Clinical and Translational Oncology (2021) 23:922–930 https://doi.org/10.1007/s12094-020-02534-0 CLINICAL GUIDES IN ONCOLOGY SEOM Clinical Guideline of management of soft‑tissue sarcoma (2020) A. de Juan Ferré1 · R. Álvarez Álvarez2 · A. Casado Herráez3 · J. Cruz Jurado4 · A. Estival González5 · J. Martín‑Broto6 · V. Martínez Marín7 · A. Moreno Vega8 · A. Sebio García9 · C. Valverde Morales10 Received: 20 November 2020 / Accepted: 21 November 2020 / Published online: 6 January 2021 © The Author(s) 2021 Abstract Soft-tissue sarcomas constitute an uncommon and heterogeneous group of tumors of mesenchymal origin. Diagnosis, treat- ment, 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. Periopera- tive 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. Keywords Sarcoma · Guidelines · Soft-tissue tumors · Uncommon tumors Introduction in Europe. They can arise anywhere in the body, but most originate in the extremities, followed by the trunk, retroperi- Soft-tissue sarcomas (STS) constitute an uncommon and toneum, head and neck, and viscera. Although more common heterogeneous group of tumors of mesenchymal origin, with in middle-aged and older adults, they can affect children and an estimated incidence of 5 cases/100,000 inhabitants/year young adults. Multidisciplinary management is crucial. STS comprises different histopathological subtypes that share All authors have contributed equally to the present manuscript and are GEIS members. * A. de Juan Ferré C. Valverde Morales anade.juan@scsalud.es cvalverde@vhio.net R. Álvarez Álvarez 1 Hospital Universitario Marqués de Valdecilla, Santander, rosa.alvarez.al@gmail.com Spain A. Casado Herráez 2 Hospital General Universitario Gregorio Marañón, Madrid, antonio.casado@salud.madrid.org Spain J. Cruz Jurado 3 Hospital Universitario Clínico San Carlos, Madrid, Spain jcruzjurado@gmail.com 4 Hospital Universitario de Canarias, Tenerife, Spain A. Estival González 5 estivalanna@gmail.com Institut Català d’Oncologia-Badalona, Barcelona, Spain 6 J. Martín‑Broto Hospital Universitario Virgen del Rocío, Sevilla, Spain jmartin@mustbesevilla.org 7 Hospital Universitario la Paz, Madrid, Spain V. Martínez Marín 8 Hospital Universitario Reina Sofía, Córdoba, Spain virgimarin9@hotmail.com 9 Hospital de la Santa Creu I Sant Pau, Barcelona, Spain A. Moreno Vega 10 almvoncomed2@gmail.com Hospital Universitario Vall d’Hebron, Barcelona, Spain A. Sebio García asebio@santpau.cat 13 Vol:.(1234567890) Clinical and Translational Oncology (2021) 23:922–930 923 several clinical and pathological features but have some spe- margins (R0) (II, A). The correct negative margins vary cific characteristics that may impact the treatment. depending on the tumour location, histology, grade or pre- The main objective of this guideline is to provide updated operative treatment but, generally, at least 1 cm or an intact and clear practical recommendations about the management anatomical barrier is recommended. Reconstructive surgery of STS and to contribute to the improvement of STS patient’s might help to achieve a R0 surgery. When a wide excision care in Spain. Some subtypes, such as rhabdomyosarcoma, is not possible, amputation/disarticulation is indicated and gastrointestinal stromal tumors, extraosseus osteosarcoma, TNFα and melphalan-based isolated limb perfusion for limb and Ewing’s sarcoma are beyond the focus of this guideline salvage could be considered [4]. Re-operation is mandatory because of their specific and differential management. in positive R2 margins and could be considered in R1 when no major morbidity is expected. The biopsy tract should be Methodology included in the surgical specimen and the incision should follow the longitudinal axis. Affected lymph nodes should These guidelines have been developed by a panel of special- be removed but staging lymphadenectomy not recommended ists in medical oncology dedicated to STS in adults. A biblio- (III, B). graphic search was performed in PubMed and international Perioperative RT reduces local recurrences with no guidelines such as NCCN, ESMO/ EURACAN as well as impact in survival [5]. RT should be given to high-grade relevant abstracts presented at international meetings were (grade 2–3), > 5 cm and deep lesions (II, A). For tumours consulted. In a telematic consensus meeting, each section was without all these high-risk features, RT should be discussed presented by one expert to the entire group for discussion and in a multidisciplinary setting. RT is also recommended in consensus. The two coordinating authors were responsible tumours resected with close/positive margins and for high- for compiling and homogenizing the different sections. All grade local recurrences previously untreated. RT can be authors revised and approved the final version of the docu- administered pre (50 Gy) or post-operatively (50 Gy and ment. The panel adopted the Infectious Disease Society of optional 10–26 Gy boost depending on the margins) (II, America levels of evidence/grades of recommendation [1]. A). Preoperative RT leads to less long-term fibrosis but increases the risk of wound complications. RT can be admin- Diagnosis: imaging, staging, and pathologic istered concomitantly with chemotherapy (III, B). Intensity- diagnosis modulated RT (IMRT) is an option with a better toxicity profile (III, B). As a general principle, both diagnostic and initial treatment R0 Surgery is the mainstay of treatment (II, A). should be performed in a coordinated and structured way in expert centers (III, A), (Table 1) and should take into Adjuvant and neoadjuvant chemotherapy consideration the patient perspective (Table 2). The goal of imaging studies is to establish tumor size, Perioperative chemotherapy in STS still represents a con- depth, site, resectability, and presence of metastases. Mag- troversial issue since a meta-analysis with individual data netic resonance with contrast is the preferred technic for indicated a non-significant absolute difference of 4% favor- tumors arising in the limbs, pelvis, and trunk and tomog- ing chemotherapy administration [6]. In these first-gener- raphy for retroperitoneal or intraabdominal STS and for ation randomized trials, a very heterogeneous population staging. The UICC TNM 8th edition [2] is the most spread was included (different grades, locations, sizes, varied his- staging system. Multiple core needle biopsies carried out by tologies), dose-intensity was low and only 5% of patients an expert after the multidisciplinary discussion is basic for received ifosfamide, the second most active drug. diagnostic. Incisional and excisional biopsy may be consid- Perioperative chemotherapy with 5 courses of full-dose ered only in selected cases. Histological diagnosis should be epirubicin and ifosfamide has demonstrated a significant made according to the 2020 WHO Classification [3] and the survival advantage in localized high-risk (G3, > 5 cm and grade following the FNCLCC-grading system. deep) STS of limbs and trunk-wall (II, A) [7]. Additionally, CT and/or MRI contrast-enhanced followed by core nee- a new meta-analysis (although not based on individual data) dle biopsy are the gold standart diagnostic methods. (II, A). incorporating 18 comparative trials including a combination of anthracyclines and ifosfamide, resulted in a significant Treatment localized disease survival advantage (recurrence, distant metastasis and OS) [8]. Neoadjuvant treatment could be preferred over adjuvant Surgery and radiotherapy (RT) since it could add potential prognostic information exploring the interaction between drugs and tumor. Three courses of Surgery is the standard treatment for localized disease. The neoadjuvant full-dose epirubicin and ifosfamide obtained surgical procedure consists of a wide excision with negative the same result as administering 2 additional courses in the 13 924 13 Table 1  Check list for diagnostic and surgical management Imaging check list Pathology check list Surgery check list * CT and/or MRI contrast-enhanced before the biopsy * Core-needle biopsy in reference centre * Patient’s position * PET scan is useful to estimate the malignancy grade and * Expert validation if diagnosis from not expert center * Pneumatic cuff (not recommended in sarcoma surgery due to response to the neoadjuvant therapy potential dissemination when released). Venous expression is not recommended for the same reason * A chest spiral CT is mandatory for mediastinal evaluation * Location, size and depth of tumor * Asepsis and antisepsis * Staging by UICC TNM 8th edition * Primary histological diagnosis by 2020 WHO classification * Surgical dress preparation * Brain CT/MRI in alveolar soft part sarcoma, clear cell sar- * Histologic grade by FNCLCC grading system (mitotic rate, * Surgical approach coma and angiosarcoma extent of necrosis and differentiation) * MRI of total spine in myxoid/round cell sarcoma * Presence or absence of invasion of adjacent structures * Progressive dissection by anatomical planes * Bone scan, whole-body MRI are optional * Surgical report: margins of excision and nodal status, * Tumour resection response after neoadjuvant therapy * Additional studies abdominal-pelvic CT/MRI (regional * Immunohistochemistry and molecular genetic testing (FISH, * Anticipated surgical margins (R0-R1-R2) to compare them to lymph node metastases) in epithelioid sarcoma, angiosar- RT-PCR or NGS) to detect fusions, translocations and other those in the pathology report coma, myxoid/round cell sarcoma, clear cell sarcoma and genetic aberrations in STS leiomyosarcoma * Vascular clipping of the tumour bed macroscopic limits * Hemostasis and surgical lavage * Surgical closure of tissue planes * In case surgical drains, use a drain (passed directly through skin incision) and apply compression dressing and sterile dressing * Bandaging and/or plastering Clinical and Translational Oncology (2021) 23:922–930 Clinical and Translational Oncology (2021) 23:922–930 925 Table 2  Patient-centered checklist Checklist for patients with STS Patients should be attended at centers belonging to a sarcoma network with a concrete expertise and multidisciplinary team Children and adolescents should be referred to centers which in addition provide age-specific expertise A clear treatment plan with objectives and estimated timelines should be discussed with the patient Psychological and educational support for patients and families is highly recommended Basal assessment ( especially cardiological with EKG and Echocardio, and endocrine) should be performed and other risk factors should be controlled to reduce toxicity burden of treatments Oncofertility consultation should be assessed as soon as possible after the diagnosis Encouraging of physical activity, adapted to patient situation, is highly recommended Nutritional advice may give a greater sense of well-being and may help to control chemo and radio-therapy side effects Basal work/ study activity should be assessed and patients should be refered to social workers as needed. Communication with school/university tutors and employers should be encouraged in order to facilitate a realistic plan for reintegration during and after treatment Getting in touch with other patients and patients’ family through patient associations may reduce isolation feeling and should be offered Quick activation of palliative care is essential (when indicated) All patients are entitled to request a second opinion from other oncologist(s)/team without any prejudice adjuvant setting [5cycles], in high-risk localized STS of Recurrence of disease after metastasectomy is frequent and limbs and trunk-wall (II, A). Of note, 61% of OS is main- there is some evidence to suggest that repeated metastasec- tained also over 10 years [9]. tomy could be associated with an improvement in the out- There is less convincing evidence for the value of peri- come (IV, C). operative chemotherapy in STS in other locations and in Stereotactic body radiotherapy (SBRT) and stereotactic lower-risk localized patients (i.e. grade 2). Nomograms are radiosurgery (SRS) can be used in selected patients who are increasingly used for the decision-making process so that poor candidates for surgery. SBRT attains excellent tumor a risk of death ≥ 40% is used as cut-off for the advice of control with limited toxicity in patients with lung metastases perioperative chemotherapy. (III, B) [11]. In subsequent relapses, repeated SBRT may Perioperative epirrubicin-ifosfamide should be discussed also be considered. with high-risk patients with tumors arising in limbs and Selected oligometastatic patients may obtain benefit from trunk-wall (II, A). complete surgical resection or from SBRT/SRS techniques (III, B). Treatment of advanced disease Systemic treatment: First Line Surgery and radiotherapy Anthracyclines are still the standard first-line treatment for advanced STS (doxorubicin 75 mg/m2 or equivalent) [12] Distant metastasis will be developed by 50% of patients (I, A). Although its combination with ifosfamide increased diagnosed with STS. Surgery of oligometastatic disease may the response rate and progression-free survival in sensitive play a role in well-selected patients, leading to an improve- histological types, it also increased toxicity and it didn´t ment in OS and 5-year survival rates, according to the ret- significantly improve survival in randomized trials (14.3 rospective, single-center data (IV, B). The presence of a vs. 12.8 months, HR 0.83) [13] and thus, its reserved for controllable primary tumor, histologic subtype, number of patients who may benefit from tumor reduction for symptom metastatic lesions (oligometastatic disease), low volume dis- palliation or improving resectability (I, B). Ifosfamide at ease, and disease-free interval should be considered by the 9–14 g/m2 is an alternative for synovial sarcoma or when multidisciplinary tumor board. In patients with exclusively anthracyclines are contraindicated (II, A) and weekly metachronous pulmonary metastases, complete resection of paclitaxel for angiosarcoma (IIIB) [14]. Other combination lung metastases may attain up to 18–43% long-term survival as doxorubicin plus dacarbazine could be considered for (III, B) [10]. However, in patients with synchronous lung patients needing a combination but relatively insensitive to metastases or short disease-free interval, systemic treatment ifosfamide like leiomyosarcoma [15] (V,B). should be considered. Subsequent surgery could be an option No drug added to doxorubicin (evofosfamide, palifosfa- if the benefit is achieved from systemic treatment (IV, C). mide, olaratumab) or alternative combination (gemcitabine 13 926 Clinical and Translational Oncology (2021) 23:922–930 plus docetaxel) has shown an advantage in overall survival, • Eribulin (1.4 mg/m2 days 1 and 8/21 days), has been in recently randomized trials (I, A). approved for liposarcoma based on a phase III trial Anthracyclines monotherapy is the first-line standard comparing eribulin vs dacarbazine after progression to treatment for metastatic patients, not a candidate for local anthracycline. OS was significantly improved (13.5 vs. treatment (I,A) and combination therapy could be consid- 11.5 m) in the whole population, without differences in ered for patients who may benefit from tumor reduction for PFS or RR, reaching a 7 month gain in OS in liposar- symptom palliation or improving resectability (I, B). coma [21]. (I, A). In spite of recent approvals, medical options for meta- Systemic treatment: second‑line chemotherapy static patients are limited and clinical trials, when available, and beyond should always be discussed. Although several treatments have been tested in this set- Second and further lines should be considered in fit and ting, none of them has been directly compared. Thus, the symptomatic patients. For asymptomatic patients, active sur- decisión of the second line is based on histology, toxicity veillance may be an option (IV, C). Several treatments have profile, and convenience of the scheme administration (IV, been tested in this setting, some of them showing higher A). responses in specific histotypes. However, none of them has been directly compared. Thus, the decision is based on Therapeutic considerations for specific STS subtypes histology, toxicity profile, and convenience of the scheme administration. Retroperitoneal sarcomas • Ifosfamide: Patients who had not received ifosfamide as Both retroperitoneal and uterine sarcoma are treated like a front line could receive it at a dose of 9 g/m2 or, in case other sarcomas in the metastasic setting, but there are some of progression to standard-dose, at high-dose (≥ 12 g/m2) special considerations. [16] (III, B). Synovial sarcoma is especially sensitive to Retroperitoneal sarcomas (RPS) are characterized by poor this drug. prognosis. More than half are high grade and adequate sur- • Gemcitabine in combination with docetaxel is more gical margins are rarely obtained. These patients should be effective in terms of PFS, OS and RR than gemcitabine managed by expert surgeons at referral centers with multi- monotherapy but with increased toxicity [17] (II, C). disciplinary units and board. En bloc resection of the tumor Gemcitabine (1800 mg/m2 at 10 mg/m2/min) with DTIC including adjacent organs is the only curative treatment for (500 mg/m2) every 14 days yielded superior OS and PFS RPS, negative margins being the main prognostic factor [22] when compared to dacarbazine alone with a good toxic- (III, A). ity profile [18] (II, B), leiomyosarcoma are especially Although retrospective studies suggested a possible benefits of these combinations. decrease in local relapses with preoperative RT in resect- • Trabectedin (1.5 mg/m2 in a 24 h infusion) has been able tumors, it has not improved survival in a recent ran- approved in Europe for patients diagnosed with all sub- domised clinical trial [23]. Therefore, it is not a stand- types of sarcoma after progression, or who are ineligi- ard treatment and should only be considered for selected ble, for doxorubicin and ifosfamide. A phase III trial, patients in a multidisciplinary sarcoma tumor board (II, including pre-treated patients with liposarcoma or leio- C). Intraoperative radiation therapy (IORT) is not standard myosarcoma, demonstrated better PFS with trabectedin nor widely available, but a small randomized trial showed over dacarbazine monotherapy (4.2 vs. 1.5 months) [19] its benefit in reducing local recurrence combined with low (I, A). It has shown better responses in myxoid lipo- dose external-beam radiation therapy (EBRT) compared sarcoma and leiomyosarcoma, and it should be given to high dose EBRT. The role of neoadjuvant chemother- until progression or intolerable toxicity, although dose apy versus resection alone for RPS is being studied in a and interval modifications may be needed in long-term randomised clinical trial. It may be considered in case of responders. technically unresectable/borderline resectable RPS, and in • Pazopanib (800 mg daily), a multitargeted tyrosine kinase chemosensitive histologies (IV, C). inhibitor, showed a benefit on PFS versus placebo (4.6 m Surgery of local recurrences should be considered, vs 1.6 m) in a phase III trial in pre-treated patients diag- especially in cases with a long disease-free interval after nosed with non-adipocytic sarcoma [20] (I, A). previous resection. (IV B). En bloc resection performed in 13 Clinical and Translational Oncology (2021) 23:922–930 927 high-volume sarcoma centres offers the best chance for long and phase II evidence for low dose methotrexate-vinblastine term survival for RPS (III, A). and imatinib (III, B). NSAID, antihormonal treatment (IV, C), vinorelbine (III, B) and liposomal doxorubicin may be Uterine sarcomas options based in retrospective data (III, B). Active surveillance by an expert team is the first approach Uterine sarcomas (US) includes leiomyosarcomas, high- (III, A). And use of the less toxic options in the first place grade uterine sarcoma, endometrial stromal sarcomas (ESS), is recommended. as well as other less frequent subtypes like PECOMA and adenosarcoma. Standard local treatment of localized US Solitary fibrous tumor (SFT) consists of total hysterectomy with full abdominal cav- ity exploration. (III, A). It is not clear whether bilateral In metastatic or locally advanced malignant SFT, pazopanib salpingo-oophorectomy is always needed. We recommend is the choice in the first line in typical and malignant sub- it for low-grade ESS or tumors expressing ER/PR. (V, B) types (III, B) [26–27]. Other antiangiogenic agents, such Prophylactic lymphadenectomy is not indicated. as sunitinib (III, B) or the combination of temozolomide Adjuvant radiotherapy decreases the local relapse rate plus bevacizumab, constitute active options (IV, B). Chemo- with no survival benefit and is therefore not routinely con- therapy in first line, in dedifferentiated SFT, and after the sidered. It is an option in selected cases with a high relapse failure of antiangiogenic agents in the rest of subtypes, risk (I, D). Although adjuvant chemotherapy in uterine LMS following the common guidelines for STS which include is not standard, due to the high risk of systemic relapse, it DTIC-gemcitabine, could be administered but its efficacy could be considered in some patients (IV, C) [24] Adjuvant is low (III, C). hormonal therapy in low-grade ESS is not standard, though Pazopanib is the first choice in SFT (III, B) except in the it might represent an alternative, given retrospective evi- dedifferentiated SFT subtype (III, B). dence of increased disease-free interval. (IV, C). Hormo- nal therapy with megestrol acetate, gonadotropin-releasing Dermatofibrosarcoma protuberans (DFSP) hormone (GnRH) analogues and aromatase inhibitors is the systemic treatment of advanced low-grade ESS (IV, B). DFSP is a cutaneous mesenchymal tumor of intermediate Standard local treatment of localized US is en bloc total behavior locally aggressive but rarely metastasizing. Surgi- hysterectomy (III, A). Adjuvant RT is not recommended cal excision with wide margins [2–4 cm] is the treatment of (I, D). localized disease. Mohs surgery can be planned to improve cosmetic results (III, B). Radiotherapy may be considered if Desmoid tumor (DT) positive margins and unfeasible re-excision. In unresectable, recurrent or metastatic DFSP, imatinib is recommended [28] DT is a rare monoclonal, fibroblastic proliferation charac- (III, B). terized by infiltrative growth and a tendency toward local Wide resection (III, B) and imatinib (III, B) if surgery is recurrence but an inability to metastasize. There are two not possible is the recommended approach for DFSP. genetic types, CTNNB1 mutations and FAP mutations. The later warrants germline testing and colonoscopy has a more Other rare specific subtypes (SS) aggressive behavior and is often multifocal. Active surveillance (clinical & MRI within 1–2 months, In advanced specific subtypes there is evidence of activity of then in 3–6 months intervals) by an experienced multidisci- several molecular targeted agents based in preclinical data plinary team is the best treatment in asymptomatic patients and small retrospective studies: (III, A), especially in unfavorable locations: chest wall, head and neck and upper limbs [25] Surgery is considered • mTor inhibitors and antiangiogenics in PECOMAS and as the second line, especially in the abdominal wall, pro- epithelioid hemangioendothelioma (IV, B) vided expected surgical morbidity is limited. Positive micro- • Crizotinib in inflammatory myofibroblastic tumor associ- scopic margins can be accepted when function or cosmesis ated with anaplastic lymphoma kinase (ALK) transloca- is an issue (IV, B). Data for radiotherapy after surgery are tions (IV, B) limited, but it should be considered when surgery is not • Sunitinib ± nivolumab, cediranib in alveolar soft part sar- an option and medical treatments fail (IV, B). There´s no coma [29] (IV, C) definitive sequence for systemic treatment options. There is • Sunitinib ± nivolumab in clear cell sarcoma [29] (IV, C) randomized data for sorafenib (II, B) and pazopanib (I, B), • Tazemetostat in epithelioid sarcoma [30] (III, B) 13 928 Clinical and Translational Oncology (2021) 23:922–930 • NTRK sarcomas: entrectinib, larotrectinib [31] (III, A) nodes (epithelioid, clear cell, synovial sarcoma or rhabdo- myosarcoma) and RPS frequently relapse locally, to the liver Targeted therapies in specific subtypes should be dis- or peritoneum. Some subtypes like alveolar soft part sar- cussed for most patients (IV, B). coma, clear cell sarcoma or extraskeletal chondrosarcoma may relapse even after 10 years and may benefit from longer Follow‑up follow up (IV, C). The individual risk of recurrence (size, grade, histological subtype, and site) must be considered to There is no standard follow-up policy. Early detection of tailor the follow-up strategy (Table 3). local or metastatic recurrence might be potentially curable Final recommendations and treatment algorithms are with surgery, SBRT or other ablative techniques. High-risk summarized in Table 4 and Fig. 1. extremity STS usually relapses within 2–3 years, mainly to the lungs, although some rare subtypes spread to the lymph Acknowledgements Isidro Gracia—Traumatology Department, Hos- pital Santa Creu i Sant Pau. Katarina Majercakova—Radiotherapy Department, Hospital Santa Creu i Sant Pau. Martina Giuppi. Table 3  Follow-up recommendation in STS Recommendations Frequency Low-grade sarcoma after radical treatment Local Physical examination First 2–3 years: Every 6 m Baseline CT/MRI/US after surgery and then annually Distant Chest X-ray, if M1 nodules, chest CT Every 6–12 months Intermediate/high grade sarcoma after radical treatment Local Physical examination Every 3–4 months Baseline CT/MRI/US after surgery Distant Chest X-ray or chest CT First 2–3 years: Every 3–4 moths 3–5 years: every 6 months after 5 years: annually Retroperitoneal sarcoma Abdomino-pelvic CT First 2–3 years: Every 6 months Chest X-ray, if M1 nodules, chest CT and then annually Metastatic disease and systemic treatment (outside clinical trial) Assessment of target lesions (CT, MRI or PET) Individualized follow- up Educate patients about self-examination Table 4  Summary of recommendations Summary of recommendations Patients should be attended at centers belonging to a sarcoma network with a concrete expertise and multidisciplinary team (III,A) CT and/or MRI contrast-enhanced followed by core needle biopsy are the gold standart diagnostic methods (II, A) R0 Surgery is the mainstay of treatment (II, A) Perioperative RT is recommended in high-risk tumours (II, A) Perioperative epirubicin-ifosfamide should be discussed with high-risk patients with tumors arising in limbs and trunk-wall (II, A) Selected oligometastatic patients may obtain benefit from complete surgical resection or from SBRT/SRS techniques (III, B) Anthracyclines monotherapy is the first-line standard treatment for metastatic patients not candidate for local treatment (I, A) Adjuvant combination therapy could be considered for patients who may benefit from tumor reduction for symptom palliation or improving resectability (I, B) Selection of the second line is based on histology, toxicity profile and convenience of the scheme administration. (IV, A) En bloc resection performed in high-volume sarcoma centres offers the best chance for long term survival for retroperitoneal sarcoma (III, A) Standard local treatment of localized US is en bloc total hysterectomy (III, A). Adjuvant RT is not recommended (I, D) Active surveillance by an expert team is the first approach for desmoid tumors (III,A) and use of the less toxic options in the first place is recom- mended Pazopanib is the first choice in SFT (III, B) except in dedifferentiated SFT subtype (III, B) Wide resection (III, B) and imatinib (III, B) if surgery is not possible is the recommended approach for DFSP Participation in adequatly designed clinical trials, if available, should be discussed with patients (V, B) 13 Clinical and Translational Oncology (2021) 23:922–930 929 Fig. 1  Algorithm for soft tissue sarcoma Compliance with ethical standards my institution): PharmaMar, Lilly, Eisai, Novartis, GSK, Karyopharm, Pfizer, Bluprint, Deciphera, Adaptimmune. Conflict of interest Alberto Moreno: Speaker honoraria and/or travel Ethical approval The current study has been performed in accordance support: Pharmamar, Roche, Astra-Zeneca, MSD, Kyowa-Kirin, Pfiz- with the ethical standards laid down in the 1964 Declaration of Hel- er. Grants for Clinical Research: FIBICO, IMIBIC. Ana de Juan: re- sinki and its later amendments. ports personal fees and other from Roche, AstraZeneca, MSD, Pharma Mar, Clovis Oncology, Tesaro, GSK, Eisai Ltd, Pierre- Fabre, Lilly Informed consent For this type of retrospective study, formal consent and Pfizer, outside the submitted work. Anna Estival: Travel expenses is not required. and educational activities: PharmaMar, Roche, Lilly, BMS. Honorary ( advisory): Roche, MSD, Astrazeneca. Ana Sebio: Research grants: Pharmamar, Terumo. Lectures and education: Pharmamar, Eisai, Lil- Open Access This article is licensed under a Creative Commons Attri- ly. Travel Expenses: Pharmamar, Merck, Roche, Lilly, Pfizer, Eisai, bution 4.0 International License, which permits use, sharing, adapta- Amgen, Sanofi. Antonio Casado: He recibido ayuda de Pharmamar, tion, distribution and reproduction in any medium or format, as long Novartis, Roche, Astra -Zeneca, Clovis Oncology, GSK-Tesaro, Lilly as you give appropriate credit to the original author(s) and the source, y en menor medida de Eisai para atender reuniones científicas/con- provide a link to the Creative Commons licence, and indicate if changes gresos nacionales e internacionales. He participado en "Advisory were made. The images or other third party material in this article are Boards" de Pharmamar, Lilly, Roche, Novartis y Eisai. Mi institución included in the article’s Creative Commons licence, unless indicated ha recibido modestas cantidades económicas para proyectos de inves- otherwise in a credit line to the material. If material is not included in tigación (Pharmamar) y organización de eventos (Pharmamar, Lilly, the article’s Creative Commons licence and your intended use is not Roche, Novartis y Eisai) en los últimos 5 años. Josefina Cruz: Entity: permitted by statutory regulation or exceeds the permitted use, you will Glaxo, AstraZeneca, Roche, Novartis, Pharmamar, Eisai, Lilly, Cel- need to obtain permission directly from the copyright holder. To view a gene, Astellas, Amgen, and Pfizer (speaker honoraria). Consultant/ copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. advisory role: Entity: AstraZeneca, Roche, Novartis, Pharmamar, Ei- sai, Lilly, Celgene,Astellas, Amgen, Glaxo, and Pfizer. Rosa Alvarez: Speaker honoraria: Bristol, Roche, Pharmamar, Eisai. Advisory role: AstraZeneca, Roche, Pharmamar, Eisai, Lilly. Travel Expenses: Phar- References mamar, Roche. Virgínia Martínez: Speaker honoraria: Pfizer, Roche, Pharmamar, Novartis, Lilly. Travel Expenses: Pfizer, Roche. Javier 1. Dykewicz CA. Summary of the guidelines for preventing oppor- Martín Broto: Honoraria (Advisory): Pharmamar, Lilly, Bayer, Ei- tunistic infections among hematopoietic stem cell transplant sai. Travel expenses: PharmaMar. Research: PharmaMar, Lilly, Eisai, recipients. Clin Infect Dis. 2001;33(2):139–44. Novartis, GSK, Lixte, Karyopharm, Celgene, Pfizer, BMS, Bluprint, 2. Brierley JD, Gospodarowicz MK, Wittekind C (eds). TNM Clas- Deciphera, Nektar, Forma, Amgen, Daiicho Sankyo. Claudia Mª Val- sification of Malignant Tumours, 8th edn. Oxford: John Wiley & verde: Honoraria (Advisory): Pharmamar, Lilly, Bayer, Eisai, Mundip- Sons, Inc. 2016. harma, Pfizer. Travel expenses: Pharmamar, Lilly, Bayer. Research (to 13 930 Clinical and Translational Oncology (2021) 23:922–930 3. Fletcher C, Bridge JA, Antonescu C, Mertens F (eds). WHO Clas- comparing gemcitabine plus dacarbazine versus dacarbazine sification of Tumours: Soft Tissue and Bone Tumours, 5th edn. alone in patients with previously treated soft tissue sarcoma: a Vol 3. April 2020. Spanish Group for Research on Sarcomas study. J Clin Oncol. 4. Deroose JP, Eggermont AM, van Geel AN, Burger JW, den Bak- 2011;29(18):2528–33. ker MA, de Wilt JH, et al. Long-term results of tumor necrosis 19. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze factor alpha- and melphalan-based isolated limb perfusion in SM, Staddon A, et al. Efficacy and safety of trabectedin or dacar- locally advanced extremity soft tissue sarcomas. J Clin Oncol. bazine for metastatic liposarcoma or leiomyosarcoma after failure 2011;29(30):4036–44. of conventional chemotherapy: results of a phase iii randomized 5. Beane JD, Yang JC, White D, Steinberg SM, Rosenberg SA, Rud- multicenter clinical trial. J Clin Oncol. 2016;34(8):786–93. loff U. Efficacy of adjuvant radiation therapy in the treatment of 20. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen soft tissue sarcoma of the extremity: 20-year follow-up of a rand- B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma omized prospective trial. Ann Surg Oncol. 2014;21(8):2484–9. (PALETTE): a randomised, double-blind, placebo-controlled 6. Adjuvant chemotherapy for localised resectable soft-tissue sar- phase 3 trial. Lancet. 2012;379(9829):1879–86. coma of adults: meta-analysis of individual data. Sarcoma Meta- 21. Schoffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, analysis Collaboration. Lancet 1997;350:1647–1654. Choy E, et al. Eribulin versus dacarbazine in previously treated 7. Frustaci S, Gherlinzoni F, De Paoli A, Bonetti M, Azzarelli A, patients with advanced liposarcoma or leiomyosarcoma: a Comandone A, et al. Adjuvant chemotherapy for adult soft tis- randomised, open-label, multicentre, phase 3 trial. Lancet. sue sarcomas of the extremities and girdles: results of the Italian 2016;387(10028):1629–37. randomized cooperative trial. J Clin Oncol. 2001;19(5):1238–47. 22. Trans-Atlantic RPS Working Group. Management of recurrent 8. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, retroperitoneal sarcoma (RPS) in the adult: a consensus approach Ghert M. A systematic meta-analysis of randomized controlled from the Trans-Atlantic RPS Working Group. Ann Surg Oncol. trials of adjuvant chemotherapy for localized resectable soft-tissue 2016;23:3531–40. sarcoma. Cancer. 2008;113(3):573–81. 23. Bonvalot S, Gronchi A, Le Pechoux C, Swallow CJ, Strauss DC, 9. Gronchi A, Stacchiotti S, Verderio P, Ferrari S, Martin Broto J, et al. STRASS (EORTC 62092): a phase III randomized study Lopez-Pousa A, et al. Short, full-dose adjuvant chemotherapy of preoperative radiotherapy plus surgery versus surgery versus (CT) in high-risk adult soft tissue sarcomas (STS): long-term surgery alone for patients with retroperitoneal sarcoma. J Clin follow-up of a randomized clinical trial from the Italian Sar- Oncol. 2019;37(15):11001. coma Group and the Spanish Sarcoma Group. Ann Oncol. 24. Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, 2016;27(12):2283–8. et al. Soft tissue and visceral sarcomas: ESMO-EURACAN Clini- 10. Cardona K, Williams R, Movva S. Multimodality therapy cal Practice Guidelines for diagnosis, treatment and follow-up. for advanced or metastatic sarcoma. Curr Probl Cancer. Ann Oncol. 2018;29(Suppl 4): iv268-iv269. 2013;37(2):74–86. 25. Desmoid Tumor Working Group. The management of desmoid 11. Loi M, Duijm M, Baker S, Rossi L, Grunhagen D, Verhoef C, tumors: a joint global consensus- based guideline approach for et al. Stereotactic body radiotherapy for oligometastatic soft tissue adult and paediatric patients. Eur J Cancer. 2020;127:96–107. sarcoma. Radiol Med. 2018;123(11):871–8. 26. Martin-Broto J, Stacchiotti S, Lopez-Pousa A, Redondo A, Ber- 12. Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, nabeu D, de Alava E, et al. Pazopanib for treatment of advanced Mulder JH, et al. Adriamycin versus epirubicin in advanced soft malignant and dedifferentiated solitary fibrous tumour: a multicen- tissue sarcomas. A randomized phase II/phase III study of the tre, single-arm, phase 2 trial. Lancet Oncol. 2019;20(1):134–44. EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin 27. Martin-Broto J, Cruz J, Penel N, Le Cesne A, Hindi N, Luna Oncol. 1987;23(10):1477–83 P, et al. Pazopanib for treatment of typical solitary fibrous 13. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schoffski P, tumours: a multicentre, single-arm, phase 2 trial. Lancet Oncol. Blay JY, et al. Doxorubicin alone versus intensified doxorubicin 2020;21(3):456–66. plus ifosfamide for first-line treatment of advanced or metastatic 28. Rutkwosky P, Debiec-Richter M. Current treatment options for soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet dermatofibrosarcoma protuberans. Expert Rev Anticancer Ther. Oncol. 2014;15(4):415–23. 2015;15(8):901–9. 14. Penel N, Italiano A, Ray-Coquard I, Chaigneau L, Delcambre C, 29. Martin Broto J, Hindi N, Redondo A, Martinez-Trufero J, Stac- Robin YM, et al. Metastatic angiosarcomas: doxorubicin-based chiotti S, Palmerini E, et al. IMMUNOSARC: a collaborative regimens, weekly paclitaxel and metastasectomy significantly Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial improve the outcome. Ann Oncol. 2012;23:517–23. of sunitinib plus nivolumab in selected bone and soft tissue sar- 15. Zalupski M, Metch B, Balcerzak S, Fletcher WS, Chapman R, coma subtypes. Results of the phase I. J Clin Oncol, 2018; 36 Bonnet JD, et al. Phase III comparison of doxorubicin and dacar- (15):11515. bazine given by bolus versus infusion in patients with soft-tissue 30. Stacchiotti S, Schoffski P, Jones R, Agulnik M, Villalobos VM, sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst. Jahan TM, et al. Safety and efficacy of tazemetostat, a first in class 1991;83:926–32. EZH2 inhibitor in patients with epithelioid sarcoma. J Clin Oncol. 16. Le Cesne A, Antoine E, Spielmann M, Le Chevalier T, Brain E, 2019;37(15):11003. Toussaint C, et al. High-dose ifosfamide: circumvention of resist- 31. Drilon A. TRK inhibitors in TRK fusion-positive cancers. Ann ance to standard-dose ifosfamide in advanced soft tissue sarcomas. Oncol. 2019; 30(Suppl 8): viii23–viii30. J Clin Oncol. 1995;13(7):1600–8. 17. Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels Publisher’s Note Springer Nature remains neutral with regard to B, et al. Randomized phase II study of gemcitabine and docetaxel jurisdictional claims in published maps and institutional affiliations. compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol. 2007;25(19):2755–63. 18. Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, Martin J, Mar- tinez-Trufero J, Casado A, et al. Randomized phase II study 13