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      Retrospective analysis of bevacizumab‐induced hypertension and clinical outcome in patients with colorectal cancer and lung cancer

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          Abstract

          Bevacizumab(Avastin ®), a humanized therapeutic monoclonal antibody that targets vascular endothelial growth factor, is widely used in cancer treatment. Patients who are treated with bevacizumab have an increased risk of developing systemic hypertension. However, the relationship between bevacizumab‐induced hypertension and clinical outcome remains unclear. We aimed to evaluate the effect of bevacizumab‐induced hypertension in terms of prognosis in patients with colorectal cancer and non‐small cell lung cancer. The study included 632 patients, 317 patients with non‐small cell lung cancer and 315 patients with colorectal cancer. All patients were treated with bevacizumab in combination with standard chemotherapy protocols, between April 2007 and December 2014. Blood pressure was measured before each treatment cycle. In the patient group with colorectal cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 27.6%. In hypertensive patients with colorectal cancer, median overall survival was 42.6 months, compared with 20.6 months for normotensive patients in this group ( = 0.00071). In the patient group with non‐small cell lung cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 20.5%. In hypertensive patients with non‐small cell lung cancer, median overall survival was 43.0 months, compared with 26.3 months for normotensive patients in this group ( = 0.00451). Patients who developed hypertension during treatment with bevacizumab for colorectal cancer and non‐small cell lung cancer had significantly prolonged overall survival when compared with normotensive patients. Bevacizumab‐induced hypertension may represent a biomarker for clinical benefit in cancer patients treated with bevacizumab.

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          Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.

          Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting. Patients were randomly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351). PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation. Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.
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            A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.

            Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P 0.20 for all comparisons). Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer. Copyright 2003 Massachusetts Medical Society
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              Mechanisms of adverse effects of anti-VEGF therapy for cancer

              Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in clinical oncology. These effects are typically downstream consequences of suppression of cellular signalling pathways important in the regulation and maintenance of the microvasculature. Downregulation of these pathways in normal organs can lead to vascular disturbances and even regression of blood vessels, which could be intensified by concurrent pathological conditions. These changes are generally manageable and pose less risk than the tumours being treated, but they highlight the properties shared by tumour vessels and the vasculature of normal organs.
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                Author and article information

                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                25 April 2016
                July 2016
                : 5
                : 7 ( doiID: 10.1002/cam4.2016.5.issue-7 )
                : 1381-1387
                Affiliations
                [ 1 ] First Department of Internal MedicineKansai Medical University OsakaJapan
                [ 2 ] Department of SurgeryKansai Medical University OsakaJapan
                Author notes
                [*] [* ] Correspondence

                Aya Nakaya, First Department of Internal Medicine, Kansai Medical University, 2‐5‐1, Shin‐machi, Hirakata, Osaka 573‐1010, Japan. Tel: +81 72 804 2503; Fax: +81‐72‐804‐2504; E‐mail: nakaya1016@ 123456yahoo.co.jp

                Article
                CAM4701
                10.1002/cam4.701
                4944863
                27109438
                e1bc56d0-c2dd-402a-8dae-26a74c1054cf
                © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 February 2015
                : 14 February 2016
                : 19 February 2016
                Page count
                Pages: 7
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                cam4701
                July 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:14.07.2016

                Oncology & Radiotherapy
                avastin®,bevacizumab,colorectal cancer,hypertension,non‐small cell lung cancer

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