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

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          Abstract

          Background

          The clinical benefit of a selective cyclooxygenase-2 inhibitor, celecoxib, combined with anticancer therapy in advanced non-small-cell lung cancer (NSCLC) remains unclear. A meta-analysis was performed to address the efficacy and safety of celecoxib in patients with advanced NSCLC.

          Materials and methods

          Three databases, including PubMed, EMBASE, and the Cochrane Library, were systematically searched for available literature until March 1, 2018. Data on tumor response rates, one-year survival, overall survival, progression-free survival, and toxicities were extracted from the included randomized clinical trials. Subgroup analysis was carried out according to the line of treatment. Review Manager 5.3 software was applied to conduct the meta-analysis.

          Results

          A total of 7 randomized controlled trials involving 1,559 patients with advanced NSCLC were enrolled for analysis. The pooled overall response rate (ORR) of celecoxib added to systemic therapy was not significantly improved (risk ratio [RR] =1.14, 95% CI =0.96–1.35, P=0.13). Additionally, no differences were observed between the celecoxib and placebo groups regarding 1-year survival (RR =0.99, 95% CI =0.88–1.12, P=0.91). Subgroup analysis showed that adding celecoxib to the first-line treatment significantly improved the ORR (RR =1.21, 95% CI =1.01–1.44, P=0.04) and partial response rate (RR =1.26, 95% CI =1.01–1.58, P=0.04). The aggregated Kaplan–Meier analysis found no significant difference between celecoxib and placebo regarding the 5-year overall survival (median, 12.9 vs 12.5 months, P=0.553) and 5-year progression-free survival (median, 7.4 vs 7.2 months, P=0.641). The increased RR of leukopenia (RR =1.25, 95% CI =1.03–1.50) and thrombocytopenia (RR =1.39, 95% CI =1.11–1.75) indicated that celecoxib increased hematologic toxicities (grade ≥III). However, celecoxib did not increase the related risks of thrombosis or embolism (RR =1.26, 95% CI =0.66–2.39) and cardiac ischemia (RR =1.16, 95% CI =0.39–3.44).

          Conclusion

          Celecoxib had no benefit on survival indices for advanced NSCLC but improved the ORR of first-line treatment. Additionally, celecoxib increased the rate of hematologic toxicities without increasing the risk of cardiovascular events.

          Most cited references37

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          American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer.

          The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy.
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            Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.

            We provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, we observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2-derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.
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              PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer.

              PointBreak (A Study of Pemetrexed, Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer) compared the efficacy and safety of pemetrexed (Pem) plus carboplatin (C) plus bevacizumab (Bev) followed by pemetrexed plus bevacizumab (PemCBev) with paclitaxel (Pac) plus carboplatin (C) plus bevacizumab (Bev) followed by bevacizumab (PacCBev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly assigned to receive pemetrexed 500 mg/m(2) or paclitaxel 200 mg/m(2) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles. Eligible patients received maintenance until disease progression: pemetrexed plus bevacizumab (for the PemCBev group) or bevacizumab (for the PacCBev group). The primary end point of this superiority study was overall survival (OS). Patients were randomly assigned to PemCBev (n = 472) or PacCBev (n = 467). For PemCBev versus PacCBev, OS hazard ratio (HR) was 1.00 (median OS, 12.6 v 13.4 months; P = .949); progression-free survival (PFS) HR was 0.83 (median PFS, 6.0 v 5.6 months; P = .012); overall response rate was 34.1% versus 33.0%; and disease control rate was 65.9% versus 69.8%. Significantly more study drug-related grade 3 or 4 anemia (14.5% v 2.7%), thrombocytopenia (23.3% v 5.6%), and fatigue (10.9% v 5.0%) occurred with PemCBev; significantly more grade 3 or 4 neutropenia (40.6% v 25.8%), febrile neutropenia (4.1% v 1.4%), sensory neuropathy (4.1% v 0%), and alopecia (grade 1 or 2; 36.8% v 6.6%) occurred with PacCBev. OS did not improve with the PemCBev regimen compared with the PacCBev regimen, although PFS was significantly improved with PemCBev. Toxicity profiles differed; both regimens demonstrated tolerability.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                07 August 2018
                : 12
                : 2455-2466
                Affiliations
                Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China, luopeng@ 123456smu.edu.cn ; blacktiger@ 123456139.com
                Author notes
                Correspondence: Peng Luo; Jian Zhang, Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510282, Guangdong, People’s Republic of China, Tel +86 139 2509 1863, Fax +86 20 6164 3888, Email luopeng@ 123456smu.edu.cn ; blacktiger@ 123456139.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-2455
                10.2147/DDDT.S169627
                6086108
                30122902
                2ff0a30e-bdd8-4512-a136-9e5a16078756
                © 2018 Yi et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                celecoxib,non-small-cell lung cancer,nsclc,systematic review,meta-analysis

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