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      Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin

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          Abstract

          Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs—pazopanib, trabectedin, and eribulin—have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs.

          Funding : Eisai Co., Ltd.

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          Most cited references26

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          Descriptive epidemiology of sarcomas in Europe: Report from the RARECARE project

          Sarcomas are a heterogeneous group of malignant neoplasms arising from mesenchymal cells which encompass dozens of histological types and can occur in virtually any anatomic site. They form one of the principal groups of rare cancers in Europe as defined in the RARECARE project. We analysed 45,568 incident cases diagnosed during 1995-2002 and registered by 76 population-based cancer registries. Total crude incidence was 5.6 per 100,000 per year with an estimated 27,908 new cases per year in the EU27 countries, of which 84% were soft tissue sarcomas and 14% were bone sarcomas. Gastrointestinal stromal tumours (GIST) were only widely recognised as an entity in the late 1990s and consequently were under-registered. Their true incidence is believed to be about 1.5 per 100,000. Age-standardised incidence of soft tissue sarcomas ranged from 3.3 per 100,000 in Eastern Europe to 4.7 per 100,000 in Northern Europe. About 280,000 persons were estimated to be alive at the beginning of 2003 with a past diagnosis of sarcoma, of which 83% were soft tissue sarcomas and 16% were bone sarcomas. Five-year relative survival for 2000-2002 by the period was 58% for soft tissue sarcomas and 62% for bone sarcomas. The diversity and rarity of sarcomas combined with the quite large number of people affected by them mean that they provide a classic example of the importance of networking in diagnosis, therapy and research for rare cancers. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Incidence of Sarcoma Histotypes and Molecular Subtypes in a Prospective Epidemiological Study with Central Pathology Review and Molecular Testing

            Background The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants, based on a central pathological review of the cases. Methodology/Principal Findings From March 2005 to February 2007, pathology reports and tumor blocks were prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year. Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000), liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000). Conclusions/Significance The observed incidence of sarcomas was higher than expected. This study is the first detailed investigation of the crude incidence of histological and molecular subtypes of sarcomas.
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              Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity.

              With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.
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                Author and article information

                Contributors
                akawai@ncc.go.jp
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                25 May 2017
                25 May 2017
                2017
                : 34
                : 7
                : 1556-1571
                Affiliations
                [1 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Department of Musculoskeletal Oncology and Rehabilitation Medicine, , National Cancer Center Hospital, ; Tokyo, Japan
                [2 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Department of Breast and Medical Oncology, , National Cancer Center Hospital, ; Tokyo, Japan
                [3 ]ISNI 0000 0001 0037 4131, GRID grid.410807.a, Department of Medical Oncology, , The Cancer Institute Hospital of Japanese Foundation for Cancer Research, ; Tokyo, Japan
                [4 ]Department of Orthopaedic Surgery, Osaka Prefectural Hospital Organization, Osaka International Cancer Institute, Osaka, Japan
                [5 ]ISNI 0000 0004 0377 7966, GRID grid.416803.8, Department of Orthopaedic Surgery, , National Hospital Organization, Osaka National Hospital, ; Osaka, Japan
                Article
                561
                10.1007/s12325-017-0561-4
                5504216
                28547734
                8ae1337d-2b41-4c58-b3bd-48d406103abf
                © The Author(s) 2017
                History
                : 31 March 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003769, Eisai;
                Categories
                Review
                Custom metadata
                © Springer Healthcare Ltd. 2017

                eribulin,evidence-based medicine,japan,leiomyosarcoma,liposarcoma,optimal use,pazopanib,proper use,soft tissue sarcoma,trabectedin

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