Randomized, double-blind, placebo-controlled phase IIb trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia.
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.
Mulshine
James L
JL
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
Atkinson
Jane C
JC
Greer
Robert O
RO
Papadimitrakopoulou
Vassiliki A
VA
Van Waes
Carter
C
Rudy
Susan
S
Martin
Jack W
JW
Steinberg
Seth M
SM
Liewehr
David J
DJ
Avis
Ingalill
I
Linnoila
R Ilona
RI
Hewitt
Stephen
S
Lippman
Scott M
SM
Frye
Robin
R
Cavanaugh
Paul F
PF
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009067:Mouthwashes; D010919:Placebos; D020910:Ketorolac