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      A network meta-analysis of short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma

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          Abstract

          The network meta-analysis was conducted to compare the short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma (RCC). We initially searched databases for randomized controlled trials (RCTs) on different single-drug targeted therapies in treating RCC. The meta-analysis combined the direct and indirect evidence to calculate the pooled odds ratios (OR) and draw surface under the cumulative ranking curves (SUCRA). A total of 14 eligible RCTs were ultimately selected. The partial response (PR) of Cabozantinib in the treatment of RCC was better than Sunitinib (OR = 2.7, 95%CI = 1.0–7.8), Everolimus (OR = 8.1, 95%CI = 3.1–25.0), and Temsirolimus (OR = 4.8, 95%CI = 1.0–31.0); the overall response rate (ORR) of Cabozantinib was better than Sorafenib, Sunitinib, Everolimus, and Temsirolimus (OR = 5.5, 95%CI = 1.1–27.0; OR = 2.6, 95%CI = 1.1–6.6; OR = 8.3, 95%CI = 3.5–20.0; OR = 5.7, 95%CI = 1.3–28.0 respectively). In addition, as for complete response (CR), PR, stable disease (SD), progressive disease (PD), ORR, and disease control rate (DCR), Cabozantinib had the best short-term efficacy among nine single-drug targeted therapies in the treatment of RCC (CR: 50.3%; PR: 93.6%; SD: 75.1%; PD: 68.0%; ORR: 95.5%; DCR: 73.2%); while Everolimus had the worst short-term efficacy (CR: 33.6%; PR: 22.3%; SD: 78.0%; PD: 35.9%; ORR: 22.9%; DCR: 19.9%). Our network meta-analysis indicated that Cabozantinib might have better short-term efficacy than other regimens in the treatment of RCC, while Everolimus might have poor short-term efficacy.

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          Hypoxia signalling through mTOR and the unfolded protein response in cancer.

          Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.
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            Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206.

            Bevacizumab is an antibody that binds to vascular endothelial growth factor (VEGF) and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN) is a historic standard first-line treatment for RCC. A prospective, randomized phase III trial of bevacizumab plus IFN versus IFN monotherapy was conducted. Patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or the same dose and schedule of IFN monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Between October 2003 and July 2005, 732 patients were enrolled. The prespecified stopping rule for OS has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P < .0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P < .0001). Bevacizumab plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% [95% CI, 9.5% to 17.3%]; P < .0001). Overall toxicity was greater for bevacizumab plus IFN, including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%). Bevacizumab plus IFN produces a superior PFS and ORR in untreated patients with metastatic RCC as compared with IFN monotherapy. Toxicity is greater in the combination therapy arm.
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              Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival.

              A phase III trial of bevacizumab combined with interferon alfa-2a (IFN) showed significant improvements in progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC). Here, we report overall survival (OS) data. Six hundred forty-nine patients with previously untreated mRCC were randomly assigned to receive bevacizumab (10 mg/kg every 2 weeks) plus IFN (9 MIU subcutaneously three times a week; n = 327) or IFN plus placebo (n = 322) in a multicenter, randomized, double-blind, phase III trial. The primary end point was OS. Final analysis of the secondary end point (PFS) was reported earlier. Median OS was 23.3 months with bevacizumab plus IFN and 21.3 months with IFN plus placebo (unstratified hazard ratio [HR] = 0.91; 95% CI, 0.76 to 1.10; P = .3360; stratified HR = 0.86; 95% CI, 0.72 to 1.04; P = .1291). Patients (> 55%) in both arms received at least one postprotocol antineoplastic therapy, possibly confounding the OS analysis. Patients receiving postprotocol therapy including a tyrosine kinase inhibitor had longer median OS (bevacizumab plus IFN arm: 38.6 months; IFN plus placebo arm: 33.6 months; HR = 0.80; 95% CI, 0.56 to 1.13). Tolerability was similar to that reported previously. Bevacizumab plus IFN is active as first-line treatment in patients with mRCC. Most patients with mRCC receive multiple lines of therapy, so considering the overall sequence of therapy when selecting first-line therapy may optimize patient benefit.
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                Author and article information

                Journal
                Biosci Rep
                Biosci. Rep
                ppbioscirep
                BSR
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                26 October 2017
                07 December 2017
                22 December 2017
                : 37
                : 6
                : BSR20170827
                Affiliations
                [1 ]Academic Journals Publishing Center of Education Department, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P.R. China
                [2 ]School of Medicine, Xi’an Peihua University, Xi’an 710125, P.R. China
                Author notes
                Correspondence: Wan-Xia Yao ( yaowanxia@ 123456mail.xjtu.edu.cn )
                Article
                10.1042/BSR20170827
                5719001
                29074560
                0a385009-0821-4468-b10e-5d0d10577b9d
                © 2017 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 18 May 2017
                : 23 October 2017
                : 25 October 2017
                Page count
                Pages: 14
                Categories
                Research Articles
                Research Article
                25
                21
                39

                Life sciences
                network meta-analysis,renal cell carcinoma,randomized controlled trial,single-drug targeted therapy,short-term efficacy

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