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).
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.
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.
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.
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
1. Scheff RJ, Schneider BJ. Non-small-cell lung cancer: treatment of late stage disease: chemotherapeutics and new frontiers. Semin Intervent Radiol. 2013;30:191–198.
2. Yokouchi H, Kanazawa K, Ishida T, et al. Cyclooxygenase-2 inhibitors for non-small-cell lung cancer: a phase II trial and literature review. Mol Clin Oncol. 2014;2:744–750.
3. Smith WL, Langenbach R. Why there are two cyclooxygenase isozymes. J Clin Invest. 2001;107:1491–1495.
4. Patel S, Chiplunkar S. Role of cyclooxygenase-2 in tumor progression and immune regulation in lung cancer. Indian J Biochem Biophys. 2007;44:419–428.
5. Sandler AB, Dubinett SM. COX-2 inhibition and lung cancer. Semin Oncol. 2004;31:45–52.
6. Altorki NK, Port JL, Zhang F, et al. Chemotherapy induces the expression of cyclooxygenase-2 in non-small cell lung cancer. Clin Cancer Res. 2005;11:4191–4197.
7. Krysan K, Reckamp KL, Sharma S, Dubinett SM. The potential and rationale for COX-2 inhibitors in lung cancer. Anticancer Agents Med Chem. 2006;6:209–220.
8. Nissen SE. Cox-2 inhibitors and cardiovascular disease: considerable heat, but not much light. Eur Heart J. 2012;33:2631–2633.
9. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954–959.
10. Hou LC, Huang F, Xu HB. Does celecoxib improve the efficacy of chemotherapy for advanced non-small cell lung cancer? Br J Clin Pharmacol. 2016;81:23–32.
11. Zhou YY, Hu ZG, Zeng FJ, Han J. Clinical profile of cyclooxygenase-2 inhibitors in treating non-small cell lung cancer: a meta-analysis of nine randomized clinical trials. PLoS One. 2016;11:e0151939.
12. Chen J, Shen P, Zhang XC, Zhao MD, Zhang XG, Yang L. Efficacy and safety profile of celecoxib for treating advanced cancers: a meta-analysis of 11 randomized clinical trials. Clin Ther. 2014;36:1253–1263.
13. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.
14. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.
15. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
16. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med. 2002;21:1575–1600.
17. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions, v.5.1; 2011 [Last updated March 5, 2011]. Available from: http://handbook-5-1.cochrane.org. Accessed December 18, 2017.
18. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.
19. Copas J, Shi JQ. Meta-analysis, funnel plots and sensitivity analysis. Biostatistics. 2000;1:247–262.
20. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634.
21. Lilenbaum R, Socinski MA, Altorki NK, et al. Randomized phase II trial of docetaxel/irinotecan and gemcitabine/irinotecan with or without celecoxib in the second-line treatment of non-small-cell lung cancer. J Clin Oncol. 2006;24:4825–4832.
22. Gridelli C, Gallo C, Ceribelli A, et al. Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol. 2007;8:500–512.
23. Koch A, Bergman B, Holmberg E, et al. Effect of celecoxib on survival in patients with advanced non-small cell lung cancer: a double blind randomised clinical phase III trial (CYCLUS study) by the Swedish Lung Cancer Study Group. Eur J Cancer. 2011;47:1546–1555.
24. Groen HJ, Sietsma H, Vincent A, et al. Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol. 2011;29:4320–4326.
25. Edelman MJ, Tan MT, Fidler MJ, et al. Randomized, double-blind, placebo-controlled, multicenter phase II study of the efficacy and safety of apricoxib in combination with either docetaxel or pemetrexed in patients with biomarker-selected non-small-cell lung cancer. J Clin Oncol. 2015;33:189–194.
26. Edelman MJ, Wang X, Hodgson L, et al. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017;35:2184–2192.
27. Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000;60:1306–1311.
28. Laskin JJ, Sandler AB. The importance of the eicosanoid pathway in lung cancer. Lung Cancer. 2003;41(Suppl 1):S73–S79.
29. Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res. 1998;58:3761–3764.
30. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003;13:176–181.
31. Liu XW, He QT, Li ZQ, et al. [Expression of cyclooxygenase-2 in bone marrow cells of leukemia patients and its association with angiogenesis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009;17:40–42. Chinese.
32. Lorenz M, Slaughter HS, Wescott DM, et al. Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice. Exp Hematol. 1999;27:1494–1502.
33. Sanaat Z, Khalili R, Almasi S, et al. Does chemotherapy change expression of VEGF A&C and MVD in acute myeloid leukemia? Int J Hematol Oncol Stem Cell Res. 2014;8:24–29.
Source: OncoTargets and Therapy.
Originally published February 5, 2018.