhesive gel on OIN lesions. Experimental Design: This placebo-controlled multicenter study investigated the effects of topical application of bioadhesive gels that contained either 10% w/w freeze-dried black raspberries (BRB) or an identical formulation devoid of BRB placebo to biopsy-confirmed OIN lesions (0.5 g q.i.d., 12 weeks). Baseline evaluative parameters (size, histologic grade, LOH events) were comparable in the randomly assigned BRB (n 1⁄4 22) and placebo (n 1⁄4 18) gel cohorts. Evaluative parameters were: histologic grade, clinical size, and LOH. Results: Topical application of the BRB gel toOIN lesions resulted in statistically significant reductions in lesional sizes, histologic grades, and LOH events. In contrast, placebo gel lesions demonstrated a significant increase in lesional size and no significant effects on histologic grade or LOH events. Collectively, these data strongly support BRB’s chemopreventive impact. A cohort of very BRB-responsive patients, as demonstrated by high therapeutic efficacy, was identified. Corresponding protein profiling studies, which demonstrated higher pretreatment levels of BRB metabolic and keratinocyte differentiation enzymes in BRB-responsive lesions, reinforce the importance of local metabolism and differentiation competency. Conclusions: Results from this trial substantiate the LOH reductions identified in the pilot BRB gel study and extend therapeutic effects to significant improvements in histologic grade and lesional size. Clin Cancer Res; 20(7); 1910–24. 2014 AACR. Introduction Oral squamous cell carcinoma (OSCC) is a worldwide health problem and one of the most challenging-to-treat humanmalignancies (1). This is due to the insidious nature of its early disease, reliance upon surgery as the primary treatment modality, and the difficulty of achieving locoregional disease control (1, 2). Many patients with OSCC die frommassive local recurrence or second primary tumors (3, 4). Also, despite treatment innovations like inductive chemotherapy and radiation intensification programs, OSCC survival rates remain among the lowest for solid tumors (4, 5). Those patients fortunate enough to be cured often encounter major esthetic and functional issues with their face and mouth (6). OSCCs arise from malignant progression of a recognized precursor surface epithelial lesion, that is, oral Authors' Affiliations: Divisions of Oral Maxillofacial Pathology & Radiology and Oral Maxillofacial Surgery & Anesthesiology, College of Dentistry, The Ohio State University; The Ohio State University Comprehensive Cancer, Columbus, Ohio; Departments of Oral & Maxillofacial Pathology and Oral & Maxillofacial Surgery, School of Dentistry, University of Louisville, Kentucky; Departments of Diagnostic Sciences and Oral and Maxillofacial Surgery, University of North Carolina at Chapel Hill School of Dentistry, Chapel Hill, North Carolina; and Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Susan R. Mallery, Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, 2191BPostle Hall, 305W12th Ave, The Ohio State University, Columbus, OH 43210-1241. Phone: 614292-5892; Fax: 614-292-9384; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-13-3159 2014 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 20(7) April 1, 2014 1910 on July 14, 2017. © 2014 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3159