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      Stereotactic radiosurgery combined with anlotinib for limited brain metastases with perilesional edema in non‐small cell lung cancer: Rvision‐001 study protocol

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          Abstract

          Introduction

          About 50% of patients with non‐small cell lung cancers (NSCLC) are diagnosed with brain metastases during treatment, and stereotactic radiosurgery (SRS) is an important treatment for brain oligometastasis. Some patients with brain metastases have cerebral edema before treatment, and radiation therapy may also cause, or aggravate brain edema. Vascular endothelial growth factor (VEGF) promotes angiogenesis and increase vascular permeability, and previous studies have shown that anti‐VEGF treatment can reduce brain edema. We hypothesized that anlotinib hydrochloride can reduce perilesional edema around brain metastases, create conditions for subsequent SRS, increase local control rate and improve patient prognosis.

          Methods

          From one week before stereotactic radiosurgery, patients begin to receive anlotinib once a day (12 mg) from day 1–14 of a 21 day cycle, with two cycles in total. Brain magnetic resonance imaging (MRI) scan is taken before treatment, one week and one month after medication. A total of 50 patients will be included in this study. The primary endpoint is the Edema Index, and the secondary endpoints are intracranial objective response rate (iORR), intracranial progression‐free survival (iPFS), objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), safety, and the rate of SRS after anlotinib treatment.

          Discussion

          This study is a multicenter, prospective, single‐arm, phase II clinical study, and explores the efficacy and tolerability of SRS with anlotinib in NSCLC patients with limited brain metastases. The aim of the study is to provide new treatment options for NSCLC patients with brain metastases.

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          Most cited references10

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          Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non–Small Cell Lung Cancer

          Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug's efficacy in advanced non-small cell lung cancer (NSCLC).
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            Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRβ and FGFR1

            Tumor cells recruit vascular endothelial cells and circulating endothelial progenitor cells to form new vessels to support their own growth and metastasis. VEGF, PDGF-BB and FGF-2 are three major pro-angiogenic factors and applied to promote angiogenesis. In this research, we demonstrated that anlotinib, a potent multi-tyrosine kinases inhibitor (TKI), showed a significant inhibitory effect on VEGF/PDGF-BB/FGF-2-induced angiogenesis in vitro and in vivo. Wound healing assay, chamber directional migration assay and tube formation assay indicated that anlotinib inhibited VEGF/PDGF-BB/FGF-2-induced cell migration and formation of capillary-like tubes in endothelial cells. Furthermore, anlotinib suppressed blood vessels sprout and microvessel density in rat aortic ring assay and chicken chorioallantoic membrane (CAM) assay. Importantly, according to our study, the anti-angiogenic effect of anlotinib is superior to sunitinib, sorafenib and nintedanib, which are three main anti-angiogenesis drugs in clinic. Mechanistically, anlotinib inhibits the activation of VEGFR2, PDGFRβ and FGFR1 as well their common downstream ERK signaling. Therefore, anlotinib is a potential agent to inhibit angiogenesis and be applied to tumor therapy.
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              Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells

              Background The efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment of advanced non-small cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by anlotinib were not fully elucidated, and the underlying mechanisms related to resistance remain largely elusive. Methods Cell viability, colony formation, apoptosis and tumor growth assays were performed to examine the effect of anlotinib on lung cancer cells in vitro and in vivo. The punctate patterns of LC3-I/II were detected by confocal microscopy. HUVECs motility was detected using Transwell and scratch wound-healing assay. To visualize the microvessels, tubular formation assay was performed. The expression of LC3-I/II and beclin-1 and the changes of JAK2/STAT3/VEGFA pathway were detected by western blotting. The VEGFA levels in tumor supernatant were measured by ELISA. Results Anlotinib treatment decreased cell viability and induced apoptosis in Calu-1 and A549 cells. Moreover, anlotinib induced human lung cancer cell autophagy in a dose- and time-dependent manner. Blocking autophagy enhanced the cytotoxicity and anti-angiogenic ability of anlotinib as evidenced by HUVECs migration, invasion, and tubular formation assay. Co-administration of anlotinib and chloroquine (CQ) further reduced VEGFA level in the tumor supernatant, compared with that of anlotinib or CQ treatment alone. When autophagy was induced by rapamycin, the JAK2/STAT3 pathway was activated and VEGFA was elevated, which was attenuated after deactivating STAT3 by S3I-201. Further in vivo studies showed that anlotinib inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3/VEGFA pathway, and CQ enhanced this effect. Conclusion Anlotinib induced apoptosis and protective autophagy in human lung cancer cell lines. Autophagy inhibition further enhanced the cytotoxic effects of anlotinib, and potentiated the anti-angiogenic property of anlotinib through JAK2/STAT3/VEGFA signaling.
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                Author and article information

                Contributors
                lily31415926@126.com
                yiduzhengmu@163.com
                hongqingzhuang@163.com
                wangem@fudan.edu.cn
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                12 March 2020
                May 2020
                : 11
                : 5 ( doiID: 10.1111/tca.v11.5 )
                : 1361-1364
                Affiliations
                [ 1 ] Department of Radiation Oncology Peking University Third Hospital Beijing China
                [ 2 ] Department of Neurosurgery, Huashan Hospital Fudan University Shanghai China
                [ 3 ] Department of Radiotherapy Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy Tianjin China
                Author notes
                [*] [* ] Correspondence

                Hongqing Zhuang, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 China.

                Tel: +86 10 8226 6699

                Fax: +86 10 8226 6699

                Email: hongqingzhuang@ 123456163.com

                Enmin Wang, Huashan Hospital, No. 12, Wu Lu Mu Qi Middle Rd., Jing An District, Shanghai 200040, China.

                Tel: +86 21 5288 9999

                Fax: +86 21 5288 9999

                Email: wangem@ 123456fudan.edu.cn

                Yongchun Song, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huan‐Hu‐Xi road, Ti‐Yuan‐Bei, He Xi District, Tianjin 300060, China.

                Tel: +86 22 2334 0123

                Fax: +86 22 2334 0123

                Email: sych1977@qq.com

                [†]

                These authors contributed equally as co‐first authors.

                [‡]

                These authors are co‐corresponding authors.

                Author information
                https://orcid.org/0000-0002-8435-0061
                Article
                TCA13386
                10.1111/1759-7714.13386
                7180568
                32163662
                aaefc4e6-6290-4345-984b-8e4cfbe4b8a2
                © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 February 2020
                : 20 February 2020
                : 20 February 2020
                Page count
                Figures: 1, Tables: 0, Pages: 4, Words: 2634
                Categories
                Study Protocol
                Study Protocol
                Custom metadata
                2.0
                May 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:24.04.2020

                anlotinib,brain metastases,non‐small cell lung cancer,perilesional edema,stereotactic radiosurgery

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