A Phase II Study of Celecoxib in Combination with Paclitaxel, Carboplatin, and Radiotherapy for Patients with Inoperable Stage IIIA/B Non–Small Cell Lung Cancer

Abstract

Purpose: Cyclooxygenase (COX)-2 up-regulation plays an important role in the pathogenesis of lung cancer. Selective COX-2 inhibitors have promoted chemosensitivity and radiosensitivity of tumor cells in preclinical trials. Experimental Design: In a single-institution phase II study, we sought to determine the effectiveness of concurrent chemoradiation given with celecoxib and examined biomarkers to predict response to COX-2 inhibition. Results: Seventeen patients with stage IIIA or IIIB non^small cell lung cancer (NSCLC) were enrolled in the study. All received 400 mg celecoxib twice daily continuously while on trial in addition to concurrent chemoradiation therapy with paclitaxel and carboplatin. Celecoxib was continued until disease progression. The overall objective response rate was 42.9%, and the median overall survival time was 203 days. In contrast to nonresponders, those patients with complete and partial responses had a significant decrease in the level of urinary 11a-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E 2 , after 1 week of celecoxib administration. Patients with very high levels of PGE-M before initiation of therapy also responded poorly to therapy. Serum vascular endothelial growth factor levels did not predict response or survival. Conclusion: The trial was terminated because it did not meet the predetermined goal of 80% overall response rate. In unselected patients, the addition of celecoxib to concurrent chemoradiotherapy with inoperable stage IIIA/B NSCLC does not improve survival. Urinary PGE-M is a promising biomarker for predicting response to COX-2 inhibition in NSCLC.Lung cancer is the most prevalent cancer in the United States and the leading cause of cancer-related mortality, killing more patients than the next three deadliest malignancies (colorectal, breast, and prostate) combined (1). Approximately one third of non -small cell lung cancer (NSCLC) cases will present with locally advanced disease with mediastinum involvement either by metastatic lymph nodes or by primary (2). Because these patients are not good candidates for surgical resection, definitive treatment combining platinum-based chemotherapy and radiotherapy is considered the standard of care (3).Cyclooxygenase (COX) is a key enzyme in arachidonic acid conversion to prostaglandins and other eicosanoids. There are two isoforms of COX known as COX-1 and COX-2. Unlike constitutively expressed COX-1, COX-2 is inducible and upregulated by a variety of factors, which include cytokines, growth factors, and tumor promoters (4). COX-2 is overexpressed by various human cancers, including lung. Furthermore, a growing body of evidence suggests that up-regulation of COX-2 and its product, prostaglandin E 2 (PGE 2 ), is important in the growth of lung cancer (5, 6). COX-2 and its derived prostaglandins play a role in stimulating angiogenesis and apoptosis inhibition and in suppressing the immune response (7). COX-2 overexpression may also enhance the metastatic...

Acquired Activation of the Akt/Cyclooxygenase-2/Mcl-1 Pathway Renders Lung Cancer Cells Resistant to Apoptosis

“…It is also warranted to determine whether this pathway is activated in COX-2-negative tumor cells and whether the activation of this pathway is associated with tumor relapse during chemotherapy. Several clinical trials combining the COX-2 inhibitor celecoxib and therapeutics such as paclitaxel, etoposide, and cisplatin showed moderate potentiated effects (Arú ajo et al, 2009;Mutter et al, 2009;Suzuki et al, 2009). However, it was noted that the responders had either low COX-2 activity or higher efficacy of COX-2 inhibition by the treatment, suggesting that to decrease the COX-2 expression or activity to lower than the responding threshold could be an important determinant for cancer patients' response (Mutter et al, 2009).…”

Cyclooxygenase-2 Genetic Variants Are Associated with Survival in Unresectable Locally Advanced Non–Small Cell Lung Cancer

“…Therefore, a personalized more intensive treatment, i.e., a combination treatment of chemoradiotherapy and COX-2 inhibitor, might be warranted to improve the survival in patients with the unfavorable COX-2 −1195AA genotype. Several phase II studies failed to show the value of eicosanoid inhibition in addition to other modalities, such as chemotherapy, and/or tyrosine kinase inhibitor target therapy, in unselected population of advanced NSCLC (35,38,(41)(42)(43). However, recent evidence suggested a potential advantage for celecoxib, a selective COX-2 inhibitor, might be obtained in the certain population (44,45).…”

Prognostic Immune Markers in Non–Small Cell Lung Cancer

“…In vivo, inhibition of COX-2 reduced Treg activity, attenuated FoxP3 expression in TILs, and decreased tumor burden (21). Furthermore, urinary PGE-M, the major metabolite of PGE 2 , was proposed as a biomarker to predict response to COX-2 inhibitors in NSCLC patients (22). Petersen and colleagues showed that the Treg/TIL combination risk index (the ratio of FoxP3þ to CD3þ) correlates with disease-specific survival (DSS) in patients with stage I NSCLC (23).…”