Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial 30203.
OBJECTIVE
Increased expression of eicosanoids in cancer has been associated with adverse prognosis. We performed a randomized phase II trial to test the hypothesis that inhibitors of two eicosanoid pathways (cyclooxygenase-2 [COX-2], celecoxib and 5-lipoxygenase [5-LOX], zileuton) added to chemotherapy would improve outcome in advanced non-small-cell lung cancer (NSCLC).


METHODS
Patients with advanced NSCLC, a performance status of 0 to 2, and no prior therapy were eligible. All patients received carboplatin area under the curve (AUC) 5.5 mg/mL x min day 1 + gemcitabine (1,000 mg/m(2)) days 1 and 8. Patients were randomly assigned to: (a) zileuton 600 mg PO qid, (b) celecoxib 400 mg PO bid, or (c) celecoxib and zileuton at the same doses. Immunohistochemical staining for COX-2 and 5-LOX was performed without knowledge of outcomes.


RESULTS
One hundred forty patients were entered and 134 were eligible and treated. There was no survival difference between the arms. COX-2 expression was a negative prognostic marker for overall survival (OS; hazard ratio [HR] = 2.51, P = .019 for index >or= 4; HR = 4.16, P = .005 for index = 9) for patients not receiving celecoxib. Patients with increased COX-2 expression (index >or= 4), receiving celecoxib had better survival than did COX-2-expressing patients not receiving drug (HR = .342, P = .005 for OS; HR = .294, P = .002 for failure-free survival). Multivariate analysis confirmed the interaction of COX-2 and celecoxib on survival. 5-LOX expression was neither prognostic nor predictive.


CONCLUSIONS
This study failed to demonstrate the value of dual eicosanoid inhibition or benefit from either agent alone in addition to chemotherapy. However, a prospectively defined subset analysis suggests an advantage for celecoxib and chemotherapy for patients with moderate to high COX-2 expression.
Edelman
Martin J
MJ
University of Maryland Greenebaum Cancer Center, Division of Hematology/Oncology (111H), 22 South Greene Street, Baltimore, MD 21201-1595, USA. medelman@umm.edu
Watson
Dee
D
Wang
Xiaofei
X
Morrison
Carl
C
Kratzke
Robert A
RA
Jewell
Scott
S
Hodgson
Lydia
L
Mauer
Ann M
AM
Gajra
Ajeet
A
Masters
Gregory A
GA
Bedor
Michelle
M
Vokes
Everett E
EE
Green
Mark J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D015777:Eicosanoids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007150:Immunohistochemistry; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D016015:Logistic Models; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D015854:Up-Regulation; D000093542:Gemcitabine
D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D003841:Deoxycytidine; D016190:Carboplatin; D051546:Cyclooxygenase 2; D000068579:Celecoxib; C063449:zileuton; D006918:Hydroxyurea; D000093542:Gemcitabine