Efficacy and Safety of COX-2 Inhibitors for Advanced Non-small-cell Lung Cancer With Chemotherapy: A Meta-analysis

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Cyclooxygenase-2 (COX-2) inhibitors improve the overall response rate to chemotherapy but does not appear to improve survival among patients with non-small cell lung cancer (NSCLC), according to these study findings.

COX-2 overexpression is commonly observed in various solid tumors and may contribute to disease progression by mediating factors such as apoptotic resistance, invasion, angiogenesis, and immune suppression. As such, clinical studies were conducted to evaluate the impact of COX-2 inhibitors in addition to chemotherapy in this patient population but findings have led to mixed results; some studies showed that COX-2 inhibition improves antitumor activity while others showed increased rates of cardiotoxicity, a serious adverse event associated with COX-2 inhibitors.

In this article, the authors present the findings of a meta-analysis of 6 studies that assessed the outcomes of 1793 patients with NSCLC treated with COX-2 inhibitors (eg, celecoxib, rofecoxib) plus chemotherapy. The authors concluded that the benefits of treating advanced NSCLC with COX-2 inhibitors need to be carefully weighed against potential harms.

OncoTargets and Therapy
OncoTargets and Therapy

Background: The 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 methods: A 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.
Results: Six 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.
Conclusion: COX-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.

Keywords: cyclooxygenase-2 inhibitors, non-small-cell lung cancer, chemotherapy, overall survival, meta-analysis 


A growing number of preclinical studies showed that overexpression of cyclooxygenase-2 (COX-2) had been implicated as a tumor-initiating and tumor-promoting event for several common solid tumors, including lung, breast, and colon cancers.1–3 Approximately 70% of adenocarcinomas in non-small-cell lung cancer (NSCLC) have been found to exhibit increased COX-2 expression.4 COX-2 expression in tumors appears to be instrumental in tumor resistance to apoptosis, angiogenesis, invasion, and immune suppression.5 Further, selective COX-2 inhibitors have been shown to inhibit the growth of lung cancer cell lines and to enhance the effectiveness of selected chemotherapy against NSCLC cell lines in xenograft models.6 These studies5,7 suggest nonsteroidal anti-inflammatory drugs (NSAIDs) may act on multiple tumor-progression targets via both COX-2-dependent and -independent pathways. Based on these observations, COX-2 inhibitors have been evaluated in combination with chemotherapy for the management of metastatic NSCLC in patients who have failed prior chemotherapy. However, current clinical trials on the benefit of COX-2 inhibitors in cancer treatment report conflicting results. Indeed, some studies2,4,6 demonstrated that COX-2 inhibitors could enhance antitumor activity of conventional anticancer agents in vitro and in vivo. However, many studies have confirmed that COX-2 inhibitors did not appear to enhance efficacy or improve patient-reported symptoms and can also lead to certain toxicity.8,9

There are three meta-analyses10–12 about the efficacy and safety profile of COX-2 inhibitors that have been published. All the three studies reported that COX-2 inhibitors could increase overall response rate (ORR) in patients with advanced NSCLC. Of these, two studies10,11 indicated that celecoxib significantly increased risk of hematologic toxicities, while Chen et al12 reported that COX-2 inhibitors plus chemotherapy was associated with a higher incidence of cardiovascular events compared with chemotherapy alone. Two meta-analyses10,12 did not carry out a hazard ratio (HR) analysis of outcome indicators overall survival (OS) and progression-free survival (PFS). While conducting meta-analysis, Hou et al10 and Chen et al12 only focused on celecoxib. Moreover, Hou et al10 included six studies with 1,181 patients, describing all end points without subgroup analysis. To better assess the efficacy and safety profile of COX-2 inhibitors combined with chemotherapy for patients with advanced NSCLC, the meta-analysis of data from published randomized controlled trials (RCTs) in this field was performed.  

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