Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial 30203.

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 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. 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.

A phase III trial evaluating the combination of cisplatin, etoposide, and radiation therapy with or without tamoxifen in patients with limited-stage small cell lung cancer: Cancer and Leukemia Group B Study (9235).

Based on both clinical and laboratory data that suggested that tamoxifen (TAM) enhanced the effectiveness of cisplatin (DDP)-based chemotherapy regimens, the Cancer and Leukemia Group B (CALGB) designed and initiated a prospective, randomized phase III trial to test the efficacy of the addition of high-dose TAM to a standard chemoradiation regimen of DDP and etoposide (VP-16) in patients with limited-stage small cell lung cancer (LS-SCLC). Between August 6, 1993, and January 15, 1999, 319 patients with LSSCLC were accrued to CALGB 9235. Patients were randomized to receive chemotherapy with or without high-dose TAM. Treatment on the non-TAM containing arm (arm 1) included DDP (80 mg/m2 intravenously day 1 only) and VP-16 (80 mg/m2 intravenously days 1-3) given every 3 weeks for a total of 5 cycles. Patients treated on arm 2 received the identical chemotherapy regimen as described here with the addition of high-dose TAM (80 mg orally twice per day), which was given for 5 days each cycle starting 1 day before the DDP. Thoracic radiation (XRT) given at 200 cGy 5 days per week to a total dose of 50 Gy began on day 1 of cycle 4 of chemotherapy and overlapped with cycle 5. Prophylactic cranial irradiation was offered to all patients who achieved a complete response or near-complete response. A total of 307 patients are evaluable for response. After the completion of the chemoradiation portion of the treatment, the overall response rate (ORR) was 88% for 154 patients treated without tamoxifen and 84% for 153 patients treated with tamoxifen with complete response (CR) rates of 49% and 50%, respectively. The median failure-free survivals of 12.3 months and 10.5 months and the overall survivals of 20.6 months and 18.4 months, respectively, were not statistically significant between the 2 arms. Toxicity was similar with and without tamoxifen. This phase III trial failed to demonstrate a positive effect on either the response or survival for the addition of TAM to standard etoposide-cisplatin-radiation management for patients with LS-SCLC. However, these data continue to support a positive effect of chemoradiation in the treatment of patients with LS-SCLC.