Efficacy and safety of COX-2 inhibitors for advanced non-small-cell lung cancer with chemotherapy: a meta-analysis

Abstract

BackgroundThe study of cyclooxygenase-2 (COX-2) inhibitors is now mired in controversy. We performed a meta-analysis to assess the efficacy and safety profile of COX-2 inhibitors in patients with advanced non-small-cell lung cancer (NSCLC).Patients and methodsA literature search of PubMed, EMBASE, the Cochrane Central databases, and ClinicalTrials.gov, up until March 26, 2017, identified relevant randomized controlled trials. Data analysis was performed using Stata 12.0.ResultsSix eligible trials (1,794 patients) were selected from the 407 studies that were identified initially. A significant difference, favoring COX-2 inhibitors plus chemotherapy over chemotherapy alone, was observed in the overall response rate (relative risk [RR] =1.25, 95% confidence interval [CI]: 1.06–1.48). Further, we conducted two subgroup analyses according to the type of COX-2 inhibitors (celecoxib, rofecoxib, or apricoxib) and treatment line (first or second chemotherapy). The first-line treatment includes: NP (changchun red bean + cisplatin or carboplatin), GP (double fluorine cytidine + cisplatin or carboplatin), or TP (paclitaxel + cisplatin or carboplatin, docetaxel + cisplatin or carboplatin). The second-line treatment includes two internationally recognized compounds, one is docetaxel and the other is the pemetrexed, both of which are individually selected. In subgroup analysis, significantly increased overall response rate (ORR) results were found for rofecoxib plus chemotherapy (RR =1.56, 95% CI: 1.08–2.25) and COX-2 inhibitor given with first-line chemotherapy (RR =1.27, 95% CI: 1.07–1.50). However, there was no difference between COX-2 inhibitors plus chemotherapy and chemotherapy alone in overall survival (hazard ratio [HR] =1.04, 95% CI: 0.91–1.18), progression-free survival (HR =0.97, 95% CI: 0.86–1.10), and 1-year survival rate (RR =1.03, 95% CI: 0.89–1.20). Toxicity did not differ significantly between COX-2 inhibitors plus chemotherapy and chemotherapy alone with the exception of leukopenia (RR =1.21, 95% CI: 1.03–1.42), thrombocytopenia (RR =1.32, 95% CI: 1.04–1.67), and cardiovascular events (RR =2.39, 95% CI: 1.06–5.42). The results of the Egger’s test indicated no significant difference in primary outcomes.ConclusionCOX-2 inhibitors improved ORR of advanced NSCLC with chemotherapy, but had no effect on survival indices. Moreover, COX-2 inhibitors may lead to higher rates of hematologic toxicities and cardiovascular events.

(−)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer

“…Induction of COX2 in NSCLC occurred through both the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 pathways [30]. COX2 has been already proved a critical clinical marker for poor prognosis in lung, colorectal, gastric, head and neck cancers [24][25][26][27][28][29]. The serum level of COX2 was also validated as a biomarker for EGFR mutation, response for EGFR TKIs, and progression-free survival in LC patients [65].…”

“…Meanwhile, inhibition of COX-2 limits the production of prostaglandins, which are known to stimulate cell proliferation, induce invasiveness and mediate angiogenesis [30]. Targeting COX2 proved acceptable strategy to control lung and other malignancies [28][29][30][31][32]. Earlier in 2005, Beauchamp et al identified OC as the non-steroidal anti-inflammatory drug (NSAID) ibuprofen-like active ingredient in EVOO [40].…”

“…Preclinical animal model studies have already documented the significant tumor reduction upon nonspecific or specific inhibition of COX2 activity. Celecoxib, a selective COX2 inhibitor has been evaluated in combination with chemotherapy for the management of metastatic NSCLC in patients who have failed prior chemotherapy [29]. Interestingly, HGF proved to increase the level of COX2 expression up to 3-fold over basal levels [30].…”

Systematic review and meta-analysis of the benefit of celecoxib in treating advanced non-small-cell lung cancer

“…A meta-analysis assessed the efficacy of COX-2 inhibitors (celecoxib, rofecoxib, or apricoxib) in combination with chemotherapy in advanced NSCLC patients. 29 The results of this study showed that COX-2 inhibitors combined with first-line chemotherapy significantly improved the overall response rate (ORR) (risk ratio [RR] =1.27, 95% CI =1.07–1.50), but subgroup analysis including only 4 studies showed that celecoxib plus chemotherapy yielded no significant difference in patients with advanced NSCLC (RR =1.18, 95% CI =0.98–1.42, I 2 =0.0%, P =0.562). Additionally, this study reported that COX-2 inhibitors with chemotherapy led to higher incidences of cardiovascular events (RR =2.39, 95% CI =1.06–5.42).…”

In vitro and in silico assessment of antiproliferative activity of new acetamides bearing 1,3,4-oxadiazole and pyrimidine cores via COX inhibition

“…repressed apoptosis, promoted tumor-cell invasion and enhanced angiogenesis in tumor cells, whereas the relevant mechanisms have not all been elucidated. Besides, higher COX-2 levels have been reported to overexpress in almost all NSCLC precursor lesions leading to a worse overall survival rate [13][14][15][16][17][18][19][20][21]. Although COX-1 has been considered not to be involved in carcinogenesis due to its homeostatic cell and tissue functions, there are many reports showing the connection between the increased levels of COX-1 and cancer pathophysiology [22][23][24][25].…”