Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

Soft tissue sarcomas (STSs) gather over 80 histological entities, with even more molecular subsets, characterised by a low to very low incidence in all populations. The majority of sarcomas arise from the soft tissue (close to 75%), with ∼15% gastrointestinal stromal tumours (GISTs) and 10% bone sarcomas. These ESMO–EURACAN (European Society for Medical Oncology–European Reference Network for rare adult solid cancers) Clinical Practice Guidelines cover STSs, while GISTs are covered by dedicated ESMO–EURACAN Clinical Practice Guidelines [1.Casali P.G. Abecassis N. Bauer S. et al.Gastrointestinal stromal tumours: ESMO--EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: iv68-iv78Abstract Full Text Full Text PDF Scopus (257) Google Scholar]. Kaposi’s sarcoma is not considered in the present document. Extraskeletal Ewing and Ewing-like sarcoma is covered by ESMO Clinical Practice Guidelines on bone sarcomas [2.Casali P.G. Bielack S. Abecassis N. et al.Bone sarcomas: ESMO--PaedCan--EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: iv79-iv95Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. In general, the same principles for these tumours in children apply to adults. This is also the case for embryonal and alveolar rhabdomyosarcomas, which are exceedingly rare in adults. On the other hand, pleomorphic rhabdomyosarcoma is viewed as a high-grade, adult-type STS. Extraskeletal osteosarcoma is also a high-grade STS, whose clinical resemblance with osteosarcoma of bone is doubtful (prospective collection of data is encouraged to generate evidence on the therapeutic implications of such a diagnosis). Adult STS pathological subtypes occurring in adolescents should be managed the same way as in adult patients, though the same histotype might display clinical peculiarities when occurring at different ages. Adult soft tissue and visceral sarcomas (excluding GIST) are rare tumours, with an estimated incidence averaging 4–5/100 000/year in Europe [3.Stiller C.A. Trama A. Serraino D. et al.Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.Eur J Cancer. 2013; 49: 684-695Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar]. STSs include over 80 different histological subtypes, and the most frequent, liposarcomas and leiomyosarcomas (LMSs), each have an incidence < 1/100 000/year. The majority of sarcoma histotypes therefore have an incidence < 2/1 000 000/year. STSs are ubiquitous in their site of origin and are often managed with multimodality treatment. A multidisciplinary approach is, therefore, mandatory in all cases, involving pathologists, radiologists, surgeons, radiation therapists, medical oncologists and paediatric oncologists, as well as nuclear medicine specialists and organ-based specialists, as applicable. Management should be carried out in reference centres for sarcomas and/or within reference networks sharing multidisciplinary expertise and treating a high number of patients annually. These centres are involved in ongoing clinical trials, in which the enrolment of sarcoma patients is common. This centralised referral should be pursued as early as at the time of the clinical diagnosis of a suspected sarcoma. In practice, referral of all patients with a lesion likely to be a sarcoma would be recommended. This would mean referring all patients with an unexplained deep mass of soft tissues, or with a superficial lesion of soft tissues having a diameter of > 5 cm. Quality criteria are needed for sarcoma reference centres and, increasingly, reference networks. These criteria may vary from country to country but, among others, should be based on: multidisciplinarity (incorporating tools such as weekly tumour boards discussing new cases), volume of patients, availability of facilities needed to properly apply clinical practice guidelines, recording and publication of outcomes and involvement in clinical and translational research. In primary soft tissue tumours, magnetic resonance imaging (MRI) is the main imaging modality in the extremities, pelvis and trunk. Standard radiographs may be useful to rule out a bone tumour, to detect bone erosion with a risk of fracture and to show calcifications. Computed tomography (CT) has a role in calcified lesions, to rule out a myositis ossificans, and in retroperitoneal tumours, where the performance is identical to MRI. Ultrasound may be the first exam, but it should be followed by CT or MRI. Following appropriate imaging assessment, the standard approach to diagnosis consists of multiple core needle biopsies, possibly by using ≥ 14–16 G needles. However, an excisional biopsy may be the most practical option for < 3 cm superficial lesions. An open biopsy may be another option in selected cases, as decided within reference centres. An immediate evaluation of tissue viability may be considered to ensure that the biopsy is adequate at the time it is carried out. However, a frozen-section technique for immediate diagnosis is not encouraged, because it does not allow a complete diagnosis, particularly when neoadjuvant (preoperative) treatment is planned. Fine needle aspiration is used only in some institutions that have developed specific expertise on this procedure and is not recommended outside these centres. A biopsy may underestimate the tumour malignancy grade. Therefore, when preoperative treatment is an option, radiological imaging [including positron emission tomography (PET)] may be useful, in addition to pathology, in providing the clinician with information that helps to estimate the malignancy grade (e.g. necrosis). The biopsy should be carried out by a surgeon or a radiologist after multidisciplinary discussion, as needed, within reference centres. It should be planned in such a way that the biopsy pathway and the scar can be safely removed by definitive surgery [except for retroperitoneal sarcomas (RPSs)]. The biopsy entrance point can be tattooed. The tumour sample should be fixed in 4% buffered formalin rapidly (Bouin fixative should not be used, since it prevents molecular analysis). The collection of fresh frozen tissue and tumour imprints (touch preparations) is encouraged to allow new molecular pathology assessments to be made at a later stage when requested. In this perspective, the availability of a blood sample could add to the value of tumour tissues. Informed consent for biobanking should be sought, enabling later analyses and research, if this is allowed by local and international rules. Pathological diagnosis should be made according to the 2013 World Health Organization (WHO) classification [4.Fletcher C.D.M. Bridge J.A. Hogendoorn P.C. Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. IARC, Lyon2013Google Scholar]. A pathological expert validation is required in all cases when the original diagnosis was made outside a reference centre/network [5.Ray-Coquard I. Montesco M.C. Coindre J.M. et al.Sarcoma: concordance between initial diagnosis and centralized expert review in a population-based study within three European regions.Ann Oncol. 2012; 23: 2442-2449Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]. The malignancy grade should be provided in all cases in which this is feasible based on available systems, because it has prognostic and predictive meaning. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is generally used, and distinguishes three malignancy grades based on differentiation, necrosis and mitotic rate [6.Trojani M. Contesso G. Coindre J.M. et al.Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system.Int J Cancer. 1984; 33: 37-42Crossref PubMed Scopus (955) Google Scholar]. Whenever possible, the mitotic rate should be provided independently. Grading cannot be assigned after preoperative medical treatment, by which the tumour tissue undergoes major therapy-related changes. Tumour site should be properly recorded. Tumour size and tumour depth (in relation to the superficial fascia) should also be recorded, since they entail a prognostic value, along with the malignancy grade. The pathology report after definitive surgery should mention whether the tumour was intact and should include an appropriate description of tumour margins (i.e. the status of inked margins and the distance in millimetres between tumour edge and the closest inked margins). This allows the assessment of margin status (i.e. whether the minimum margin is intralesional, marginal or wide and distances from surrounding tissues). The pathological assessment of margins should be made in collaboration with the surgeon. If preoperative treatment was carried out, the pathology report should include an assessment of the pathological response of the tumour. In contrast to osteosarcoma and Ewing sarcoma, however, no validated system is available at present. A multidisciplinary judgement is recommended, involving the pathologist and the radiologist. Pathological diagnosis relies on morphology and immunohistochemistry. It should be complemented by molecular pathology, especially when: •the specific pathological diagnosis is doubtful;•the clinical pathological presentation is unusual; and•it may have prognostic and/or predictive relevance. External quality assurance programmes are strongly encouraged for laboratories performing molecular pathology assessments. Available staging classifications have limited relevance and should be improved. The Union for International Cancer Control (UICC) stage classification system, 8th edition (Table 1) stresses the importance of the malignancy grade in sarcoma [7.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar]. In general, in addition to grading, other prognostic factors are tumour size and tumour depth for limb sarcomas. Of course, site, tumour resectability and presence of metastases are also important. Nomograms are available, which can help personalise risk assessment and thus clinical decision making, especially on adjuvant/neoadjuvant treatments [8.Callegaro D. Miceli R. Bonvalot S. 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: 671-680Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 9.Gronchi A. Miceli R. Shurell E. 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: 1649-1655Crossref PubMed Scopus (234) Google Scholar].Table 1STS UICC TNM 8 staging system [7.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar]T—primary tumourTXPrimary tumour cannot be assessedT0No evidence of primary tumourExtremity and superficial trunkT1Tumour 5 cm or less in greatest dimensionT2Tumour more than 5 cm but no more than 10 cm in greatest dimensionT3Tumour more than 10 cm but no more than 15 cm in greatest dimensionT4Tumour more than 15 cm in greatest dimensionRetroperitoneumT1Tumour 5 cm or less in greatest dimensionT2Tumour more than 5 cm but no more than 10 cm in greatest dimensionT3Tumour more than 10 cm but no more than 15 cm in greatest dimensionT4Tumour more than 15 cm in greatest dimensionHead and neckT1Tumour 2 cm or less in greatest dimensionT2Tumour more than 2 cm but no more than 4 cm in greatest dimensionT3Tumour more than 4 cm in greatest dimensionT4aTumour invades the orbit, skull base or dura, central compartment viscera, facial skeleton, and or pterygoid musclesT4bTumour invades the brain parenchyma, encases the carotid artery, invades prevertebral muscle or involves the central nervous system by perineural spreadThoracic and abdominal visceraT1Tumour confined to a single organT2aTumour invades serosa or visceral peritoneumT2bTumour with microscopic extension beyond the serosaT3Tumour invades another organ or macroscopic extension beyond the serosaT4aMultifocal tumour involving no more than two sites in one organT4bMultifocal tumour involving more than two sites but not more than five sitesT4cMultifocal tumour involving more than five sitesN—regional lymph nodesNXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisM—distant metastasisM0No distant metastasisM1Distant metastasisStage—extremity and superficial trunk and retroperitoneumStage IAT1N0M0G1, GX Low GradeStage IBT2, T3, T4N0M0G1, GX Low GradeStage IIT1N0M0G2, G3 High GradeStage IIIAT2N0M0G2, G3 High GradeStage IIIBT3, T4N0M0G2, G3 High GradeStage IIIBAny TN1aAJCC classifies N1 as stage IV for extremity and superficial trunk.M0Any GStage IVAny TAny NM1Any GStage—head and neck and thoracic and abdominal visceraThere is no stage for soft tissue sarcoma of the head and neck and thoracic and abdominal viscera.pTNM Pathological Classification: the pT and pN categories correspond to the T and N categories. The only pM category is pM1 (distant metastasis microscopically confirmed), pM0 is not a valid category.AJCC, American Joint Committee on Cancer; STS, soft tissue sarcoma; TNM, tumour, node, metastasis; UICC, Union for International Cancer Control.Reprinted from [7.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar] with permission from John Wiley & Sons, Inc.a AJCC classifies N1 as stage IV for extremity and superficial trunk. Open table in a new tab pTNM Pathological Classification: the pT and pN categories correspond to the T and N categories. The only pM category is pM1 (distant metastasis microscopically confirmed), pM0 is not a valid category. AJCC, American Joint Committee on Cancer; STS, soft tissue sarcoma; TNM, tumour, node, metastasis; UICC, Union for International Cancer Control. Reprinted from [7.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar] with permission from John Wiley & Sons, Inc. A chest spiral CT scan is mandatory for staging purposes. Regional lymph node metastases are rare, with the exception of some histologies, e.g. epithelioid sarcoma and clear cell sarcoma, for which regional assessment through CT/MRI may be added to the usual staging procedures. Likewise, an abdominal CT scan may be added for limb myxoid liposarcoma. The brain CT scan may be added for alveolar soft part sarcoma, clear cell sarcoma and angiosarcoma. Bone scan, whole-body MRI and PET scan are optional. Cost-effectiveness studies on their incorporation into the staging procedures are required. The surgical report, or patient chart, should provide details on: •preoperative and intraoperative diagnosis;•surgical conduct, including possible contaminations (i.e. it should mention whether the tumour was opened and was ‘seen’ during the excision, etc.); and•surgical actual completeness vis-a-vis planned quality of margins. Surgery is the standard treatment of all patients with an adult type, localised STS. It must be carried out by a surgeon specifically trained in the treatment of this disease. The standard surgical procedure is a wide excision with negative margins (no tumour at the margin, R0). This implies removing the tumour with a rim of normal tissue around it [II, A] [10.Rosenberg S.A. Tepper J. Glatstein E. et al.The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.Ann Surg. 1982; 196: 305-315Crossref PubMed Scopus (1032) Google Scholar]. The minimal margin on fixed tissue to be considered adequate may depend on several factors, including histological subtype, preoperative therapies and the presence of resistant anatomical barriers, such as muscular fasciae, periosteum and epineurium. As an individualised option, marginal excision can be acceptable in carefully selected cases, in particular for extracompartmental atypical lipomatous tumours [IV, B].Figure 2Management of localised, clinically unresectable STS. aOptional: isolated limb perfusion in selected cases. ChT, chemotherapy; R0, no tumour at the margin; R1, microscopic tumour at the margin; RT, radiotherapy; STS, soft tissue sarcoma.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The typical wide excision is followed by radiotherapy (RT) as the standard treatment of high-grade (G2–3), deep, > 5 cm lesions [II, B] [11.Pisters P.W. Harrison L.B. Leung D.H. et al.Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma.J Clin Oncol. 1996; 14: 859-868Crossref PubMed Scopus (777) Google Scholar, 12.Yang J.C. Chang A.E. Baker A.R. 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: 197-203Crossref PubMed Scopus (1180) Google Scholar, 13.Beane J.D. Yang J.C. White D. et al.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: 2484-2489Crossref PubMed Scopus (147) Google Scholar]. RT is not given in the case of a currently unusual, truly compartmental resection of a tumour entirely contained within the compartment [IV, A]. Exceptions may be made after multidisciplinary discussion considering several variables [14.Cahlon O. Brennan M.F. Jia X. et al.A postoperative nomogram for local recurrence risk in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation.Ann Surg. 2012; 255: 343-347Crossref PubMed Scopus (108) Google Scholar]. With exceptions to be discussed in a multidisciplinary setting and faced with a lack of consensus across reference centres, high-grade, deep, < 5 cm lesions are also treated with surgery, followed by RT [IV, A]. RT is added in selected cases in the case of low- or high-grade, superficial, > 5 cm and low-grade, deep, < 5 cm STSs [II, B]. In the case of low-grade, deep, > 5 cm STSs, RT should be discussed in a multidisciplinary fashion, considering the anatomical site and the related expected sequelae versus the pathological aggressiveness. Local control and survival are not influenced by the timing of RT, but early and late complications are. If it is anticipated that wound complications will be severe, surgery followed by adjuvant RT may be the best option. RT should then be administered with the best technique available, to a total dose of 50 Gy in 1.8–2 Gy fractions, possibly with a boost up to 66 Gy, depending on presentation and resection margins. If it is anticipated that wound complications will be a manageable problem, neoadjuvant RT, possibly in combination with chemotherapy (ChT) to a total dose of 50 Gy in 1.8–2 Gy fractions, followed by surgery may be considered [15.O'Sullivan B. Davis A.M. Turcotte R. et al.Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial.Lancet. 2002; 359: 2235-2241Abstract Full Text Full Text PDF PubMed Scopus (1089) Google Scholar]. In addition, with modern RT techniques such as image-guided RT and intensity-modulated radiotherapy (IMRT), the anticipated incidence of wound complications after preoperative RT is lower than historically published incidence rates. The main advantage of preoperative RT is that, with prolonged follow-up, late morbidity (fibrosis, bone fracture, etc.) is lower, translating into improved long-term functional outcome and quality of life (QoL). Reoperation in reference centres must be considered in the case of R1 resections (microscopic tumour at the margin), if adequate margins can be achieved without major morbidity, taking into account tumour extent and tumour biology (e.g. re-excision can be spared in extracompartmental atypical lipomatous tumours) [IV, A]. In the case of R2 surgery (macroscopic tumour at the margin), reoperation in reference centres is mandatory, possibly following preoperative treatments if adequate margins cannot be achieved, or if surgery is mutilating. In the latter case, the use of multimodal therapy with less radical surgery is optional and requires shared decision making with the patient in cases of uncertainty. Plastic repairs and vascular grafting should be used as needed, and the patient should be properly referred as necessary. RT will follow marginal or R1–R2 excisions, if these cannot be rescued through re-excision, tailoring the decision depending on further considerations, including impact on future surgeries. Mutilating surgery may be of choice in some cases. Options for limb-preserving surgery can be discussed with the patient, including ChT and/or RT [III, A], or isolated hyperthermic limb perfusion with tumour necrosis factor alpha (TNF-α) plus melphalan [III, A], if the tumour is confined to an extremity, or regional hyperthermia combined with ChT [I, B] [16.Issels R.D. Lindner L.H. Verweij J. et al.Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.Lancet Oncol. 2010; 11: 561-570Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar]. These options are also proposed for non-resectable tumours, i.e. in truly locally advanced disease. Regional lymph node metastases should be distinguished from soft tissue metastases involving lymph nodes. They are rare and constitute an adverse prognostic factor in adult-type STSs. More aggressive treatment planning is, therefore, felt to be appropriate for these patients, although there is a lack of formal evidence to indicate that this improves clinical results. Surgery through wide excision (mutilating surgery is exceptionally done, given the prognosis of these patients) may be coupled with adjuvant RT and adjuvant ChT for sensitive histological types, as the standard treatment of these presentations [IV, B]. ChT may be administered as preoperative treatment, at least in part. Given the paucity of published data on adjuvant RT after lymph node dissections in regional metastatic STS, the indication should probably be reserved for patients with a relatively large number of tumour-positive lymph nodes and/or extranodal spread in the absence of haematogenic metastases. The increase in local control should be balanced against toxicity (especially peripheral lymphoedema). These treatment modalities added to surgery should not be viewed as truly ‘adjuvant’, the context being, in fact, that of a likely systemic disease. In one large, randomised phase III study (in patients with G2–3, deep, > 5 cm STSs), regional hyperthermia in addition to systemic ChT was associated with a local control and disease-free survival (DFS) advantage when compared with ChT alone [I, B]. Isolated limb perfusion may be an option in this patient population. This modality obviously has no impact on systemic control (but it can be combined with other modalities) [III, A] [17.Deroose J.P. Eggermont A.M. van Geel A.N. et al.Long-term results of tumor necrosis factor alpha- and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas.J Clin Oncol. 2011; 29: 4036-4044Crossref PubMed Scopus (75) Google Scholar]. There is no consensus on the current role of adjuvant ChT. Study results are conflicting, in the presence of negative results from the largest studies, though data are available from smaller studies suggesting that adjuvant ChT might improve, or at least delay, distant and local recurrence in high-risk patients [18.Frustaci S. Gherlinzoni F. De Paoli 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: 1238-1247Crossref PubMed Scopus (567) Google Scholar, 19.Woll P.J. Reichardt P. Le Cesne A. 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: 1045-1054Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar]. A meta-analysis on published data found a statistically significant limited benefit in terms of both relapse-free survival (RFS) and overall survival (OS) [20.Pervaiz N. Colterjohn N. Farrokhyar F. et al.A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma.Cancer. 2008; 113: 573-581Crossref PubMed Scopus (642) Google Scholar]. Gain in OS was not significant on the only meta-analysis using source data [21.Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration.Lancet. 1997; 350: 1647-1654Abstract Full Text Full Text PDF PubMed Scopus (902) Google Scholar]. Given the conflicting results of trials included in the meta-analyses, adjuvant ChT is not standard treatment in adult-type STS. It can be proposed as an option to the high-risk individual patient (high-grade, deep, > 5 cm tumour) for a shared decision making with the patient [II, C]. ChT was used as neoadjuvant treatment, aiming at a local benefit facilitating surgery, in addition to the systemic one. A randomised trial showed no differences between three (preoperative) and five (pre- and postoperative) courses of full-dose ChT in high-risk STS patients [22.Gronchi A. Frustaci S. Mercuri M. 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. 2012; 30: 850-856Crossref PubMed Scopus (133) Google Scholar]. A subsequent trial compared preoperative ChT with full-dose epirubicin plus ifosfamide versus a histology-driven ChT. This trial was closed slightly in advance because three interim analyses showed a statistically significant benefit in terms of both RFS and OS in favour of neoadjuvant therapy with epirubicin and ifosfamide. Since there is no obvious evidence that histology-driven ChT could be detrimental, this may be viewed as providing randomised evidence of the efficacy of neoadjuvant therapy with full-dose anthracyclines plus ifosfamide in high-risk extremity and superficial trunk STS ‘fit’ patients (i.e. with lesions > 5 cm, deep, of a high-grade histology including undifferentiated pleomorphic sarcoma, liposarcoma, LMS, malignant peripheral nerve sheet tumour and synovial sarcoma). However, this evidence currently corresponds to an interim planned analysis within a trial statistically conceived to test the superiority of a histology-driven ChT [23.Gronchi A. Ferrari S. Quagliuolo V. 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: 812-822Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar]. The trial has been amended to test the superiority of epirubicin plus ifosfamide over the histology-driven therapy at the time of the final analysis. While awaiting these results, neoadjuvant ChT with anthracyclines plus ifosfamide for at least three cycles can be viewed as an option in the high-risk individual patient, for shared decision making [II, Ca] (see note a in Table 2). The evolution of the tumour lesion during preoperative ChT should be closely monitored to exclude progression, while considering possible patterns of non-dimensional tumour response.Table 2Summary of recommendationsDiagnosis and pathology/molecular biology•Management of STS should be carried out in reference centres for sarcomas•Pathological diagnosis should be made according to the 2013 WHO classificationManagement of local/locoregional disease•Surgery is the standard treatment of all patients with an adult type, localised STS. It must be carried out by a surgeon specifically trained in the treatment of this disease. The standard surgical procedure is a wide excision with negative margins (absence of residual tumour, R0) [II, A]•The typical wide excision is followed by RT as the standard treatment of high-grade (G2–3), deep, > 5 cm lesions [II, B]. Exceptions may be made after multidisciplinary discussion considering several variables•Options for limb-preserving surgery include ChT and/or RT [III, A], or isolated hyperthermic limb perfusion with tumour necrosis factor-alpha + melphalan [III, A], or regional hyperthermia combined with ChT [I, B]•Adjuvant ChT is not standard treatment in adult-type STS. It can be proposed as an option to the high-risk individual patient [II, C]•Neoadjuvant ChT with anthracyclines plus ifosfamide for at least 3 cycles is an option in the high-risk individual patient [II, CaThe experts noted that no GoR described the accurate situation in term of scientific evidence. GoR B is ’Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended’, and GoR C is ‘Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvanta