Publication bias

No publication bias was observed for any of the outcomes based on the symmetry of the funnel plots. Furthermore, the results of the Egger’s test indicated no significant difference in primary outcomes: OS (bias =0.708, 95% CI: −3.086 to 4.051, P=0.632), PFS (bias =−0.387, 95% CI: −4.508 to 3.733, P=0.807), ORR (bias =−0.835, 95% CI: −6.033 to 4.363, P=0.561), and 1-year SR (bias =−0.940, 95% CI: −3.748–1.869, P=0.365).


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DISCUSSION

In this meta-analysis, we evaluated six clinical trials that included 1,794 advanced NSCLC patients. Our meta-analysis indicated a significantly increased ORR with COX-2 inhibitors plus chemotherapy over chemotherapy alone. COX-2 is reported to interfere with angiogenesis, apoptosis, and tumor invasiveness.27 Increased expression of COX-2 has been found in lung cancer and has been associated with worse prognosis.28,29 COX-2 inhibitors inhibit the growth of human lung cancer cells as single agents as well as in combination with chemotherapy. Subgroup analysis reported that rofecoxib rather than celecoxib may produce a significantly increased ORR of advanced NSCLC with chemotherapy. Zhou et al11 found that both celecoxib and rofecoxib can improve the ORR of advanced NSCLC with chemotherapy. Inconsistencies in these results may be due to a different sample size. The celecoxib plus chemotherapy subgroup of Zhou et al contained six RCTs, whereas this study included four RCTs. In addition, Zhou et al and this meta-analysis included only one trial on rofecoxib, and so the reliability of the results may be reduced and further research with a large sample is needed to confirm these results. According to treatment line, we observed a statistically significant favorable effect of first-line chemotherapy with COX-2 inhibitors on ORR but no change in second-line chemotherapy. Since there was only one study (by Lilenbaum et al21) which included COX-2 inhibitors as second-line chemotherapy, more research is needed to verify this conclusion. However, there was no significant difference found in 1-year SR of advanced NSCLC between COX-2 inhibitors plus chemotherapy and chemotherapy alone. In the subgroup analysis that was based on the type of COX-2 inhibitors and treatment line, 1-year SR also did not change between COX-2 inhibitors plus chemotherapy and chemotherapy alone. Similar results were obtained for OS and PFS. In all subgroup analyses, COX-2 inhibitors plus chemotherapy showed no significant influence on OS and PFS compared with chemotherapy alone. Three studies10–12 reported results consistent with this study, where COX-2 inhibitors plus chemotherapy had no advantage over 1-year SR compared to chemotherapy alone. Only Zhou et al11 calculated pooled HR of OS and PFS, and indicated that difference in OS and PFS durations of patients on COX-2 inhibitors plus chemotherapy and chemotherapy alone was not statistically significant. There has been no research to report that COX-2 inhibitors plus chemotherapy can reduce mortality of patients with advanced NSCLC. Therefore, further study on how to improve the 1-year SR, OS, or PFS of patients with advanced NSCLC is still necessary. The abovementioned results showed that COX-2 inhibitors may increase ORR of chemotherapy with advanced NSCLC, especially combined with first-line treatment. However, no similar change was found in the survival indices.

Toxicities were graded according to Common Terminology Criteria for Adverse Events v3.0 of the National Cancer Institute.30 This meta-analysis included both hematological and nonhematological grade 3 and grade 4 side effects of treatment. A higher frequency of leukopenia, thrombocytopenia, and cardiotoxicity was observed in COX-2 inhibitors plus chemotherapy compared to chemotherapy alone. Few studies31–33 reported that coordination of COX-2 with vascular endothelial growth factor (VEGF) may promote angiogenesis in bone marrow after chemotherapy. Pharmacodynamic studies suggested that COX-2 inhibitors can inhibit angiogenesis by inhibiting the VEGF, basic fibroblast growth factor, platelet-derived growth factor, and endothelin 21,31 which was a possible explanation for a higher frequency of leukopenia and thrombocytopenia in COX-2 inhibitors plus chemotherapy. The induction of cardiovascular events by COX-2 inhibitors limits its applications and research for cancer. Chen et al12 reported that the risk of cardiovascular events was significantly increased in patients with long-term use of celecoxib, whereas the other meta-analyses did not find that COX-2 inhibitors used for treating NSCLC could increase the risk of cardiovascular events.10,11 In an attempt to answer the questions about the cardiovascular safety of NSAIDs and COX-2 inhibitors, many physician-scientists have undertaken research efforts. Innumerable observational studies examining larger and larger administrative databases have been sought to answer these critical questions. However, cardiovascular toxicity of COX-2 inhibitors still remains a debated topic in the field.

There are several limitations to this study that should be addressed. First, only a few clinical trials met the inclusion and exclusion criteria. Consequently, more clinical studies will be required to confirm our results. Second, not all RCTs provided sufficient data on response rates and survival indices, which affected the pooled results in the present meta-analysis. Finally, one study had lost large amounts of data, and there may be a certain attrition bias.

CONCLUSION

This meta-analysis indicated that COX-2 inhibitors, especially rofecoxib, improved ORR of advanced NSCLC with chemotherapy, but had no effect on survival indices. Accordingly, COX-2 inhibitors may lead to higher rates of hematologic toxicities and cardiovascular events. Based on these findings, benefits versus hazards of COX-2 inhibitors for treating advanced NSCLC need to be carefully considered.

Acknowledgments

This study was supported by the Project supported by science and technology activities among overseas students and Molecular Genetics and Mechanism of EGFR Gene Mutation in Uygur and Han People with NSCLC in Xinjiang Applying Circulating Tumor DNA Detection (No. 81560381). The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

PD and PG had full access to all of the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. PD, XPM, and JH designed the study. JH and JJM developed and tested the data collection forms. PD and XPM acquired the data. XPM and PG conducted the analysis and interpreted the data. XPM and JH drafted the manuscript. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work. 


Ping Dai, Jing Li, Xiao-Ping Ma, Jian Huang, Juan-Juan Meng, Ping Gong

Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People’s Republic of China 


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Source: OncoTargets and Therapy.
Originally published February 5, 2018.