A phase I clinical trial of thoracic radiotherapy and concurrent celecoxib for patients with unfavorable performance status inoperable/unresectable non-small cell lung cancer.

OBJECTIVES Preclinical observations that selective cyclooxygenase-2 inhibitors enhance in vitro cell radiosensitivity and in vivo tumor radioresponse led to clinical trials testing therapeutic efficacy of these agents. Our study was designed to determine whether the COX-2 inhibitor celecoxib could be safely administered in doses within those approved by the Food and Drug Administration when used concurrently with thoracic radiotherapy in patients with poor prognosis non-small cell lung cancer (NSCLC). PATIENTS AND METHODS The trial consisted of three cohorts of patients: (a) locally advanced NSCLC with obstructive pneumonia, hemoptysis, and/or minimal metastatic disease treated with 45 Gy in 15 fractions; (b) medically inoperable early-stage NSCLC treated with definitive radiation of 66 Gy in 33 fractions; and (c) patients who received induction chemotherapy but who were not eligible for concurrent chemoradiotherapy trials. These patients received 63 Gy in 35 fractions. Celecoxib was administered p.o. on a daily basis 5 days before and throughout the course of radiotherapy. Celecoxib doses were escalated from 200, 400, 600, to 800 mg/d given in two equally divided doses. Two to eight patients of each cohort were assigned to each dose level of celecoxib. RESULTS Forty-seven patients were enrolled in this protocol (19 in cohort I, 22 in cohort II, and 6 in cohort III). The main toxicities were grades 1 and 2 nausea and esophagitis, and they were independent of the dose of celecoxib or radiotherapy schedule. Only two patients in group II developed grade 3 pneumonitis 1 month after treatment, one on 200 mg, and the other on 400 mg celecoxib. Celecoxib-related toxicity developed in 3 of 47 patients: an uncontrolled hypertension in one patient on 800 mg celecoxib and hemorrhagic episodes in 2 patients (shoulder hematoma in one and hemoptysis in the other) on 200 mg celecoxib who were on warfarin for other medical reasons. Of 37 patients evaluable for tumor response, 14 had complete response, 13 partial responses, and 10 stable or progressive disease. The actuarial local progression-free survival was 66.0% at 1 year and 42.2% at 2 years following initiation of radiotherapy. CONCLUSIONS These results show that celecoxib can be safely administered concurrently with thoracic radiotherapy when given up to the highest Food and Drug Administration-approved dose of 800 mg/d, which we used. A maximal tolerated dose was not reached in this study. The treatment resulted in actuarial local progression-free survival of 66.0% at 1 year and 42.2% at 2 years, an encouraging outcome that warrants further assessment in a phase II/III trial.