Cancer Treatment Reviews 102 (2022) 102312 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevier.com/locate/ctrv Tumour Review SELNET clinical practice guidelines for soft tissue sarcoma and GIST J.Y. Blay a, *, N. Hindi b, J. Bollard a, S. Aguiar Jr. c, M. Angel d, B. Araya e, R. Badilla e, D. Bernabeu f, F. Campos c, C.H.S. Caro-Sánchez g, B. Carvajal h, A. Carvajal Montoya e, S. Casavilca-Zambrano i, V. Castro-Oliden i, M. Chacón d, M. Clara g, P. Collini j, R. Correa Genoroso k, F.D. Costa c, M. Cuellar h, A.P. dei Tos l, H.R. Dominguez Malagon g, D. Donati m, A. Dufresne a, M. Eriksson n, M. Farias-Loza i, P. Fernandez o, A.M. Frezza j, T. Frisoni m, D.Y. Garcia-Ortega g, H. Gelderblom p, F. Gouin a, M.C. Gómez-Mateo q, A. Gronchi j, J. Haro i, L. Huanca i, N. Jimenez e, M. Karanian a, B. Kasper r, B.B. Lopes David j, A. Lopez-Pousa s, G. Lutter d, H. Martinez-Said t, J. Martinez-Tlahuel g, C.A. Mello c, J. M. Morales Pérez u, S. Moura David u, A.G. Nascimento c, E.J. Ortiz-Cruz v, E. Palmerini m, S. Patel w, Y. Pfluger d, S. Provenzano j, A. Righi m, A. Rodriguez d, R. Salas h, T.T.G. Santos c, K. Scotlandi m, T. Soule d, S. Stacchiotti j, C. Valverde x, F. Waisberg d, E. Zamora Estrada e, J. Martin-Broto b a Léon Bérard Center, 28 rue Laennec 69373 Lyon Cedex 08, France b Research Health Institute Fundacion Jimenez Diaz (IIS/FJD), 28015 Madrid, Spain; Hospital Fundación Jimenez Diaz University Hospital, 28040 Madrid, Spain; General de Villalba University Hospital, 28400 Madrid, Spain c A.C.Camargo Cancer Center, Rua prof Antonio Prudente, 211 - Liberdade, São Paulo - SP 01509-010, Brazil d Instituto Alexander Fleming. Av. Cramer 1180. CP C1426ANZ, Buenos Aires, Argentina e Hospital Dr. R. A. Calderón Guardia, 7-9 Av, 15-17 St, Aranjuez, San José, Costa Rica f Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain g Instituto Nacional de Cancerologia. Torre Nueva de Hospitalización, primer piso. Av. San Fernando 86, Colonia Niño Jesus. CP 14080, Tlalpan Mexico h Fundación GIST México, Altadena 59, Nápoles, Benito Juárez, 03810 Ciudad de Mexico, CDMX, Mexico i Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima 34, Peru j Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milano, Italy k Hospital Clínico Universitario Virgen de la Victoria, Campus Universitario de Teatinos s/n, 29010 Malaga, Spain l Treviso General Hospital Treviso, University of Padua, Padova, Italy m IRCCS Istituto Ortopedico Rizzoli, University of Bologna, Via Pupilli, 1, 40136 Bologna, Italy n Skane University Hospital and Lund University, Lund, Sweden o Fundación GIST Chile p Leiden University Medical Center, Leiden, the Netherlands q Hospital Universitario Miguel Servet, Paseo Isabel la Católica, 1-3, 50009 Zaragoza, Spain r University of Heidelberg, Mannheim Cancer Center, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany s Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08041 Barcelona, Espagne t Centro Oncologico Integral, Hospital Medica Sur, Planta Baja Torre III - Cons. 305, Col. Toriello Guerra, Deleg. Tlalpan. C.P. 14050, Mexico, D.F u Hospital Universitario Virgen del Rocio, Av Manuel Siurot s/n, 41013 Sevilla, Spain v Hospital Universitario La Paz, MD Anderson Cancer Center, Calle de Arturo Soria, 270 28033 Madrid, Spain w UT MD Anderson Cancer Center, Houston, TX, USA x Vall d́ Hebrón University Hospital, Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain Introduction quarter of sarcoma arise from soft-tissue, about 15% are gastrointestinal stromal tumours (GISTs) and bone sarcoma represent the remaining Soft tissue sarcoma (STS) is a heterogeneous group of neoplasms, 10%. The current guidelines will focus on soft-tissue and GIST, encompassing > 80 different histologic subtypes. Approximately three excluding Kaposi sarcoma and non-pleomorphic rhabdomyosarcoma. * Corresponding author at: Centre Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, France. E-mail address: jean-yves.blay@lyon.unicancer.fr (J.Y. Blay). https://doi.org/10.1016/j.ctrv.2021.102312 Received 20 October 2021; Accepted 30 October 2021 Available online 14 November 2021 0305-7372/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). J.Y. Blay et al. Cancer Treatment Reviews 102 (2022) 102312 Bone sarcomas are covered in a different paper. recommended [III, A]. An abdominal and pelvic CT scan is recom­ mended to rule out metastasis in special histologic subtypes with high General statements metastatic potential (myxoid liposarcoma, epithelioid sarcoma, angio­ sarcoma, leiomyosarcoma, small-cell sarcomas) [III, A] [10]. Currently, • Management of soft tissue, visceral, and bone sarcoma should be spine and pelvic MRI is preferred in myxoid liposarcoma [IV, A], and a carried out within multidisciplinary reference centres for sarcoma baseline brain MRI should be considered in alveolar soft-part sarcoma [III, A] [1]. Multidisciplinary tumour boards (MDTB) should include (ASPS), angiosarcoma and clear cell sarcoma [IV, A] due to their high at least the following specialties: medical oncology, paediatrics (if risk of central nervous system spread. PET/CT scan and/or bone scin­ paediatric patients are discussed), radiology, surgery, pathology and tigraphy are optional and are advised in case of equivocal images and/or radiation oncology. clinical bone involvement suspicion. • A MDTB cannot be defined only by the volume of patients followed, Risk stratification is assessed using composite tools which may vary but also by the periodicity of meeting (weekly MDTB is recom­ according to histological subtype after central review, grade, primary mended), its contribution to clinical trials and scientific production site (see GIST section), tumour size and presence of metastasis [IV, A]. and its participation in national or international guidelines. These Nomograms are available for several locations [11–13] and those with MDTB should ideally be periodically audited to ensure quality. reported validation studies (retroperitoneal and limb soft tissue sar­ • All diagnostic procedures and therapeutic decisions should be dis­ comas) should be used. cussed within a MDTB. • Several reports indicate better clinical results and better cost- Management of local disease effectiveness if sarcoma or presumptive sarcoma patients are managed in sarcoma reference centres with MDTB discussion [III, A] For patients with an adult type localized STS, surgery is the standard [2–5]. treatment. This procedure must be performed by a surgeon, specifically trained for the treatment of this group of diseases [1]. Surgery should Soft tissue sarcoma always be preceded by an expert sarcoma MDTB discussion. The stan­ dard surgical procedure is a wide excision (en bloc resection) with Incidence negative margins (R0) [II, A] [14] and limb salvage procedure whenever feasible. In some special situations, reconstructive surgery should be Soft tissue sarcomas are rare tumours, with an estimated incidence of taken into account and plastic surgery can facilitate the reconstruction approximately 9 new cases/100,000 inhabitants/ year in Europe [6]. of wide soft-tissue sarcoma surgeries. When despite of neo- or adjuvant Incidence in other areas, such as Latin-American countries is difficult to treatments the achievement of an adequate margin with a functional estimate due to the lack of registries [7,8]. limb is not feasible, amputation should be considered and discussed in a specialized MDTB [III, A] [14]. Pathologically confirmed or clinically Diagnosis and pathology/molecular biology evident lymph nodes should be resected but elective node dissection is not recommended. Adjuvant RT or chemotherapy (ChT) do not All diagnostic procedures in patients with suspicion of soft-tissue compensate for an improper first or second surgery. Re-excision by an sarcoma should be discussed within a multidisciplinary tumour board expert team should be discussed in a MDTB in this situation, especially (MDTB). when surgery was performed outside a reference centre [III, A]. Local re- During the diagnostic course, in patients with superficial lesions > 5 staging has to be performed in order to plan an adequate re-excision. cm and deep lesions of any size, imaging and biopsy before surgery are Postoperative hematoma is considered a tumour contamination and strongly recommended. For primary tumours of the limb, trunk wall and must be included in the surgical tumour bed of re-excision. In the case of pelvis, MRI is the preferred recommended imaging test. CT scan is rec­ R2 surgery (macroscopic residual tumour after surgery), re-operation is ommended for any other site, or as a MRI alternative [III, A]. A core mandatory, and preoperative treatments should be considered when needle biopsy is recommended for the diagnosis of soft tissue or visceral adequate oncology margins cannot be achieved, depending on the his­ lesions > 3 cm [III, A]. An adequate procedure to perform biopsies tological subtype. Re-excision should be discussed when the oncological should include imaging guidance to avoid any suspected area of ne­ margins are not satisfactory even after planned surgeries. However, if it crosis, use of G14 or G16 needles with coaxial introducer for a single skin is impossible to obtain a greater or better margin, due to its anatomical entrance, and 4 to 6 cores varying the angle into the tumour [III, A]. location, radiotherapy (RT) should be considered. Marginal resections Pathological diagnosis should be made according to the most recent with microscopically positive margins (R1) may be appropriate for WHO classification and histological grading should be based on the extracompartimental atypical lipomatous tumours. Wide excision pro­ FNCLCC system [III, A]. Central pathological review by an expert sar­ cedure is followed by RT as the standard treatment in cases with at least coma pathologist is strongly recommended [III, A]. Cases should be one of the following risk factors: high-grade (G2-3), deep, >5 cm lesions referred to molecular pathology tests whenever morphology and [II, A] [15–17]. Exception may be made after MDTB discussions immunohistochemistry are not enough for a precise diagnosis and/or considering site and comorbidities [II, A] [16]. RT may be avoided for when additional prognostic/predictive information is required [III, A]. G1, R0, <5cm, superficial tumours of the limbs and trunk wall [IV, B]. In Grade should be established always prior to treatment based on the core cases of G1, > 5 cm and deep tumours, RT should be validated with a biopsy. When neoadjuvant treatment is administered, pathological MDTB [18]. Preoperative or postoperative RT are equally acceptable findings should be quantified and reported in terms of residual viable with different side-effect profile in a mid and long-term [II, A] [19]. In (stainable) tumour cells and their mitotic index, and percentage of post- some locations (e.g. head and neck), postoperative RT is preferred. As treatment changes (necrosis, sclerohyalinosis, fibrosis, fibrohistiocytic for surgery, preoperative RT should always be discussed on MDTB [18]. reaction, haemorrhage). Percentage of hypercellular/round cell The time frame between end of preoperative RT and surgery or surgery component and adipocytic maturation should be noted in case of myxoid and the initiation of adjuvant RT should be 4–6 weeks, though longer liposarcoma [9]. intervals may be needed in case of clinical constraints (delayed wound healing) [IV, D] [20,21]. Staging and risk assessment Adjuvant ChT is not a standard treatment and is not recommended in chemotherapy non-responsive histologic subtypes (for example, ASPS, Imaging studies to evaluate the presence of distant metastasis are clear cell sarcoma, well/dedifferentiated liposarcoma) [22]. There are mandatory. To assess the presence of lung metastases, a chest CT scan is conflicting results in literature regarding its value, mainly in relation to 2 J.Y. Blay et al. Cancer Treatment Reviews 102 (2022) 102312 Fig. 1. Algorithm for selection of first line therapy in advanced STS CT: clinical trial; Epi: epirubicin; Doxo: doxorubicin; Ifo: ifosfamide. the poor selection of high-risk patients and inadequate use of dose in­ Table 1 tensity in the administered regimens. The application of validated no­ Recommendations on second line options in advanced STS based on histologic mograms in a negative large randomized trial evaluating the role of subtype UPS: undifferentiated pleomorphic sarcoma; HDIFO: high-dose ifosfa­ adjuvant ChT [23], virtually converted it into a positive study, showing mide; MPNST: Malignant peripheral nerve stealth tumour. a significant benefit in disease-free survival and overall survival (OS) in HISTOLOGIC PREFERENTIAL OPTIONS LESS PREFERENTIAL the high-risk population [24]. SUBTYPE Those randomized trials selecting high-risk localized limb or trunk- wall STS with the highest dose intensity of the two most active drugs LEIOMYOSARCOMA Gemcitabine combinations, Ifosfamide Trabectedin, Pazopanib (anthracyclines and ifosfamide) consistently showed a 5-y OS above UPS Gemcitabine combinations, Pazopanib 70% [22,25,26]. A meta-analysis that incorporated comparative trials Trabectedin, Ifosfamide with these drugs reported statistically significant survival benefit SYNOVIAL SARCOMA HDIFO, Trabectedin Gemcitabine favouring ChT arm. Yet, this meta-analysis was not based on individual combinations, Pazopanib data [27]. WD/DD Eribulin, Trabectedin, HDIFO Gemcitabine Perioperative ChT (preferably neoadjuvant) should be considered in LIPOSARCOMA combinations the context of patients with high-risk localized STS of limbs and trunk- MYXOID Trabectedin, Eribulin Gemcitabine wall [II, A] [22,25,28,29]. Tumours > 5 cm, G3 and deep located LIPOSARCOMA combinations, have been used as high-risk population criteria. However, high-risk Ifosfamide MPNST Ifosfamide-etoposide, HDIFO Trabectedin, could be more precisely defined by validated nomograms as death risk Gemcitabine, Pazopanib higher than 40% [26]. The combination of anthracycline and ifosfamide ANGIOSARCOMA Taxanes, Gemcitabine, Trabectedin at full doses with G-CSF and MESNA support is the recommended Pazopanib scheme being three cycles as effective as five in a randomized trial [II, A] [22]. Further randomized clinical trials evaluating the role of periop­ patients with good performance status multi-agent ChT with adequate- erative ChT are needed, and patient participation is strongly dose anthracyclines plus ifosfamide may be the preferential treatment encouraged. option [I, B]. [36,37]. For leiomyosarcoma, doxorubicin and dacarba­ zine could be considered, instead of anthracyclines plus ifosfamide, Management of advanced/metastatic disease since this latter could be even detrimental in this specific subtype ac­ cording to retrospective comparisons. [IV, B] [38]. The combination of The presence of distant metastasis is a poor prognostic factor for OS, gemcitabine plus docetaxel is not recommended as a first-line option for ranging currently 18–20 months [30,31]. However, a fraction of patients the treatment of advanced STS [39]. The inclusion of patients with with advanced sarcoma could benefit from long term remission, espe­ advanced STS in clinical trials should be encouraged whenever available cially those reaching a complete response and a smaller percentage of (Fig. 1). those obtaining partial response after first line of treatment for advanced Beyond first-line, there are several second-line options (Table 1, disease [32]. Fig. 2): Supportive care and quality of life evaluation should be included in the early management of all patients with advanced sarcoma [33]. When • High-dose ifosfamide (12–14 g/m2/cycle, administered in 6 days or complete excision of all lesions is feasible, surgery can be a preferable in 14 days with G-CSF and MESNA support) can circumvent the treatment option for metachronous (disease-free interval ≥ 1 year) tumour resistance to regimens with moderate doses of ifosfamide [I, metastatic appearance when the number of nodes is limited (i.e. 3–5) D] [40]. and without extrapulmonary disease [IV, B]. This strategy could also be • If available, trabectedin can be used for second line in pretreated offered to patients with oligometastatic disease located at others sites STS, especially but not exclusively in liposarcoma, leiomyosarcoma (liver, soft tissue) [V, B] [34], after discussion in MDTB. In selected and translocation-related sarcomas [II, B] [41–43]. Nevertheless, the cases, stereotactic radiotherapy might also be recommended in this EU approval does not limit its use to these entities since it can be setting after discussion in MDTB [IV, C] [35]. active in other histological subtypes [44]. First-line standard ChT treatment is based on anthracyclines [I, A]. In • The combination of trabectedin and low dose of radiation therapy particular subtypes, with greater sensitivity to ifosfamide, such as sy­ has been observed to be feasible and active [45]. This could be taken novial sarcoma and undifferentiated pleomorphic sarcoma (UPS), and/ into account when shrinkage is crucial to palliate symptoms in sec­ or when a tumour response could be potentially advantageous, and in ond line [III, A]. 3 J.Y. Blay et al. Cancer Treatment Reviews 102 (2022) 102312 Fig. 2. Algorithm for selection of second line therapies in advanced STS CT: clinical trial; RT: radiotherapy; HDIFO: high-dose ifosfamide. • Pazopanib is an option except for adipogenic STS after progression to studies are assessing the efficacy of preoperative ChT or Ch-RT. standard chemotherapy [II, E] [46]. Postoperative RT should be avoided [IV, D]. • For patients with extraskeletal myxoid chondrosarcoma [47], soli­ • Uterine sarcomas. Uterine sarcomas include several sub-entities (LMS, tary fibrous tumour [48,49], and other anti-angiogenic sensitive endometrial stromal sarcoma -ESS-, undifferentiated uterine sar­ histotypes such as ASPS [50], pazopanib, if available, could be coma) with completely different natural history. Pathology review considered as upfront therapy. If it is not available as first line, it and molecular biology tests are recommended. In localized disease, should be considered for second line [III, A]. morcellation should be avoided [III, E] [76,77], and en bloc total • Eribulin is a therapeutic option in second-lines for the treatment of hysterectomy is the standard local treatment. Adjuvant RT is not patients with liposarcomas who have progressed after doxorubicin recommended as routine treatment [II, C] [78]. Adjuvant ChT is not [II, B] [51]. recommended as routine treatment either but might be proposed by • Despite not formally approved for sarcomas, the combination of specialized MDTB in specific situations based on histologic subtype, gemcitabine and dacarbazine or gemcitabine and docetaxel are op­ clinical presentation or in case of tumour fragmentation [IV, C] tions in doxorubicin-pretreated patients especially, but not exclu­ [79,80]. For low-grade unresectable ESS, endocrine therapy such as sively, in leiomyosarcoma and UPS [II, B] [52,53]. aromatase inhibitors are recommended as first-line treatment [IV, B] • Imatinib is standard medical therapy for those rare patients with [81,82]. These treatments should be proposed in clinical trials. locally advanced, unresectable or metastatic dermatofibrosarcoma • Desmoid-type fibromatosis (DF). A wait-and-see policy can be advised protuberans [III, A] [55]. in tumours which are not life threatening or asymptomatic [III, B] • Regorafenib is an option in doxorubicin-pretreated advanced, non- [83]. Surgery might be indicated for selected cases after discussion in adipogenic STS patients, even after pazopanib [II, B] [56,57]. MDTB. In symptomatic or progressive patients, if systemic therapy is • There is some evidence, from non-randomized trials, that several feasible, sorafenib and pazopanib can be recommended as an option molecular targeted agents are active in specific rare histologies. If after MDTB discussion [II, B], as both showed to improve available, the use of these agents could be an option after discussion progression-free survival (PFS) over placebo and methotrexate- in MTDB: vinblastine respectively in 2 randomized trials [84,85]. NSAIDs, o mTOR inhibitors in malignant PEComas [III, B] [58–60]; tamoxifen, toremifene, cytotoxics (methotrexate plus vinca alka­ o Crizotinib in inflammatory myofibroblastic tumours preferably loids, anthracyclines) and imatinib can be options in view of pro­ associated with ALK translocations [III, B] [61,62]; spective uncontrolled clinical trials [III, B] [86–90]. Radiotherapy is o If available, NTRK inhibitors (entrectinib, larotrectinib) are an active an option that has demonstrated long term tumour control in pro­ option for advanced sarcomas with NTRK fusions [III, A] [63–65]. spective and retrospective series [III, C] [91]. Symptomatic • Weekly paclitaxel [III, B] [66] and liposomal doxorubicin [IV, B] improvement and dimensional responses were reported after cry­ [67] are active options in angiosarcoma. The combination of pro­ oablation, in small series after short follow-up [IV, C] [92]. pranolol plus vinblastine [IV, B] [68] has also shown some activity. • Tenosynovial Giant Cell Tumour (TGCT). Surgery represents the • Pazopanib, sorafenib or regorafenib are recommended as second line standard treatment in patients with localized and diffuse TGCT [III, in vascular sarcomas [III, B] [56,69,70]. A] [93,94]. Local relapse after surgery is common in diffuse-type • Gemcitabine has shown single agent activity for both angiosarcoma TGCT, with reduced recurrence rates after open access approach as and leiomyosarcoma [54]. It was equivalent to the gemcitabine/ compared with arthroscopy in patients with knee TGCT [III, A] [95]. docetaxel combination in leiomyosarcoma -LMS- in a single clinical For unresectable patients, follow-up is an option. For symptomatic trial [II, C] [71]. patients or to avoid surgical morbidities, imatinib [III, B], nilotinib • Immune checkpoint inhibitors (anti-PD1) should be used in the [III, B] and pexidartinib [II, B] are recommended, if available context of clinical trials. Nevertheless, notorious activity has been [96–98]. described in the context of advanced ASPS. In sarcoma, predictive • Dermatofibrosarcoma protuberans: Surgical removal is the mainstay of biomarkers for these drugs are still lacking. Physicians should be DFSP management. Mohs surgery is recommended when possible; encouraged to enrol patients into clinical trials to further refine their large tumours may require wide local excision (margins of 3 cm) and indications. reconstruction [99,100]. DFSP often present translocation involving a ligand of platelet-derived growth factor receptor (PDFGR). PDGFRs Special presentation and entities kinase inhibitor imatinib is the standard medical therapy for patients with DFSP not candidate for a mutilating surgery or with distant • Retroperitoneal sarcomas (RPS). Patients with suspicion of RPS must metastases [III, A] [55 101]. be referred to centres with multidisciplinary teams and expertise in the management of RPS [III, A] [72]. Surgery (compartmental or en bloc resection) is the cornerstone for the treatment [73,74]. Based on Follow-up a recently reported negative clinical trial on preoperative RT, this strategy is not recommended outside of a clinical trial [II, C] [75]. There is limited published evidence on the best follow-up program in Ad-hoc analysis of STRASS study found a significant local control resected localized STS. The main site of distant metastasis of STS is lung. favouring RT administration in low-grade liposarcoma. Ongoing Follow-up should include a physical examination, especially of the pri­ mary tumour site to rule out local relapse. Imaging studies of the local site should be preferably MRI in limb, trunk-wall and pelvic primary 4 J.Y. Blay et al. Cancer Treatment Reviews 102 (2022) 102312 tumours, and CT scan in abdominal and pulmonary primary tumours. implies major functional sequelae, and preoperative medical treatment Chest X-ray or thoracic CT scan usually are enough to rule out distant is not effective, the decision can be made with the patient to accept the metastasis. In selected subtypes (see staging section), abdominal CT scan possibility of a R1 resection [IV, B]. Neoadjuvant imatinib is the stan­ is included also. dard treatment for locally advanced GIST for which upfront surgery with The recommended follow-up policy after treatment completion is major sequelae cannot be avoided and/or R0 surgery is not feasible different between low-grade and high-grade STS. For high grade STS [115,116]. The optimal duration of neoadjuvant treatment is not known visits every 3–4 month for the first 2–3 years are recommended, then but the recommendation ranges between 6 and 12 months, based on every 6 months for the fourth and fifth year, and then yearly at least up emerging time of resistant clones [III, C]. Close monitoring of the to the tenth year. For low grade STS patients, follow-up could be per­ response is recommended to avoid delayed local therapy in case of lack formed every 6 months for 5 years and annually thereafter [101]. of response to neoadjuvant therapy [110,115,116]. Adjuvant therapy with imatinib for 3 years improves overall survival for patients with a Gastrointestinal stromal tumours (Gists) significant risk of relapse [I, A] [117,118]. In case of neoadjuvant and postoperative imatinib, the overall duration of treatment should be Incidence completed up to 3 years. Wild-Type GIST, PDGFRA D842V-mutated GIST, succinate dehydrogenase (SDH)-deficient GIST and Neurofibro­ GISTs are rare tumours, with an estimated incidence of 1–2.8 new matosis (NF-1)-related GIST have not demonstrated to experience cases/100 000 inhabitants/year in Europe [102–104], but data on their benefit from imatinib treatment. Thus, adjuvant imatinib in these con­ incidence in other areas, such as Latin-American countries is unknown. texts should be avoided. In patients with KIT exon 9 mutation, only a GIST is the most frequent sarcoma in the gastrointestinal tract, being dose of 400 mg/d has been prospectively tested in the adjuvant setting more frequent in stomach (50–60%), followed by ileum and jejunum [III, C] [119,120]. Given the data from advanced disease, the utility of (20–30%), duodenum (3–5%), rectum-anus (2–4.4%) and other sites adjuvant treatment at 800 mg/d should be considered within the MDTB (<2%). Extra-gastrointestinal GIST cases have been anecdotally and discussed with the patient, explaining potential risks and benefits of described [105]. this strategy. Diagnosis and pathology/molecular biology Management of advanced/metastatic disease If accessible, endoscopic ultrasound assessment should be carried out Tumour genotyping for driver molecular alterations (at least of KIT in patients with oesophagogastric or duodenal nodules < 2 cm. If not and PDGFRA) is strongly recommended [IV, A] [107,114]. accessible, follow-up by CT scan is the initial standard approach [III, A]. Imatinib, at 400 mg daily, is the standard upfront treatment of The exception is rectal GIST, in which a biopsy and further local treat­ locally advanced inoperable and metastatic disease, [I, A] [121,122]. ment should always be considered, irrespectively of size [III, A]. Biopsy Imatinib is also the standard treatment for patients with completely (with transparietal microbiopsy) or excision is the standard approach to resected metastatic disease, although surgery is not recommended as a tumours ≥ 2 cm in size [III, A] [106]. Mitotic count (expressed if primary approach in the metastatic setting. Standard treatment of pa­ possible as the number of mitoses per 5 mm2), size, site and intra- tients with KIT exon 9 mutation is 800 mg daily of imatinib [III, B] abdominal tumour rupture need to be assessed and included in patho­ [123,124]. In the metastatic setting, treatment with imatinib should be logical report for risk stratification [III, A] [107]. KIT and platelet- indefinitely continued up to progression, intolerance or specific patient derived growth factor alpha (PDGFRA) mutational analysis should al­ interruption request [I, A] [125]. Dose reductions (i.e. 300 mg or even ways be considered especially for patients under treatment or who are lower doses) in the context of intolerance and efficacious treatment candidates to systemic therapy [III, A] [105,108,109]. should be explored. A randomized clinical trial exploring the utility of surgical rescue of residual metastatic disease after imatinib was inter­ Staging and risk assessment rupted due to poor accrual [II, C]. Hence, this option should be indi­ vidualized after the decision-making process with the patient [126,127]. Endoscopy ultrasound is recommended for the initial assessment of Interventional techniques (radiosurgery, radiofrequency ablation -RFA-) oesophagogastric and duodenal nodules. Abdominal and pelvic CT scan are options in selected cases [IV, C] [128,129]. In the case of tumour (at least biphasic at baseline for a better detection of liver metastasis) progression on 400 mg of imatinib, the dose can be increased to and chest X-ray or CT scan, are recommended in addition to histological 600–800 mg daily if accessible [III, B] (with the exception of insensitive and molecular diagnosis [III,A]. MRI is recommended for pelvic and mutations) [123,130]. rectal GIST, and for the rare forms of oesophageal GIST [IV, B]. PET scan In the case of confirmed progression or rare intolerance to imatinib, is not mandatory and could be an option for unknown primary, equiv­ standard second-line treatment is sunitinib (50 mg/d, 4 weeks of ther­ ocal images, and anticipated evaluation of response to neoadjuvant apy/2 weeks off) [I, A] [131]. The continuous dosing of 37.5 mg/d is an treatment [IV, B] [110]. Chest CT scan (in addition to abdominal CT alternative option, although there is no formal prospective comparison scan) is recommended in case of syndromic GIST [IV, B]. with the intermittent dosing [132]. Risk assessment following heat maps are the recommended classifi­ Regorafenib, at the dose of 160 mg daily for 3 out of every 4 weeks, is cation risk to take decisions. A higher than 40% recurrence risk should the standard third-line therapy for patients progressing on or failing to be taken into account to offer adjuvant imatinib [111]. The worse respond to imatinib and sunitinib [I, A] [133,134]. Treatment schedule prognostic impact of some mutation types (i.e. deletions involving 557 (dose, duration, interruption) should be adapted to patient’s tolerability. and/or 558 in exon 11 of KIT gene) [112], could be also considered. Rechallenge with imatinib could be an option with limited activity in patients progressing to all approved tyrosin-kinase inhibitors (TKI) op­ Management of local disease tions. [II, B] [135,136]. Some evidence exists that continuing a treat­ ment with TKI is effective even in the context of slow progression. If The standard treatment of localized GISTs is complete surgical available, ripretinib is recommended as 4th line for GIST progressing excision of the lesion (en bloc resection with no rupture), with no after imatinib, sunitinib and regorafenib [II, A] [137]. dissection of clinically negative lymph nodes [III, A]. Whenever If available, avapritinib is recommended for PDGFRA D842V- possible, sparing surgery is recommended. If laparoscopic excision is mutated GIST [III, A] [138]. planned by an expert surgical team, the technique needs to follow the principles of surgical oncology [III, A] [113,114]. When R0 surgery 5 J.Y. Blay et al. Cancer Treatment Reviews 102 (2022) 102312 Table 2 Declaration of Competing Interest Levels of evidence and grades of recommendations (adapted from the Infectious Disease Society of America-United States Public Health Service Grading System). The authors declare that they have no known competing financial LEVES OF EVIDENCE DEFINITION interests or personal relationships that could have appeared to influence I Evidence from meta-analyses (based on well the work reported in this paper. conducted clinical trials) or at least one large randomized controlled trial with low potential for Acknowledgements bias) II Small randomised trial or large randomized trials/ The authors would like to thank the SELNET project, which has meta-analyses with suspicion of bias or heterogeneity III Prospective cohort studies received funding from the EU Horizon 2020 research and innovation IV Case-control or retrospective cohort studies programme (grant number 825806). JMB, NH, JB, APDT, AMF, SS, HG, V Case reports, expert opinions, studies without control FG, AG, MK, JYB, EP, are also supported by EURACAN ERN (EC group 739521). GRADES OF RECOMMENTATION A Strong evidence for efficacy and meaningful clinical References benefit: strongly recommended. B Strong or moderate evidence for efficacy but [1] Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, et al. Soft tissue and restricted clinical benefit: generally recommended visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, C Inadequate evidence for efficacy or clinical benefit treatment and follow-up. Ann Oncol 2018;29:iv268–9. 10.1093/annonc/ not exceeding risks: optional mdy321. [2] Perrier L, Buja A, Mastrangelo G, Vecchiato A, Sandonà P, Ducimetière F, et al. D Moderate evidence against efficacy or poor outcome: Clinicians’ adherence versus non adherence to practice guidelines in the generally not recommended management of patients with sarcoma: a cost-effectiveness assessment in two E Strong evidence against efficacy or poor outcome: European regions. BMC Health Serv Res 2012;12(1). https://doi.org/10.1186/ never recommended or contraindicated 1472-6963-12-82. [3] Martin-Broto J, Hindi N, Cruz J, Martinez-Trufero J, Valverde C, De Sande LM, et al. Relevance of Reference Centers in Sarcoma Care and Quality Item Follow-up Evaluation: Results from the Prospective Registry of the Spanish Group for Research in Sarcoma (GEIS). Oncologist 2019;24(6). https://doi.org/10.1634/ theoncologist.2018-0121. Evidence on the optimal follow-up procedures of resected localized [4] Blay J-Y, Honoré C, Stoeckle E, Meeus P, Jafari M, Gouin F, et al. Surgery in GIST is lacking. Liver and peritoneum are the most frequent sites of reference centers improves survival of sarcoma patients: a nationwide study. Ann metastatic spread, being lymph nodes, bone and lungs much more Oncol Off J Eur Soc Med Oncol 2019;30:1407. https://doi.org/10.1093/annonc/ mdz170. infrequent sites, and usually associated to heavily pretreated patients or [5] Trovik CS. Scanadinavian Sarcoma Group Project. Local recurrence of soft tissue with syndromic GIST. Thus, follow-up has to include abdominal CT scan sarcoma. A Scandinavian Sarcoma Group Project. Acta Orthop Scand Suppl 2001; or MRI. Follow-up procedures should be adapted to risk. High-risk pa­ 72:1–31. [6] de Pinieux G, Karanian M, Le Loarer F, et al. Nationwide incidence of sarcomas tients are at a higher risk of relapse in the first 3 years after completion of and connective tissue tumors of intermediate malignancy over four years using an adjuvant therapy. We recommend follow-up with an abdominal CT scan expert pathology review network. PLoS One. 2021;16:e0246958. https://doi.org/ or MRI every 3–6 months during adjuvant therapy and then, after 10.1371/journal.pone.0246958. [7] Chávez M, Ziegler G, Cotrina J, Galarreta J, de la Cruz M, Mantilla R. Current completion of adjuvant therapy, CT scan or MRI every 3 months for 2–3 situation of soft tissue sarcomas: Registry of a Latin American cancer institute. years, then every 6 months until the fifth year from adjuvant comple­ Cirugia Espanola 2019;97(4):203–12. https://doi.org/10.1016/j. tion, and then annually. For low-risk tumours, the utility of a periodic cireng.2019.04.001. follow-up is unknown. We recommend, if possible, abdominal CT scan [8] García-Ortega DY, Clara-Altamirano MA, Martín-Tellez KS, Caro-Sánchez CHS, Álvarez-Cano A, Lino-Silva LS, et al. Epidemiological profile of soft tissue or MRI, every 6–12 months for 5 years. sarcomas of the extremities: Incidence, histological subtypes, and primary sites. J Orthop 2021;25:70–4. https://doi.org/10.1016/j.jor.2021.03.021. Methodology [9] Wardelmann E, Haas RL, Bovée JVMG, Terrier Ph, 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 The Sarcoma European Latin-American Network (SELNET) aims to Bone Sarcoma Group (EORTC-STBSG) recommendations for pathological improve clinical outcome in sarcoma care, with a special focus in Latin- examination and reporting. Eur J Cancer Oxf Engl 2016;53:84–95. https://doi. org/10.1016/j.ejca.2015.09.021. American countries. [10] Rosenthal J, Cardona K, Sayyid SK, Perricone AJ, Reimer N, Monson D, et al. These Clinical Practice Guidelines (CPG) have been agreed by a Nodal metastases of soft tissue sarcomas: risk factors, imaging findings, and multidisciplinary group of the SELNET consortium, with representatives implications. Skeletal Radiol 2020;49(2):221–9. https://doi.org/10.1007/ s00256-019-03299-6. of all partner entities including patient’s advocacy groups (SPAEN). 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