A Phase I Clinical Trial of Thoracic Radiotherapy and Concurrent Celecoxib for Patients with Unfavorable Performance Status Inoperable/Unresectable Non–Small Cell Lung Cancer

Abstract

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 in15 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 1and 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 1year 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.

Growth inhibition of non-small-cell lung carcinoma by BN/GRP antagonist is linked with suppression of K-Ras, COX-2, and pAkt

“…Inhibition of COX-2 by selective COX-2 inhibitors enhances the response to chemotherapeutic regimens and leads to a prolonged progression-free survival when used in combination with radiotherapy (35,36). As can be seen in Table 2, treatment of orthotopic xenografts of NSCLC H460 with BN antagonist RC-3940-II caused a significant down-regulation (Յ85%) of the protein expression of COX-2.…”

A Phase II study of acute toxicity for Celebrex™ (celecoxib) and chemoradiation in patients with locally advanced cervical cancer: Primary endpoint analysis of RTOG 0128

“…Celecoxib has been combined with RT in a number of settings including the treatment of lung, CNS, and GI malignancies and shown to be safe (31---34). In a Phase I study performed at MD Anderson Cancer Center in unfavorable performance nonsmall lung cancer patients treated to 66 Gy in 33 fractions with concurrent celecoxib, the maximally tolerated dose was not reached; and 800 mg bid of celecoxib was observed to be safe (31). Celecoxib related toxicity was observed in 3 of 47 patients in their study.…”

Amfenac increases the radiosensitivity of uveal melanoma cell lines

“…30 Systemic COX-2 inhibitors are being used in clinical trials for lung cancer and the results are promising. 20,31 To the best of our knowledge, this is the first time that a drug has been shown to increase the radiosensitivity of UM cell lines. Furthermore, we demonstrated that no such synergistic effect was seen in a non-neoplastic human fibroblast cell line, that was, on the contrary, protected by the addition of amfenac.…”

“…30 The concept that an eyedrop, without significant side effects, 38 can deliver the drug to an intraocular UM is even more appealing since the systemic complications related to COX-2 inhibition can be circumvented. 20 In light of our preliminary results, we would encourage the use of nepafenac as an adjunct to radiotherapy in the treatment of UM. However, further studies are needed to characterize the exact mechanism behind the observed synergism.…”

“…18 The effectiveness of these selective inhibitors has been investigated in a variety of tumours and shows promise for use as an adjuvant therapy. 19 COX-2 inhibitors have also previously been shown to increase the radiosensitivity of lung 20 and breast 21 cancer cell lines. Moreover, it has been demonstrated that a COX-2 inhibitor is capable of minimizing radiation damage to non-neoplastic tissues.…”