title: Randomized, double-blind, placebo-controlled phase IIb trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Intervention Section, Cell and Cancer Biology Branch, Department of Pathology and Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1906, USA. mulshinj@mail.nih.gov
authors.forename: James L
authors.initials: JL
authors.lastname: Mulshine
authors.forename: Jane C
authors.initials: JC
authors.lastname: Atkinson
authors.forename: Robert O
authors.initials: RO
authors.lastname: Greer
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Papadimitrakopoulou
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.forename: Susan
authors.initials: S
authors.lastname: Rudy
authors.forename: Jack W
authors.initials: JW
authors.lastname: Martin
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.forename: Ingalill
authors.initials: I
authors.lastname: Avis
authors.forename: R Ilona
authors.initials: RI
authors.lastname: Linnoila
authors.forename: Stephen
authors.initials: S
authors.lastname: Hewitt
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Robin
authors.initials: R
authors.lastname: Frye
authors.forename: Paul F
authors.initials: PF
authors.lastname: Cavanaugh
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D020910:Ketorolac / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007972:Leukoplakia, Oral / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009067:Mouthwashes; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010919:Placebos; D012907:Smoking / Q000009:adverse effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009067:Mouthwashes; D010919:Placebos; D020910:Ketorolac