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      Real‐world outcomes of patients with locally advanced or metastatic epithelioid sarcoma

      , MD 1 , , , MD 2 , , MD 3 , , MD 3 , , MD 4 , , MD, PhD 5 , 6 , , MD, PhD 7 , , MD, PhD 8 , , MBBCH, PGCert 2 , , DHS, MSc, MBA 9 , , PhD 9 , , MD 9 , , MPH, ScD 10 , , ScD, MS 10 , , MPH, MBA, DrPH 10 , , MBA 10 , , MPH 10 , , MBBS, MIS, MPH 9 , , MD 2 , 11
      John Wiley and Sons Inc.
      chemotherapy, epithelioid, natural history, personal medical records, review of reported cases, sarcoma, treatment efficacy

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          Limited data are available on the real‐world effectiveness and safety of systemic therapies for advanced (surgically unresectable and/or metastatic) epithelioid sarcoma (ES).


          A retrospective medical records review was conducted in patients with advanced ES who were initiating first‐line or ≥2 lines of systemic therapy (2000‐2017) at 5 US cancer centers. The real‐world overall response rate (rwORR), the duration of response (rwDOR), the disease control rate (rwDCR) (defined as stable disease for ≥32 weeks or any duration of response), and progression‐free survival (rwPFS) were assessed by radiology reports. Overall survival (OS), rwDOR, and rwPFS were estimated from the time therapy was initiated using the Kaplan‐Meier method. Serious adverse events were assessed.


          Of 74 patients (median age at diagnosis, 33 years; range, 10.6‐76.3 years), 72% were male, and 85% had metastatic disease. The median number of lines of therapy was 2 (range, 1‐7 lines of therapy), and 46 patients (62%) received ≥2 lines of systemic therapy. First‐line regimens were usually anthracycline‐based (54%) or gemcitabine‐based (24%). For patients receiving first‐line systemic therapy, the rwORR was 15%, the rwDCR was 20%, the median rwDOR was 3.3 months (95% CI, 2.1‐5.2 months), the median rwPFS was 2.5 months (95% CI, 1.7, 6.9 months), and the median OS was 15.2 months (95% CI, 11.4‐21.7 months). For those who received ≥2 lines of systemic therapy, the rwORR was 9%, the rwDCR was 20%, the median rwDOR was 4.5 months (95% CI, 0.7‐5.6 months), and the median rwPFS was 6.0 months (95% CI, 3.2‐7.4 months). Over one‐half of patients (51.4%) experienced an adverse event, most frequently febrile neutropenia (14%), pain (10%), anemia, dyspnea, fever, thrombocytopenia, or transaminitis (5% each).


          Systemic therapies demonstrate limited efficacy in patients with advanced ES and have associated toxicities.


          This retrospective medical records review of patients with advanced epithelioid sarcoma receiving first‐line or ≥2 lines of systemic therapies indicates that cytotoxic chemotherapies have limited efficacy, and more than one‐half of patients experience adverse events. The results highlight the unmet medical need in patients with this ultrarare and aggressive subtype of soft tissue sarcoma.

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          Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.

          Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone.
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            Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.

            Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial

              Summary Background For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. Methods The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m2 on days 1 and 8 and intravenous docetaxel 75 mg/m2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009–014907–29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. Findings Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7–29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5–54·6] vs 46·4% [37·5–54·8]); median progression-free survival (23·3 weeks [95% CI 19·6–30·4] vs 23·7 weeks [18·1–20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99–1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. Interpretation Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. Funding Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.

                Author and article information

                John Wiley and Sons Inc. (Hoboken )
                09 December 2020
                15 April 2021
                : 127
                : 8 ( doiID: 10.1002/cncr.v127.8 )
                : 1311-1317
                [ 1 ] Sarcoma Medical Oncology Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College New York New York
                [ 2 ] Sarcoma and Bone Cancer Treatment Center Dana‐Farber Cancer Institute and Harvard Medical School Boston Massachusetts
                [ 3 ] Department of Sarcoma Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston Texas
                [ 4 ] Division of Hematology/Oncology University of Michigan Comprehensive Cancer Center Ann Arbor Michigan
                [ 5 ] Division of Medical Oncology University of Colorado Cancer Center University of Colorado Aurora Colorado
                [ 6 ] Janssen Pharmaceuticals, Inc. Spring House Pennsylvania
                [ 7 ] Sarcoma Foundation of America Damascus Maryland
                [ 8 ] Division of Medical Oncology Washington University School of Medicine St Louis Missouri
                [ 9 ] Epizyme, Inc Cambridge Massachusetts
                [ 10 ] Analysis Group, Inc Boston Massachusetts
                [ 11 ] Ludwig Center at Harvard Harvard Medical School Boston Massachusetts
                Author notes
                [*] [* ] Corresponding Author: Mrinal M. Gounder, MD, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, 300 East 66th Street, BAIC 1455, New York, NY, 10065 ( gounderm@ 123456mskcc.org ).

                Author information
                © 2020 Epizyme, Inc. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                : 29 October 2020
                : 09 July 2020
                : 10 November 2020
                Page count
                Figures: 1, Tables: 1, Pages: 7, Words: 5554
                Funded by: Epizyme, Inc.
                Original Article
                Original Articles
                Outcomes Research
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                April 15, 2021
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                Oncology & Radiotherapy
                chemotherapy,epithelioid,natural history,personal medical records,review of reported cases,sarcoma,treatment efficacy


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