Phase I clinical trial using selective cyclooxygenase-2 (COX-2) inhibitor celecoxib with concurrent thoracic irradiation in patients with poor prognosis non-small cell lung cancer (NSCLC)

Abstract

Preclinical investigations have demonstrated that inhibition of COX-2 with selective COX-2 inhibitors preferentially enhances tumor response to radiation and chemotherapeutic agents, and suggested that these agents have potential to improve radiatiotherapy. This phase I study was designed to determine the maximum tolerated dose (MTD) of celecoxib, a selective COX-2 inhibitor, when used concurrently with standard fractionation thoracic radiotherapy for patients with poor prognosis NSCLC. The trial consisted of 3 separate patient groups. Group I was comprised of patients with locally advanced cancer who presented with obstructive pneumonia or minimal metastatic disease received palliative radiotherapy with 45 Gy total-dose delivered in 15 fractions. Patients in Group II presented with inoperable early stage tumors, and these patients received definitive radiation therapy consisting of 66 Gy total-dose delivered in 33 fractions. Group III included patients who received induction chemotherapy followed by radiotherapy to 63 Gy total-dose in 35 fractions. Three dimensional conformal treatment planning was used for all patients. Celecoxib in the escalation dose schedule of 200 mg, 400 mg, 600 mg, and 800 mg was administered orally in two equally divided daily doses starting 5 days prior to and continuing through the course of radiotherapy. Three to 4 patients of each radiotherapy group were assigned to each dose level of celecoxib. Forty-seven patients were enrolled in this protocol (19 in Group I, 22 in Group II, and 6 in Group III), with the 800 mg dose level completed only in Groups I and II. Group III was closed after 6 patients enrolled due to the fact that concurrent chemoradiation became a more accepted treatment modality. The main toxicities were grades 1 and 2 nausea and esophagitis. Two patients in Group II, one on 200mg and the other on 400mg celecoxib dose schedule developed grade 3 pneumonitis one month after radiotherapy plus celecoxib treatment. Two patients who were taking warfarin for other medical reasons had developed hemoragic episodes (one with hemotoma in the shoulder (grade 3) after 2 weeks of 200 mg per day celecoxib, the other had one episode of hemoptysis (grade 1) after one dose of 200 me per day celecoxib). One patient developed hypertension that did not normalize following discontinuation of the drug 2 weeks after starting 400mg celecoxib twice daily, and the event was considered grade 3 drug toxicity. In 23 patients evaluable for tumor response, 9 had complete response, 8 had partial response, 6 had stable or progression of the treated tumors radiographicly. The rate of local progression free survival was 67% at 20 months, following starting initiation of radiotherapy. These results suggest that celecoxib can be safely administered concurrently with thoracic radiotherapy. Importantly, the local progression free survival rate for all patients on the study was 67% at 20 months, a result similar to that after concurrent chemoradiotherapy, which is highly encouraging. A phase II/III trial is planned to test the efficacy of this treatment