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Purpose: A randomized trial was conducted to compare neoadjuvant standard (S) anthracycline + ifosfamide (AI) regimen with histology-tailored (HT) regimen in selected localized high-risk soft tissue sarcoma (STS). The results of the trial demonstrated the superiority of S in all STS histologies except for high-grade myxoid liposarcoma (HG-MLPS) where S and HT appeared to be equivalent. To further evaluate the noninferiority of HT compared with S, the HG-MLPS cohort was expanded., Patients and Methods: Patients had localized high-grade (cellular component >5%; size ≥5 cm; deeply seated) MLPS of extremities or trunk wall. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). The trial used a noninferiority Bayesian design, wherein HT would be considered not inferior to S if the posterior probability of the true hazard ratio (HR) being >1.25 was <5%., Results: From May 2011 to June 2020, 101 patients with HG-MLPS were randomly assigned, 45 to the HT arm and 56 to the S arm. The median follow-up was 66 months (IQR, 37-89). Median size was 107 mm (IQR, 84-143), 106 mm (IQR, 75-135) in the HT arm and 108 mm (IQR, 86-150) in the S arm. At 60 months, the DFS and OS probabilities were 0.86 and 0.73 (HR, 0.60 [95% CI, 0.24 to 1.46]; log-rank P = .26 for DFS) and 0.88 and 0.90 (HR, 1.20 [95% CI, 0.37 to 3.93]; log-rank P = .77 for OS) in the HT and S arms, respectively. The posterior probability of HR being >1.25 for DFS met the Bayesian monitoring cutoff of <5% (4.93%). This result confirmed the noninferiority of trabectedin to AI suggested in the original study cohort., Conclusion: Trabectedin may be an alternative to standard AI in HG-MLPS of the extremities or trunk when neoadjuvant treatment is a consideration.

Importance: Preclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring., Objective: To explore the effectiveness and safety of trabectedin combined with RT., Design, Setting, and Participants: This international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall., Interventions: Trabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment., Main Outcomes and Measures: The primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response., Results: A total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated., Conclusions and Relevance: Although the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.

Background: Undifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients., Methods: URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC-rearranged round cell sarcomas, (2) BCOR::CCNB3-rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed., Results: In total, 148 patients were identified [88/148 (60%) CIC-rearranged sarcoma (median age 32 years, range 7-78), 33/148 (22%) BCOR::CCNB3-rearranged (median age 17 years, range 5-91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4-70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5-98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7-51.3) in CIC-rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1-90.6; p < 0.0001)., Conclusions: This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet need in this population. Among second-line treatments for advanced STS, eribulin is an anti-microtubule agent that has been approved for liposarcoma. Here, we tested the combination of eribulin with gemcitabine in preclinical models of L-sarcoma. The effect in cell viability was measured by MTS and clonogenic assay. Cell cycle profiling was studied by flow cytometry, while apoptosis was measured by flow cytometry and Western blotting. The activity of eribulin plus gemcitabine was evaluated in in vivo patient-derived xenograft (PDX) models. In L-sarcoma cell lines, eribulin plus gemcitabine showed to be synergistic, increasing the number of hypodiploid events (increased subG1 population) and the accumulation of DNA damage. In in vivo PDX models of L-sarcomas, eribulin combined with gemcitabine was a viable scheme, delaying tumour growth after one cycle of treatment, being more effective in leiomyosarcoma. The combination of eribulin and gemcitabine was synergistic in L-sarcoma cultures and it showed to be active in in vivo studies. This combination deserves further exploration in the clinical context.

Background and Objectives: Diffuse-tenosynovial giant cell tumor (D-TGCT) is a rare, locally aggressive, typically benign neoplasm affecting mainly large joints, representing a wide clinical spectrum. We provide a picture of the treatment journey of D-TGCT patients as a 2-year observational follow-up., Methods: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study at tertiary sarcoma centers spanning seven European countries and two US sites. Histologically confirmed D-TGCT patients were categorized as either those who remained on initial treatment strategy (determined at baseline visit) or those who changed treatment strategy with specific changes documented (e.g., systemic treatment to surgery) at the 1-year and/or 2-year follow-up visits., Results: A total of 176 patients were assessed, mean diagnosis age was 38.4 (SD ± 14.6) years; most patients had a knee tumor (120/176, 68.2%). For the 2-year observation period, most patients (75.5%) remained on the baseline treatment strategy throughout, 54/79 patients (68.4%) remained no treatment, 30/45 patients (66.7%) remained systemic treatment, 39/39 patients (100%) remained surgery. Those who changed treatment strategy utilized multimodal treatment options., Conclusions: This is the first prospectively collected analysis to describe D-TGCT patient treatments over an extended follow-up and demonstrates the need for multidisciplinary teams to determine an optimal treatment strategy., (© 2022 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS., Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021)., Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice., Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The goal of second-line therapy for most patients with advanced soft tissue sarcoma is long-term tumor control without detriment to quality of life. Clinical practice guidelines recommend trabectedin as a second-line option for advanced soft tissue sarcoma as it can provide the necessary balance between these interwoven goals. Cumulative experience with trabectedin in clinical trials and clinical practice has informed its usage such that greater benefit can be derived. In particular, use in earlier lines allows more patients to achieve prolonged tumor control (six or more cycles). Efficacy outcomes are superior when trabectedin is administered as second- versus later-line therapy and when it is used continuously until disease progression.

The choice of second- and later-line options for advanced soft tissue sarcoma (aSTS) should always be considered from the patient's perspective, taking into account the potential impact of treatment on daily activities and quality of life. This review examines data on the safety of trabectedin in the management of patients with aSTS as reported in clinical trials and real-world studies. Evidence indicates that trabectedin exhibits an acceptable and manageable safety profile and is compatible with daily activities. Trabectedin is associated with low rates of toxicity-related discontinuations, few potentially life-threatening toxicities, a lack of apparent cumulative toxicities and low rates of grade 3/4 nausea, vomiting and fatigue. Trabectedin represents a valuable second-line option for aSTS, including in elderly patients.

Bone sarcoma are infrequent diseases, representing < 0.2% of all adult neoplasms. A multidisciplinary management within reference centers for sarcoma, with discussion of the diagnostic and therapeutic strategies within an expert multidisciplinary tumour board, is essential for these patients, given its heterogeneity and low frequency. This approach leads to an improvement in patient's outcome, as demonstrated in several studies. The Sarcoma European Latin-American Network (SELNET), aims to improve clinical outcome in sarcoma care, with a special focus in Latin-American countries. These Clinical Practice Guidelines (CPG) have been developed and agreed by a multidisciplinary expert group (including medical and radiation oncologist, surgical oncologist, orthopaedic surgeons, radiologist, pathologist, molecular biologist and representatives of patients advocacy groups) of the SELNET consortium, and are conceived to provide the standard approach to diagnosis, treatment and follow-up of bone sarcoma patients in the Latin-American context., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS., Methods: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%)., Results: The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105)., Conclusions: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS., Lay Summary: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high., (© 2021 American Cancer Society.)

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.

Among all Soft Tissue sarcomas there are some subtypes with low incidence and/or peculiar clinical behaviour, that need to be consider separately. Most of them are orphan diseases, whose biological characteristics imply a clearly different diagnostic and therapeutic approach from other more common sarcoma tumors. We present a brief and updated multidiciplinary review, focused on practical issues, aimed at helping clinicians in decision making. In this second part we review these subtypes: Alveolar Soft Part Sarcoma, Epithelioid Sarcoma, Clear Cell Sarcoma, Desmoplastic Small Round Cell Tumor, Rhabdoid Tumor, Phyllodes Tumor, Tenosynovial Giant Cell Tumors, Myoepithelial Tumor, Perivascular Epithelioid Cell Neoplasms (PEComas), Extraskeletal Myxoid Chondrosarcoma, NTRK-fusions Sarcomas. Most of them present their own radiological and histopathological feautures, that are essential to know in order to achieve early diagnosis. In some of them, molecular diagnosis is mandatory, not only in the diagnosis, but also to plan the treatment. On the other hand, and despite the low incidence, a great scientific research effort has been made to achieve new treatment opportunities for these patients even with approved indications. These include new treatments with targeted therapies and immunotherapy, which today represent possible therapeutic options. It is especially important to be attentive to new and potential avenues of research, and to promote the conduct of specific clinical trials for rare sarcomas., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies., Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan., Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types., Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients., (© 2021 American Cancer Society.)

Purpose: Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943)., Patients and Methods: Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m 2 . The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%., Results: A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m 2 (range, 72.3-634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m 2 , 88.5% receiving 450-<600 mg/m 2 , and 90% receiving ≥600 mg/m 2 ) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose <450 mg/m 2 , 82 of 159 patients (51.6%) who received 450-<600 mg/m 2 , and 50 of 89 patients (56.2%) who received ≥600 mg/m 2 . Grade ≥3 cardiac dysfunction occurred in 2% of patients at <450 mg/m 2 , 3% at 450-<600 mg/m 2 , and 1.1% at ≥600 mg/m 2 . Incidence of treatment-related cardiac AEs was low across all dose ranges., Conclusions: Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m 2 ), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration. See related commentary by Benjamin and Minotti, p. 3809 ., (©2021 American Association for Cancer Research.)

Purpose of Review: The aim is to bring latest evidence of the role of perioperative chemotherapy in localized soft-tissue sarcomas (STS) of limbs and to review the risk classification systems of retroperitoneal and extremity STS., Recent Findings: High-risk subset of localized STS of limbs and trunk-wall, defined with classic prognostic factors, consistently obtained 5-year overall survival ranging from 69 to 76% in randomized patients treated with full-dose of anthracycline and ifosfamide. Validated nomograms accurately predict, on individual basis, the risk of death and recurrence in localized STS of retroperitoneum and limbs, enabling a better selection of high-risk patients (usually those with death risk of ≥40%) that potentially could benefit with perioperative systemic treatment. Nomograms have virtually converted a negative large perioperative trial into a positive, favouring chemotherapy arm in the high-risk selection., Summary: Perioperative three cycles of full-dose of anthracycline and ifosfamide should be proposed on an individual basis, in reference sarcoma centres, to high-risk localized STS of limbs or trunk-wall in certain histologies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Soft-tissue sarcomas constitute an uncommon and heterogeneous group of tumors of mesenchymal origin. Diagnosis, treatment, and management should be performed by an expert multidisciplinary team. MRI/CT of the primary tumor and biopsy is mandatory before any treatment. Wide surgical resection with tumor-free tissue margin is the mainstay for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not suitable for re-excision. Perioperative chemotherapy should be discussed for high-risk sarcomas of the extremities and trunk-wall. In the case of oligometastatic disease, patients should be considered for local therapies. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. Other drugs have shown activity in second-line therapy and in specific histological subtypes but options are limited and thus, a clinical trial should always be discussed.

The coronavirus disease-2019 (COVID-19) pandemic is deeply impacting the accessibility of cancer patients to surgery. In resource-limited conditions, the standard of care might not be deliverable, but evidence to support alternative management strategies often exists. By revisiting available treatment options, this review provides surgical oncologists with an evidence-based framework for treating patients with gastrointestinal stromal tumor, extremity/truncal soft tissue sarcoma, and retroperitoneal sarcoma to rapidly adapt their decision-making to the constant evolution of the COVID-19 pandemic., (© 2020 Wiley Periodicals LLC.)

Purpose: To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall., Patients and Methods: This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176)., Results: Between May 2011 and May 2016, 287 patients (UPS: n = 97 [33.8%]; HG-MLPS: n = 65 [22.6%]; SS: n = 70 [24.4%]; MPNST: n = 27 [9.4%]; and LMS: n = 28 [9.8%]) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank P = .323) and 0.76 and 0.66 (log-rank P = .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed., Conclusion: In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.

Introduction : Although rapid evolution over the past few years in advanced soft tissue sarcoma (STS) management has not been without its challenges, it has brought clarity in several areas. Areas covered : This article summarizes the proceedings of the third edition of the Soft Tissue Sarcoma: Evidence and Experience symposium held March 2019 in Madrid, Spain. An update is provided of current approaches to advanced STS management. Case studies illustrate the role of trabectedin in advanced STS management. Expert opinion : First-line treatment of advanced STS requires distinct therapeutic strategies depending on goal: tumor shrinkage or tumor control. Since all sarcoma patients benefit from active treatment irrespective of age or line of therapy, oncologists have a duty to offer active systemic therapies unless the patient is unfit for treatment or chooses to end active treatment. Beyond the first line, histology becomes increasingly relevant for treatment selection. Agents with activity in specific sarcoma subtypes have been identified. Rare tumors represent a substantial medical need requiring strong international collaboration between research groups, pharmaceutical companies, regulatory agencies, and patients to identify active drugs per subtype. Multidisciplinary care in an expert sarcoma center is the primary means of reducing morbidity and mortality in patients with sarcoma.

Background: Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma., Methods: In this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285., Findings: Between June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18-30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1-36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%])., Interpretation: Pazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients., Funding: Spanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here., Methods: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15., Findings: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%])., Interpretation: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials., Funding: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background Sorafenib is a potent targeted-therapy that blockades angiogenesis and has demonstrated activity against some sarcoma subtypes. Preclinical studies suggested that treatment with sorafenib plus cytotoxic agents could result in additive efficacy. Methods Patients with advanced soft tissue sarcoma, with or without anthracycline pretreatment were included. Patients received oral sorafenib 400 mg twice daily starting on Day +2, ifosfamide 2.0 g/m2 iv infusion lasting 4 h on days 1, 2 and 3 with concurrent mesna 400 mg/m 2 every three weeks until disease progression or unacceptable toxicity or up to a maximum of 6 cycles of ifosfamide (sorafenib could be continued until progressive disease or unacceptable toxicity). Primary objective was progression-free rate (PFR) at 3 and 6 months; secondary objectives were overall response rate (ORR), Progression-free survival (PFS), Overall survival (OS) and safety. This article reports the phase II part of a phase I/II clinical trial. Results Thirty-five patients were enrolled. PFR at 3 and 6 months was 66% (95% CI 48-81) and 37% (95% CI 22-55). Six patients (17%) achieved partial response and 17 (49%) stable disease. Median PFS was 4.8 months (CI 95% 1.94-6.36) and overall survival 16.2 months (95% CI 8.75-NA). Conclusion Treatment with sorafenib plus ifosfamide achieved a significant clinical benefit with an acceptable safety profile in patients with advanced soft tissue sarcoma resistant to anthracyclines, which warrants a more detailed study in randomized clinical trials.

Multidisciplinary teams (MDTs) are necessary to deliver the best sarcoma care. Planning the optimal therapeutic strategy per patient requires input and expertise from several disciplines. Case/cohort studies have reported improved patient outcomes associated with treatment by MDTs and/or treatment in sarcoma centres. Many countries have established national networks of sarcoma reference centres and most have developed evidence-based clinical practice guidelines agreed using multidisciplinary expertise. In many countries, sarcoma networks are organised as cooperative groups. These groups are committed to delivering continuing medical education and are open to collaboration with other groups. Among their many benefits, cooperative groups have huge capacity for accrual, which is essential for rare cancers such as sarcoma. Since its beginnings in 1994 with a small core of oncologists focussing on soft tissue sarcoma, the Spanish Group for Research on Sarcomas (GEIS) has expanded to 376 members from more than 10 disciplines (as at June 2017). GEIS is currently actively collaborating with several international cooperative groups. As MDTs are essential to offer the best outcome in sarcoma care, and international cooperation between sarcoma groups is essential to address the many unanswered questions in sarcoma management, both approaches should be made mandatory., (© 2018 S. Karger AG, Basel.)

Soft-tissue sarcomas are uncommon and heterogeneous tumors of mesenchymal origin. A soft-tissue mass that is increasing in size, greater than 5 cm, or located under deep fascia are criteria for suspicion of sarcoma. Diagnosis, treatment, and management should preferably be performed by a multidisciplinary team in reference centers. MRI and lung CT scan are mandatory for local and distant assessment. A biopsy indicating histological type and grade is needed previous to the treatment. Wide surgical resection with tumor-free tissue margin is the primary treatment for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not likely of being improved with reexcision. Neoadjuvant and adjuvant chemotherapy improve survival in selected cases, usually in high-grade sarcomas of the extremities. In the case of metastatic disease, patients with exclusive lung metastasis could be considered for surgery. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. New drugs have shown activity in second-line therapy and in specific histological subtypes., Competing Interests: The authors declare that they have no conflict of interest relating to the publication of this manuscript and compliance with ethical standards.

Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours, which require a complex and specialized multidisciplinary management. The diagnostic approach should include imaging studies and core needle biopsy performed prior to undertaking surgery. Wide excision is the mainstay of treatment for localized sarcoma, and associated preoperative or postoperative radiotherapy should be administered in high-risk patients. Adjuvant chemotherapy was associated with a modest improvement in survival in a meta-analysis and constitutes a standard option in selected patients with high-risk STS. In metastatic patients, surgery must be evaluated in selected cases. In the rest of patients, chemotherapy and, in some subtypes, targeted therapy often used in a sequential strategy constitutes the treatment of election. Despite important advances in the understanding of the pathophysiology of the disease, the advances achieved in therapeutic results may be deemed still insufficient. Moreover, due to the rarity and complexity of the disease, the results in clinical practice are not always optimal. For this reason, the Spanish Group for Research on Sarcoma (GEIS) has developed a multidisciplinary clinical practice guidelines document, with the aim of facilitating the diagnosis and treatment of these patients in Spain. In the document, each practical recommendation is accompanied by level of evidence and grade of recommendation on the basis of the available data.

Purpose: We report on feasibility of preoperative chemotherapy with or without radiation therapy (RT) in the context of a phase III randomized clinical trial involving localized, high-risk, soft tissue sarcomas., Patients and Methods: Of 321 eligible patients, 161 were randomly assigned to three preoperative cycles of epirubicin 120 mg/m(2) plus ifosfamide 9 g/m(2), and 160 were randomly assigned to three preoperative plus two postoperative cycles. Among them, 303 patients were included in this analysis; 169 were male and 134 were female, with a median age of 48 years (range, 15 to 79 years). One hundred fifty-two patients received concurrent RT preoperatively at a total dose of 44 to 50 Gy. Preoperative chemotherapy-related hematologic toxicity and early postoperative complications were reported. The influence of RT, age, and sex on hematologic grade 3 or 4 toxicities and wound complications was analyzed. Chemotherapeutic dose intensity (DI) was analyzed., Results: Among the patients, 61.4%, 22.4%, and 23.8% experienced, grade 4 leucopenia, grade 3 or 4 anemia, and grade 3 or 4 thrombocytopenia, respectively. Respective rates were 66.4%, 24.3%, and 31.6% when RT was added preoperatively, and 56.3%, 20.5%, and 15.9% when preoperative chemotherapy was administered alone. Patient age affected grade 3 or 4 thrombocytopenia. Grade 4 leucopenia and grade 3 or 4 anemia presented 2.5 times more frequently in female patients than in male patients. Wound complications were observed in 13.5% of patients: 17% with preoperative RT and 10% without. Chemotherapeutic DI was greater than 90%, even in patients receiving preoperative RT and in patients age 65 years or older., Conclusion: This preoperative chemotherapy is feasible and can also be proposed for selected elderly patients. Grade 3 or 4 hematologic toxicity was common, but DI was excellent. Concurrent preoperative RT is safe, although an increased rate of grade 4 thrombocytopenia and limited increase in wound complications may be observed., (© 2015 by American Society of Clinical Oncology.)

Background: Key distinguishing characteristics of trabectedin in the treatment of advanced soft tissue sarcoma are its prolonged tumor control activity in multiple histological subtypes, positive outcomes in translocation-related sarcomas, maintenance of response, option to rechallenge after treatment interruption and lack of cumulative toxicity. Trabectedin is indicated for use in advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or as front-line treatment in patients unsuited to receive these agents., Methods: In this review, cases studies are presented in which trabectedin was used according to its indication but in diverse clinical settings., Results: As second-line treatment of uterine leiomyosarcoma, trabectedin produced prolonged tumor control with good quality of life. In treatment of recurrent synovial sarcoma, the best objective response (partial response) and longest disease control (37 months) was achieved under treatment with trabectedin. As neoadjuvant treatment of undifferentiated pleomorphic sarcoma in a patient unsuited to receive doxorubicin-based chemotherapy, trabectedin induced a pathological response with 85% of necrosis., Conclusion: These cases illustrate the broad range of indications for trabectedin in advanced soft tissue sarcoma and highlight how its unique characteristics can be optimized to achieve maximum clinical benefit.