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Pilot Randomized Phase II Study of Celecoxib in Oral Premalignant Lesions

Authors' Affiliations: Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Biostatistics and Applied Mathematics, and ³ Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁴ Department of Medicine, Weill Cornell Medical College and New York Presbyterian Hospital; ⁵ Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; ⁶ Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota; ⁷ School of Dental Medicine and Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, Connecticut; ⁸ Department of Otolaryngology-Head and Neck Surgery, Louisiana State University, Shreveport, Louisiana; ⁹ Department of Maxillofacial Surgery, University of Michigan, Ann Arbor, Michigan; and ¹⁰ Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, Washington

Requests for reprints: Vassiliki A. Papadimitrakopoulou, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220; E-mail: vpapadim{at}mdanderson.org.

Purpose: Cyclooxygenase-2 (COX-2)–specific inhibition suppresses carcinogenesis in preclinical models and is a promising strategy for preventing oral cancer. In this pilot randomized phase II study, we evaluated the efficacy and safety of the COX-2 inhibitor celecoxib in patients with oral premalignant lesions (OPL).

Experimental Design: Patients were randomly assigned to placebo (n = 18), celecoxib 100 mg twice daily (n = 17), or celecoxib 200 mg twice daily (n = 15) for 12 weeks. Six additional patients received celecoxib (400 mg twice daily) in an unblinded extension of the study. Biopsies were obtained at baseline and week 12. All patients entering the study were required to have at least one histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate to severe dysplasia) OPL.

Results: Forty-nine patients (46 of 50 randomized and 3 of 6 open label) were evaluable for efficacy analyses. There were no statistically significant differences between the response rates of the randomly assigned arms: placebo, 33.3% (6 of 18); celecoxib 100 mg twice daily, 41.2% (7 of 17); and celecoxib 200 mg twice daily, 20.0% (3 of 15). Two patients responded on celecoxib 400 mg twice daily. Celecoxib was generally well tolerated. Patients with higher baseline COX-2 mRNA levels had an increased risk of disease progression within 3 months.

Conclusions: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial. This result and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention. Better methods for identifying high-risk patients and more active interventions are needed for future oral cancer chemoprevention trials.