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 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 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 and 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