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Eicosanoid Modulation in Advanced Lung Cancer: Cyclooxygenase-2 Expression Is a Positive Predictive Factor for Celecoxib + Chemotherapy—Cancer and Leukemia Group B Trial 30203

Martin J. Edelman, Dee Watson, Xiaofei Wang, Carl Morrison, Robert A. Kratzke, Scott Jewell, Lydia Hodgson, Ann M. Mauer, Ajeet Gajra, Gregory A. Masters, Michelle Bedor, Everett E. Vokes, Mark J. Green

From the University of Maryland Greenebaum Cancer Center, Baltimore, MD; Duke University, Durham, NC; CALGB Pathology Central Office, Ohio State University, Columbus, OH; University of Minnesota, Minneapolis, MN; University of Chicago, Chicago, IL; Upstate Medical University and VA Medical Center, Syracuse, NY; Christiana Hospital, Wilmington, DE; and the Medical University of South Carolina, Charleston, SC

Corresponding author: Martin J. Edelman, MD, University of Maryland Greenebaum Cancer Center, Division of Hematology/Oncology (111H), 22 South Greene Street, Baltimore, MD 21201-1595; e-mail: medelman{at}umm.edu

Purpose: 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).

Patients and 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 · min day 1 + gemcitabine (1,000 mg/m²) 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 4; HR = 4.16, P = .005 for index = 9) for patients not receiving celecoxib. Patients with increased COX-2 expression (index 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.

Conclusion: 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.

Supported in part by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B and to the CALGB Statistical Center (CA33601); and by Grant Nos. CA31983, CA47577, CA77658, CA16450, CA41287, CA45389, CA45418, and CA03927.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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  Michael G. Backlund, Joseph M. Amann, and David H. Johnson
  JCO 2008 26: 825-827 [Full Text]

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