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Competing Interests: Disclosure PGC has received honoraria for participation in advisory board for Bayer, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint, Deciphera, Eli Lilly, Epizyme, Daiichi, GlaxoSmithKline (GSK), Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks, AROG Pharmaceuticals and Eisai and carried out nonremunerated activities for the Italian Sarcoma Group, European School of Oncology, Federation of Italian Cooperative Groups and Rare Cancers Europe; JYB received research support from Merck Sharp & Dohme (MSD), Roche, GSK, Novartis, Bayer, PharmaMar outside the present work; NA reports nonremunerated leadership and advisory roles for Sociedade Portuguesa de Cirurgia; JB reports no personal financial disclosure, received research grants (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis, Paxman Coolers Ltd., Sun Pharma and reports nonremunerated advisory role for Novartis, nonremunerated leadership activities for Immuno-Oncology Society of India, Indian Society of Medical and Paediatric Oncology, Teenage and Young Adult Cancer Foundation and Indian Cooperative Oncology Network; SB has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Lilly, Novartis, Daiichi-Sankyo, Plexxikon, Roche, GSK and reports invited speaker fees from Pfizer and PharmaMar, institutional research grant from Novartis, performed institutional research as principal investigator (PI) for Daiichi-Sankyo, Roche, Deciphera, Lilly, Novartis, Blueprint Medicines, Bristol Myers Squibb (BMS), Incyte and carried out nonrenumerated activities for Federal Institute for Drugs and Medical Devices (BfArm) and is the founding member of German Sarcoma Foundation; RB reports nonrenumerated activities as PI for IRCSS Galeazzi Orthopaedic Institute and IRE-ISG Regina Elena Institute and participation at the Clinical Experience Exchange Meeting, III IDBN National Congress 2019, Italian Association of Medical Oncology (AIOM), IRE-ISG Regina Elena Institute and Lazio Association of Orthopaedic Hospital Traumatologists (A.L.O.T.O.); SBi has received honoraria for participation in advisory boards from Bayer Healthcare, Boehringer Ingelheim, Clinigen, Hoffmann-La Roche, Ipsen, Eli Lilly and Sensorion and reports nonremunerated activities for Bayer and membership of the German Paediatric Oncology Society and European Musculoskeletal Oncology Society; SBon has received honoraria for advisory board from Nanobiotix and as an invited speaker for PharmaMar, trial research grant from the Institut National du Cancer (INCa); IB has received honoraria for participation in advisory boards for Roche, Lilly, Sanofi, Pierre Fabre, Ipsen and as an invited speaker for Amgen, BMS, Novartis, Leo Pharma, AstraZeneca and Genesis and is a member of Board of Directors for Hellenic Society of Medical Oncology, Hellenic Society of Sarcomas and Rare Tumors, Hellenic Oncology Research Group (HORG) and reports PI trial research support from Novartis, BMS, Regeneron, MSD, Lilly and Roche; JVMGB receives royalties from UpToDate and Wolters Kluwer, and direct research funding from TRACON pharmaceuticals; KB has received honoraria for expert testimony and advisory boards for Bayer, invited speaker fees and research grant from Eli Lilly, PI for Deciphera and Novartis; TB has received honoraria for participation in advisory boards for Bayer and Eli Lilly, invited speaker fees from PharmaMar and Novartis; EDÁ has received honoraria for participation in advisory board for Bayer, invited speaker for Lilly, PharmaMar and Roche and institutional research support from Pfizer, Roche and AstraZeneca; APDT has received honoraria for participation in advisory boards for Bayer and Roche, invited speaker for PharmaMar and Novartis; XGDM has received honoraria for participation in advisory boards for Ipsen, EUSAPharma, BMS, Pfizer, Roche and PharmaMar and is an invited speaker for Lilly, Astellas Pharma, Eisai and Pfizer and received institutional research grant from Astra Zeneca; ME has received honoraria for participation in advisory boards for Clinigen and Bayer, consulting fees from Blueprint Medicines, institutional research funding from Novartis; AF has received honoraria for participation in advisory board for Novartis and invited speaker fees for MSD and Amgen; VF has received honoraria for participation in advisory boards and speaker fees for BMS, Novartis and MSD and speaker fees from Pierre Fabre; SG has reported institutional research for Blueprint Medicines and is a member of American Society of Clinical Oncology (ASCO) and AIOM; HG has reported PI research for Daiichi, Deciphera and Novartis and co-ordinating PI for Boehringer Ingelheim and AmMax Bio; FG has received honoraria for participation in advisory board for Amgen and expert testimony for Deciphera, stock ownership for Atlanthera, licencing fees from Zimmer, nonrenumerated activities for 3D-Side and INCa DGOS funding and is a member of the board of NetSarc, the French clinical reference network for soft tissue and visceral sarcomas; GG has received honoraria for participation in advisory boards for Lilly, Eisai, Merck, Bayer and GSK, invited speaker fees from PharmaMar and Novartis and institutional grants from PharmaMar, Bayer and Novartis; RH has received honoraria from GSK; ABH is a member of Board of Directors for EIT Health UK and Ireland and received or currently receives direct research funding as a PI from Roche, performs work in clinical trials or contracted research for the institution and as the Clinical Director of the Oncology and Haematology Directorate, Oxford Cancer Centre; NH has received honoraria as expert testimony and invited speaker from PharmaMar and performs work in clinical trials or contracted research for which the author’s institution received financial support from PharmaMar, Lilly, Adaptimmune Therapeutics, AROG Pharmaceuticals, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint Medicines, Nektar Therapeutics, Forma, Amgen and Daiichi-Sankyo and reports nonremunerated leadership roles for Grupo Español de Investigación en Sarcomas (GEIS) and SELNET and has nonremunerated membership or affiliation with ESMO, Sociedad Española de Oncología Médica (SEOM), ASCO, Connective Tissue Oncology Society (CTOS) and European Organisation for Research and Treatment of Cancer (EORTC); PH has received honoraria for participation in advisory boards for Pfizer, Roche and GSK, invited speaker fees from PharmaMar and Lilly, clinical expert fees from Boehringer Ingelheim and institutional research funding for clinical trials from Siemens, Novartis, Blueprint Medicines and meeting sponsorship from PEKKIP Oncology and reports carrying out nonremunerated activities for the German Sarcoma Foundation (DSS), German Interdisciplinary Sarcoma Group (GISG) and Interdisciplinary Working Party on Sarcomas (IAWS) of the German Cancer Society (DKG) and advisory role for the German Cancer Aid (DKH) Committee on Health Technology Assessment and Sarcoma Patients EuroNet (SPAEN); HJ has received honoraria for participation in advisory boards for Orion Pharma, Neutron Therapeutics and Maud Kuistila Memorial Foundation and had full time or part time employment at Orion Pharma (until 31 August 2020), stocks in Orion Pharma and Sartar Therapeutics; RLJ has received honoraria for expert testimony consultancy for Adaptimmune, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immune Design, Lilly, SpringWorks, Tracon, UpToDate, PharmaMar and is on the advisory board for Athenex and received institutional research grant from MSD; CJ has received travel grants from Ipsen and PharmaMar; BK has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, Boehringer Ingelheim, SpringWorks, GSK and PharmaMar, institutional research support from PharmaMar and SpringWorks and is a member of EORTC and Chair of the EORTC soft tissue and bone sarcoma group (STBSG); AK has received honoraria for participation in advisory boards for Daiichi-Sankyo and Otsuka and invited speaker fees from Novartis, Taiho and Eisai; KK has received honoraria for participation in the advisory board for Bayer and expert testimony for Eli Lilly and Roche; ALC has received honoraria for participation in advisory boards for Deciphera and Lilly and invited speaker fees from PharmaMar and Bayer; EL received honoraria from SpringWorks Therapeutics for scientific advisory board participation and is a member of the European Reference Network GENTURIS; AL has received institutional research grants from Johnson & Johnson, Alphamed, Medacta and ImplanTec and reports nonremunerated activities for European Musculoskeletal Society (EMSOS), Austrian Society of Orthopaedic Surgeons (OGO) and membership of CTOS; AL-P has received honoraria as invited speaker for PharmaMar, institutional research funding from the Spanish Health Ministry, reported nonrenumerated activities as PI for PharmaMar, Cebiotex, Deciphera, Lilly, GSK, Daiichi, Epizyme, Advenchen Laboratories, Novartis, Karyopharm, Blueprint medicines, GEIS and other activity for EORTC; JM-B has received honoraria for expert testimony for Lilly, PharmaMar, Eisai, Bayer, invited speaker fee from PharmaMar and carried out institutional research for PharmaMar, Eisai, Novartis, Immix Biopharma, Lixte, Karyopharm, Bayer, Celgene, Pfizer, BMS, Blueprint Medicines, Deciphera, Nektar Therapeutics, Forma, Amgen, Daiichi-Sankyo, Lilly, AROG Pharmaceuticals, Adaptimmune and GSK; OM has received honoraria for participation in advisory boards for MSD, Megapharm, AstraZeneca, Takeda and ProGenetics and invited speaker fees from MSD and Roche; CM has performed nonremunerated activities for International Cancer Imaging Society and EORTC STBSG; OMi has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, MSD, Pfizer, invited speaker fees from BMS, Eli-Lilly, Ipsen, Roche and Servier and institutional research for Blueprint Medicines, Bayer, Epizyme and Eli-Lilly; EP has received honoraria for participation in advisory boards for SynOx, Daiichi-Sankyo and Deciphera Pharmaceuticals and invited speaker fees from Peer View Educational; MAP has received honoraria for participation in advisory boards for Roche, invited speaker fees from Eli-Lilly, Pfizer and Novartis and expert testimony from Blueprints Medicine and institutional research grant from Novartis; SP-N has received honoraria for participation in advisory board for Immunocore; PR has received honoraria for participation in advisory boards for Bayer, Clinigen, Roche, MSD, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, invited speaker fees from Lilly, PharmaMar and institutional research for PharmaMar, Karyopharm, SpringWorks, AROG Pharmaceuticals, Blueprint, Deciphera, Amgen, Astellas, Epizyme, Lilly, MSD, Pfizer, Novartis and Philogen and has membership of the German Sarcoma Foundation; PRu has received honoraria for participation in advisory boards for MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, invited speaker fees from MSD, BMS, Pierre Fabre, Merck, Sanofi, Novartis and institutional research funding from Pfizer, BMS and reports carrying out nonremunerated activities for the Polish Society of Surgical Oncology and ASCO; MS has received honoraria for travel grant from PharmaMar and writing engagement for Lilly; SS has reported a research grant from Johnson & Johnson and research funding from Roche Austria; PS has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Boehringer Ingelheim, Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios, Modus Outcomes, Studiecentrum voor Kernenergie, Curio Science and institutional honoraria for advisory boards for Blueprint Medicines, Ellipses Pharma, IntelliSphere, expert testimony for Advanced Medical/Teladoc Health and institutional research funding from CoBioRes NV, Eisai, G1 Therapeutics, Novartis and PharmaMar; SSl is the Chair of Centre for Personalised Cancer Treatment and Route Personalised Medicine, Dutch Science Agenda, a member of supervisory board for SkylineDx and Scientific advisory committee Pan-Cancer T BV; SJS has received honoraria for participation in advisory board for GSK; KSH reports nonrenumerated activity for CTOS as President 2020 and membership of the Scandinavian Sarcoma Group; MAJvdS has performed work in clinical trials or contracted research for which the institution received financial support from Daiichi Sankyo, implantcast and CarboFix; WTAvdG has received institutional honoraria for participation in advisory boards of Bayer and GSK, institutional research grants from Novartis and Lilly and performed consultancy work for SpringWorks; WJvH has received institutional honoraria for participation in advisory board for Belpharma, invited speaker fees from Amgen and reports expert testimony for Sanofi and MSD and personal travel grant from Novartis and institutional research grant from BMS; TF reports institutional research funding from the Foundation ARC and Ligue Régionale contre le Cancer and leadership role for ERN GENTURIS; AG has received honoraria for participation in advisory boards for Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks and Nanobiotix and is an invited speaker for Lilly, PharmaMar and reports research grant from PharmaMar; SSta has received honoraria for participation in advisory boards for Bayer, Deciphera, Eli Lilly, Daiichi, MaxiVAX, Novartis, invited speaker fees from GSK and PharmaMar, expert testimony fee from Bavarian Nordic and Epizyme and institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint Medicines, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks and Hutchinson MediPharma International Inc. and carried out nonremunerated activities for CTOS, Chordoma Foundation, Epithelioid Haemangioendothelioma Foundation, Desmoid Foundation, EORTC STBSG and Italian Sarcoma Group Onlus. AB, AD, AFer, AMF, PJ, DAK, FLG, ABM, MM, CMo, RP, AAS, CS, DS, AT and MU have declared no conflicts of interests.

Competing Interests: Disclosure SJS has received honoraria for participation in advisory board for GlaxoSmithKline (GSK); NA non-remunerated leadership and advisory roles for Sociedade Portuguesa de Cirurgia; JB has no personal financial disclosure, received research grants (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis, Paxman Coolers Ltd, Sun Pharma and non-remunerated advisory role for Novartis, non-remunerated leadership activities for Immuno-oncology society of India, Indian Society of Medical and Paediatric Oncology, Teenage and Young Adult Cancer Foundation and Indian cooperative oncology network; SB has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Lilly, Novartis, Daiichi-Sankyo, Plexxikon, Roche, GSK, invited speaker fees from Pfizer and PharmaMar, institutional research grant from Novartis, institutional research as principal investigator (PI) for Daiichi-Sankyo, Roche, Deciphera, Lilly, Novartis, Blueprint Medicines, Bristol Myers Squibb (BMS), Incyte, non-remunerated activities for Federal Institute for Drugs and Medical Devices (BfArm) and founding member of German Sarcoma Foundation; RB reports non-remunerated activities as PI for IRCSS Galeazzi Orthopedic Institute and IRE-ISG Regina Elena Institute, participation at the Clinical Experience Exchange Meeting, III IDBN National Congress 2019, Italian Association of Medical Oncology (AIOM), IRE-ISG Regina Elena Institute and Lazio Association of Orthopaedic Hospital Traumatologists (ALOTO); SBi has received honoraria for participation in advisory boards from Bayer Healthcare, Boehringer Ingelheim, ClinGen, Hofmann La Roche, Ipsen, Eli Lilly and Sensorion, non-remunerated activities for Bayer and membership of the German Pediatric Oncology Society and European Musculoskeletal Oncology Society; JYB received research support from Merck Sharp & Dohme (MSD), Roche, GSK, Novartis, Bayer, PharmaMar outside the present work; SBon has received honoraria for advisory board from Nanobiotix and as invited speaker for PharmaMar, trial research grant from the Institut National du Cancer (INCa); IB has received honoraria for participation in advisory boards for Roche, Lilly, Sanofi, Pierre Fabre, Ipsen, and as invited speaker for Amgen, BMS, Novartis, Leo Pharma, AstraZeneca and Genesis, member of Board of Directors for Hellenic Society of Medical Oncology, Hellenic Society of Sarcomas and Rare Tumors, Hellenic Oncology Research Group (HORG), PI trial research support from Novartis, BMS, Regeneron, MSD, Lilly and Roche; JVMGB receives royalties from UpToDate and Wolters Kluwer, and direct research funding from TRACON pharmaceuticals; KB has received honoraria for expert testimony and advisory boards for Bayer, invited speaker fees and research grant from Eli Lilly, PI for Deciphera and Novartis; TB has received honoraria for participation in advisory boards for Bayer and Eli Lilly, invited speaker fees from PharmaMar and Novartis; EDÁ has received honoraria for participation in advisory board for Bayer, invited speaker for Lilly, PharmaMar and Roche, institutional research support from Pfizer, Roche and AstraZeneca; APDT has received honoraria for participation in advisory boards for Bayer and Roche, invited speaker for PharmaMar and Novartis; XGDM has received honoraria for participation in advisory boards for Ipsen, EUSA Pharma, BMS, Pfizer, Roche and PharmaMar, invited speaker for Lilly, Astellas Pharma, Eisai and Pfizer and institutional research grant from AstraZeneca; ME has received honoraria for participation in advisory boards for Clinigen and Bayer, consulting fees from Blueprint Medicines, institutional research funding from Novartis; AF has received honoraria for participation in advisory board for Novartis and invited speaker fees for MSD and Amgen; VF has received honoraria for participation in advisory boards and speaker fees for BMS, Novartis and MSD and speaker fees from Pierre Fabre; NG has received honoraria as invited speaker for Eisai and reports membership of the European Society for Paediatric Oncology (SIOPE), ACCELERATE, Societe Francaise de lutte contre les cancers et leucemies de l'enfant et de l'adolescent (SFCE) and Groupe Onco- hématologie Adolescents et Jeunes Adultes (GO-AJA); SG has reported institutional research for Blueprint Medicines and member of American Society of Clinical Oncology (ASCO) and AIOM; HG has reported PI research for Daiichi, Deciphera and Novartis, co-ordinating PI for Boehringer Ingelheim and AmMax Bio; FG has received honoraria for participation in advisory board for Amgen and expert testimony for Deciphera, stock ownership for Atlanthera, licensing fees from Zimmer, non-remunerated activities for 3D-Side and INCa DGOS funding and member of the board of NetSarc the French clinical reference network for soft tissue and visceral sarcomas; GG has received honoraria for participation in advisory boards for Lilly, Eisai, Merck, Bayer and GSK, invited speaker fees from PharmaMar and Novartis, institutional grants from PharmaMar, Bayer and Novartis; AG has received honoraria for participation in advisory boards for Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks and Nanobiotix, invited speaker for Lilly, PharmaMar and research grant from PharmaMar; RH has received honoraria from GSK; ABH is a member of Board of Directors for EIT health UK and Ireland, received or currently receives direct research funding as a PI from Roche, performs work in clinical trials or contracted research for the Institution and Clinical Director of the Oncology and Haematology Directorate, Oxford Cancer Centre; SHN reports institutional research role as deputy PI for Eisai, non-remunerated activity for Harmonization International Bones Sarcoma Consortium (HIBISCus), membership of SIOPE, German, Swiss, Austrian Society of Paediatric Oncology and Hematology (GPOH) and German Society of Pediatrics and Adolescent Medicine (DGKJ); NH has received honoraria as expert testimony and invited speaker from PharmaMar, performs work in clinical trials or contracted research for which his/her institution received financial support from PharmaMar, Lilly, Adaptimmune Therapeutics, AROG Pharmaceuticals, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint Medicines, Nektar Therapeutics, Forma, Amgen and Daiichi-Sankyo, non-remunerated leadership roles for Grupo Español de Investigación en Sarcomas (GEIS) and SELNET, and has non-remunerated membership or affiliation with ESMO, Sociedad Española de Oncología Médica (SEOM), ASCO, Connective Tissue Oncology Society (CTOS) and European Organisation for Research and Treatment of Cancer (EORTC); PH has received honoraria for participation in advisory boards for Pfizer, Roche and GSK, invited speaker fees from PharmaMar and Lilly, clinical expert fees from Boehringer Ingelheim, institutional research funding for clinical trials from Siemens, Novartis, Blueprint Medicines and meeting sponsorship from PEKKIP Oncology, non-remunerated activities for the German Sarcoma Foundation (DSS), German Interdisciplinary Sarcoma Group (GISG) and Interdisciplinary Working Party on Sarcomas (IAWS) of the German Cancer Society (DKG), advisory role for the German Cancer Aid (DKH) Committee on Health Technology Assessment and Sarcoma Patients EuroNet (SPAEN); HJ has received honoraria for participation in advisory boards for Orion Pharma, Neutron Therapeutics and Maud Kuistila Memorial Foundation, had full time or part time employment at Orion Pharma, until 31 August 2020, stocks in Orion Pharma and Sartar Therapeutics; RLJ has received honoraria for expert testimony consultancy for Adaptimmune, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immune Design, Lilly, SpringWorks, Tracon, UpToDate, PharmaMar, advisory board for Athenex, institutional research grant from MSD; CJ has received travel grants from Ipsen and PharmaMar; LK has received honoraria for participation in advisory boards for Bayer, Novartis and Agios; BK has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, Boehringer Ingelheim, SpringWorks, GSK and PharmaMar, institutional research support from PharmaMar and SpringWorks, member of EORTC and Chair of the EORTC soft tissue and bone sarcoma group (STBSG); AK has received honoraria for participation in advisory boards for Daiichi-Sankyo and Otsuka and invited speaker fees from Novartis, Taiho and Eisai; KK has received honoraria for participation in advisory board for Bayer and expert testimony for Eli Lilly and Roche; ALC has received honoraria for participation in advisory boards for Deciphera and Lilly, invited speaker fees from PharmaMar and Bayer; EL received honoraria from SpringWorks Therapeutics for scientific advisory board participation and member of the European Reference Network GENTURIS; AL has received institutional research grants from Johnson & Johnson, Alphamed, Medacta and ImplanTec, non-remunerated activities for European Musculoskeletal Society (EMSOS), Austrian Society of Orthopaedic Surgeons (OGO) and membership of CTOS; ALP has received honoraria as invited speaker for PharmaMar, institutional research funding from the Spanish Health Ministry, reported non-remunerated activities as PI for PharmaMar, Cebiotex, Deciphera, Lilly, GSK, Daiichi, Epizyme, Advenchen Laboratories, Novartis, Karyopharm, Blueprint medicines, GEIS and other activity for EORTC; JMB has received honoraria for expert testimony for Lilly, PharmaMar, Eisai, Bayer, invited speaker fee from PharmaMar, institutional research for PharmaMar, Eisai, Novartis, Immix Biopharma, Lixte, Karyopharm, Bayer, Celgene, Pfizer, BMS, Blueprint Medicines, Deciphera, Nektar Therapeutics, Forma, Amgen, Daiichi-Sankyo, Lilly, AROG Pharmaceutcials, Adaptimmune and GSK; OM has received honoraria for participation in advisory boards for MSD, Megapharm, AstraZeneca, Takeda and Progenetics, invited speaker fees from MSD and Roche; CM has performed non-remunerated activities for International Cancer Imaging Society and EORTC STBSG; OMi has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, MSD, Pfizer, invited speaker fees from BMS, Eli Lilly, Ipsen, Roche and Servier, institutional research for Blueprint Medicines, Bayer, Epizyme and Eli-Lilly; BM has received honoraria from Clinigen as invited speaker; EP has received honoraria for participation in advisory boards for SynOx, Daiichi-Sankyo and Deciphera Pharmaceuticals and invited speaker fees from Peer View Educational; MAP has received honoraria for participation in advisory boards for Roche, invited speaker fees from Eli Lilly, Pfizer, and Novartis, expert testimony from Blueprints Medicine and institutional research grant from Novartis; SPN has received honoraria for participation in advisory board for Immunocore; PR has received honoraria for participation in advisory boards for Bayer, Clinigen, Roche, MSD, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, invited speaker fees from Lilly, PharmaMar, institutional research for PharmaMar, Karyopharm, SpringWorks, AROG Pharmaceuticals, Blueprint, Deciphera, Amgen, Astellas, Epizyme, Lilly, MSD, Pfizer, Novartis and Philogen, membership of German Sarcoma Foundation; PRu has received honoraria for participation in advisory boards for MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, invited speaker fees from MSD, BMS, Pierre Fabre, Merck, Sanofi, Novartis, institutional research funding from Pfizer, BMS and non-remunerated activities for the Polish Society of Surgical Oncology and ASCO; MS has received honoraria for travel grant from PharmaMar and writing engagement for Lilly; SS has reported a research grant from Johnson & Johnson and research funding from Roche Austria; PS has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Boehringer Ingelheim, Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios, Modus Outcomes, Studiecentrum voor Kernenergie, Curio Science, institutional honoraria for advisory boards for Blueprint Medicines, Ellipses Pharma, Intellisphere, expert testimony for Advanced Medical/Teladoc Health, institutional research funding from CoBioRes NV, Eisai, G1 Therapeutics, Novartis and PharmaMar; SSl Chair of Centre for Personalised Cancer Treatment and Route Personalised Medicine, Dutch Science Agenda, member of supervisory board for SkylineDX and Scientific advisory committee Pan-Cancer T BV; KSH reports non-remunerated activity for CTOS as President 2020 and membership of the Scandinavian Sarcoma Group; MAJvdS has performed work in clinical trials or contracted research for which the institution received financial support from Daiichi-Sankyo, Implantcast and Carbofix; WTAvdG has received institutional honoraria for participation in advisory boards for Bayer and GSK, institutional research grants from Novartis and Lilly and consultancy work for SpringWorks; WJvH has received institutional honoraria for participation in advisory board for Belpharma, invited speaker fees from Amgen, expert testimony for Sanofi and MSD, personal travel grant from Novartis and institutional research grant from BMS; TF reported institutional research funding from the Foundation ARC and Ligue Régionale contre le Cancer, leadership role for ERN GENTURIS; PGC has received honoraria for participation in advisory board for Bayer, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks, AROG Pharmaceuticals and Eisai, non-remunerated activities for the Italian Sarcoma Group, European School of Oncology, Federation of Italian Cooperative Groups and Rare Cancers Europe; SSta has received honoraria for participation in advisory boards for Bayer, Deciphera, Eli Lilly, Daiichi, Maxivax, Novartis, invited speaker fees from GSK and PharmaMar, expert testimony fee from Bavarian Nordic and Epizyme, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint Medicines, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks and Hutchinson MediPharma International Inc., non-remunerated activities for CTOS, Chordoma Foundation, Epithelioid Haemangioendothelioma Foundation, Desmoid Foundation, EORTC STBSG and Italian Sarcoma Group Onlus. AMF, AB, SBo, BB, AD, FF, AFer, PJ, DAK, FLG, ABM, MM, CMo, RP, AAS, CS, DS, AT, MU and RL have declared no conflicts of interests.

Competing Interests: Disclosure AG has received honoraria for participation in advisory boards for Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks and Nanobiotix, invited speaker for Lilly, PharmaMar and research grant from PharmaMar; APDT has received honoraria for participation in advisory boards for Bayer and Roche, invited speaker for PharmaMar and Novartis; NA Non-remunerated leadership and advisory roles for Sociedade Portuguesa de Cirurgia; JB has no personal financial disclosure, received research grants (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis, Paxman Coolers Ltd, Sun Pharma and non-remunerated advisory role for Novartis, non-remunerated leadership activities for Immuno-oncology society of India, Indian society of Medical and Paediatric Oncology, Teenage and Young Adult Cancer Foundation and Indian cooperative oncology network; SB has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Lilly, Novartis, Daiichi-Sankyo, Plexxikon, Roche, GlaxoSmithKline (GSK), invited speaker fees from Pfizer and PharmaMar, institutional research grant from Novartis, institutional research as principal investigator (PI) for Daiichi-Sankyo, Roche, Deciphera, Lilly, Novartis, Blueprint Medicines, Bristol-Myers Squibb (BMS), Incyte, non-remunerated activities for Federal Institute for Drugs and Medical Devices (BfArm) and founding member of German Sarcoma Foundation; RB reports non-remunerated activities as PI for IRCSS Galeazzi Orthopedic Institute and IRE-ISG Regina Elena Institute, participation at the Clinical Experience Exchange Meeting, III IDBN National Congress 2019, Italian Association of Medical Oncology (AIOM), IRE-ISG Regina Elena Institute and Lazio Association of Orthopaedic Hospital Traumatologists (ALOTO); SBI has received honoraria for participation in advisory boards from Bayer Healthcare, Boehringer Ingelheim, Clinigen, Hoffmann-La Roche, Ipsen, Eli Lilly and Sensorion, non-remunerated activities for Bayer and membership of the German Paediatric Oncology Society and European Musculoskeletal Oncology Society; JYB received research support from Merck Sharp & Dohme (MSD), Roche, GSK, Novartis, Bayer, PharmaMar outside the present work; SBon has received honoraria for advisory board from Nanobiotix and as invited speaker for PharmaMar, trial research grant from the Institut National du Cancer (INCa); IB has received honoraria for participation in advisory boards for Roche, Lilly, Sanofi, Pierre Fabre, Ipsen, and as invited speaker for Amgen, BMS, Novartis, Leo Pharma, AstraZeneca and Genesis, member of Board of Directors for Hellenic Society of Medical Oncology, Hellenic Society of Sarcomas and Rare Tumors, Hellenic Oncology Research Group (HORG), PI trial research support from Novartis, BMS, Regeneron, MSD, Lilly and Roche; JVMGB receives royalties from UpToDate and Wolters Kluwer, and direct research funding from TRACON pharmaceuticals; KB has received honoraria for expert testimony and advisory boards for Bayer, invited speaker fees and research grant from Eli Lilly, PI for Deciphera and Novartis; TB has received honoraria for participation in advisory boards for Bayer and Eli Lilly, invited speaker fees from PharmaMar and Novartis; EDÁ has received honoraria for participation in advisory board for Bayer, invited speaker for Lilly, PharmaMar and Roche, institutional research support from Pfizer, Roche and AstraZeneca; XGDM has received honoraria for participation in advisory boards for Ipsen, EusaPharma, BMS, Pfizer, Roche and PharmaMar, invited speaker for Lilly, Astellas Pharma, Eisai and Pfizer and institutional research grant from AstraZeneca; ME has received honoraria for participation in advisory boards for Clinigen and Bayer, consulting fees from Blueprint Medicines, institutional research funding from Novartis as PI; AF has received honoraria for participation in advisory board for Novartis and invited speaker fees for MSD and Amgen; VF has received honoraria for participation in advisory boards and speaker fees for BMS, Novartis and MSD and speaker fees from Pierre Fabre; SG has reported institutional research for Blueprint Medicines and member of American Society of Clinical Oncology (ASCO) and AIOM; HG has reported PI research for Daiichi, Deciphera and Novartis, Co-ordinating PI for Boehringer Ingelheim and AmMax Bio; FG has received honoraria for participation in advisory board for Amgen and expert testimony for Deciphera, stock ownership for Atlanthera, licensing fees from Zimmer, non-remunerated activities for 3D-Side and INCa DGOS funding and member of the board of NetSarc the French clinical reference network for soft tissue and visceral sarcomas; GG has received honoraria for participation in advisory boards for Lilly, Eisai, Merck, Bayer and GSK, invited speaker fees from PharmaMar and Novartis, institutional grants from PharmaMar, Bayer and Novartis; RH has received Honoraria from GSK; ABH is a member of Board of Directors for EIT Health UK and Ireland, received or currently receives direct research funding as a PI from Roche, performs work in clinical trials or contracted research for the Institution and Clinical Director of the Oncology and Haematology Directorate, Oxford Cancer Centre; SHN received invited speaker fee from University Hospital Basel, Switzerland for Swiss sarcoma symposium, reports institutional research role as deputy PI for Eisai, non-remunerated activity for Harmonization International Bones Sarcoma Consortium (HIBISCus), membership of European Society for Paediatric Oncology (SIOP), German, Swiss, Austrian Society of Paediatric Oncology and Hematology (GPOH) and German Society of Pediatrics and Adolescent Medicine (DGKJ); NH has received honoraria as expert testimony and invited speaker from PharmaMar, performs work in clinical trials or contracted research for which his/her institution received financial support from PharmaMar, Lilly, Adaptimmune Therapeutics, AROG Pharmaceutcials, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint Medicines, Nektar Therapeutics, Forma, Amgen and Daiichi-Sankyo, non-remunerated leadership roles for Grupo Español de Investigación en Sarcomas (GEIS) and SELNET, and has non-remunerated membership or affiliation with ESMO, Sociedad Española de Oncología Médica (SEOM), ASCO, Connective Tissue Oncology Society (CTOS) and European Organisation for Research and Treatment of Cancer (EORTC); PH has received honoraria for participation in advisory boards for Pfizer, Roche and GSK, invited speaker fees from PharmaMar and Lilly, clinical expert fees from Boehringer Ingelheim, institutional research funding for clinical trials from Siemens, Novartis, Blueprint Medicines and meeting sponsorship from PEKKIP Oncology, non-remunerated activities for the German Sarcoma Foundation (DSS), German Interdisciplinary Sarcoma Group (GISG) and Interdisciplinary Working Party on Sarcomas (IAWS) of the German Cancer Society (DKG), advisory role for the German Cancer Aid (DKH) Committee on Health Technology Assessment and Sarcoma Patients EuroNet (SPAEN); HJ has received honoraria for participation in advisory boards for Orion Pharma, Neutron Therapeutics and Maud Kuistila Memorial Foundation, had full-time or part-time employment at Orion Pharma, until 31 August 2020, stocks in Orion Pharma and Sartar Therapeutics; RLJ has received honoraria for expert testimony consultancy for Adaptimmune, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immunedesign, Lilly, SpringWorks, TRACON, UpToDate, PharmaMar, advisory board for Athenex, institutional research grant from MSD; CJ has received travel grants from Ipsen and PharmaMar; LK has received honoraria for participation in advisory boards for Bayer, Novartis and Agios; BK has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, Boehringer Ingelheim, SpringWorks, GSK and PharmaMar, institutional research support from PharmaMar and SpringWorks, member of EORTC and Chair of the EORTC soft tissue and bone sarcoma group (STBSG); AK has received honoraria for participation in advisory boards for Daiichi-Sankyo and Otsuka and invited speaker fees from Novartis, Taiho and Eisai; KK has received honoraria for participation in advisory board for Bayer and expert testimony for Eli Lilly and Roche; ALC has received honoraria for participation in advisory boards for Deciphera and Lilly, invited speaker fees from PharmaMar and Bayer; EL received honoraria from SpringWorks Therapeutics for scientific advisory board participation and member of the European Reference Network GENTURIS; AL has received institutional research grants from Johnson & Johnson, Alphamed, Medacta and Implantec, non-remunerated activities for European Musculoskeletal Society (EMSOS), Austrian Society of Orthopaedic Surgeons (OGO) and membership of CTOS; AL-P has received honoraria as invited speaker for PharmaMar, institutional research funding from the Spanish Health Ministry, reported non-remunerated activities as PI for PharmaMar, Cebiotex, Deciphera, Lilly, GSK, Daiichi, Epizyme, Advenchen Laboratories, Novartis, Karyopharm, Blueprint Medicines, GEIS and other activity for EORTC; JMB has received honoraria for expert testimony for Lilly, PharmaMar, Eisai, Bayer, invited speaker fee from PharmaMar, institutional research for PharmaMar, Eisai, Novartis, Immix Biopharma, Lixte, Karyopharm, Bayer, Celgene, Pfizer, BMS, Blueprint Medicines, Deciphera, Nektar Therapeutics, Forma, Amgen, Daiichi-Sankyo, Lilly, AROG Pharmaceuticals, Adaptimmune and GSK; OM has received honoraria for participation in advisory boards for MSD, Megapharm, AstraZeneca, Takeda and Progenetics, invited speaker fees from MSD and Roche; CM has performed non-remunerated activities for International Cancer Imaging Society and EORTC STBSG; OMi has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, MSD, Pfizer, invited speaker fees from BMS, Eli Lilly, Ipsen, Roche and Servier, institutional research for Blueprint Medicines, Bayer, Epizyme and Eli Lilly; BM has received honoraria from Clinigen as invited speaker; EP has received honoraria for participation in advisory boards for SynOx, Daiichi-Sankyo and Deciphera Pharmaceuticals and invited speaker fees from Peer View Educational; MAP has received honoraria for participation in advisory boards for Roche, invited speaker fees from Eli Lilly, Pfizer and Novartis, expert testimony from Blueprints Medicine and institutional research grant from Novartis; SPN has received honoraria for participation in advisory board for Immunocore; PR has received honoraria for participation in advisory boards for Bayer, Clinigen, Roche, MSD, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, invited speaker fees from Lilly, PharmaMar, institutional research for PharmaMar, Karyopharm, SpringWorks, AROG Pharmaceuticals, Blueprint, Deciphera, Amgen, Astellas, Epizyme, Lilly, MSD, Pfizer, Novartis and Philogen, membership of German Sarcoma Foundation; PRu has received honoraria for participation in advisory boards for MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, invited speaker fees from MSD, BMS, Pierre Fabre, Merck, Sanofi, Novartis, institutional research funding from Pfizer, BMS and non-remunerated activities for the Polish Society of Surgical Oncology and ASCO; MS has received honoraria for travel grant from PharmaMar and writing engagement for Lilly; SS has reported a research grant from Johnson & Johnson and research funding from Roche Austria; PS has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Boehringer Ingelheim, Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios, Modus Outcomes, Studiecentrum voor Kernenergie, Curio Science, institutional honoraria for advisory boards for Blueprint Medicines, Ellipses Pharma, Intellisphere, expert testimony for Advanced Medical/Teladoc Health, institutional research funding from CoBioRes NV, Eisai, G1 Therapeutics, Novartis and PharmaMar; SSl Chair of Centre for Personalised Cancer Treatment and Route Personalised Medicine, Dutch Science Agenda, Member of supervisory board for SkylineDX and Scientific advisory committee Pan-Cancer T BV; SSt has received honoraria for participation in advisory board for GSK; KSH reports non-remunerated activity for CTOS as President 2020 and membership of the Scandinavian Sarcoma Group; MAJvdS has performed work in clinical trials or contracted research for which the institution received financial support from Daiichi-Sankyo, Implantcast and Carbofix; WTAvdG has received institutional honoraria for participation in advisory boards of Bayer and GSK, institutional research grants from Novartis and Lilly, and consultancy work for SpringWorks; WJvH has received institutional honoraria for participation in advisory board for Belpharma, invited speaker fees from Amgen, expert testimony for Sanofi and MSD, personal travel grant from Novartis and institutional research grant from BMS; TF reported institutional research funding from the Foundation ARC and Ligue Régionale contre le Cancer, leadership role for ERN GENTURIS; PGC has received honoraria for participation in advisory board for Bayer, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks, AROG Pharmaceuticals and Eisai, non-remunerated activities for the Italian Sarcoma Group, European School of Oncology, Federation of Italian Cooperative Groups and Rare Cancers Europe; SSta has received honoraria for participation in advisory boards for Bayer, Deciphera, Eli Lilly, Daiichi, Maxivax, Novartis, invited speaker fees from GSK and PharmaMar, expert testimony fee from Bavarian Nordic and Epizyme, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint Medicines, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks and Hutchinson MediPharma International Inc., non-remunerated activities for CTOS, Chordoma Foundation, Epithelioid Haemangioendothelioma Foundation, Desmoid Foundation, EORTC STBSG and Italian Sarcoma Group Onlus; AAS, AB, ABM, AD, AFer, AMF, AT, BB, CMo, CS, DAK, DS, FF, FLG, MM, MU PJ, RP and SBo have declared no conflicts of interests.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication., Competing Interests: Disclosure SS: Honoraria, consultancy or advisory role: Adaptimmune, Bayer, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, Immune Design, Karyopharm, MaxiVAX, Novartis, PharmaMar; Institutional financial interests: Advenchen, Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Glaxo, Hutchison MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks. AMF: Institutional financial interests: Advenchen, Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Glaxo, Hutchison MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks. AC: Advisory board: Angelini Holding S.p.A, Shionogi B.V., L. Molteni & C., Kyowa Kirin S.r.l.; invited speaker King Faisal Specialist Hospital & Research Center. JB: Uncompensated advisory board: Novartis; research funding (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis Co. Ltd, Paxman Coolers Ltd, Sun Pharma. SB: Personal fees from Bayer, Deciphera, Lilly, Daiichi Sankyo, Plexxikon, Exelixis, PharmaMar, Lilly, Roche, GlaxoSmithKline (GSK); grants from Incyte, grants and personal fees from Blueprint Medicines, Novartis; research funding (institutional) Pfizer. SB: Research support from Novartis, Incyte, Blueprint Medicines; honoraria or consultation fees from Novartis, Lilly, Pfizer, PharmaMar, Bayer. JYB: Research support and honoraria from Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Roche, Bayer, Novartis, GSK, Deciphera, OSE Pharma, AstraZeneca. Member of the supervisory board: Innate Pharma. SB: Honoraria from PharmaMar. JVMGB: Research funding from TRACON Pharmaceuticals; Royalties from UptoDate and Wolters Kluwer. KB: Advisory: Bayer; expert testimony: Bayer; invited speaker: Lilly; institutional research funding: Lilly. TB: Advisory board from Bayer; honoraria: Novartis, PharmaMar, Eli Lilly. ME: Consultant for Blueprint Medicines; advisory boards for Clinigen and Bayer. AF; Honoraria: Amgen, Lilly, Roche, MSD; research funding; MSD, Roche, Clovis, AstraZeneca. BMS; Abbvie. VF: Consulting or advisory role: BMS, MSD, Novartis; speakers' bureau: BMS, MSD, Novartis, Pierre Fabre. XGdM: Advisory boards for Ipsen, EUSA Pharma, BMS, Pfizer, Roche, PharmaMar; honoraria from Lilly, Astellas Pharma, Eisai, Pfizer. HG: Reports institutional funding from Novartis, Deciphera. FG: Honoraria from Deciphera, Amgen; stock ownership from Atlanthera; royalties from Zimmer. GG: Grants/research supports: PharmaMar, Novartis, Bayer; honoraria or consultation fees: PharmaMar, Bayer, Merck, Eisai, Novartis, Glaxo. NH: Research grants from PharmaMar, Eisai, Immix BioPharma and Novartis; honoraria and travel grants from PharmaMar; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Adaptimmune Therapeutics, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. PH: Honoraria for consultations and speaker's fees from Roche, GSK, AstraZeneca, Pfizer, PharmaMar, Lilly, Nanobiotix, Novartis, EISAI, Nektar, Sirtex and Pekkip Oncology; research funding and educational grants from Novartis, Siemens, Boehringer, Merck, BLUMedicine and Springer; trial support to my institution by Novartis and Siemens. PH: Advisory roles for Sarcoma UK and National Leiomyosarcoma Foundation; research grants from Sarcoma UK, Desmoid Tumor Research Foundation, Children's Cancer and Leukemia Group and Cancer Research UK, funding from EHE Rare Cancer Charity (UK). HJ: Chair of the Orion Pharma Scientific Advisory Board, chair of Neutron Therapeutics Advisory Board; he has been employed by Orion Pharma, and owns stocks of Orion Pharma and Sartar Therapeutics. RJ: Advisory board Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immune Design, Lilly, Merck, PharmaMar, SpringWorks, TRACON, UptoDate; honoraria: BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi. CJ: Travel grants from PharmaMar, Ipsen. BK: Reports advisory board Bayer, Blueprint, Boehringer Ingelheim, GSK, PharmaMar, SpringWorks; research funding (institutional) PharmaMar, SpringWorks. AK: Advisory board Otsuka; invited speaker for Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Taiho. ALC: Advisory boards with Lilly, PharmaMar, Deciphera, Blueprint. AL: Reports institutional financial interest, and educational grant from Alphamed, ImplanTec, Johnson & Johnson, Medacta. JMB: Research grants from PharmaMar, Eisai, Immix BioPharma and Novartis; honoraria from PharmaMar, Lilly, Bayer, Eisai, Daichii. Travel grants from PharmaMar; advisory board: Roche, Lilly, PharmaMar; research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Adaptimmune Therapeutics, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen, Celgene, Pfizer, BMS, and Daiichi Sankyo. OMe: Consultation fees from MSD, AstraZeneca, Takeda, Megapharm, Medison, Progenetics; supported lecture: MSD, AstraZeneca, Roche, BMS. OMi: Consultancy for Amgen, AstraZeneca, Bayer, BMS, Eli Lilly, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor Pharma; Speakers bureau: Eli Lilly, Roche, Servier; Stock ownership: Amplitude Surgical, Ipsen, Transgene. EP: Advisory boards for Amgen, Daiichi Sankyo, Lilly, Deciphera, EUSA Pharma, and SynOx Therapeutics; research support from BMS, Pfizer, PharmaMar, Daiichi Sankyo, Incyte; travel support from Lilly, PharmaMar and Takeda. MAP: Advisory board Lilly, Pfizer, Roche. SP: Consultant: Deciphera, Daichi Sankyo, Dova, Epizyme, MaxiVAX; Research/Grant Support: Blueprint Medicines, Hutchison MediPharma. SPN: Advisory board for Immunocore. AR: Consulting role with Lilly, Merck, Boehringer Ingelheim; research funding from CASI Pharmaceuticals, Boehringer Ingelheim, Lilly, Novartis, Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, Boston Biomedical, BMS, MedImmune, Amgen, GSK, Blueprint Medicines, Merck, AbbVie, Adaptimmune. PRe: Advisory roles for Bayer, Clinigen, Roche, MSD, Deciphera, PharmaMar, Mundibiopharma, and speaker's honoraria from Lilly, PharmaMar. BPR: Reports advisory board from Deciphera. PRu: Advisory board MSD, BMS, Merck, Sanofi, Pierre Fabre, Blueprint Medicines; honoraria from BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi. MS: Travel grant from PharmaMar. SJS: Advisory boards for Lilly and GSK. WDT: Reports fees from Eli Lilly, EMD Serono, Eisai, Mundipharma, C4 Therapeutics, Daiichi Sankyo, Blueprint, GSK, Agios Pharmaceuticals, NanoCarrier, Deciphera; patent Companion Diagnostic for CDK4 inhibitors - 14/854 329 pending to MSKCC/SKI, and patent Enigma and CDH18 as companion Diagnostics for CDK4 inhibition – SKI2016-021-03 pending to MSKCC/SKI and Scientific Advisory Board - Certis Oncology Solutions, Stock Ownership Üo-Founder - Atropos Therapeutics; Stock Ownership/scientific advisory board Innova Therapeutics. WTAWDG: Reports consultancy from SpringWorks to her institute; research grant support from Novartis and Lilly to her institute; advisory for Bayer to her institute. AJW: Consulting: Daiichi Sankyo, Deciphera, Epizyme, Mundipharma; research support to my Institution: Aadi Bioscience, Daiichi Sankyo, Deciphera, Eli Lilly, Karyopharm, Plexxikon. PGC: Honoraria, consultancy or advisory role: Bayer, Deciphera, Eisai, Eli Lilly, Pfizer. Institutional financial interest: Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme, Glaxo, Hutchinson MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar. APDT: Honoraria: Roche, Bayer, Pharmamar, MSD. AG: Compensations for Advisory boards from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, Nanobiotix; honoraria from Lilly and PharmaMar; institutional research grants from PharmaMar. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Sarcoma: essential requirements for quality care • Sarcomas - which can be classified into soft tissue and bone sarcomas - are rare, but all rare cancers make up more than 20% of cancers in Europe, and there are substantial inequalities in access to high-quality care. Sarcomas, of which there are many subtypes, comprise a particularly complex and demanding challenge for healthcare systems and providers. This paper presents essential requirements for quality cancer care of soft tissue sarcomas in adults and bone sarcomas. • High-quality care must only be carried out in specialised sarcoma centres (including paediatric cancer centres) which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. • It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis and follow-up, to treatment, to improve survival and quality of life for patients., Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for soft tissue sarcomas in adults and bone sarcomas. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams is guaranteed to all patients with sarcoma., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

The definition of soft tissue and bone sarcomas include a large group of several heterogeneous subtypes of mesenchymal origin that may occur at any age. Among the different sarcomas, rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma and osteosarcoma are aggressive high-grade malignancies that often arise in adolescents and young adults. Managing these malignancies in patients in this age bracket poses various clinical problems, also because different therapeutic approaches are sometimes adopted by pediatric and adult oncologists, even though they are dealing with the same condition. Cooperation between pediatric oncologists and adult medical oncologists is a key step in order to assure the best treatment to these patients, preferably through their inclusion into international clinical trials., (© 2016 S. Karger AG, Basel.)

Background: It is known that antineoplastic treatment may induce secondary immunodeficiency, but studies after childhood sarcoma are rare. Since 1998, the Late Effects Surveillance System (LESS) of the German Society for Paediatric Oncology and Haematology (GPOH) prospectively registers late effects in soft tissue-, osteo- and Ewing's sarcoma patients treated within the therapy trials EICESS-92/EURO-E.W.I.N.G.-99, CWS-96/CWS-2002P, COSS-96 in Austria, Germany and Switzerland., Patients and Methods: Antibody levels (AL) against diphtheria and tetanus were used as markers for immunity and classified according to established guidelines for protective AL values. There were 47 eligible relapse-free patients<21 years of age (31 males; 10 osteosarcoma, 12 Ewing's and 25 soft tissue sarcoma patients). Median age at diagnosis was 9.6 (interquartile range: 4.4-14.7) years., Results: A median 7.2 (3.7-12.2) months after end of antineoplastic therapy, in 28% (13/47; 95% CI 16-43%) of patients there were no protective AL (<0.1 IU/ml) against diphtheria and/or tetanus. Diphtheria and tetanus AL were positively correlated (r=0.39; p=0.007). In multivariable analysis, the type of treatment had no effect on AL, similar to tumour type and time of examination after treatment end. Younger patients had significantly lower AL against tetanus (p=0.009) and girls had significantly lower AL against diphtheria than boys (p=0.015)., Conclusion: Lack of protective AL against tetanus and/or diphtheria is frequent after childhood sarcoma treatment. Prospective surveillance of immunity and, if indicated, re-immunization is warranted in patients treated for childhood cancer., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: The role of chemotherapy in thyroid sequelae after cancer treatment has not been studied systematically, especially in sarcoma patients. The aim of this study was to determine the incidence of post-therapeutic thyroid disorders and their contributing factors in a cohort of paediatric sarcoma patients., Design: Late effects of sarcoma treatment have been collected prospectively within the Late Effects Surveillance System (LESS) in Germany, Austria and Switzerland since 1998., Patients: We studied 340 relapse-free paediatric patients (median age at diagnosis 12.2 [interquartile range (IQR) = 7.3-15.6 years] treated for osteosarcoma, soft tissue sarcoma or Ewing's sarcoma within the COSS-96, CWS-96/CWS-2002P or EICESS-92/EURO-E.W.I.N.G.-99 therapy trials. In addition to polychemotherapy, 127 patients were irradiated (mean cumulative dose 47 +/- 9.7 Gy), including 51 patients with irradiation to the head/neck region. Median follow-up was 24.6 (IQR = 11.9-44.9) months., Measurements: We reviewed the results of yearly examinations of serum TSH and fT4 levels and thyroid ultrasound examinations., Results: The incidence of thyroid disorders was 37% (19/51, 95% CI 24-52%) in patients with head/neck irradiation, and 11% (32/289, 95% CI 8-15%) in patients without irradiation to the head/neck. Thyroid disorders were more frequent in patients treated with idarubicin (P = 0.027) and trofosfamide (P = 0.016). We also found a significant association between raised TSH levels and treatment with trofosfamide (P = 0.008) or idarubicin (P = 0.037) (n = 250)., Conclusions: The incidence of thyroid disorders in the head/neck-irradiated group was high. Even without head/neck irradiation, we found an increased proportion of patients with thyroid disorders, possibly as a result of chemotherapy.

Background: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far., Procedure: Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria., Results: After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence., Conclusion: Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment.

Background: Cisplatin and carboplatin are both nephrotoxic and can induce, to a different degree, impairment in glomerular function and hypomagnesemia. Prospective longitudinal studies on these renal impairments are rare in children and adolescents., Procedure: Six hundred and fifty one sarcoma patients were investigated prospectively for nephrotoxicity in the Late Effects Surveillance System (LESS) network (median follow-up 2 years). Median cumulative dose was 360 mg/m(2) for cisplatin, and 1,500 mg/m(2) for carboplatin. Patients not treated with any platinum derivative were used as controls. Most patients (including controls) also received ifosfamide. Renal function was tested by serum magnesium, serum creatinine, and the GFR as estimated by the Schwartz formula. We evaluated incidence, dependencies, and the course of impairments., Results: There was no observed platinum-induced reduction of glomerular function over time. After cessation of antineoplastic therapy, hypomagnesemia (<0.7 mmol/L) occurred in 12.1% (95% CI: 6.8%-19.4%) of patients after cisplatin therapy, and in 15.6% (95% CI: 5.3%-32.8%) after carboplatin therapy, in comparison with 4.5% (95% CI: 2.0%-8.7%) in patients without any treatment with platinum derivatives (P = 0.008). In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum treated patients throughout the study period., Conclusion: Nephrotoxicity after treatment with cisplatin and carboplatin was mild in our study. Further studies have to show if serum magnesium is permanently decreased in platinum treated patients and if this will result in any clinically relevant impairment.

Background: Prospective longitudinal examinations of anthracycline-induced cardiomyopathy in a homogeneous cohort are rare in pediatric oncology. We herein report the results of observations on the frequency of cardiomyopathy in doxorubicin-treated sarcoma patients in Germany, Austria, and Switzerland., Procedure: The Late Effects Surveillance System (LESS) prospectively collects longitudinal data on late sequelae of antineoplastic therapy in Ewing-, soft tissue-, and osteosarcoma patients treated within the therapy trial protocols of the German Society of Pediatric Oncology and Hematology. Two hundred sixty-five relapse-free patients who had received doxorubicin for the treatment within the EICESS-92/EURO-E.W.I.N.G.-99, COSS-96, and CWS-96 therapy trials were serially examined by echocardiography. The analyzed population consisted of 142 males and 123 females. Their mean age at the end of therapy was 13 +/- 5 years. The mean follow-up time was 34 +/- 12 months. The mean cumulative doxorubicin dose was 290 +/- 91 mg/m(2)., Results: In this cohort, the total cumulative incidence of doxorubicin-induced cardiomyopathy was 7.5%. Four patients (1.5%) suffered from a symptomatic cardiomyopathy and 16 (6%) from a subclinical cardiomyopathy. Cardiomyopathy manifested in 11 cases already under antineoplastic therapy and in the remaining nine cases at a median of 26 days (range: 17-174 days) after stopping antineoplastic therapy. Univariate and multivariable analysis did not confirm any of the known risk factors for developing anthracycline-induced cardiomyopathy in our patient group within the described time interval., Conclusions: After a mean follow-up of 34 +/- 12 months, cumulative incidence of doxorubicin-induced cardiomyopathy in our pediatric sarcoma patients was at the lower end of that reported by other groups.

Cancer therapy and supportive measures entail the risk of infection with hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus (HIV). The objective of this analysis was to establish the incidence of infections with these viruses during antineoplastic treatment in our paediatric sarcoma patients, who are being followed-up within the Late Effects Surveillance System (LESS), which prospectively registers sequelae of therapy for Ewing's-, soft tissue- and osteosarcoma in patients treated in Germany, Austria and Switzerland within the trials EICESS-92/EURO-E.W.I.N.G.-99, CWS-96/CWS-2002P and COSS-96. We studied 264 eligible relapse-free paediatric patients [median age at diagnosis 14.3 (IQR 11.1-16.4) years], treated from January 7, 1998 until April 24, 2004. According to the LESS protocol, serological examinations for HBV, HCV and HIV were scheduled 4 weeks and 6 months after cessation of antineoplastic treatment. The median follow-up was 20.6 (IQR 12.4-26) months. None of the patients was reported to have acquired HBV, HCV or HIV during antineoplastic treatment. Blood donor screening and prophylactic measures employed in Germany, Austria and Switzerland to prevent infections of cancer patients with HBV, HCV and HIV seem to be very effective, having fully prevented new infections in this large cohort of paediatric sarcoma patients.

Background: In 1998, a prospective multicenter pilot study of the 'Late Effects Surveillance System' (LESS) was started to investigate late effects of patients with Ewing, osteo- or soft-tissue sarcoma., Procedure: Two hundred thirty patients were included in this pilot study. The patients were treated between 1/1/1998 and 6/30/1999 according to the sarcoma protocols COSS-96, CWS-96, and EICESS-92, the median cumulative doses of the focussed drugs were for cisplatin: 360 mg/m(2), for doxorubicin: 270 mg/m(2), and for ifosfamide: 24 g/m(2). The patients were investigated using an organ related standardized screening methodology. We report on toxicities in the first year after cessation of therapy-the beginning of the patient follow-up-and the feasibility of LESS., Results: Cardiotoxicity: 16/129 (12%) patients treated with doxorubicin exhibited a reduced systolic heart function (fractional shortening (FS) <29%). Altogether three patients required cardiac drug therapy. Ototoxicity: In 5/73 (7%) patients treated with cisplatin a hearing deficit <4 kHz (>20 dB) was found. One patient needed a hearing aid. Nephrotoxicity: 2 of 214 (1%) patients treated with ifosfamide suffered from a tubulopathy, which required supplementation therapy. 10/50 (20%) showed a reduced fractional phosphate reabsorption. Incidence of hypomagnesemia was significantly increased in patients additionally treated with cisplatin., Conclusions: Some relevant impairments are noted in the first year after antineoplastic therapy. We expect to detect more major late sequelae in our prospective study during the increasing posttherapeutic interval. Our pilot study shows the feasibility of the methodology., (Copyright 2003 Wiley-Liss, Inc.)

Purpose. A high serum level of beta human chorionic gonadotropin (hCG) normally indicates pregnancy in healthy women. We were confused by this finding in one of our patients. This 18-year-old girl presented with amenorrhoea of 1-month duration, a positive pregnancy test and a high beta-hCG serum level although taking contraceptives. Pregnancy was excluded by ultrasound. Three years previously, she had had an osteosarcoma of the humerus. The tumour initially had been wide resected and had shown a good response to neoadjuvant chemotherapy with COSS-96-protocol. Methods. We reviewed the original histological result and the literature about possible similar findings. We analysed therapeutic options and the value of beta-hCG levels as a therapy monitor. Results. During examination we detected a recurrent osteosarcoma of the left humerus. The local relapse evidently expressed beta-hCG which, retrospectively, could only sparsely be shown in the primary resectate. After intralesional surgery, chemotherapy and radiotherapy levels of beta-hCG normalised. Conclusion. Osteosarcoma very rarely is able to produce a paraneoplastic syndrome by high levels of beta-hCG. This may well be of diagnostic value and offer an additional monitoring tool. It can indicate tumour recurrrence and dedifferentiation. [ABSTRACT FROM AUTHOR]

Abstract To evaluate the role of fibrinolytic and proteolytic proteins in children and adolescents suffering from Ewing sarcoma or osteosarcoma with respect to postoperative complications and late outcome, a prospective two-arm two-centre study was conducted. Plasminogen, plasminogen activator inhibitor (PAI)-1, tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA) were investigated in the pre-surgical period and in the postoperative follow-up period in children suffering from Ewing sarcoma (ES; n = 36) or osteosarcoma (OS; n = 39). In addition, the factor V mutation (FV) Q[sup 506], protein C, protein S, antithrombin and lipoprotein (a) were determined. All children received LMWH (Enoxaparin[sup R]) 1 mg/kg sc. once daily over a period of 6 weeks to 3 months. Besides a short-lasting increase of PAI-1 in patients with OS on day I and in children with Es on day 14, a small and significant but clinically irrelevant difference was found on days 710 for plasminogen, t-PA and u-PA. No thromboembolic complications occurred in patients treated with LMWH and having a prothrombotic genetic risk factor. Within one year of surgery 7 out of 36 patients with ES and 5 out of 39 children with OS showed a relapse of their disease. Prior to the first local tumour therapy, 5 out of 7 children with ES and relapse had elevated u-PA concentrations compared with 2 out of 5 children in the OS group. No such differences were found for PAI-1- or t-PA antigen. Conclusion The role of u-PA as a possible follow-up marker for a poorer outcome in children with ES should be evaluated in a prospective multicentre study. [ABSTRACT FROM AUTHOR]

The European Musculo Skeletal Oncology Society (EMSOS) has carried out a retrospective review of patients over the age of 40 years with osteosarcoma. 481 patients from 12 centres or multicentric groups were included. 42 patients had osteosarcoma arising in Paget''s disease, median survival was 9 months. Patients with axial or metastatic tumours also did badly whilst 41 patients with radiation-induced osteosarcoma had a prognosis paralleling conventional osteosarcoma matched for patient age and site of the tumour. 238 patients had high grade non-metastatic osteosarcoma and had a survival of 46% at 5 years. Older patients had less chemotherapy and fared worse. Osteosarcoma in the elderly is a curable condition and warrants intensive treatment with chemotherapy and surgical resection. [Copyright &y& Elsevier]