SELNET clinical practice guidelines for soft tissue sarcoma and GIST

Abstract

•Soft tissue sarcoma (STS) and gastrointestinal tumors (GIST) encompass > 80 different histologic subtypes.•Clinical practice guidelines for STS and GIST still lack in Latin-American countries.•Tailored clinical guidelines are instrumental to improve outcome in sarcoma patients in LatinAmerican countries.•This is the first review establishing STS and GIST guidelines for the purpose of LatinAmerican clinical practices to our knowledge. Soft tissue sarcoma (STS) is a heterogeneous group of neoplasms, encompassing > 80 different histologic subtypes. Approximately three quarter of sarcoma arise from soft-tissue, about 15% are gastrointestinal stromal tumours (GISTs) and bone sarcoma represent the remaining 10%. The current guidelines will focus on soft-tissue and GIST, excluding Kaposi sarcoma and non-pleomorphic rhabdomyosarcoma. Bone sarcomas are covered in a different paper. •Management of soft tissue, visceral, and bone sarcoma should be carried out within multidisciplinary reference centres for sarcoma [III, A] [[1]Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv268–9. 10.1093/annonc/mdy321.Google Scholar]. Multidisciplinary tumour boards (MDTB) should include at least the following specialties: medical oncology, paediatrics (if paediatric patients are discussed), radiology, surgery, pathology and radiation oncology.•A MDTB cannot be defined only by the volume of patients followed, but also by the periodicity of meeting (weekly MDTB is recommended), its contribution to clinical trials and scientific production and its participation in national or international guidelines. These MDTB should ideally be periodically audited to ensure quality.•All diagnostic procedures and therapeutic decisions should be discussed within a MDTB.•Several reports indicate better clinical results and better cost-effectiveness if sarcoma or presumptive sarcoma patients are managed in sarcoma reference centres with MDTB discussion [III, A] [2Perrier L. Buja A. Mastrangelo G. Vecchiato A. Sandonà P. Ducimetière F. et al.Clinicians’ adherence versus non adherence to practice guidelines in the management of patients with sarcoma: a cost-effectiveness assessment in two European regions.BMC Health Serv Res. 2012; 12https://doi.org/10.1186/1472-6963-12-82Crossref PubMed Scopus (48) Google Scholar, 3Martin‐Broto J. Hindi N. Cruz J. Martinez‐Trufero J. Valverde C. De Sande L.M. et al.Relevance of Reference Centers in Sarcoma Care and Quality Item Evaluation: Results from the Prospective Registry of the Spanish Group for Research in Sarcoma (GEIS).Oncologist. 2019; 24https://doi.org/10.1634/theoncologist.2018-0121Crossref Scopus (23) Google Scholar, 4Blay J.-Y. Honoré C. Stoeckle E. Meeus P. Jafari M. Gouin F. et al.Surgery in reference centers improves survival of sarcoma patients: a nationwide study.Ann Oncol Off J Eur Soc Med Oncol. 2019; 30: 1407https://doi.org/10.1093/annonc/mdz170Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 5Trovik C.S. Scanadinavian Sarcoma Group Project. Local recurrence of soft tissue sarcoma. A Scandinavian Sarcoma Group Project.Acta Orthop Scand Suppl. 2001; 72: 1-31Crossref PubMed Google Scholar]. Soft tissue sarcomas are rare tumours, with an estimated incidence of approximately 9 new cases/100,000 inhabitants/ year in Europe [[6]de Pinieux G. Karanian M. Le Loarer F. et al.Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.PLoS One. 2021; 16e0246958https://doi.org/10.1371/journal.pone.0246958Crossref Scopus (31) Google Scholar]. Incidence in other areas, such as Latin-American countries is difficult to estimate due to the lack of registries [7Chávez M. Ziegler G. Cotrina J. Galarreta J. de la Cruz M. Mantilla R. Current situation of soft tissue sarcomas: Registry of a Latin American cancer institute.Cirugia Espanola. 2019; 97: 203-212https://doi.org/10.1016/j.cireng.2019.04.001Crossref PubMed Google Scholar, 8García-Ortega D.Y. Clara-Altamirano M.A. Martín-Tellez K.S. Caro-Sánchez C.H.S. Álvarez-Cano A. Lino-Silva L.S. et al.Epidemiological profile of soft tissue sarcomas of the extremities: Incidence, histological subtypes, and primary sites.J Orthop. 2021; 25: 70-74https://doi.org/10.1016/j.jor.2021.03.021Crossref PubMed Scopus (2) Google Scholar]. All diagnostic procedures in patients with suspicion of soft-tissue sarcoma should be discussed within a multidisciplinary tumour board (MDTB). During the diagnostic course, in patients with superficial lesions > 5 cm and deep lesions of any size, imaging and biopsy before surgery are strongly recommended. For primary tumours of the limb, trunk wall and pelvis, MRI is the preferred recommended imaging test. CT scan is recommended for any other site, or as a MRI alternative [III, A]. A core needle biopsy is recommended for the diagnosis of soft tissue or visceral lesions > 3 cm [III, A]. An adequate procedure to perform biopsies should include imaging guidance to avoid any suspected area of necrosis, use of G14 or G16 needles with coaxial introducer for a single skin entrance, and 4 to 6 cores varying the angle into the tumour [III, A]. Pathological diagnosis should be made according to the most recent WHO classification and histological grading should be based on the FNCLCC system [III, A]. Central pathological review by an expert sarcoma pathologist is strongly recommended [III, A]. Cases should be referred to molecular pathology tests whenever morphology and immunohistochemistry are not enough for a precise diagnosis and/or when additional prognostic/predictive information is required [III, A]. Grade should be established always prior to treatment based on the core biopsy. When neoadjuvant treatment is administered, pathological findings should be quantified and reported in terms of residual viable (stainable) tumour cells and their mitotic index, and percentage of post-treatment changes (necrosis, sclerohyalinosis, fibrosis, fibrohistiocytic reaction, haemorrhage). Percentage of hypercellular/round cell component and adipocytic maturation should be noted in case of myxoid liposarcoma [[9]Wardelmann E. Haas R.L. Bovée J.V.M.G. Terrier P.h. Lazar A. Messiou C. et al.Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) recommendations for pathological examination and reporting.Eur J Cancer Oxf Engl. 2016; 53: 84-95https://doi.org/10.1016/j.ejca.2015.09.021Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. Imaging studies to evaluate the presence of distant metastasis are mandatory. To assess the presence of lung metastases, a chest CT scan is recommended [III, A]. An abdominal and pelvic CT scan is recommended to rule out metastasis in special histologic subtypes with high metastatic potential (myxoid liposarcoma, epithelioid sarcoma, angiosarcoma, leiomyosarcoma, small-cell sarcomas) [III, A] [[10]Rosenthal J. Cardona K. Sayyid S.K. Perricone A.J. Reimer N. Monson D. et al.Nodal metastases of soft tissue sarcomas: risk factors, imaging findings, and implications.Skeletal Radiol. 2020; 49: 221-229https://doi.org/10.1007/s00256-019-03299-6Crossref PubMed Scopus (10) Google Scholar]. Currently, spine and pelvic MRI is preferred in myxoid liposarcoma [IV, A], and a baseline brain MRI should be considered in alveolar soft-part sarcoma (ASPS), angiosarcoma and clear cell sarcoma [IV, A] due to their high risk of central nervous system spread. PET/CT scan and/or bone scintigraphy are optional and are advised in case of equivocal images and/or clinical bone involvement suspicion. Risk stratification is assessed using composite tools which may vary according to histological subtype after central review, grade, primary site (see GIST section), tumour size and presence of metastasis [IV, A]. Nomograms are available for several locations [11Callegaro D. Miceli R. Bonvalot S. Ferguson P. Strauss D.C. Levy A. et al.Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis.Lancet Oncol. 2016; 17: 671-680https://doi.org/10.1016/S1470-2045(16)00010-3Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 12Gronchi A. Miceli R. Shurell E. Eilber F.C. Eilber F.R. Anaya D.A. et al.Outcome prediction in primary resected retroperitoneal soft tissue sarcoma: histology-specific overall survival and disease-free survival nomograms built on major sarcoma center data sets.J Clin Oncol. 2013; 31: 1649-1655https://doi.org/10.1200/JCO.2012.44.3747Crossref PubMed Scopus (207) Google Scholar, 13Callegaro D. Miceli R. Bonvalot S. Ferguson P.C. Strauss D.C. van Praag V.V.M. et al.Development and external validation of a dynamic prognostic nomogram for primary extremity soft tissue sarcoma survivors.EClinicalMedicine. 2019; 17: 100215https://doi.org/10.1016/j.eclinm.2019.11.008Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] and those with reported validation studies (retroperitoneal and limb soft tissue sarcomas) should be used. For patients with an adult type localized STS, surgery is the standard treatment. This procedure must be performed by a surgeon, specifically trained for the treatment of this group of diseases [[1]Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv268–9. 10.1093/annonc/mdy321.Google Scholar]. Surgery should always be preceded by an expert sarcoma MDTB discussion. The standard surgical procedure is a wide excision (en bloc resection) with negative margins (R0) [II, A] [[14]Rosenberg S.A. Tepper J. Glatstein E. Costa J. Baker A. Brennam M. et al.The Treatment of Soft-tissue Sarcomas of the Extremities: Prospective Randomized Evaluations of (1) Limb-sparing surgery Plus Radiation Therapy Compared with Compared with amputation and (2) the Role of adjuvant Chemotherapy.Ann Surg. 1982; 196: 305-315Crossref PubMed Google Scholar] and limb salvage procedure whenever feasible. In some special situations, reconstructive surgery should be taken into account and plastic surgery can facilitate the reconstruction of wide soft-tissue sarcoma surgeries. When despite of neo- or adjuvant treatments the achievement of an adequate margin with a functional limb is not feasible, amputation should be considered and discussed in a specialized MDTB [III, A] [[14]Rosenberg S.A. Tepper J. Glatstein E. Costa J. Baker A. Brennam M. et al.The Treatment of Soft-tissue Sarcomas of the Extremities: Prospective Randomized Evaluations of (1) Limb-sparing surgery Plus Radiation Therapy Compared with Compared with amputation and (2) the Role of adjuvant Chemotherapy.Ann Surg. 1982; 196: 305-315Crossref PubMed Google Scholar]. Pathologically confirmed or clinically evident lymph nodes should be resected but elective node dissection is not recommended. Adjuvant RT or chemotherapy (ChT) do not compensate for an improper first or second surgery. Re-excision by an expert team should be discussed in a MDTB in this situation, especially when surgery was performed outside a reference centre [III, A]. Local re-staging has to be performed in order to plan an adequate re-excision. Postoperative hematoma is considered a tumour contamination and must be included in the surgical tumour bed of re-excision. In the case of R2 surgery (macroscopic residual tumour after surgery), re-operation is mandatory, and preoperative treatments should be considered when adequate oncology margins cannot be achieved, depending on the histological subtype. Re-excision should be discussed when the oncological margins are not satisfactory even after planned surgeries. However, if it is impossible to obtain a greater or better margin, due to its anatomical location, radiotherapy (RT) should be considered. Marginal resections with microscopically positive margins (R1) may be appropriate for extracompartimental atypical lipomatous tumours. Wide excision procedure is followed by RT as the standard treatment in cases with at least one of the following risk factors: high-grade (G2-3), deep, >5 cm lesions [II, A] [15Pisters P.W. Harrison L.B. Leung D.H. Woodruff J.M. Casper E.S. Brennan M.F. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma.J Clin Oncol. 1996; 14: 859-868https://doi.org/10.1200/JCO.1996.14.3.859Crossref PubMed Scopus (739) Google Scholar, 16Beane J.D. Yang J.C. White D. Steinberg S.M. Rosenberg S.A. Rudloff U. Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial.Ann Surg Oncol. 2014; 21: 2484-2489https://doi.org/10.1245/s10434-014-3732-4Crossref PubMed Scopus (128) Google Scholar, 17Yang J.C. Chang A.E. Baker A.R. Sindelar W.F. Danforth D.N. Topalian S.L. et al.Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity.J Clin Oncol. 1998; 16: 197-203https://doi.org/10.1200/JCO.1998.16.1.197Crossref PubMed Scopus (1121) Google Scholar]. Exception may be made after MDTB discussions considering site and comorbidities [II, A] [[16]Beane J.D. Yang J.C. White D. Steinberg S.M. Rosenberg S.A. Rudloff U. Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial.Ann Surg Oncol. 2014; 21: 2484-2489https://doi.org/10.1245/s10434-014-3732-4Crossref PubMed Scopus (128) Google Scholar]. RT may be avoided for G1, R0, <5cm, superficial tumours of the limbs and trunk wall [IV, B]. In cases of G1, > 5 cm and deep tumours, RT should be validated with a MDTB [[18]Cahlon O. Brennan M.F. Jia X. Qin L.X. Singer S. Alektiar K.M. A postoperative nomogram for local recurrence risk in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation.Ann Surg. 2012; 255: 343-347https://doi.org/10.1097/SLA.0b013e3182367aa7Crossref PubMed Scopus (99) Google Scholar]. Preoperative or postoperative RT are equally acceptable with different side-effect profile in a mid and long-term [II, A] [[19]DAVIS A. OSULLIVAN B. TURCOTTE R. BELL R. CATTON C. CHABOT P. et al.Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma.Radiother Oncol J Eur Soc Ther Radiol Oncol. 2005; 75: 48-53https://doi.org/10.1016/j.radonc.2004.12.020Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar]. In some locations (e.g. head and neck), postoperative RT is preferred. As for surgery, preoperative RT should always be discussed on MDTB [[18]Cahlon O. Brennan M.F. Jia X. Qin L.X. Singer S. Alektiar K.M. A postoperative nomogram for local recurrence risk in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation.Ann Surg. 2012; 255: 343-347https://doi.org/10.1097/SLA.0b013e3182367aa7Crossref PubMed Scopus (99) Google Scholar]. The time frame between end of preoperative RT and surgery or surgery and the initiation of adjuvant RT should be 4–6 weeks, though longer intervals may be needed in case of clinical constraints (delayed wound healing) [IV, D] [20Al Yami A. Griffin A.M. Ferguson P.C. Catton C.N. Chung P.W.M. Bell R.S. et al.Positive surgical margins in soft tissue sarcoma treated with preoperative radiation: is a postoperative boost necessary?.Int J Radiat Oncol Biol Phys. 2010; 77: 1191-1197https://doi.org/10.1016/j.ijrobp.2009.06.074Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 21O'Sullivan B. Davis A.M. Turcotte R. Bell R. Catton C. Chabot P. et al.Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial.Lancet. 2002; 359: 2235-2241https://doi.org/10.1016/S0140-6736(02)09292-9Abstract Full Text Full Text PDF PubMed Scopus (998) Google Scholar]. Adjuvant ChT is not a standard treatment and is not recommended in chemotherapy non-responsive histologic subtypes (for example, ASPS, clear cell sarcoma, well/dedifferentiated liposarcoma) [[22]Gronchi A. Frustaci S. Mercuri M. Martin J. Lopez-Pousa A. Verderio P. et al.Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.J Clin Oncol Off J Am Soc Clin Oncol. 2012; 30: 850-856https://doi.org/10.1200/JCO.2011.37.7218Crossref PubMed Scopus (123) Google Scholar]. There are conflicting results in literature regarding its value, mainly in relation to the poor selection of high-risk patients and inadequate use of dose intensity in the administered regimens. The application of validated nomograms in a negative large randomized trial evaluating the role of adjuvant ChT [[23]Woll P.J. Reichardt P. Le Cesne A. Bonvalot S. Azzarelli A. Hoekstra H.J. et al.Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial.Lancet Oncol. 2012; 13: 1045-1054https://doi.org/10.1016/S1470-2045(12)70346-7Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar], virtually converted it into a positive study, showing a significant benefit in disease-free survival and overall survival (OS) in the high-risk population [[24]Pasquali S. Pizzamiglio S. Touati N. Litiere S. Marreaud S. Kasper B. et al.The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial.Eur J Cancer Oxf Engl. 2019; 109: 51-60https://doi.org/10.1016/j.ejca.2018.12.009Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. Those randomized trials selecting high-risk localized limb or trunk-wall STS with the highest dose intensity of the two most active drugs (anthracyclines and ifosfamide) consistently showed a 5-y OS above 70% [22Gronchi A. Frustaci S. Mercuri M. Martin J. Lopez-Pousa A. Verderio P. et al.Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.J Clin Oncol Off J Am Soc Clin Oncol. 2012; 30: 850-856https://doi.org/10.1200/JCO.2011.37.7218Crossref PubMed Scopus (123) Google Scholar, 25Frustaci S. Gherlinzoni F. De Paoli A. Bonetti M. Azzarelli A. Comandone A. et al.Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.J Clin Oncol. 2001; 19: 1238-1247https://doi.org/10.1200/JCO.2001.19.5.1238Crossref PubMed Scopus (550) Google Scholar, 26Gronchi A. Palmerini E. Quagliuolo V. Martin Broto J. Lopez Pousa A. Grignani G. et al.Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups.J Clin Oncol Off J Am Soc Clin Oncol. 2020; 38: 2178-2186https://doi.org/10.1200/JCO.19.03289Crossref PubMed Scopus (53) Google Scholar]. A meta-analysis that incorporated comparative trials with these drugs reported statistically significant survival benefit favouring ChT arm. Yet, this meta-analysis was not based on individual data [[27]Pervaiz N. Colterjohn N. Farrokhyar F. Tozer R. Figueredo A. Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma.Cancer. 2008; 113: 573-581https://doi.org/10.1002/cncr.v113:310.1002/cncr.23592Crossref PubMed Scopus (0) Google Scholar]. Perioperative ChT (preferably neoadjuvant) should be considered in the context of patients with high-risk localized STS of limbs and trunk-wall [II, A] [22Gronchi A. Frustaci S. Mercuri M. Martin J. Lopez-Pousa A. Verderio P. et al.Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.J Clin Oncol Off J Am Soc Clin Oncol. 2012; 30: 850-856https://doi.org/10.1200/JCO.2011.37.7218Crossref PubMed Scopus (123) Google Scholar, 25Frustaci S. Gherlinzoni F. De Paoli A. Bonetti M. Azzarelli A. Comandone A. et al.Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.J Clin Oncol. 2001; 19: 1238-1247https://doi.org/10.1200/JCO.2001.19.5.1238Crossref PubMed Scopus (550) Google Scholar, 28Gronchi A. Ferrari S. Quagliuolo V. Broto J.M. Pousa A.L. Grignani G. et al.Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial.Lancet Oncol. 2017; 18: 812-822https://doi.org/10.1016/S1470-2045(17)30334-0Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, 29Lu E. Perlewitz K.S. Hayden J.B. Hung A.Y. Doung Y.-C. Davis L.E. et al.Epirubicin and Ifosfamide with Preoperative Radiation for High-Risk Soft Tissue Sarcomas.Ann Surg Oncol. 2018; 25: 920-927https://doi.org/10.1245/s10434-018-6346-4Crossref PubMed Scopus (3) Google Scholar]. Tumours > 5 cm, G3 and deep located have been used as high-risk population criteria. However, high-risk could be more precisely defined by validated nomograms as death risk higher than 40% [[26]Gronchi A. Palmerini E. Quagliuolo V. Martin Broto J. Lopez Pousa A. Grignani G. et al.Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups.J Clin Oncol Off J Am Soc Clin Oncol. 2020; 38: 2178-2186https://doi.org/10.1200/JCO.19.03289Crossref PubMed Scopus (53) Google Scholar]. The combination of anthracycline and ifosfamide at full doses with G-CSF and MESNA support is the recommended scheme being three cycles as effective as five in a randomized trial [II, A] [[22]Gronchi A. Frustaci S. Mercuri M. Martin J. Lopez-Pousa A. Verderio P. et al.Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.J Clin Oncol Off J Am Soc Clin Oncol. 2012; 30: 850-856https://doi.org/10.1200/JCO.2011.37.7218Crossref PubMed Scopus (123) Google Scholar]. Further randomized clinical trials evaluating the role of perioperative ChT are needed, and patient participation is strongly encouraged. The presence of distant metastasis is a poor prognostic factor for OS, ranging currently 18–20 months [30Tap W.D. Jones R.L. Van Tine B.A. Chmielowski B. Elias A.D. Adkins D. et al.Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.Lancet Lond Engl. 2016; 388: 488-497https://doi.org/10.1016/S0140-6736(16)30587-6Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar, 31Italiano A. Mathoulin-Pelissier S. Cesne A.L. Terrier P. Bonvalot S. Collin F. et al.Trends in survival for patients with metastatic soft-tissue sarcoma.Cancer. 2011; 117: 1049-1054https://doi.org/10.1002/cncr.25538Crossref PubMed Scopus (179) Google Scholar]. However, a fraction of patients with advanced sarcoma could benefit from long term remission, especially those reaching a complete response and a smaller percentage of those obtaining partial response after first line of treatment for advanced disease [[32]Blay J.-Y. van Glabbeke M. Verweij J. van Oosterom A.T. Le Cesne A. Oosterhuis J.W. et al.Advanced soft-tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy.Eur J Cancer Oxf Engl. 2003; 39: 64-69https://doi.org/10.1016/S0959-8049(02)00480-XAbstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar]. Supportive care and quality of life evaluation should be included in the early management of all patients with advanced sarcoma [[33]Hudgens S. Forsythe A. Kontoudis I. D’Adamo D. Bird A. Gelderblom H. Evaluation of Quality of Life at Progression in Patients with Soft Tissue Sarcoma.Sarcoma. 2017; 2017: 1-8https://doi.org/10.1155/2017/2372135Crossref Scopus (11) Google Scholar]. When complete excision of all lesions is feasible, surgery can be a preferable treatment option for metachronous (disease-free interval ≥ 1 year) metastatic appearance when the number of nodes is limited (i.e. 3–5) and without extrapulmonary disease [IV, B]. This strategy could also be offered to patients with oligometastatic disease located at others sites (liver, soft tissue) [V, B] [[34]Blackmon S.H. Shah N. Roth J.A. Correa A.M. Vaporciyan A.A. Rice D.C. et al.Resection of pulmonary and extrapulmonary sarcomatous metastases is associated with long-term survival.Ann Thorac Surg. 2009; 88: 877-885https://doi.org/10.1016/j.athoracsur.2009.04.144Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar], after discussion in MDTB. In selected cases, stereotactic radiotherapy might also be recommended in this setting after discussion in MDTB [IV, C] [[35]Falk A.T. Moureau-Zabotto L. Ouali M. Penel N. Italiano A. Bay J.-O. et al.Effect on survival of local ablative treatment of metastases from sarcomas: a study of the French sarcoma group.Clin Oncol R Coll Radiol G B. 2015; 27: 48-55https://doi.org/10.1016/j.clon.2014.09.010Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. First-line standard ChT treatment is based on anthracyclines [I, A]. In particular subtypes, with greater sensitivity to ifosfamide, such as synovial sarcoma and undifferentiated pleomorphic sarcoma (UPS), and/or when a tumour response could be potentially advantageous, and in patients with good performance status multi-agent ChT with adequate-dose anthracyclines plus ifosfamide may be the preferential treatment option [I, B]. [36Judson I. Verweij J. Gelderblom H. Hartmann J.T. Schöffski P. Blay J.-Y. et al.Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.Lancet Oncol. 2014; 15: 415-423https://doi.org/10.1016/S1470-2045(14)70063-4Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 37Antman K. Crowley J. Balcerzak S.P. Rivkin S.E. Weiss G.R. Elias A. et al.An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas.J Clin Oncol. 1993; 11: 1276-1285https://doi.org/10.1200/JCO.1993.11.7.1276Crossref PubMed Scopus (393) Google Scholar]. For leiomyosarcoma, doxorubicin and dacarbazine could be considered, instead of anthracyclines plus ifosfamide, since this latter could be even detrimental in this specific subtype according to retrospective comparisons. [IV, B] [[38]Kasper B. The challenge of finding new therapeutic avenues in soft tissue sarcomas.Clin Sarcoma Res. 2019; 9: 5https://doi.org/10.1186/s13569-019-0115-4Crossref PubMed Google Scholar]. The combination of gemcitabine plus docetaxel is not recommended as a first-line option for the treatment of advanced STS [[39]Seddon B. Strauss S.J. Whelan J. Leahy M. Woll P.J. Cowie F. et al.Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.Lancet Oncol. 2017; 18: 1397-1410https://doi.org/10.1016/S1470-2045(17)30622-8Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar]. The inclusion of patients with advanced STS in clinical trials should be encouraged whenever available (Fig. 1). Beyond first-line, there are several second-line options (Table 1, Fig. 2):•High-dose ifosfamide (12–14 g/m2/cycle, administered in 6 days or in 14 days with G-CSF and MESNA support) can circumvent the tumour resistance to regimens with moderate doses of ifosfamide [I, D] [[40]Le Cesne A. Antoine E. Spielmann M. Le Chevalier T. Brain E. Toussaint C. et al.High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas.J Clin Oncol. 1995; 13: 1600-1608https://doi.org/10.1200/JCO.1995.13.7.1600Crossref PubMed Scopus (194) Google Scholar].•If available, trabectedin can be used for second line in pretreated STS, especially but not exclusively in liposarcoma, leiomyosarcoma and translocation-related sarcomas [II, B] [41Demetri G.D. Chawla S.P. von Mehren M. Ritch P. Baker L.H. Blay J.Y. et al.Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules.J Clin Oncol. 2009; 27: 4188-4196https://doi.org/10.1200/JCO.2008.21.0088Crossref PubMed Scopus (414) Google Scholar, 42Demetri G.D. von Mehren M. Jones R.L. Hensley M.L. Schuetze S.M. Staddon A. et al.Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial.J Clin Oncol. 2016; 34: 786-793https://doi.org/10.1200/JCO.2015.62.4734Crossref PubMed Scopus (444) Google Scholar, 43Kawai A. Araki N. Sugiura H. Ueda T. Yonemoto T. Takahashi M. et al.Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a random