title: Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel.
abstract: Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in prostaglandin (PG) synthesis and is overexpressed in 70% to 90% of non-small cell lung cancers (NSCLC). Preclinical studies suggest inhibition of COX-2 can enhance the cytotoxic effect of docetaxel. To test this concept clinically, we administered celecoxib (400 mg p.o. twice daily) plus docetaxel (75 mg/m(2) every 3 weeks) to a cohort of patients with recurrent, previously treated NSCLC. Patients first received single agent celecoxib for 5 to 10 days to ascertain the effectiveness of COX-2 inhibition, which was determined by measuring pre- and post-celecoxib levels of urinary 11alpha-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E(2) (PGE(2)). We enrolled 56 patients (35 men, 21 women; median age, 61 years). All patients had received at least one prior chemotherapy regimen. The overall response rate was 11% and median survival was 6 months, similar to that observed with docetaxel alone. Pre-celecoxib urinary PGE-M decreased from a mean level of 27.2 to 12.2 ng/mg Cr after 5 to 10 days of celecoxib (P = 0.001). When grouped by quartile, patients with the greatest proportional decline in urinary PGE-M levels experienced a longer survival compared to those with no change or an increase in PGE-M (14.8 versus 6.3 versus 5.0 months). Our data suggest that combining celecoxib with docetaxel using the doses and schedule employed does not improve survival in unselected patients with recurrent, previously treated NSCLC. However, in light of the apparent survival prolongation in the subset with a marked decline in urinary PGE-M levels, further investigation of strategies designed to decrease PGE(2) synthesis in NSCLC seems warranted.
authors.affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Csiki
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Alan
authors.initials: A
authors.lastname: Sandler
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: John
authors.initials: J
authors.lastname: Oates
authors.forename: Myles K
authors.initials: MK
authors.lastname: Williams
authors.forename: Thao
authors.initials: T
authors.lastname: Dang
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: David H
authors.initials: DH
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043925:Angiogenesis Inducing Agents / Q000097:blood; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000068579:Celecoxib; D015331:Cohort Studies; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000378:metabolism; D000077143:Docetaxel; D043169:Endostatins / Q000097:blood; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000652:urine; D011720:Pyrazoles / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014839:Vomiting / Q000139:chemically induced
chemical_list: D043925:Angiogenesis Inducing Agents; D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D043169:Endostatins; D008565:Membrane Proteins; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; C060526:7-hydroxy-5,11-dioxotetranorprostane-1,16-dioic acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone