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Randomized, Double-Blind, Placebo-Controlled Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia

¹ Intervention Section, Cell and Cancer Biology Branch, ² Biostatistics and Data Management Section, ³ Department of Pathology and ⁴ Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ⁵ Clinical Research Core, National Institute of Dental and Craniofacial Research, Bethesda, MD; ⁶ Division of Oral Pathology and Oncology, University of Colorado School of Dentistry and University of Colorado Cancer Center, Denver, Colorado; Departments of ⁷ Thoracic/Head and Neck Medical Oncology, ⁸ Head and Neck Surgery, and ⁹ Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, Texas; ¹⁰ Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland; and ¹¹ Over the Counter Health Care Technology Division, The Procter and Gamble Company, Mason, Ohio

ABSTRACT

Purpose: Nonselective cyclooxygenase (COX) inhibitors have been reported to decrease the frequency of upper aerodigestive cancers. Ketorolac tromethamine oral rinse has been shown to resolve another COX-dependent process, periodontal disease, without incurring gastrointestinal side effects. This trial evaluated if a topically delivered oral rinse containing ketorolac was as safe as and more effective than oral rinse alone in reducing the area of oral leukoplakia.

Experimental Design: 57 patients were randomized (2:1 ratio) in a double-blind, placebo-controlled study of ketorolac (10 ml of a 0.1% ketorolac rinse solution; n = 38) or placebo (10 ml of rinse solution; n = 19) given twice daily for 30 s over 90 days. Primary end point was evaluated visually obtaining bidimensional measurement of the size of leukoplakia lesion(s) at entry and at 90 days. Secondary end point was histological assessment of the leukoplakia as sampled by serial punch biopsy and independently reviewed by three pathologists.

Results: The patients included 67% males, 11% non-Caucasian, and 86% used tobacco with no significant differences between the two arms. Both rinses were well tolerated with good compliance, and there was no significant difference in adverse events (P = 0.27). Major response rate (complete response and partial response) was 30% for ketorolac and 32% for the placebo arm. There was no significant difference in change in histology between the two arms.

Conclusion: Local delivery of a COX-containing oral rinse was well tolerated but produced no significant reduction in the extent of leukoplakia compared with the placebo. However, the favorable response rate to placebo arm remains unexplained and additional investigation of the tissue penetration with ketorolac is warranted.

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