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      Stereotactic ablative radiotherapy for the comprehensive treatment of 4–10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial

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          Abstract

          Background

          Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1–3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4–10 metastatic cancer lesions.

          Methods

          One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival.

          Discussion

          This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4–10 oligometastatic lesions.

          Trial registration

          Clinicaltrials.gov identifier: NCT03721341. Date of registration: October 26, 2018.

          Electronic supplementary material

          The online version of this article (10.1186/s12885-019-5977-6) contains supplementary material, which is available to authorized users.

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          Most cited references23

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          Oligometastases.

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            Control of Metastasis by NK Cells.

            The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.
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              Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

              Summary Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
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                Author and article information

                Contributors
                +1 519 685-8500 , david.palma@lhsc.on.ca
                rolson2@bccancer.bc.ca
                Stephen.Harrow@ggc.scot.nhs.uk
                rohann.correa@lhsc.on.ca
                f.schneiders@vumc.nl
                CJA.Haasbeek@vumc.nl
                george.rodrigues@lhsc.on.ca
                michael.lock@lhsc.on.ca
                brian.yaremko@lhsc.on.ca
                glenn.bauman@lhsc.on.ca
                belal.ahmad@lhsc.on.ca
                dschellenberg@bccancer.bc.ca
                mliu@bccancer.bc.ca
                Stewart.Gaede@lhsc.on.ca
                joanna.laba@lhsc.on.ca
                Liam.Mulroy@nshealth.ca
                S.Senthi@alfred.org.au
                alexander.louie@sunnybrook.ca
                anandswaminath@gmail.com
                Anthony.Chalmers@glasgow.ac.uk
                andrew.warner@lhsc.on.ca
                bj.slotman@vumc.nl
                TD.deGruijl@vumc.nl
                Alison.allan@lhsc.on.ca
                s.senan@vumc.nl
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                19 August 2019
                19 August 2019
                2019
                : 19
                : 816
                Affiliations
                [1 ]ISNI 0000 0000 9132 1600, GRID grid.412745.1, Department of Oncology Western University, , London Health Sciences Centre, ; 790 Commissioners Rd. E, London, Ontario N6A4L6 Canada
                [2 ]Department of Radiation Oncology, British Columbia Cancer, Centre for the North, Prince George, BC Canada
                [3 ]ISNI 0000 0004 0606 0717, GRID grid.422301.6, Beatson West of Scotland Cancer Centre, ; Glasgow, UK
                [4 ]Department of Radiation Oncology, Amsterdam UMC Vrije Universiteit Amsterdam Radiation Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands
                [5 ]GRID grid.477724.5, Nova Scotia Cancer Centre, ; Halifax, NS Canada
                [6 ]ISNI 0000 0004 0432 5259, GRID grid.267362.4, Alfred Health Radiation Oncology, ; Melbourne, Australia
                [7 ]Department of Radiation Oncology, Sunnybrook Cancer Centre, Toronto, Canada
                [8 ]ISNI 0000 0004 0408 1469, GRID grid.477522.1, Juravinski Cancer Centre, ; Hamilton, ON Canada
                [9 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Institute of Cancer Sciences, , University of Glasgow, ; Glasgow, UK
                Author information
                http://orcid.org/0000-0002-9542-0627
                Article
                5977
                10.1186/s12885-019-5977-6
                6699121
                31426760
                111e0176-e04c-496d-a3b7-93e6976b58dd
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 February 2019
                : 24 July 2019
                Funding
                Funded by: London Health Sciences Foundation
                Award ID: N/A; philanthropic donations
                Funded by: FundRef http://dx.doi.org/10.13039/100012118, Ontario Institute for Cancer Research;
                Award ID: Clinician Scientist Grant
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                oligometastases,stereotactic radiotherapy,quality of life,cancer,survival
                Oncology & Radiotherapy
                oligometastases, stereotactic radiotherapy, quality of life, cancer, survival

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