Diagnosis and treatment of primary soft tissue sarcomas: comprehensive review

Fahima Dossa; Eldad Elnekave; Aisha B Miah; Catherine Mitchell; Sarah Watson; Alessandro Gronchi; Marco Fiore

doi:10.1093/bjsopen/zraf177

. 2026 Mar 9;10(2):zraf177. doi: 10.1093/bjsopen/zraf177

Diagnosis and treatment of primary soft tissue sarcomas: comprehensive review

Fahima Dossa ¹, Eldad Elnekave ², Aisha B Miah ³, Catherine Mitchell ⁴, Sarah Watson ⁵, Alessandro Gronchi ⁶, Marco Fiore ^7,^✉

PMCID: PMC12971019 PMID: 41802245

Abstract

Background

Soft tissue sarcomas (STSs) comprise a group of rare malignancies with anatomic- and histologic-specific patterns of local and distant recurrence. Due to their rarity and histology-specific tumour behaviour, their natural history and the efficacy of various interventions may be challenging to assess. The aim of this review is thus to provide a comprehensive overview of diagnostic and treatment options for localized extremity and retroperitoneal STSs.

Methods

A literature search was conducted to identify articles related to the diagnosis and management of localized extremity and retroperitoneal STSs. English-language articles published until June 2025 were identified using Medical Subject Heading terms on PubMed. Results were reported using a narrative approach. Topics highlighted in this review include diagnosis, institutional volumes, treatment options, and multimodal management of STSs based on location.

Results

Accurate diagnosis of STS relies on carefully planned preoperative biopsies and in selected cases is supplemented by advanced molecular diagnostic tools. Surgery remains the cornerstone of curative-intent treatment for localized STSs; however, resectability criteria for retroperitoneal STSs vary by institution. Institutional case volumes are prognostic of outcome, with 10–20 retroperitoneal sarcoma cases per year considered by experts to be indicative of high-volume sarcoma centres. The role of adjunctive therapies, including chemotherapy, radiation, and/or other locoregional treatments, is dictated by histological and molecular characteristics associated with local and distant recurrence rates.

Conclusion

The management of localized STSs is multidisciplinary in nature, requiring consideration of tumour and patient characteristics, and treatment factors. The rarity of STSs and the variable biological behaviour of the various histologic subtypes have impacted research in this field. Ongoing international collaborations and innovative study designs are essential for advancing the understanding of tumour behaviour and in optimizing treatment approaches.

Keywords: sarcoma, retroperitoneal sarcoma, limb sarcoma, sarcoma guidelines, surgical treatment of sarcoma

This review outlines current diagnostic and treatment strategies for localized primary soft tissue sarcomas, with a separate focus on extremity/trunk and retroperitoneal disease. Key points include recent therapeutic advances, multidisciplinary management, and the centralization of care in high-volume centres to optimize outcomes.

Introduction

Soft tissue sarcomas (STSs) comprise a histologically diverse group of rare tumours of mesenchymal origin. Accounting for < 1% of adult malignancies, most STSs arise sporadically with few identified genetic, immunologic, and environmental risk factors. Approximately 50% of STSs originate in the extremity or trunk, where well differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS), myxoid/round cell liposarcoma, leiomyosarcoma, myxofibrosarcoma, and undifferentiated pleomorphic sarcoma (UPS) represent the major histologic subtypes, whereas about 15% develop in the retroperitoneum, predominated by WDLPS/DDLPS and leiomyosarcoma¹. Tumour location, histologic subtype, and tumour grade are key prognostic factors, with higher-grade tumours demonstrating the poorest disease-free survival (DFS) and overall survival (OS)^1–3. The rarity of STS has made focus on histology-specific evaluation challenging; however, previous studies^2,3 demonstrate strong associations between histologic subtype and tumour behaviour, such as the propensity for local recurrence among retroperitoneal WDLPS, as opposed to the high risk of distant metastases present for similarly located leiomyosarcoma. Histology-specific tumour behaviour is particularly relevant when evaluating the effectiveness of available treatments. However, for practical purposes, previous studies often distinguish tumours by anatomic location rather than histology, complicating the understanding of the natural history of STS and the efficacy of various interventions. Herein, the aim was to provide a comprehensive summary of the diagnosis and current management of localized STS by anatomic site, highlighting nuances based on histologic variability, where data are available.

Methods

A comprehensive review was conducted by a panel of international experts in STSs. To this end, English language articles published up to June 2025 were identified using Medical Subject Heading ‘sarcoma’ (classification, diagnosis, diagnostic imaging, epidemiology, mortality, pathology, radiotherapy, surgery, OR therapy) or the text word ‘soft tissue sarcoma’ on PubMed. The most relevant and recent literature for each area was reviewed, current scientific gaps were highlighted, and future directions were discussed. The review was divided into sections starting with a revision of current guidelines and addressing diagnosis, the impact of Institutional volumes, treatment options, and multimodal management of STSs according to their location (extremities and retroperitoneal disease), including local treatments. Guidelines and consensus statements on the workup and treatment of localized STSs were also retrieved and compared. To this end, the most recent version of the International guidelines in use in Western countries was retrieved and appraised. Results are reported using a narrative approach. Finally, future challenges arising in clinical practice and scientific research are discussed.

Results

STS guidelines

The review of STS guidelines included those published by the European Society for Medical Oncology (ESMO), the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the National Comprehensive Cancer Network (NCCN), and those from the UK. The recommendations revealed a general consensus among recommendations for referral to high-volume/specialized centres, principles of biopsy and pathologic assessment, staging imaging, and recommendations for extent of surgery and use of neoadjuvant/adjuvant radiation and chemotherapy^4–7. A summary of relevant guideline recommendations and consensus statements is provided in Table 1, and individual elements are discussed below.

Table 1.

Comparison of guidelines and consensus statements regarding diagnosis and treatment of localized STS

ESMO (Gronchi et al. 2021)⁵	UK (Hayes et al. 2025)⁶	NCCN (2025)⁴	TARPSWG (Swallow et al. 2021)⁷
Treatment at specialized centres
Management should be carried out in sarcoma reference centres or tertiary paediatric oncology centres, as appropriate for age. Patients with suspected RPS need to be referred to high-volume sarcoma centres.	All patients with a suspected STS should be managed by a specialist sarcoma MDT as specified in the NICE guidance. Patients with retroperitoneal/intra-abdominal masses suspicious for sarcoma should be referred to a specialist MDT before biopsy or surgical treatment.		Volume-outcome relationships in the surgical care of RPS support the regionalization of care to high-volume hospitals (10–20 RPS cases/year). The MDT that makes decisions should include a surgeon with specialized training in resection of RPS. The decision-making team should also include a radiologist, pathologist, medical oncologist, and radiation oncologist with a practice focused on caring for patients with RPS.
Biopsy
	A pretreatment histopathological diagnosis should be made, if possible, by percutaneous core biopsy. The optimal management of RPS is facilitated by pretreatment diagnosis and an image-guided percutaneous CNB is strongly recommended. Laparotomy and open biopsy or laparoscopic biopsies of suspected RPS should be avoided.	A pretreatment biopsy (CNB) is highly preferred for the diagnosis and grading of STS. Biopsy should be performed by an experienced surgeon or radiologist, placed along the future resection axis with minimal dissection and careful attention to haemostasis.	An image-guided percutaneous coaxial CNB (14–18 gauge) is strongly recommended as the standard of care. Biopsy may occasionally be omitted if the imaging is judged pathognomonic (for example, heterogeneous WDLPS/DDLPS) by an expert radiologist within an expert multidisciplinary tumour board, and no preoperative treatment is planned. Sampling of the more solid tumour component represented by well perfused areas on contrast-enhanced CT or MRI is encouraged to avoid undergrading, as these areas are more likely to represent high-grade/dedifferentiated disease. Elective surgery for resection of an RP tumour without preoperative biopsy, without referral to a specialist centre, and/or without multidisciplinary tumour board discussion is strongly discouraged. Laparotomy and open biopsy (and laparoscopic biopsy) of suspected RPS should be avoided.
Pathology
Pathological diagnosis should be made by a sarcoma expert pathologist according to the 2020 WHO classification.	Biopsy should be reviewed by a specialist sarcoma pathologist for diagnostic confirmation and appropriate molecular and genomic analysis.	Pathologists with expertise in STS should review the pathologic assessment of biopsies and resected specimens, especially for initial histopathological classification. Margins must be thoroughly evaluated in these specimens. Morphologic assessment based on microscopic examination of histologic sections remains the standard of sarcoma diagnosis. Molecular testing should be performed by a pathologist with expertise in the use of molecular diagnostic techniques for the diagnosis of STS. In addition, technical limitations associated with molecular testing suggest that molecular evaluation should be considered only as an ancillary technique.	A selective approach should be applied to testing for specific translocations to elucidate the histologic subtype.
Extremity STS
Imaging and staging
Staging is routinely carried out with contrast-enhanced chest, abdomen, and pelvis CT. Whole-body MRI may be an alternative, especially in selected histotypes. Brain CT/MRI may be indicated only in ASPS, CCS, and angiosarcoma. FDG-PET is indicated as a problem-solving tool in equivocal cases.	Cross-sectional imaging of the primary tumour, usually in the form of MRI, is recommended before definitive surgery. Imaging of the thorax by CT scan for lung metastases should be performed before radical treatment. Further staging may be considered depending on subtype and location of the sarcoma.	Recommendation for MRI with contrast, with or without CT with contrast. Given the risk of haematogenous spread from a high-grade sarcoma to the lungs, imaging of the chest (CT without contrast (preferred) or X-ray) is essential for accurate staging. Abdominal/pelvic CT should be considered for angiosarcoma, leiomyosarcoma, myxoid/round cell liposarcoma, or epithelioid sarcoma as well as STS without definitive pathology before final resection. MRI of the total spine should be considered for myxoid/round cell liposarcoma due to the higher risk of metastasis to the spine compared with other STSs. CNS MRI should be considered for patients with alveolar soft part sarcoma and angiosarcoma.
Surgery
Surgery is the standard treatment for all patients. It must be carried out by a surgeon specifically trained in the treatment of STSs. The standard surgical procedure is an en bloc wide excision with R0 margins.	Surgery is the standard treatment for most patients with localized STS. For patients with resectable disease, a wide excision through normal uninvolved tissues is the surgical procedure of choice. With the addition of adjuvant RT, a close but tumour-free margin (R0) may be adequate. Where a wide excision is not possible due to anatomical constraints, a planned marginal or microscopically positive margin against a critical structure, plus RT, for intermediate- and high-grade tumours, may be an appropriate means of achieving tumour control while maintaining physical function.	Limb-sparing surgery is recommended for most patients with STS of extremities to achieve local control with minimal morbidity. Surgical resection (with appropriately negative margins) is the standard primary treatment for most patients with STS, although close margins may be necessary to preserve uninvolved critical neurovascular structures. Radical excision or entire anatomic compartment resection is not routinely necessary.
Radiation
Wide excision and RT are the standard treatments for high-grade (G2–3) lesions. The sequence of the two treatments varies among institutions, but there is an overall shift towards the use of preoperative RT, especially when preserving a critical structure is one of the goals. RT can be omitted only after multidisciplinary discussion in reference centres considering several variables.	For patients with borderline resectable tumours, preoperative treatment with chemotherapy and/or RT should be considered depending on histology. Pre- or postoperative RT is recommended along with surgical resection of the primary tumour for the majority of patients with intermediate- and high-grade tumours, and for selected patients with large or marginally excised, low-grade tumours.	RT and/or chemotherapy are often used before surgery to downstage large high-grade tumours to enable effective surgical resection. Postoperative RT should be considered following resection with close soft tissue margins (<1 cm) or a microscopically positive margin on bone, major blood vessels, or a nerve. Because postoperative radiation fields are typically larger than preoperative fields, the panel has expressed a general preference for preoperative radiation, particularly when treatment volumes are large.
Chemotherapy and other adjunctive treatments
Adjuvant/neoadjuvant anthracycline–ifosfamide chemotherapy for at least three cycles can be proposed to patients at high risk of death. Neoadjuvant chemotherapy with regional hyperthermia is another individualized option in patients at high risk of death	For patients with borderline resectable tumours, preoperative treatment with chemotherapy and/or RT should be considered depending on histology.Neoadjuvant or adjuvant chemotherapy is not routinely recommended but should be considered in situations where achieving local control is likely to be compromised, or the prognosis is poor, particularly in more chemosensitive sarcoma subtypes. Risk-stratification can be performed using nomograms such as Sarculator where patients with 5-year predicted survival < 60% may be most likely to benefit.	RT and/or chemotherapy are often used before surgery to downstage large high-grade tumours to enable effective surgical resection.
Retroperitoneal STS
Imaging and staging
		CT is the preferred imaging modality, although MRI can also be utilized in certain situations. Chest imaging should be performed for histologies that have the potential for lung metastases.	Thorough review of cross-sectional imaging by a sarcoma tumour board is required. The standard method for staging for the extent of primary tumour and for distant metastases is CT of the chest/abdomen/pelvis with i.v. contrast. A baseline PET scan may be considered before the treatment of high-grade RPS, but is not regarded as essential.
Intraoperative suspicion for RPS
		If a retroperitoneal STS is encountered unexpectedly when a laparotomy is performed for some other reason, a CNB should be performed to establish the diagnosis as well as the histopathologic type and grade of the tumour.	If at open or laparoscopic exploration for suspected adnexal mass no abnormalities of the uterus, fallopian tubes, or ovaries are found but an RP mass is detected, it is recommended that nothing further be done at that time. The patient should undergo subsequent dedicated imaging and referral to a sarcoma referral centre.
Surgery
Standard treatment of RPS consists of surgical resection en bloc with adherent organs.	The standard of care is en bloc macroscopically complete resection of the tumour and involved/adjacent organs, performed in high-volume specialist sarcoma centres. In the case of retroperitoneal liposarcoma, surgery to resect the tumour and adjacent viscera, irrespective of involvement and clearing all ipsilateral fat, to minimize microscopic positive margins, should be considered. Resection often necessitates ipsilateral nephrectomy, hemicolectomy, psoas fascia/muscle resection, and distal pancreatectomy/splenectomy on the left.		Complete en bloc gross resection is the cornerstone of management. In the case of primary RPS, surgery should be aimed at achieving macroscopically complete resection, with a single specimen encompassing the tumour and involved contiguous organs. Given the uncertainty regarding margin definition, an extended approach to systematically resect adherent viscera, irrespective of expected microscopic infiltration, should be considered for retroperitoneal liposarcoma.
Radiation
Neoadjuvant RT has shown signs of efficacy in primary low/intermediate-grade retroperitoneal liposarcoma. Intraoperative/postoperative RT is of no proven value in RPS.	Abdominal recurrence-free survival is significantly improved in the low–intermediate grade liposarcoma subgroup (with administration of preoperative RT) and preoperative RT should be discussed with this group. Postoperative RT following complete resection is of limited value and associated with significant toxicities and should only be considered in selected cases with a well defined area at risk of local recurrence.	Neoadjuvant RT can be considered for selected patients with retroperitoneal/intra-abdominal STS who are at high risk for local recurrence. The panel discourages adjuvant RT for retroperitoneal/intra-abdominal STS except in highly selected cases where local recurrence would cause undue morbidity.	Routine use of neoadjuvant RT is not recommended in patients with high-grade RPS, but may be considered in those with high risk of local (abdominal)-only recurrence, that is WDLPS and low-grade DDLPS. Postoperative/adjuvant external beam radiation after complete gross resection is of no proven benefit and is associated with significant short- and long-term toxicities.
Chemotherapy
The role of adjuvant/neoadjuvant chemotherapy is not yet established.	Preoperative chemotherapy can be considered for chemo-sensitive subtypes such as synovial sarcomas and borderline resectable leiomyosarcoma. The value of adjuvant chemotherapy is not established and cases at high risk for metastatic disease should be individually discussed. The Sarculator nomogram can be used for prognostication.		Postoperative/adjuvant chemotherapy after complete gross resection is of no proven benefit. Neoadjuvant chemotherapy can be discussed for use in individual patients with chemosensitive histologies such as synovial sarcoma and high-grade LMS, among others, or within prospective clinical studies.

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STS, soft tissue sarcoma; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network; TARPSWG, Transatlantic Australasian Retroperitoneal Sarcoma Working Group; RPS, retroperitoneal sarcoma; MDT, multidisciplinary tumor board; NICE, National Institute for Health Care Excellence; CNB, core needle biopsy; WDLPS, well differentiated liposarcoma; DDLPS, dedifferentiated liposarcoma; CT, computerized tomography; RP, retroperitoneal; WHO, World Health Organization; ASPS, alveolar soft part sarcoma; CCS, clear cell sarcoma; FDG-PET, fluorodeoxyglucose-positron emission tomography; CNS, central nervous system; RT, radiation therapy/radiotherapy; i.v., intravenous; LMS, leiomyosarcoma.

Diagnostic considerations for STS

Local staging

The diagnostic pathway for STS begins with imaging of the primary site to assess the mass’s size, location, composition, and relationship to neighbouring organs and neurovascular structures⁸. For extremity and trunkal STS, magnetic resonance imaging (MRI) is the preferred modality for assessing local extent, including signal intensity on T1- and T2-weighted images, contrast enhancement patterns, and fat-saturated sequences, and provides insight into the suspected histologic subtype and informs treatment planning. MRI can also serve as the primary local imaging modality for pelvic tumours. For most retroperitoneal and intra-abdominal tumours, computerized tomography (CT) with intravenous contrast is preferred for assessment of local disease and involvement of visceral and vascular structures, with arterial phases used, as needed, for surgical planning⁷. Nodal basin-directed imaging is typically not required due to the low likelihood of nodal metastases secondary to the primarily haematogenous spread of sarcomas, except in specific subtypes with known proclivity for nodal metastases (that is, angiosarcoma, clear cell sarcoma, epithelioid sarcoma, and rhabdomyosarcoma).

Biopsy and histopathological assessment

Whereas select tumours demonstrate pathognomonic imaging features allowing for reliable diagnosis (for example, angiomyolipoma), radiologic assessment alone is typically insufficient for diagnosis of STS. In a study⁹ of 291 patients with retroperitoneal sarcoma (RPS), standardized radiologic assessment demonstrated only moderately favourable performance characteristics for diagnosing mesenchymal adipocytic tumours (sensitivity 79.1%, specificity 99.4%) and poor discrimination for non-adipocytic tumours (sensitivity 55.4%, specificity 0%). Biopsy is, therefore, strongly recommended. An exception can be made for retroperitoneal tumours judged by an expert sarcoma radiologist as demonstrating features highly suggestive of WDLPS if no preoperative treatment is planned and this decision is agreed upon by an expert multidisciplinary tumour board⁷. For extremity masses, biopsy can be omitted for superficial, purely adipocytic tumours measuring ≤ 10 cm, with no radiologic features suspicious for malignancy, often classified as atypical lipomatous tumours⁸. Biopsy is particularly important for patients being considered for preoperative therapy, where histologic subtype or tumour grade may dictate treatment eligibility or sequencing, as it can impact treatment choice and/or timing in up to 46% of cases¹⁰.

A percutaneous core needle biopsy (CNB) is the preferred approach for tissue sampling, with high accuracy for ascertaining histologic subtype (> 80% concordance with final pathology^11–14). However, accuracy for grade via biopsy is lower (60 and 70%^15–18), often due to undergrading of the biopsy specimen. This is exemplified by the common misclassification of DDLPS as WDLPS, often due to sampling error^11,15,16 but can be observed in cases of leiomyosarcoma as well¹⁷. Intratumoural heterogeneity, especially for tumours comprised of both well differentiated and dedifferentiated liposarcomatous components, contributes to this issue. As such, Tirotta et al.¹⁹ have demonstrated that targeting solid areas of tumours on biopsy can improve sensitivity for identifying DDLPS. This practice is further supported by the TARPSWG guidelines, which recommend tissue sampling from solid, well perfused components on contrast-enhanced CT or MRI or from high standardized uptake value areas on fluorodeoxyglucose-positron emission tomography/CT, if performed, to increase the probability of detecting high-grade disease⁷. Whereas sampling from solid, non-necrotic regions can improve the accuracy of grading, degree of necrosis is a component of tumour grading, and, as such, correlating pathologic assessment with radiographic features in highly necrotic tumours may aid in accurate preoperative estimation of tumour grade.

A CNB carries low risks. Early complications occur in about 3% of cases^10,11,15, most commonly bleeding or pain. Needle tract seeding has been a theoretical concern, as malignant cells were found to be present in 13% of needle tracts excised in the context of musculoskeletal sarcomas^20–23. However, pooled results of two studies^20,24,25 in which biopsy tracts were not excised showed no events consistent with needle tract seeding. This suggests that the presence of malignant cells alone is likely insufficient to allow for tumour growth. In the retroperitoneum, seeding rates are estimated at ≤ 0.5%^10,11,26,27, rising to 2.0% in one study involving non-coaxial transabdominal biopsies²⁸. Concerns regarding biopsy-related tumour pseudocapsule breach compromising oncologic outcomes have also been investigated, with studies^26,28 showing no increase in local recurrence when a CNB is performed.

To minimize complications and avoid compromising future surgery, best practices for a CNB are recommended. These include use of a 14–18 gauge needle via a coaxial technique with four to six passes, targeting higher-density/solid areas, to maximize diagnostic yield^7,19,29,30. Within the extremity, the biopsy site should be placed such that the tract can be easily excised en bloc with the specimen at the time of definitive surgery. For retroperitoneal tumours, where the biopsy tract is not typically excised, retroperitoneal approaches to biopsy should be favoured over transabdominal routes to minimize the risk of seeding (Fig. 1, panel A).

For image description, please refer to the figure legend and surrounding text. — Biopsy techniques for a retroperitoneal soft tissue sarcoma approached with retroperitoneal biopsy with coaxial needle technique

a Image-guided biopsy can target the highest-grade areas of the tumour. The retroperitoneal, rather than transabdominal, approach reduces the potential risk of intra-abdominal seeding. Additionally, the confined retroperitoneal space provides tamponade in cases of post-biopsy bleeding. b Extremity soft tissue sarcoma approached with incisional/excisional biopsy. Longitudinal, as opposed to transverse, biopsy prevents contamination of uninvolved fascial compartments and reduces the need for unnecessary complex skin and soft-tissue coverage at the time of definitive resection.

A CNB may not always be feasible and may require consideration of alternative biopsy techniques. Small (< 3 cm) superficial extremity/truncal lesions may be best sampled via excisional biopsy^5,8; however, this method is generally avoided for larger lesions as re-excision for residual disease may necessitate creation of a large defect with associated functional losses¹² and preclude patients from neoadjuvant therapies. Incisional biopsy, once common, is now infrequently performed, as complication rates, including haematoma, infection, and wound dehiscence, are higher than for a CNB. However, it may be considered in select cases discussed at referral centres⁵. When performed, incisions should be made longitudinally in the extremities to minimize the extent of soft tissue resection required at definitive surgery (Fig. 1, Panel B). Dissection should avoid uninvolved tissues and attempt not to violate fascial planes. Meticulous haemostasis is additionally important, as post-biopsy haematomas, considered contaminated by malignant cells, can dissect through tissues, further contaminating initially uninvolved compartments^29,31. Laparotomy or laparoscopy for biopsy should generally not be performed, as a lack of image guidance can lead to undersampling, risks of peritoneal contamination, and distorted planes for future surgery⁷. Similarly, when a retroperitoneal mass is unexpectedly encountered during surgery, then surgery should be aborted, and postoperative imaging and percutaneous biopsy pursued⁷.

Histopathological diagnosis is typically made using morphology and immunohistochemistry, with molecular diagnostics offering valuable adjuncts. These tests leverage known genetic alterations in various sarcomas, including translocations, specific oncogenic mutations, and gene amplifications or deletions,³² such as MDM2 amplification in WDLPS/DDLPS, as detected by fluorescence in situ hybridization³³. GENSARC³⁴, a prospective study of the utility of molecular assays for sarcoma diagnosis, demonstrated that routine molecular genetic testing can modify diagnoses in up to 23% of cases. As such, molecular diagnostic adjuncts are recommended for specific histologic subtypes that require molecular confirmation for diagnosis; when there is diagnostic uncertainty, including cases of unusual clinical presentations or discordance between clinical and pathological appearances; for subtypes where specific diagnoses will influence use of neoadjuvant therapeutic strategies (for example, synovial sarcoma, myxoid/round cell liposarcoma, and Ewing’s family sarcoma); or for prognostication or prediction⁵.

Radiomics is an emerging adjunctive tool under investigation to improve the ascertainment of histologic subtype and grade. Although promising results are emerging, these methods remain investigational at this time.

Distant staging

Following diagnostic confirmation and evaluation of local extent of disease, distant staging is required. Sarcomas typically spread via haematogenous routes. Given the predilection for pulmonary metastases in extremity sarcomas, distant staging is usually performed with chest CT. Abdominopelvic imaging is additionally performed for histologic subtypes with a proclivity for intra-abdominal or retroperitoneal metastases, including angiosarcoma, leiomyosarcoma, myxoid/round cell liposarcoma, and epithelioid sarcoma⁴. Further histology-specific patterns of spread should also be considered. Some examples include the various sites of extrapulmonary metastases possible in myxoid liposarcoma (intra-abdominal/retroperitoneal, osseous, truncal, cardiac/mediastinal)^35,36 and the risk of brain metastases in alveolar soft part sarcoma⁵. Distant staging for RPS includes thoracic, abdominal, and pelvic CT.

Importance of high-volume centres

Current guidelines^5,7 recommend that patients with STS be managed within designated sarcoma referral centres or networks. The rationale for these recommendations comes from numerous studies demonstrating improved outcomes when patients with sarcoma are treated at high-volume centres, including greater guideline-concordant care^37–39, greater R0 and fewer R2 resections^{37,38,40–43}, and improved survival outcomes^{37,39,42,44–48}. Thresholds for defining high-volume hospitals vary across studies; however, a US study⁴⁹ using data from the National Cancer Database suggested improved survival for RPS with increasing hospital case volume, which plateaued at 13 cases/year. This threshold has subsequently been used to update sarcoma nomograms to incorporate volume–outcome relationships⁴⁵. Surveyed members of TARPSWG similarly suggested RPS case volumes of 11–20 per year as indicative of high-volume RPS centres⁴⁹. Importantly, although guidelines recommend treatment at referral centres, many patients with sarcoma continue to be treated in low-volume hospitals that manage > 90% of patients with sarcoma⁴². Although this proportion varies by jurisdiction, with some countries reporting that over half of patients are treated in high-volume hospitals, the rate of regionalization adoption is slower than that observed in other cancers, such as pancreatic cancer⁵⁰.

Critically, hospital case volume alone does not entirely account for improved outcomes observed in high-volume hospitals. In fact, in one study, as the number of cases of RPS treated at community hospitals increased, mortality also increased—a trend not seen in academic hospitals⁵¹. Such data illustrate that the superior outcomes attained at high-volume centres are attributable to systems of care, comprising multidisciplinary teams (including experts in sarcoma radiology and pathology), resources to deliver guideline-concordant treatments, and patient access to clinical and translational research studies—all factors recommended as quality criteria for sarcoma reference centres^5,52. For example, patients who present to multidisciplinary tumour boards at sarcoma reference centres before initiation of therapy are more often guideline-concordant and have higher rates of R0 resections⁵³. The development of the TARPSWG international tumour board⁵⁴ is one example of an innovation seeking to extend these benefits to the broader sarcoma community; however, as detailed above, care administered at high-volume centres capitalizes on several processes associated with improved outcomes and should be pursued, when possible.

Within high-volume centres, individual surgeon case volumes may also influence outcomes. Only one study⁵⁵ has evaluated the learning curve for RPS surgery based on operative metrics for a single surgeon, demonstrating a plateau in improvements in operative time after 16 cases and a post-learning phase signalled by greater case complexity after 46 cases; however, studies⁵⁶ in other cancer types emphasize an interplay between hospital and surgeon case volumes on surgical morbidity and mortality. Together, these highlight opportunities for both regional and local centralization of sarcoma surgical expertise to optimize patient outcomes.

Treatment of extremity STS

Surgery

The goal of surgery for extremity STS is a limb-sparing, function-preserving, margin-negative resection. The foundation for this approach was laid by the seminal trial by Rosenberg et al.⁵⁷, which randomized patients to amputation, the previously favoured approach, or limb-sparing resection with adjuvant radiation therapy/radiotherapy (RT); patients in both groups additionally received adjuvant chemotherapy. Although patients randomized to the limb-sparing arm had higher rates of local recurrence, DFS and OS were comparable to those with amputation, leading to the acceptance of limb-sparing resection as the standard of care.

Appropriate limb- and function-preserving surgery requires a detailed understanding of histotype-specific recurrence patterns and functional anatomy, the latter aided by a thorough review of high-resolution imaging for surgical planning⁶. Importantly, malignant cells frequently extend beyond the tumour pseudocapsule⁵⁸ and, as such, wide resections (into surrounding uninvolved tissue) are recommended over marginal excisions (extending just outside the pseudocapsule). An exception to this rule is made for atypical lipomatous tumours, for which marginal excision may be appropriate, given the low recurrence rate even with positive margins^5,59. Surgical planning should consider whether skin or soft-tissue coverage will be required, necessitating collaboration with an oncoplastic surgeon.

Where extremity STSs abut critical neurovascular structures, planned R1 resections are justified to preserve these structures⁵. Several studies demonstrate low rates of local recurrence in the setting of planned R1 resections, compared with the high rates observed with unexpected positive margins^59,60. However, if critical vasculature or nerves are encased, resection and reconstruction is feasible, particularly when required to facilitate limb salvage. Arterial reconstruction can be accomplished with synthetic or autologous grafts. Whereas acceptable functional outcomes may be achievable with resection of select major nerves^61–63, reconstructive techniques, when possible, can restore some sensory and motor function⁶⁴. Contemporary cohorts estimate amputation rates of < 5%. Indications for primary amputations have included multifocal disease, bone invasion, neurovascular bundle involvement with loss of function, and comorbidities precluding major reconstructive surgery^65,66.

A not infrequent scenario encountered by the sarcoma surgeon is referral of a patient after marginal excision of a presumed benign mass elsewhere, with final pathology unexpectedly demonstrating sarcoma. When such patients undergo re-excision to obtain wider margins, residual malignancy is identified in 24–63% of specimens^67,68. On initial consultation, such patients should be appropriately staged, including imaging of the involved limb to rule out gross residual disease⁶. In the absence of radiologically evident disease, re-excision at a sarcoma centre can be considered to optimize local control if it can be achieved without excessive morbidity^5,6. However, systematic re-excision is not associated with improvements in metastasis-free or OS and, as such, watchful waiting with delayed re-excision at the time of local recurrence is an alternate option⁶⁹.

Radiation

RT is used adjunctively in the treatment of extremity STS to improve local control. A synthesis of the evidence is provided in Table 2. The basis for this approach arises from Rosenberg et al.’s seminal paper, which introduced external beam radiotherapy (EBRT) following function-preserving surgery as an alternative to amputation in 43 patients in a randomized clinical trial (RCT)⁵⁷. The limb-sparing resection group received wide local excision followed by 50 Gy in 25 fractions to the entire anatomic area at risk for local spread (commonly 5 cm longitudinal margin and 2 cm axial margin) and 60–70 Gy (additional 10–20 Gy at 2 Gy per fraction) to the tumour bed. There were four recurrences in the limb-sparing group associated with marginal resection compared with zero recurrences in the amputation group. Further, in the National Cancer Institute study by Yang et al.^70,71 patients with extremity STS were randomized to receive or forgo adjuvant EBRT; all patients with high-grade disease additionally received adjuvant chemotherapy. This trial demonstrated improvements in local control with adjuvant RT, with benefits observed in both low- and high-grade disease. Neither study found improvements in rates of distant recurrence or survival, thus concluding that function-preserving surgery with EBRT was an acceptable standard of care.

Table 2.

Seminal trials in RT and systemic therapy for eSTS

Study	Population	Interventions	Outcomes	Conclusions
RT
Adjuvant external beam RT
Rosenberg et al. (1982)⁵⁷	High-grade eSTS (n = 43).	Amputation versus limb-sparing resection + adjuvant RT (both groups received adjuvant chemotherapy).	Increased local recurrence with limb salvage (15% versus 0%; P = 0.06). No difference in 5-year DFS between limb salvage versus amputation (71% versus 78%; P = 0.75). No difference in 5-year OS between limb salvage versus amputation (83% versus 88%; P = 0.99).	Limb-sparing surgery + adjuvant RT is a safe alternative to amputation.
NCI trial (Yang et al. 1998)⁷⁰	Low-grade (n = 50) and high-grade (n = 91) eSTS.	Low-grade: surgery +/− adjuvant RT. High-grade: surgery + adjuvant chemotherapy +/− adjuvant RT.	High-grade: decreased local recurrence with adjuvant RT (P = 0.003) with no difference in OS. Low grade: decreased local recurrence with adjuvant RT (P = 0.02) with no difference in OS.	Adjuvant RT improves local control but not survival.
Neoadjuvant versus adjuvant RT
NCIC SR2 trial (O’Sullivan et al. 2002, Davis et al. 2005)^72,73	eSTS (n = 190).	Preoperative RT (50 Gy in 25 fractions) versus postoperative RT (66 Gy in 33 fractions).	Higher rate of wound complications in the preoperative RT versus postoperative group (35.2% versus 17.0%). Higher rate of long-term joint fibrosis in the postoperative versus preoperative RT group (48.2% versus 31.5%).	Preoperative RT associated with greater risk of early wound complications (particularly for lower extremity lesions), whereas postoperative RT associated with higher risk for long-term joint complications.
Adjuvant brachytherapy
Pisters et al. (1996)⁷⁴	Extremity or superficial trunk STS (n = 164).	Surgery alone versus surgery plus adjuvant brachytherapy (iridium-192 implant; 42–45 Gy over 4–6 days)	Improved 5-year local control with brachytherapy (82% versus 69%; P = 0.04). Effect limited to patients with high-grade disease (89% versus 66%; P = 0.003). No significant difference in distant recurrence or disease-specific survival.	Adjuvant brachytherapy can improve local control in high-grade disease, with no improvement in survival.
IGRT
RTOG-0630 phase II trial (Wang et al. 2015)⁷⁵	eSTS (n = 79).	Preoperative IGRT followed by limb-sparing resection.	Grade ≥ 2 toxicity = 10.5% (historic comparator: 36.4% from NCIC-SR2 study). Wound complication rate = 36.6%.	Reduction of late but not early toxicity with IGRT.
Hypofractionated RT
HYPORT-STS phase II trial (Guadagnolo BA et al. 2022, Bishop AJ et al. 2025)^76,77	Extremity or superficial trunk STS (n = 120).	Preoperative moderately hypofractionated RT (15 fractions × 2.85 Gy).	Four-year local recurrence-free survival = 93%. Major wound complications = 30.8%. Two-year grade ≥ 2 toxicity = 9.1%. Bone fractures = 3.3%.	Suggests safety and efficacy of moderately hypofractionated RT (biologically equivalent dose 49 Gy).
Kosela-Paterczyk H et al. (2014)⁷⁸	Extremity or truncal STS (n = 272).	Preoperative ultra-hypofractionated RT (5 fractions × 5 Gy).	Local recurrence = 19.1% (median f/u 35 months). Treatment toxicity (any grade) = 41.9%.	Compromised local control when biologically equivalent dose is lower than conventional RT (37.5 Gy).
Kalbasi A et al. (2020)⁷⁹	Extremity or truncal STS (n = 52) planned for neoadjuvant RT.	Preoperative ultra-hypofractionated RT (5 fractions × 6 Gy).	Major wound complications = 32%. Grade ≥ 2 toxicity = 16%.	Ultra-hypofractionated regimens can demonstrate similar acute wound complication rates as conventionally fractionated RT when a biologically equivalent dose similar to conventional RT is used (50 Gy).
Leite ETT et al. (2021)⁸⁰	eSTS (n = 25).	Preoperative SABR (40 Gy in 5 fractions administered every other day).	Wound complications = 28%. Grade ≥ 2 late toxicity = 41%. 2-year local recurrence = 0%. Amputation rate = 16%, fracture = 4%.	High amputation rate at high biologically equivalent doses (80 Gy).
Bedi M et al. (2022)⁸¹	Extremity or truncal STS (n = 32).	Preoperative ultra-hypofractionated RT (5 fractions × 7 Gy).	Local recurrence = 0% (median follow-up 36.4 months). Major wound complications = 25%. Amputation rate = 6%.	Acceptable local control at biologically equivalent dose similar to conventional RT (64 Gy).
Mayo ZS et al. (2023)⁸²	Extremity and truncal STS (n = 22).	Preoperative ultra-hypofractionated RT (5 fractions × 6 Gy).	Local recurrence = 0% (median follow-up 24.5 months). Major wound complication = 41%. Wound complications requiring reoperation = 36%. Fracture rate = 5%.	High wound complication and fracture rates even at biologically equivalent dose similar to conventional RT (50 Gy).
Systemic therapy
Chemotherapy
Meta-analysis of RCTs (Pervaiz et al. 2008)⁸³	RCTs of adjuvant chemotherapy for localized STS (n = 18 studies).	Adjuvant chemotherapy versus surgery alone.	Decreased odds of local recurrence with chemotherapy (OR 0.73, 95% c.i. 0.56, 0.94). Improved odds of survival with combination doxorubicin + ifosfamide versus no chemotherapy (OR 0.56, 95% c.i. 0.36, 0.85).	Marginal efficacy of chemotherapy for resectable STS that needs to be balanced against toxicity.
EORTC 62 931 (Woll et al. 2012)⁸⁴ and post hoc analysis (Pasquali et al. 2019)⁸⁵	STS of any site (n = 351).	Adjuvant chemotherapy (doxorubicin + ifosfamide) or no chemotherapy.	No difference in OS (HR 0.94, 95% c.i. 0.68, 1.31). No difference in relapse-free survival (HR 0.91, 95% c.i. 0.67, 1.22). Post hoc analysis: improvement in DFS (HR 0.49, 95% c.i. 0.28, 0.85) and OS (HR 0.50, 95% c.i. 0.30, 0.90) among high-risk patients (10-year predicted OS < 60%).	No benefit to chemotherapy in the overall population. High-risk patients (as determined by Sarculator-predicted 10-year OS < 60%) may benefit from chemotherapy.
ISG-STS 1001 (Gronchi et al. 2017, Gronchi et al. 2020)^86,87	High-risk (high grade, ≥ 5 cm, deep-seated) extremity or truncal STS; inclusion of five histological subtypes (myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, undifferentiated pleomorphic sarcoma) (n = 287).	Three doses of neoadjuvant standard chemotherapy (epirubicin + ifosfamide) or histotype-tailored chemotherapy.	Stopped early for futility—improved 46-month DFS projected standard versus histotype-tailored chemotherapy arm (62% versus 38%; P = 0.004). In long-term follow-up, improved 5-year survival in standard versus histotype-tailored arm (76% versus 66%; P = 0.02).	When neoadjuvant chemotherapy is administered, standard regimens (not histotype-tailored regimens) are preferred.
Immunotherapy
SARC028 (Tawbi et al. 2017)⁸⁸	Advanced/metastatic soft tissue (n = 40) or bone sarcomas (n = 40) had received up to three lines of previous therapy.	Pembrolizumab 200 mg i.v. every 3 weeks.	Notable objective response rate: Undifferentiated pleomorphic sarcoma = 40% DDLPS = 20%.	Suggestion of efficacy of immunotherapy in undifferentiated pleomorphic sarcoma and DDLPS.
Alliance A091401 (D’Angelo et al. 2018)⁸⁹	Advanced/metastatic sarcoma, at least one line of previous systemic therapy (n = 85).	Nivolumab 3 mg/kg every 3 weeks OR nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks × 4 doses (independent, non-comparative arms).	Response rate: Nivolumab alone = 5%. Ipilimumab/nivolumab = 16%. Serious treatment-related adverse events: Nivolumab alone = 19%. Ipilimumab/nivolumab = 26%.	Nivolumab alone ineffective in advanced sarcoma. Combination ipilimumab/nivolumab may have efficacy but with increased toxicity.
Roland et al. (2024)⁹⁰	Resectable DDLPS (n = 17) and extremity/truncal undifferentiated pleomorphic sarcoma (n = 10).	DDLPS: neoadjuvant nivolumab 3 mg/kg or nivolumab 3 mg/kg + ipilimumab 1 mg/kg. Undifferentiated pleomorphic sarcoma: nivolumab 3 mg/kg + radiation or nivolumab 3 mg/kg + ipilimumab 1 mg/kg + RT.	Pathologic response (percent hyalinization): DDLPS = 8.8%. Undifferentiated pleomorphic sarcoma = 89%.	Suggestive of sensitivity of resectable undifferentiated pleomorphic sarcoma to combination of immunotherapy plus RT
SARC032 (Mowery et al. 2024)⁹¹	Grade 2–3 extremity/limb girdle undifferentiated pleomorphic sarcoma or DDLPS or pleomorphic liposarcoma (n = 127).	Preoperative RT then surgery versus preoperative pembrolizumab (3 cycles) + RT + surgery + adjuvant pembrolizumab (14 cycles).	Improved DFS with administration of pembrolizumab (HR 0.61, 90% c.i. 0.39, 0.96). Absolute improvement of 15% in 2-year DFS with pembrolizumab (67% versus 52%). Greater effect seen in grade 3 versus grade 2 disease.	Addition of perioperative pembrolizumab to preoperative RT and surgery in resectable undifferentiated pleomorphic sarcoma improves DFS. Long-term results (OS) pending.

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eSTS, extremity soft tissue sarcoma; RT, radiation therapy/radiotherapy; DFS, disease-free survival; OS, overall survival; IGRT, image-guided radiation therapy; SABR, stereotactic ablative radiotherapy; RCT, randomized clinical trial; OR, odds ratio; c.i., confidence interval, HR, hazard ratio; i.v., intravenously; DDLPS, dedifferentiated liposarcoma.

Alternative RT delivery methods, such as brachytherapy, have also been evaluated. Pisters et al.⁷⁴ randomized 164 patients with STS to adjuvant brachytherapy (iridium-192, 42–46 Gy over 4–6 days) or no further treatment after complete resection, demonstrating improvements in local control, limited to patients with high-grade disease (5-year local control 89% with adjuvant brachytherapy versus 66% without). Brachytherapy, when utilized as monotherapy, is currently limited to low-risk cases (for example, small-to-mid-sized high-grade tumours) or for re-irradiation (in order to minimize normal tissue toxicity); it is not routinely considered for high-risk deep-seated tumours⁹².

Although the above prospective trials firmly established the role of adjuvant RT in optimizing local control after limb-sparing surgery and set 5-year local recurrence rates < 10% as the benchmark for future studies, several potential benefits of neoadjuvant treatment have increasingly been recognized. Adjuvant RT is usually administered as 50–50.4 Gy in 1.8–2 Gy fractions, with an additional 10–16 Gy boost (total 60–66 Gy) targeted to the tumour bed and volume at risk of local recurrence^4,6,93. In contrast, neoadjuvant RT allows for lower doses, typically 50 Gy with no boost, administered to a smaller volume, as the in situ tumour facilitates accurate delineation of a tumour and the at-risk region for RT planning. Preoperative RT can effectively render a tumour non-viable and, in select cases, downsize tumours⁹⁴, particularly important in borderline resectable cases. Finally, for planned R1 resections, preoperative RT may sterilize tumour margins, offsetting the impact of a positive margin⁹⁵.

Preoperative versus postoperative RT was evaluated in the landmark National Cancer Institutes of Canada NCIC-SR2 trial⁷², in which patients with extremity STS were randomized to 50 Gy RT in 25 daily fractions given before surgery or to 66 Gy in 33 fractions after surgery. In the preoperative group, those with positive margins also received a postoperative boost of 16–20 Gy. No differences in OS or local control were seen, a finding subsequently replicated by others⁹⁶. However, the toxicity profiles of preoperative and postoperative RT differed widely. Preoperative RT was associated with higher rates of major wound complications (35.2% preoperative RT versus 17.0% postoperative RT), which included second operations or invasive procedures, deep packing, or admission to hospital for wound care⁷². These occurred almost exclusively in patients with STS of the lower extremity (1 major wound complication reported in the upper extremity), more often in the thigh than the lower leg. However, longer-term results demonstrated a higher rate of late toxicity among those who received postoperative RT⁷³, including high rates of grade ≥ 2 fibrosis (48.2%), joint stiffness (23.2%), and oedema (23.2%), with toxicity rate associated with higher dose, larger RT volume, and poorer functional outcome. In addition, the application of an additional postoperative boost to those who received preoperative RT did not improve local control.

Further advances in surgery and RT have aided in reducing morbidity and improving functional outcomes. Intensity-modulated radiotherapy (IMRT), which utilizes multiple beams of varying intensity to provide greater dose conformality and tumour coverage, was shown to provide comparable or slightly improved local control compared with 3D-conformal radiation therapy (3DCRT), with lower rates of late toxicity, including a 12% rate of fibrosis at 2 years^97–99. Further to this, image-guided radiation therapy (IGRT) utilizes pretreatment MRI allowing for at-risk margin adaptation of the target volume and assessment of treatment CT imaging to ensure accurate, reproducible, patient setup and treatment delivery. IGRT was tested in the phase 2 Radiation Therapy Oncology Group RTOG-0630 trial⁷⁵, in which 10.5% of patients treated before surgery with image-guided (IG)-IMRT or IG-3DCRT developed at least one grade ≥ 2 late toxicity, compared with 37% in the NCIC-SR2 trial. Wound complication rates after preoperative RT to the lower extremity remained high, as also seen by O’Sullivan et al. (2013)¹⁰⁰, where 30.5% of patients who received preoperative IG-IMRT developed significant wound complications.

Given the comparable efficacy but higher rates of long-term, often permanent, toxicities of postoperative RT, many societies have endorsed the use of preoperative image-guided IMRT-based RT for extremity STS^4,5,93. However, this decision remains an individualized one, taking account of specific patient, tumour, and technical factors. The common exception for preoperative RT are patients who present with a rapidly growing symptomatic tumour who would be unable to tolerate preoperative RT. Tumour location is integral to decision-making, particularly when critical surrounding structures may be at risk from postoperative RT (for example, brachial plexus), or lower extremity location results in high risk of acute complications from preoperative RT. Borderline tumours, where downsizing will facilitate resectability, stand to benefit from preoperative treatment, which has been shown to reduce tumour volumes by a median of 33%⁹⁴. Downsizing can be safely attempted with RT alone, particularly in myxoid/round cell liposarcoma, or considered with sequential or concurrent chemotherapy¹⁰¹. Finally, preoperative RT may also contribute to reducing viability of tumour cells and so should be used in all cases where an R1 resection is planned for preservation of critical structures^95,102.

Beyond the decision of timing of RT, an additional consideration is whether low-risk groups can be identified in whom RT can be safely omitted. In a retrospective study¹⁰³ of patients with mostly small and low-grade extremity and truncal STS, 10-year local control without RT was > 90%. These results were further confirmed prospectively in a trial of selective use of postoperative RT, where RT was omitted in patients with extremity or truncal STS ≤ 5 cm unless pathology demonstrated a positive margin¹⁰⁴. At 5 and 10 years, local recurrence in the group where RT was omitted remained favourable (7.9% and 10.6%, respectively), suggesting safety of omission in this low-risk group. Based on this, a more selective approach is now undertaken, considering tumour size, grade, histology, and margins, such that RT is omitted for small (< 5 cm), low-grade, superficial tumours^5,6. Published nomograms can further assist in identifying patients at low risk for recurrence who may be spared from RT^105,106. In the setting of higher-grade or larger tumours, retrospective data suggest that an approximately 90% local control rate is attainable without RT when patients are treated by expert sarcoma surgeons at high-volume centres^103,107.

An emerging area of investigation in extremity STS is the use of hypofractionated preoperative RT regimens. Acknowledging that the conventional 5-week course of radiation can be costly and difficult for patients, especially those living far from a specialist treatment centre, an inefficient use of hospital resources, and prolongs the time from diagnosis to surgery, moderately hypofractionated and ultra-hypofractionated regimens, which deliver larger daily doses of RT over a shorter duration, are attractive. Preoperative moderately hypofractionated RT (15 fractions of 2.85 Gy over 3 weeks, total dose 42.75 Gy) has shown promising 30-month local recurrence-free survival (LRFS) of 93% and major wound complication rates of 30.8% in a single phase II trial⁷⁶. Recent longer-term follow-up from this study demonstrated a 4-year LRFS of 93%. Nine percent of patients had grade ≥2 toxicity at 2 years, including skin toxicity (2%), fibrosis (2%), oedema (3%), and joint stiffness (1%). Four patients (3%) experienced bone fractures, all of which occurred in the femur⁷⁷. The ongoing SCOPES phase II trial (NCT04425967)¹⁰⁸ seeks to explore further the oncologic outcomes, toxicity, health-related quality of life, and cost-effectiveness associated with a moderately hypofractionated regimen (14 fractions × 3 Gy) in patients with intermediate- and high-grade localized STS.

Preoperative ultra-hypofractionated RT has also been evaluated in several studies, delivering 5–8 Gy per fraction daily over 1–2 weeks. When the biologically equivalent dose is below that used in conventional fractionation (for example, 5 Gy × 5 fractions, biologically equivalent dose 37.5 Gy), local control is compromised⁷⁸. However, when doses are similar to or higher than conventional RT (for example, 6 Gy × 5 fractions, biologically equivalent dose 50Gy^79,82; 7 Gy × 5 fractions, biologically equivalent dose 64Gy⁸¹; or 8 Gy × 5 fractions, biologically equivalent dose 80Gy⁸⁰), local control reaches > 90%. Acute wound complications rates remain similar to those observed in the NCIC-SR2 trial. Lower rates of long-term toxicity, including fibrosis, oedema, and joint stiffness, are observed but emerging long-term data suggest the possibility of higher rates of amputation for treatment-related complications (up to 16%⁸⁰) and late severe skin toxicity (up to 14%⁷⁹). As data mature, follow-up on long-term toxicities of ultra-hypofractionated regimens will require further evaluation, particularly for those regimens with higher biologically equivalent doses than conventionally fractionated RT. The current consensus is to continue with conventional fractionation and consider hypofractionated schedules in the context of an RCT¹⁰⁹.

Chemotherapy

The use of chemotherapy in the treatment of extremity STS is not routinely recommended due to a conflicting evidentiary base marked by differences in regimens used and results obtained, Table 2. However, several guidelines^5,6 encourage individualized treatment, including consideration of chemotherapy for patients with high-risk disease. The first generation of trials evaluating the efficacy of chemotherapy for STS were meta-analysed in the 1997 review by the Sarcoma Meta-analysis Collaboration (SMAC)¹¹⁰. This individual patient data meta-analysis included 1568 patients with mixed histologies and anatomic locations of STSs across 14 randomized trials. Adjuvant doxorubicin-based chemotherapy was shown to improve rates of local recurrence (hazard ratio (HR) 0.73, 95% confidence interval (c.i.) 0.56 to 0.94; absolute risk reduction (ARR) 6% at 10 years) and distant recurrence (HR 0.70, 95% c.i. 0.57 to 0.85; ARR 10% at 10 years) but did not result in a statistically significant improvement in OS (HR 0.89, 95% c.i. 0.76 to 1.03; ARR 4% at 10 years). Subgroup analyses suggested largest benefits among patients with extremity STS, where a 7% absolute benefit in OS was observed.

In the 1990s, a second generation of randomized trials, which included combination treatment of dose-intensified doxorubicin with ifosfamide, emerged. Of note, only one study in the original SMAC meta-analysis administered this combination. An updated meta-analysis⁸³ was therefore performed, adding four studies in which the combination of doxorubicin plus ifosfamide was tested. This meta-analysis again demonstrated improvements in rates of both local and distant recurrence, but also demonstrated an improvement in OS, greatest among studies utilizing doxorubicin plus ifosfamide (HR 0.56, 95% c.i. 0.36 to 0.85; ARR 11%). Although encouraging, the benefits observed were tempered by the added toxicity of combination therapy.

Further concerns about the utility of chemotherapy for STS arose following the publication of the results of the EORTC 62 931 trial, a randomized study⁸⁴ of five cycles of adjuvant dose-intense doxorubicin and ifosfamide administered to patients with grade 2–3 resected STSs of any site. No differences in relapse-free survival or OS were observed, questioning its use among this patient group. However, subgroup analyses performed in this trial, as well as in previous meta-analyses, suggested larger effects of chemotherapy among patients with high-risk extremity STS. In a post hoc analysis of the EORTC 62 931 trial, Pasquali et al. (2019)⁸⁵ stratified patients by risk, assessed using the Sarculator nomogram¹¹¹, and demonstrated improvements in DFS (HR 0.49, 95% c.i. 0.28 to 0.85) and OS (HR 0.50, 95% c.i. 0.30 to 0.90) among high-risk patients (defined as Sarculator-determined 10-year predicted probability of survival < 60%) treated with chemotherapy. A retrospective study¹¹² of 5683 patients similarly demonstrated improvements in OS with the administration of combination anthracycline and ifosfamide-based chemotherapy that was limited to patients with high-risk disease (PERSARC-predicted 5-year OS < 65.8%). In neither study were significant benefits observed when chemotherapy was administered to lower-risk patients, supporting selective rather than routine use of chemotherapy for extremity STS.

With support for chemotherapy building, the benefits of neoadjuvant chemotherapy, including the ability to evaluate in situ tumour response and provide early treatment of undetected disseminated disease, were increasingly being acknowledged and studies^113,114 moving chemotherapy into the preoperative setting were conducted. Further to this, efforts to optimize dose regimens and intensity were undertaken, including the ISG-STS 1001 trial^86,87. In this study, patients with high-grade, ≥ 5 cm, deep STS of the extremity or trunk were randomized to three cycles of epirubicin plus ifosfamide or a regimen tailored to histologic subtype (high-grade myxoid liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumour, or UPS). Unexpectedly, patients treated with a histotype-tailored neoadjuvant chemotherapy regimen demonstrated significantly worse DFS and OS compared with those treated with standard epirubicin and ifosfamide. Although discouraging, this trial provides important prospective data on the efficacy of standard chemotherapy. As was done previously, patients enrolled in this trial were also subsequently stratified by Sarculator-predicted 10-year OS, again demonstrating an improvement in OS restricted to high-risk patients (that is, 10-year predicted OS < 60%) treated with standard chemotherapy (5-year Sarculator-predicted OS 58% versus study-observed OS 66%; P = 0.04)¹¹⁵.

Based on these studies, current recommendations for chemotherapy in extremity STS include individualized use, considering tumour size, grade, histologic subtype, and patient performance status and comorbidities. Among patients considered to be at high risk for recurrence and death, such as those with Sarculator-predicted 10-year OS < 60%, neoadjuvant chemotherapy may be administered either alone or concurrently with RT¹⁰¹. Response among patients treated with neoadjuvant chemotherapy should be tracked to ensure absence of progression^5,6.

Immunotherapy

A developing area of investigation in the treatment of STS is the utility of immune checkpoint blockade, also reported in Table 2. Despite sarcoma being a relatively non-immunogenic tumour, 18% of patients with metastatic/unresectable STS treated with pembrolizumab in the SARC028 trial demonstrated objective responses⁸⁸. Greatest efficacy was observed among patients with UPS and DDLPS (objective response rate (ORR) of 23 and 10%, respectively, in the expansion cohort¹¹⁶). Subsequent correlative analyses demonstrated an association between baseline PD-L1 expression, as well as density of tumour-associated T-cell infiltrates, with immunotherapy response¹¹⁷. Further studies^118,119, including gene expression profiling of STS and the phase 2 PEMBROSARC trial, have demonstrated an association between the presence of intratumoural tertiary lymphoid structures and response to pembrolizumab, suggesting its use as a biomarker for immunotherapy response. Of note, however, patient cohorts in early studies of immunotherapy may have included patients with undifferentiated or dedifferentiated melanoma, which can lack expression of melanocytic markers by immunohistochemistry and be misclassified as UPS¹²⁰—such patients demonstrate robust responses to immunotherapy, akin to other melanoma patients, possibly contaminating the results of initial studies.

Alternate immune checkpoint blockade regimens have shown variable success. For example, in the Alliance A091401 trial⁸⁹, patients with metastatic/unresectable STS treated with nivolumab monotherapy exhibited only a 5% ORR. Although the ORR increased to 16% when combination nivolumab plus ipilimumab was administered, serious treatment-related adverse events also occurred at higher rates compared with monotherapy (26% versus 19%, respectively).

The finding in the advanced STS population of immunosensitivity of UPS and DDLPS, as well as the observation of synergistic effects of RT with immunotherapy¹²¹, has ignited interest in evaluating the role of combination RT plus immunotherapy as neoadjuvant treatment for patients with resectable UPS and DDLPS. Analysis of immune infiltrate in UPS of the extremity and trunk in response to RT suggests that RT may change the tumour immune microenvironment and potentially enhance the efficacy of immunotherapy in UPS¹²². In a non-comparative phase 2 study in which patients with extremity/truncal UPS received neoadjuvant 50 Gy RT concurrently with up to four doses of either nivolumab monotherapy or nivolumab plus ipilimumab, Roland et al.⁹⁰ demonstrated a median pathologic response (as measured by percent hyalinization) of 89% among patients with UPS. Of note, although all patients completed preoperative RT, completion of all doses of immunotherapy was higher in the monotherapy versus combination therapy arm (83% versus 50%, respectively), as was the median pathologic response (90% versus 62%, respectively). Although the relationship between percent hyalinization and recurrence/survival is unclear, this study demonstrated feasibility of combination treatment.

Compelling data for the use of immunotherapy in select histologic subtypes are presented in the randomized SARC032 trial⁹¹. In this study, patients with stage III extremity/limb girdle UPS or DDLPS were randomized to neoadjuvant RT followed by surgery with or without the addition of perioperative immunotherapy, comprised of three cycles of neoadjuvant pembrolizumab (before, during, and after RT) and up to 14 cycles of adjuvant pembrolizumab. With a median follow-up of 43 months, patients treated with perioperative pembrolizumab demonstrated superior DFS (HR 0.61, 95% c.i. 0.39 to 0.96; 2-year absolute difference 15%) with no increase in major surgical complications. In subgroup analyses, this effect appeared driven by efficacy in patients with grade 3 disease; the majority of patients (75%) harboured UPS, with few patients with DDLPS (6%) enrolled in this trial, limiting conclusions that can be drawn from subgroup analyses stratified by histologic subtype. Although robust assessment of differences in OS hinge on longer term follow-up, and the efficacy of cytotoxic chemotherapy in lieu of or in addition to immunotherapy remains uncertain, SARC032 establishes the regimen of perioperative immunotherapy in combination with preoperative RT as an option for patients with extremity UPS.

Treatment of retroperitoneal STS

Surgery

Surgery is the mainstay of treatment for retroperitoneal STS, with the initial operation providing the greatest opportunity for cure^5–7. As with surgery in the extremity, the goal remains complete resection en bloc with adherent structures; however, anatomic constraints of the retroperitoneum and pelvis present unique challenges when attempting to achieve this. A thorough understanding of retroperitoneal anatomy and resectional techniques, in-depth imaging review, multidisciplinary discussion with an expert sarcoma team, and involvement of additional surgical specialists, as needed, are critical to the success of surgery for RPS. Improvements in survival observed in recent years¹²³ are believed to be partly attributable to refinement in patient selection, highlighting the importance of considering patient, tumour, and technical factors when approaching RPS surgery¹²⁴.

Candidacy for surgery necessarily includes assessment of performance status and comorbidities to ensure patients can withstand the physiologic insult of surgery and potential postoperative complications⁷. When patients are deemed upfront unresectable, this determination is made due to prohibitive performance status in nearly 50% of cases^125,126.

Technical inoperability is most commonly due to superior mesenteric artery/vein involvement¹²⁵; however, even among expert sarcoma surgeons, opinions vary on criteria for unresectability. For tumours deemed unresectable, consensus opinion should be sought from an experienced sarcoma multidisciplinary team⁷.

Surgical planning additionally requires consideration of histotype-specific tumour behaviour, including risk of local versus distant recurrence and primary tumour growth patterns, to which operative approach is generally adapted⁷. In the case of both WDLPS and DDLPS, local progression is the primary mechanism of disease-related death¹²⁷ and, as such, techniques aimed at reducing local recurrence are paramount. Whereas one surgical approach includes resection of the lipomatous mass en bloc with only those structures suspected of being directly invaded, margins between WDLPS and normal retroperitoneal fat can be ill-defined. Additionally, histopathologic organ invasion can be present in more than a quarter of cases where it is not suspected during surgery¹²⁸ and infiltration of capsule/serosa/fascia can be present in almost 40% of cases¹²⁹.

In 2009, two retrospective studies^130,131 presented data arguing in support of more extensive surgery in the frontline setting. Borrowing from the approach in extremity STS, in which a wide resection with a margin of uninvolved muscle is recommended, the idea of compartmental resection was introduced for RPS. As the margins of retroperitoneal tumours often abut viscera rather than muscle, this approach involves en bloc resection of uninvolved surrounding organs and soft tissue—most commonly ipsilateral colon, kidney, partial psoas muscle, and peritonectomy—to maximize the ability to achieve R0 resections along these surfaces. Marginal excision is still performed along critical structures that are not frankly invaded, such as the duodenum, pancreas, major vessels and bony structures, as is done in the extremity. The original reports of this technique demonstrated significant reductions in local recurrence with extended surgery^130,131, in one series reaching as low as 10% local recurrence at 3 years¹³¹. A follow-up study¹³² additionally demonstrated improvements in survival for patients with grade 1–2 retroperitoneal STS, a group among whom rates of distant recurrence are low and so benefits of reducing local recurrence would be expected to be most pronounced.

The approach of resecting uninvolved organs to improve local control has been criticized for several reasons, including concerns about the biases inherent to retrospective studies, the postoperative morbidity and functional consequences of these extensive resections, an inability to replicate the low rates of local recurrence seen in initial studies, and the observation that recurrences can be multifocal and sometimes outside the initial operative field^133–137. Whereas prospective data to settle this debate are unlikely to be collected, current guidelines support macroscopic tumour resection en bloc with involved organs, including consideration for extended resection to adjacent but not overtly invaded organs for retroperitoneal liposarcoma^5–7. Codification of the steps of compartmental resection for liposarcoma aims to standardize this procedure among sarcoma experts^138,139 (Figs 2 and 3); however, decisions regarding organ resection or preservation should continue to be individualized^6,7.

In tandem with technical factors, surgical planning requires consideration of the cost inherent to resection in terms of potential postoperative morbidity. Severe postoperative morbidity from RPS surgery is reported in the range of 16 to 30%, with 10–15% of patients requiring reoperation^136,140,141. Postoperative morbidity is influenced by the number and types of organs removed, with morbidity increasing when greater than three organs are resected¹⁴², or resection entails pancreaticoduodenectomy, vascular resection, or combined resection of colon, kidney, spleen, and pancreas¹⁴⁰. The recently developed Surgical Complexity Score, which incorporates patient factors and resection patterns (that is, resection of lower- versus higher-risk organs), can be used to predict postoperative morbidity for patients undergoing resection of primary RPS¹⁴³. Additionally, malnutrition, which can be present in over 50% of patients with RPS, is associated with reduced survival and higher rates of postoperative complications^144–146. A structured perioperative nutritional rehabilitation programme can improve these rates¹⁴⁷. As such, nutritional assessment should be performed early and enteral or parenteral supplementation provided for at least 2 weeks before surgery and in the early postoperative period, as needed⁷. Benchmark values for postoperative outcomes among low-risk patients undergoing resection of primary retroperitoneal liposarcoma are now available¹⁴⁸. The benchmark value for major complications among such patients is ≤ 21% and can be used by institutions for audit and quality improvement.

Longer-term complications have also been evaluated, though to a lesser degree. Nephrectomy, such as performed routinely for compartmental resection, is associated with reductions in the estimated glomerular filtration rate; however, development of stage 4 or 5 chronic kidney disease and need for dialysis are rare^141,149. Long-term functional consequences are understudied; however, existing data demonstrate 12-month postoperative global quality of life to be comparable to the general population, with minor decrements in physical/lower limb function. Chronic pain, when present, is usually of low intensity. Neuropathic pain, associated with psoas muscle resection, can occur with frequency but necessitates pharmacologic treatment in only 5% of patients at 1 year^141,150.

Whereas compartmental resection is considered in cases of liposarcoma, a more selective approach to organ resection is recommended for histologies where the primary pattern of failure is distant disease^5–7 and borders more clearly defined, such as leiomyosarcoma. In such cases, surgery should involve complete macroscopic resection en bloc with involved organs (including vein of origin), with preservation of adjacent but uninvolved structures^7,151. These principles hold true for other histologies with similarly well defined borders and low rates of local recurrence, such as solitary fibrous tumours.

Radiation

Several studies have evaluated the role of RT in the treatment of RPS. Whereas intraoperative RT, brachytherapy, and adjuvant external-beam RT are of unclear benefit and are associated with significant short- and long-term toxicities^152–165 neoadjuvant RT remains among the adjunctive therapies for RPS. Compared with adjuvant RT, when administered before surgery, a lower dose is delivered and radiosensitive organs (for example, small bowel) are displaced by tumour, reducing their RT exposure and related toxicity, thereby improving the risk–benefit balance.

Prospective evaluation of the efficacy of preoperative RT for retroperitoneal STS has proven challenging. ACOSOG Z9031 (NCT00091351), a National Cancer Institute phase III trial, which randomized patients with retroperitoneal or pelvic STS to surgery with or without preoperative RT, was closed early due to slow accrual. The EORTC STRASS trial¹⁶⁶ is the first study to provide robust prospective data informing the role of preoperative RT for retroperitoneal STS. This phase III trial randomized patients with operable retroperitoneal STS to preoperative RT and surgery versus surgery alone; the primary outcome was abdominal recurrence-free survival (ARFS). With a median follow-up of 43.1 months, there was no improvement in ARFS with administration of preoperative RT (HR 1.01, 95% c.i. 0.71 to 1.44). Although not powered for subgroup analyses, in a post hoc exploratory analysis limited to patients with liposarcoma (where preoperative progression on RT was not included as an event for patients still able to undergo macroscopically complete resection), RT was associated with improvements in ARFS (HR 0.64, 95% c.i. 0.40 to 1.01; 3-year ARFS 71.6% with RT versus 60.4% without RT). To evaluate better the utility of RT in the liposarcoma subgroup with adequate power, in a separate post hoc analysis, data from patients enrolled in STRASS were combined with data from patients who were eligible but not enrolled (STREXIT cohort)¹⁶⁷. This combined STRASS and STREXIT cohort analysis again demonstrated a benefit to preoperative RT for patients with liposarcoma. The improvement in local control was limited to patients with WDLPS and grade 1 and grade 2 DDLPS (HR 0.63, 95% c.i. 0.40 to 0.97); preoperative RT was not associated with improvements in ARFS for patients with high-grade DDLPS or leiomyosarcoma. Based on these results, preoperative RT can be considered for patients with WDLPS and grade 1 and grade 2 DDLPS, balancing reductions in late relapse with long-term RT-related toxities^5,7. However, given the propensity for late recurrences in patients with WDLPS , long-term data are awaited to determine the durability of the effects observed in STRASS and to assess whether survival differences emerge.

Chemotherapy

Evidence pertaining to the use of chemotherapy in RPS is generally sparse, with no proven benefits demonstrated for adjuvant chemotherapy in this setting. Two ongoing trials evaluating the role of neoadjuvant chemotherapy are noteworthy. Given the significant risk of distant disease among patients with high-grade DDLPS and leiomyosarcoma, the ongoing EORTC STRASS2 randomized trial (NCT04031677)¹⁶⁸ is designed to evaluate the efficacy of neoadjuvant histology-tailored chemotherapy for patients with resectable grade 3 DDLPS and leiomyosarcoma. The multi-arm phase I-II TRASTS trial (NCT02275286) will additionally assess the safety and activity of neoadjuvant trabectedin with concurrent RT in patients with upfront resectable retroperitoneal liposarcoma and leiomyosarcoma. Both trials are expected to be completed in 2028. In the interim, outside of the clinical trial setting, neoadjuvant chemotherapy may be considered for the purpose of cytoreduction in patients with borderline resectable disease⁷; however, such treatment decisions should be individualized.

Locoregional adjuncts for the treatment of STS

Whereas surgery remains the basis for the curative treatment of localized STS, several locoregional therapies have been investigated as adjuncts or alternatives to surgery for the purposes of improving surgical or oncologic outcomes or as bridging or definitive treatments.

Transarterial embolization

Minimally invasive endovascular and percutaneous techniques offered by interventional radiology can further contribute to the comprehensive treatment of patients with STS. In the setting of resectable but hypervascular tumours, preoperative devascularization can be achieved via transarterial embolization (TAE). By occluding tumour-feeding arteries, this technique is shown to reduce the need for intraoperative blood transfusion and can potentially reduce tumour bulk¹⁶⁹. Although not often needed, preoperative TAE can be beneficial in select cases with challenging anatomy where early vascular contrast is documented and targetable.

Isolated limb perfusion

For patients with unresectable extremity STS, isolated limb perfusion (ILP) is a locoregional method aimed at avoiding or delaying amputation¹⁷⁰. This technique involves obtaining surgical vascular access to the limb for the purpose of delivering hyperthermic chemotherapy via extracorporeal circulation. Its efficacy in STS is enhanced by combining melphalan with tumour necrosis factor-alpha (TNF-α); however, broad use is currently restricted by the limited availability of TNF-α. ILP must be performed in specialized centres due to the technical complexity of the procedure and need for leakage monitoring¹⁷¹. Currently accepted indications for its use include extremity STS not amenable to limb-sparing surgery, multifocal or multiply recurrent tumours, and locally recurrent tumours in previously irradiated fields. A more recently developed alternative of isolated limb infusion offers a less invasive alternative; however, efficacy data remain preliminary.

Regional hyperthermia

Regional hyperthermia (RHT) combined with chemotherapy or RT has been prospectively evaluated as a treatment strategy for high-risk STS of the extremities and retroperitoneum. The EORTC 62961-ESHO 95 trial, which randomized patients with localized, high-risk extremity and retroperitoneal STS (defined as ≥ 5 cm, grade 2 or 3, deep to fascia) undergoing local therapy (surgery +/− adjuvant RT) to perioperative chemotherapy with or without the addition of RHT. Patients treated with RHT exhibited superior local progression-free survival, DFS, and OS that persisted in analyses limited to patients with macroscopically completely resected abdominal/retroperitoneal STS^172–174. Despite positive data, this approach has not gained widespread consensus within the sarcoma community and remains a subject of debate. Its clinical use is further restricted by the scarcity of dedicated RHT facilities, limiting access to this modality in most centres.

Electroporation

For palliation of superficial tumours not amenable to curative therapies, percutaneous electroporation can be used to enhance local drug delivery. This technique utilizes electric pulses to permeabilize transiently tumour cells, markedly increasing cytotoxicity of chemotherapy. In the recent InspECT study of patients with advanced cutaneous angiosarcoma, electrochemotherapy yielded an 80% ORR (40% complete responses) with manageable grade 3 skin ulceration or pain; bleeding was controlled in 13 of 14 patients¹⁷⁵. However, limited data are available for this technique.

Future challenges

The early closure of several RCTs investigating therapies for STS highlights the challenge in adequately powering and recruiting patients to trials of novel treatments in localized STS. Whereas histotype-specific and biomarker-driven studies are highly desirable and are most likely to demonstrate the benefits of novel therapeutic approaches, the rarity and ultra-rarity of sarcoma subtypes, and the low frequency of biomarkers, hinder the ability to keep pace with discoveries in other cancer types. However, several lessons can be gleaned from previous experiences. Namely, the success of the STRASS trial underscores the importance of international collaboration through organizations such as TARPSWG, as few institutions globally see sufficient sarcoma volume to run local trials adequately. Future studies that seek to improve trial efficiency and the likelihood of sufficient patient accrual will additionally require novelty not only in therapeutic approaches but also in study design and execution. This can potentially be achieved through the adoption of emerging methodologies, such as adaptive platform trial designs for earlier evaluation of treatment efficacy or futility, and incorporation of robust synthetic controls, such as through digital and molecular twin technologies. The success of these endeavours will rely on partnership with regulatory agencies to explore jointly scientifically acceptable approaches to the study of this rare cancer in ways that do not compromise the certainty in the efficacy and safety of new treatments or unnecessarily impede progress.

Conclusion

Individualized treatment of STS requires careful consideration of anatomic location, tumour grade, histologic subtype, and patterns of local and distant failure. Surgery remains the cornerstone of treatment for both localized extremity and retroperitoneal STS; however, deliberate integration of neoadjuvant and adjuvant therapies, including systemic and locoregional treatments, can facilitate the goal of cure. Optimal outcomes are achieved when patients are treated at high-volume centres by dedicated multidisciplinary teams. Considering the rarity of this diagnosis, international collaborative efforts remain crucial to ongoing progress in diagnosis and treatment.

Contributor Information

Fahima Dossa, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Eldad Elnekave, Unit of Interventional Radiology, Shaare Tzedek Medical Center, Jerusalem, Israel.

Aisha B Miah, Sarcoma Unit, The Royal Marsden Hospital and the Institute of Cancer Research, London, UK.

Catherine Mitchell, Department of Pathology, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

Sarah Watson, Department of Medical Oncology, Institut Curie Hospital, Paris, France.

Alessandro Gronchi, Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Marco Fiore, Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Funding

The authors have no funding to declare.

Author contributions

Fahima Dossa (Conceptualization, Data curation, Methodology, Writing—original draft), Eldad Elnekave (Validation, Visualization, Writing—review & editing), Aisha B. Miah (Validation, Visualization, Writing—review & editing), Catherine Mitchell (Validation, Visualization, Writing—review & editing), Sarah Watson (Validation, Visualization, Writing—review & editing), Alessandro Gronchi (Validation, Visualization, Writing—review & editing), and Marco Fiore (Conceptualization, Methodology, Supervision, Visualization, Writing—review & editing)

Disclosures

The authors declare no conflict of interest.

Data availability

Not applicable.

References

1. Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg 2014;260:416–421. discussion 421-412 [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Gronchi A, Strauss DC, Miceli R, Bonvalot S, Swallow CJ, Hohenberger P et al. Variability in patterns of recurrence after resection of primary retroperitoneal sarcoma (RPS): a report on 1007 patients from the multi-institutional collaborative RPS working group. Ann Surg 2016;263:1002–1009 [DOI] [PubMed] [Google Scholar]
3. Tan MCB, Brennan MF, Kuk D, Agaram NP, Antonescu CR, Qin L-X et al. Histology-based classification predicts pattern of recurrence and improves risk stratification in primary retroperitoneal sarcoma. Ann Surg 2016;263:593–600 [DOI] [PMC free article] [PubMed] [Google Scholar]
4. National Comprehensive Cancer Network . Soft Tissue Sarcoma (Version 1.2025). https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf (accessed 25 October 2025)
5. Gronchi A, Miah AB, Dei Tos AP, Abecassis N, Bajpai J, Bauer S et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS clinical practice guidelines for diagnosis, treatment and follow-up(⋆). Ann Oncol 2021;32:1348–1365 [DOI] [PubMed] [Google Scholar]
6. Hayes AJ, Nixon IF, Strauss DC, Seddon BM, Desai A, Benson C et al. UK guidelines for the management of soft tissue sarcomas. Br J Cancer 2025;132:11–31 [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Swallow CJ, Strauss DC, Bonvalot S, Rutkowski P, Desai A, Gladdy RA et al. Management of primary retroperitoneal sarcoma (RPS) in the adult: an updated consensus approach from the Transatlantic Australasian RPS Working Group. Ann Surg Oncol 2021;28:7873–7888 [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Moulin B, Messiou C, Crombe A, Kind M, Hohenberger P, Rutkowski P et al. Diagnosis strategy of adipocytic soft-tissue tumors in adults: a consensus from European experts. Eur J Surg Oncol 2022;48:518–525 [DOI] [PubMed] [Google Scholar]
9. Morosi C, Stacchiotti S, Marchianò A, Bianchi A, Radaelli S, Sanfilippo R et al. Correlation between radiological assessment and histopathological diagnosis in retroperitoneal tumors: analysis of 291 consecutive patients at a tertiary reference sarcoma center. Eur J Surg Oncol 2014;40:1662–1670 [DOI] [PubMed] [Google Scholar]
10. Berger-Richardson D, Burtenshaw SM, Ibrahim AM, Gladdy RA, Auer R, Beecroft R et al. Early and late complications of percutaneous core needle biopsy of retroperitoneal tumors at two tertiary sarcoma centers. Ann Surg Oncol 2019;26:4692–4698 [DOI] [PubMed] [Google Scholar]
11. Nardi W, Nicolas N, El Zein S, Tzanis D, Bouhadiba T, Helfre S et al. Diagnostic accuracy and safety of percutaneous core needle biopsy of retroperitoneal tumours. Eur J Surg Oncol 2024;50:107298. [DOI] [PubMed] [Google Scholar]
12. Strauss DC, Qureshi YA, Hayes AJ, Thway K, Fisher C, Thomas JM. The role of core needle biopsy in the diagnosis of suspected soft tissue tumours. J Surg Oncol 2010;102:523–529 [DOI] [PubMed] [Google Scholar]
13. Heslin MJ, Lewis JJ, Woodruff JM, Brennan MF. Core needle biopsy for diagnosis of extremity soft tissue sarcoma. Ann Surg Oncol 1997;4:425–431 [DOI] [PubMed] [Google Scholar]
14. Hoeber I, Spillane AJ, Fisher C, Thomas JM. Accuracy of biopsy techniques for limb and limb girdle soft tissue tumors. Ann Surg Oncol 2001;8:80–87 [DOI] [PubMed] [Google Scholar]
15. Almond LM, Tirotta F, Tattersall H, Hodson J, Cascella T, Barisella M et al. Diagnostic accuracy of percutaneous biopsy in retroperitoneal sarcoma. Br J Surg 2019;106:395–403 [DOI] [PubMed] [Google Scholar]
16. Ikoma N, Torres KE, Somaiah N, Hunt KK, Cormier JN, Tseng W et al. Accuracy of preoperative percutaneous biopsy for the diagnosis of retroperitoneal liposarcoma subtypes. Ann Surg Oncol 2015;22:1068–1072 [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Schneider N, Strauss DC, Smith MJ, Miah AB, Zaidi S, Benson C et al. The adequacy of core biopsy in the assessment of smooth muscle neoplasms of soft tissues: implications for treatment and prognosis. Am J Surg Pathol 2017;41:923–931 [DOI] [PubMed] [Google Scholar]
18. Borghi A, Fiore M, Tiné G, Strauss DC, Bonvalot S, Raut CP et al. Accuracy of Histology and Malignancy Grade between Preoperative Biopsy and Surgical Specimens in Primary Retroperitoneal Sarcoma. A Study from the Prospective Retroperitoneal Sarcoma Registry (Resar). Ann Surg 2025. 10.1097/SLA.0000000000007001. Epub ahead of print [DOI] [PubMed] [Google Scholar]
19. Tirotta F, Morosi C, Hodson J, Desai A, Barisella M, Ford SJ et al. Improved biopsy accuracy in retroperitoneal dedifferentiated liposarcoma. Ann Surg Oncol 2020;27:4574–4581 [DOI] [PubMed] [Google Scholar]
20. Berger-Richardson D, Swallow CJ. Needle tract seeding after percutaneous biopsy of sarcoma: risk/benefit considerations. Cancer 2017;123:560–567 [DOI] [PubMed] [Google Scholar]
21. Oliveira MP, de Lima PMA, de Mello RJV. Tumor contamination in the biopsy path of primary malignant bone tumors. Rev Bras Ortop 2012;47:631–637 [DOI] [PMC free article] [PubMed] [Google Scholar]
22. Ribeiro MB, de Oliveira CRGCM, Filippi RZ, Baptista AM, Caiero MT, Saito CF et al. Estudo histopatológico do trajeto de biópsia de tumores musculoesqueléticos malignos. Acta Ortopédica Bras 2009;17:279–281 [Google Scholar]
23. Mohana R, Faisham WI, Zulmi W, Nawfar AS, Effat O, Salzihan MS. The incidence of malignant infiltration in the biopsy tract of osteosarcoma. Malays Orthop J 2007;1:7–10 [Google Scholar]
24. Kaffenberger BH, Wakely PE Jr, Mayerson JL. Local recurrence rate of fine-needle aspiration biopsy in primary high-grade sarcomas. J Surg Oncol 2010;101:618–621 [DOI] [PubMed] [Google Scholar]
25. Saghieh S, Masrouha KZ, Musallam KM, Mahfouz R, Abboud M, Khoury NJ et al. The risk of local recurrence along the core-needle biopsy tract in patients with bone sarcomas. Iowa Orthop J 2010;30:80–83 [PMC free article] [PubMed] [Google Scholar]
26. Wilkinson MJ, Martin JL, Khan AA, Hayes AJ, Thomas JM, Strauss DC. Percutaneous core needle biopsy in retroperitoneal sarcomas does not influence local recurrence or overall survival. Ann Surg Oncol 2015;22:853–858 [DOI] [PubMed] [Google Scholar]
27. Hwang SY, Warrier S, Thompson S, Davidson T, Yang JL, Crowe P. Safety and accuracy of core biopsy in retroperitoneal sarcomas. Asia Pac J Clin Oncol 2016;12:e174–e178 [DOI] [PubMed] [Google Scholar]
28. Van Houdt WJ, Schrijver AM, Cohen-Hallaleh RB, Memos N, Fotiadis N, Smith MJ et al. Needle tract seeding following core biopsies in retroperitoneal sarcoma. Eur J Surg Oncol 2017;43:1740–1745 [DOI] [PubMed] [Google Scholar]
29. Tuttle R, Kane JM 3rd. Biopsy techniques for soft tissue and bowel sarcomas. J Surg Oncol 2015;111:504–512 [DOI] [PubMed] [Google Scholar]
30. Wu JS, Goldsmith JD, Horwich PJ, Shetty SK, Hochman MG. Bone and soft-tissue lesions: what factors affect diagnostic yield of image-guided core-needle biopsy? Radiology 2008;248:962–970 [DOI] [PubMed] [Google Scholar]
31. Bickels J, Jelinek JS, Shmookler BM, Neff RS, Malawer MM. Biopsy of musculoskeletal tumors. Current concepts. Clin Orthop Relat Res 1999;368:212–219 [PubMed] [Google Scholar]
32. Antonescu CR. The role of genetic testing in soft tissue sarcoma. Histopathology 2006;48:13–21 [DOI] [PubMed] [Google Scholar]
33. Thway K, Wang J, Swansbury J, Min T, Fisher C. Fluorescence in situ hybridization for MDM2 amplification as a routine ancillary diagnostic tool for suspected well-differentiated and dedifferentiated liposarcomas: experience at a tertiary center. Sarcoma 2015;2015:812089. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Italiano A, Di Mauro I, Rapp J, Pierron G, Auger N, Alberti L et al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol 2016;17:532–538 [DOI] [PubMed] [Google Scholar]
35. Schwab JH, Boland PJ, Antonescu C, Bilsky MH, Healey JH. Spinal metastases from myxoid liposarcoma warrant screening with magnetic resonance imaging. Cancer 2007;110:1815–1822 [DOI] [PubMed] [Google Scholar]
36. Fiore M, Grosso F, Lo Vullo S, Pennacchioli E, Stacchiotti S, Ferrari A et al. Myxoid/round cell and pleomorphic liposarcomas: prognostic factors and survival in a series of patients treated at a single institution. Cancer 2007;109:2522–2531 [DOI] [PubMed] [Google Scholar]
37. Bonvalot S, Gaignard E, Stoeckle E, Meeus P, Decanter G, Carrere S et al. Survival benefit of the surgical management of retroperitoneal sarcoma in a reference center: a nationwide study of the French Sarcoma Group from the NetSarc database. Ann Surg Oncol 2019;26:2286–2293 [DOI] [PubMed] [Google Scholar]
38. Bagaria SP, Chang Y-H, Gray RJ, Ashman JB, Attia S, Wasif N. Improving long-term outcomes for patients with extra-abdominal soft tissue sarcoma regionalization to high-volume centers, improved compliance with guidelines or both? Sarcoma 2018;2018::8141056. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Derbel O, Heudel PE, Cropet C, Meeus P, Vaz G, Biron P et al. Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort). PLoS One 2017;12:e0158406. [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Berger NG, Silva JP, Mogal H, Clarke CN, Bedi M, Charlson J et al. Overall survival after resection of retroperitoneal sarcoma at academic cancer centers versus community cancer centers: an analysis of the National Cancer Data Base. Surgery 2018;163:318–323 [DOI] [PubMed] [Google Scholar]
41. Hoekstra HJ, Haas RLM, Verhoef C, Suurmeijer AJH, van Rijswijk CSP, Bongers BGH et al. Adherence to guidelines for adult (non-GIST) soft tissue sarcoma in The Netherlands: a plea for dedicated sarcoma centers. Ann Surg Oncol 2017;24:3279–3288 [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Keung EZ, Chiang Y-J, Cormier JN, Torres KE, Hunt KK, Feig BW et al. Treatment at low-volume hospitals is associated with reduced short-term and long-term outcomes for patients with retroperitoneal sarcoma. Cancer 2018;124:4495–4503 [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Maurice MJ, Yih JM, Ammori JB, Abouassaly R. Predictors of surgical quality for retroperitoneal sarcoma: volume matters. J Surg Oncol 2017;116:766–774 [DOI] [PubMed] [Google Scholar]
44. Blay J-Y, Honoré C, Stoeckle E, Meeus P, Jafari M, Gouin F et al. Surgery in reference centers improves survival of sarcoma patients: a nationwide study. Ann Oncol 2019;30:1143–1153 [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Callegaro D, Barretta F, Raut CP, Johnston W, Strauss DC, Honoré C et al. New Sarculator prognostic nomograms for patients with primary retroperitoneal sarcoma: case volume does matter. Ann Surg 2024;279:857–865 [DOI] [PubMed] [Google Scholar]
46. 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 evaluation: results from the prospective registry of the Spanish group for research in sarcoma (GEIS). Oncologist 2019;24:e338–e346 [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Tirotta F, Bacon A, Collins S, Desai A, Liu H, Paley L et al. Primary retroperitoneal sarcoma: a comparison of survival outcomes in specialist and non-specialist sarcoma centres. Eur J Cancer 2023;188:20–28 [DOI] [PubMed] [Google Scholar]
48. Vos M, Blaauwgeers HGT, Ho VKY, van Houdt WJ, van der Hage JA, Been LB et al. Increased survival of non low-grade and deep-seated soft tissue sarcoma after surgical management in high-volume hospitals: a nationwide study from The Netherlands. Eur J Cancer 2019;110:98–106 [DOI] [PubMed] [Google Scholar]
49. Villano AM, Zeymo A, Chan KS, Shara N, Al-Refaie WB. Identifying the minimum volume threshold for retroperitoneal soft tissue sarcoma resection: merging national data with consensus expert opinion. J Am Coll Surg 2020;230:151–160.e152 [DOI] [PubMed] [Google Scholar]
50. Villano AM, Zeymo A, McDermott J, Barrak D, Unger KR, Shara NM et al. Regionalization of retroperitoneal sarcoma surgery to high-volume hospitals: missed opportunities for outcome improvement. J Oncol Pract 2019;15:e247–e261 [DOI] [PubMed] [Google Scholar]
51. Villano AM, Zeymo A, Chan KS, Unger KR, Shara N, Al-Refaie WB. Variations in retroperitoneal soft tissue sarcoma outcomes by hospital type: a national cancer database analysis. JCO Oncol Pract 2020;16:e991–e1003 [DOI] [PubMed] [Google Scholar]
52. Andritsch E, Beishon M, Bielack S, Bonvalot S, Casali P, Crul M et al. ECCO essential requirements for quality cancer care: soft tissue sarcoma in adults and bone sarcoma. A critical review. Crit Rev Oncol Hematol 2017;110:94–105 [DOI] [PubMed] [Google Scholar]
53. Blay J-Y, Soibinet P, Penel N, Bompas E, Duffaud F, Stoeckle E et al. Improved survival using specialized multidisciplinary board in sarcoma patients. Ann Oncol 2017;28:2852–2859 [DOI] [PMC free article] [PubMed] [Google Scholar]
54. Sicklick JK, Swallow CJ, Raut CP, Callegaro D, Fiore M, Strauss DC et al. Creation and implementation of a monthly international tumor board: experience of the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG). Ann Surg Oncol 2023;30:6287–6289 [DOI] [PubMed] [Google Scholar]
55. Samà L, Kumar S, Ruspi L, Sicoli F, D’Amato V, Mintemur Ö et al. Learning curve in retroperitoneal sarcoma surgery. Eur J Surg Oncol 2024;50:108612. [DOI] [PubMed] [Google Scholar]
56. Hannan EL, Radzyner M, Rubin D, Dougherty J, Brennan MF. The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer. Surgery 2002;131:6–15 [DOI] [PubMed] [Google Scholar]
57. Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennam M et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315 [DOI] [PMC free article] [PubMed] [Google Scholar]
58. Bowden L, Booher RJ. The principles and technique of resection of soft parts for sarcoma. Surgery 1958;44:963–977 [PubMed] [Google Scholar]
59. Gerrand CH, Wunder JS, Kandel RA, O’Sullivan B, Catton CN, Bell RS et al. Classification of positive margins after resection of soft-tissue sarcoma of the limb predicts the risk of local recurrence. J Bone Joint Surg Br 2001;83:1149–1155 [DOI] [PubMed] [Google Scholar]
60. Gundle KR, Kafchinski L, Gupta S, Griffin AM, Dickson BC, Chung PW et al. Analysis of margin classification systems for assessing the risk of local recurrence after soft tissue sarcoma resection. J Clin Oncol 2018;36:704–709 [DOI] [PubMed] [Google Scholar]
61. Bickels J, Wittig JC, Kollender Y, Kellar-Graney K, Malawer MM, Meller I. Sciatic nerve resection: is that truly an indication for amputation? Clin Orthop Relat Res 2002;399:201–204 [PubMed] [Google Scholar]
62. Brooks AD, Gold JS, Graham D, Boland P, Lewis JJ, Brennan MF et al. Resection of the sciatic, peroneal, or tibial nerves: assessment of functional status. Ann Surg Oncol 2002;9:41–47 [DOI] [PubMed] [Google Scholar]
63. Jones KB, Ferguson PC, Deheshi B, Riad S, Griffin A, Bell RS et al. Complete femoral nerve resection with soft tissue sarcoma: functional outcomes. Ann Surg Oncol 2010;17:401–406 [DOI] [PubMed] [Google Scholar]
64. Martin E, Dullaart MJ, Verhoef C, Coert JH. A systematic review of functional outcomes after nerve reconstruction in extremity soft tissue sarcomas: a need for general implementation in the armamentarium. J Plast Reconstr Aesthet Surg 2020;73:621–632 [DOI] [PubMed] [Google Scholar]
65. Conti L, Buriro F, Baia M, Pasquali S, Miceli R, De Rosa L et al. Contemporary role of amputation for patients with extremity soft tissue sarcoma. Eur J Surg Oncol 2023;49:934–940 [DOI] [PubMed] [Google Scholar]
66. Erstad DJ, Ready J, Abraham J, Ferrone ML, Bertagnolli MM, Baldini EH et al. Amputation for extremity sarcoma: contemporary indications and outcomes. Ann Surg Oncol 2018;25:394–403 [DOI] [PubMed] [Google Scholar]
67. Fiore M, Casali PG, Miceli R, Mariani L, Bertulli R, Lozza L et al. Prognostic effect of re-excision in adult soft tissue sarcoma of the extremity. Ann Surg Oncol 2006;13:110–117 [DOI] [PubMed] [Google Scholar]
68. Karakousis CP, Driscoll DL. Treatment and local control of primary extremity soft tissue sarcomas. J Surg Oncol 1999;71:155–161 [DOI] [PubMed] [Google Scholar]
69. Decanter G, Stoeckle E, Honore C, Meeus P, Mattei JC, Dubray-Longeras P et al. Watch and wait approach for re-excision after unplanned yet macroscopically complete excision of extremity and superficial truncal soft tissue sarcoma is safe and does not affect metastatic risk or amputation rate. Ann Surg Oncol 2019;26:3526–3534 [DOI] [PubMed] [Google Scholar]
70. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL 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;16:197–203 [DOI] [PubMed] [Google Scholar]
71. Beane JD, Yang JC, White D, Steinberg SM, Rosenberg SA, Rudloff U. Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial. Ann Surg Oncol 2014;21:2484–2489 [DOI] [PMC free article] [PubMed] [Google Scholar]
72. O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235–2241 [DOI] [PubMed] [Google Scholar]
73. Davis A, O’Sullivan B, Turcotte R, Bell R, Catton C, Chabot P et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48–53 [DOI] [PubMed] [Google Scholar]
74. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–868 [DOI] [PubMed] [Google Scholar]
75. Wang D, Zhang Q, Eisenberg BL, Kane JM, Li XA, Lucas D et al. Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: results of Radiation Therapy Oncology Group RTOG-0630 trial. J Clin Oncol 2015;33:2231–2238 [DOI] [PMC free article] [PubMed] [Google Scholar]
76. Guadagnolo BA, Bassett RL, Mitra D, Farooqi A, Hempel C, Dorber C et al. Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial. Lancet Oncol 2022;23:1547–1557 [DOI] [PMC free article] [PubMed] [Google Scholar]
77. Bishop AJ, Mitra D, Farooqi A, Swanson DM, Hempel C, Willis T et al. Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS): updated local control, late toxicities, and patient-reported outcomes. Cancer 2025;131:e35542. [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Koseła-Paterczyk H, Szacht M, Morysiński T, Ługowska I, Dziewirski W, Falkowski S et al. Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol 2014;40:1641–1647 [DOI] [PubMed] [Google Scholar]
79. Kalbasi A, Kamrava M, Chu F-I, Telesca D, Van Dams R, Yang Y et al. A phase II trial of 5-day neoadjuvant radiotherapy for patients with high-risk primary soft tissue sarcoma. Clin Cancer Res 2020;26:1829–1836 [DOI] [PMC free article] [PubMed] [Google Scholar]
80. Leite ETT, Munhoz RR, de Camargo VP, Lima LGCAd, Rebolledo DCS, Maistro CEB et al. Neoadjuvant stereotactic ablative radiotherapy (SABR) for soft tissue sarcomas of the extremities. Radiother Oncol 2021;161:222–229 [DOI] [PubMed] [Google Scholar]
81. Bedi M, Singh R, Charlson JA, Kelly T, Johnstone C, Wooldridge A et al. Is 5 the new 25? Long-term oncologic outcomes from a phase II, prospective, 5-fraction preoperative radiation therapy trial in patients with localized soft tissue sarcoma. Adv Radiat Oncol 2022;7:100850. [DOI] [PMC free article] [PubMed] [Google Scholar]
82. Mayo ZS, Parsai S, Asha W, Dinh M, Mesko N, Nystrom L et al. Early outcomes of ultra-hypofractionated preoperative radiation therapy for soft tissue sarcoma followed by immediate surgical resection. Radiother Oncol 2023;180:109439. [DOI] [PubMed] [Google Scholar]
83. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008;113:573–581 [DOI] [PubMed] [Google Scholar]
84. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 2012;13:1045–1054 [DOI] [PubMed] [Google Scholar]
85. Pasquali S, Pizzamiglio S, Touati N, Litiere S, Marreaud S, Kasper B et al. The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial. Eur J Cancer 2019;109:51–60 [DOI] [PubMed] [Google Scholar]
86. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol 2017;18:812–822 [DOI] [PubMed] [Google Scholar]
87. Gronchi A, Palmerini E, Quagliuolo V, Martin Broto J, Lopez Pousa A, Grignani G et al. Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: final results of a randomized trial from Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups. J Clin Oncol 2020;38:2178–2186 [DOI] [PubMed] [Google Scholar]
88. Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 2017;18:1493–1501 [DOI] [PMC free article] [PubMed] [Google Scholar]
89. D’Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 2018;19:416–426 [DOI] [PMC free article] [PubMed] [Google Scholar]
90. Roland CL, Nassif Haddad EF, Keung EZ, Wang W-L, Lazar AJ, Lin H et al. A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma. Nat Cancer 2024;5:625–641 [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Mowery YM, Ballman KV, Hong AM, Schuetze SM, Wagner AJ, Monga V et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. Lancet 2024;404:2053–2064 [DOI] [PMC free article] [PubMed] [Google Scholar]
92. Naghavi AO, Fernandez DC, Mesko N, Juloori A, Martinez A, Scott JG et al. American Brachytherapy Society consensus statement for soft tissue sarcoma brachytherapy. Brachytherapy 2017;16:466–489 [DOI] [PubMed] [Google Scholar]
93. Salerno KE, Alektiar KM, Baldini EH, Bedi M, Bishop AJ, Bradfield L et al. Radiation therapy for treatment of soft tissue sarcoma in adults: executive summary of an ASTRO clinical practice guideline. Pract Radiat Oncol 2021;11:339–351 [DOI] [PubMed] [Google Scholar]
94. le Grange F, Cassoni AM, Seddon BM. Tumour volume changes following pre-operative radiotherapy in borderline resectable limb and trunk soft tissue sarcoma. Eur J Surg Oncol 2014;40:394–401 [DOI] [PubMed] [Google Scholar]
95. Dagan R, Indelicato DJ, McGee L, Morris CG, Kirwan JM, Knapik J et al. The significance of a marginal excision after preoperative radiation therapy for soft tissue sarcoma of the extremity. Cancer 2012;118:3199–3207 [DOI] [PubMed] [Google Scholar]
96. Al-Absi E, Farrokhyar F, Sharma R, Whelan K, Corbett T, Patel M et al. A systematic review and meta-analysis of oncologic outcomes of pre- versus postoperative radiation in localized resectable soft-tissue sarcoma. Ann Surg Oncol 2010;17:1367–1374 [DOI] [PubMed] [Google Scholar]
97. Alektiar KM, Brennan MF, Healey JH, Singer S. Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity. J Clin Oncol 2008;26:3440–3444 [DOI] [PubMed] [Google Scholar]
98. Folkert MR, Singer S, Brennan MF, Kuk D, Qin L-X, Kobayashi WK et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol 2014;32:3236–3241 [DOI] [PMC free article] [PubMed] [Google Scholar]
99. Seddon B, Grange FL, Simões R, Stacey C, Shelly S, Forsyth S et al. The IMRiS trial: a phase 2 study of intensity modulated radiation therapy in extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2024;120:978–989 [DOI] [PubMed] [Google Scholar]
100. O’Sullivan B, Griffin AM, Dickie CI, Sharpe MB, Chung PWM, Catton CN et al. Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modality morbidities in lower extremity soft tissue sarcoma. Cancer 2013;119:1878–1884 [DOI] [PubMed] [Google Scholar]
101. Palassini E, Ferrari S, Verderio P, De Paoli A, Martin Broto J, Quagliuolo V et al. Feasibility of preoperative chemotherapy with or without radiation therapy in localized soft tissue sarcomas of limbs and superficial trunk in the Italian Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized Clinical Trial: three versus five cycles of full-dose epirubicin plus ifosfamide. J Clin Oncol 2015;33:3628–3634 [DOI] [PubMed] [Google Scholar]
102. Gronchi A, Verderio P, De Paoli A, Ferraro A, Tendero O, Majò J et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Ann Oncol 2013;24:817–823 [DOI] [PubMed] [Google Scholar]
103. Baldini EH, Goldberg J, Jenner C, Manola JB, Demetri GD, Fletcher CDM et al. Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol 1999;17:3252–3259 [DOI] [PubMed] [Google Scholar]
104. Pisters PWT, Pollock RE, Lewis VO, Yasko AW, Cormier JN, Respondek PM et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg 2007;246:675–681. discussion 681-672 [DOI] [PubMed] [Google Scholar]
105. Cahlon O, Brennan MF, Jia X, Qin L-X, Singer S, Alektiar KM. A postoperative nomogram for local recurrence risk in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation. Ann Surg 2012;255:343–347 [DOI] [PMC free article] [PubMed] [Google Scholar]
106. Rueten-Budde AJ, van Praag VM, van de Sande MAJ, Fiocco M. External validation and adaptation of a dynamic prediction model for patients with high-grade extremity soft tissue sarcoma. J Surg Oncol 2021;123:1050–1056 [DOI] [PMC free article] [PubMed] [Google Scholar]
107. Fiore M, Ford S, Callegaro D, Sangalli C, Colombo C, Radaelli S et al. Adequate local control in high-risk soft tissue sarcoma of the extremity treated with surgery alone at a reference centre: should radiotherapy still be a standard? Ann Surg Oncol 2018;25:1536–1543 [DOI] [PubMed] [Google Scholar]
108. Foppele GF, Fiocco M, Husson O, Kramer A, Retèl VP, van den Noort V et al. SCOPES: short course of preoperative radiotherapy in head and neck, trunk and extremity soft tissue sarcomas; a randomized phase II clinical trial. ESMO Rare Cancers 2025;4:100029 [Google Scholar]
109. Baldini EH, Guadagnolo BA, Salerno KE, Chung P, Bishop AJ, Kalbasi A et al. Hypofractionated preoperative radiation should not yet be used as standard of care for extremity and truncal soft tissue sarcoma. J Clin Oncol 2024;42:4240–4245 [DOI] [PubMed] [Google Scholar]
110. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma meta-analysis collaboration. Lancet 1997;350:1647–1654 [PubMed] [Google Scholar]
111. Callegaro D, Miceli R, Bonvalot S, Ferguson P, Strauss DC, Levy A et al. Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis. Lancet Oncol 2016;17:671–680 [DOI] [PubMed] [Google Scholar]
112. Acem I, van Houdt WJ, Grünhagen DJ, van der Graaf WTA, Rueten-Budde AJ, Gelderblom H et al. The role of perioperative chemotherapy in primary high-grade extremity soft tissue sarcoma: a risk-stratified analysis using PERSARC. Eur J Cancer 2022;165:71–80 [DOI] [PubMed] [Google Scholar]
113. Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol 2012;30:850–856 [DOI] [PubMed] [Google Scholar]
114. Gronchi A, Stacchiotti S, Verderio P, Ferrari S, Martin Broto J, Lopez-Pousa A et al. Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol 2016;27:2283–2288 [DOI] [PubMed] [Google Scholar]
115. Pasquali S, Palmerini E, Quagliuolo V, Martin-Broto J, Lopez-Pousa A, Grignani G et al. Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: a Sarculator-based risk stratification analysis of the ISG-STS 1001 randomized trial. Cancer 2022;128:85–93 [DOI] [PubMed] [Google Scholar]
116. Burgess MA, Bolejack V, Schuetze S, Van Tine BA, Attia S, Riedel RF et al. Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): final results of SARC028 expansion cohorts. J Clin Oncol 2019;37:11015 [Google Scholar]
117. Keung EZ, Burgess M, Salazar R, Parra ER, Rodrigues-Canales J, Bolejack V et al. Correlative analyses of the SARC028 trial reveal an association between sarcoma-associated immune infiltrate and response to pembrolizumab. Clin Cancer Res 2020;26:1258–1266 [DOI] [PMC free article] [PubMed] [Google Scholar]
118. Petitprez F, de Reyniès A, Keung EZ, Chen TW-W, Sun C-M, Calderaro J et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 2020;577:556–560 [DOI] [PubMed] [Google Scholar]
119. Italiano A, Bessede A, Pulido M, Bompas E, Piperno-Neumann S, Chevreau C et al. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nat Med 2022;28:1199–1206 [DOI] [PubMed] [Google Scholar]
120. Kasago IS, Chatila WK, Lezcano CM, Febres-Aldana CA, Schultz N, Vanderbilt C et al. Undifferentiated and dedifferentiated metastatic melanomas masquerading as soft tissue sarcomas: mutational signature analysis and immunotherapy response. Mod Pathol 2023;36:100165. [DOI] [PMC free article] [PubMed] [Google Scholar]
121. Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 2015;16:e498–e509 [DOI] [PubMed] [Google Scholar]
122. Keung EZ, Tsai J-W, Ali AM, Cormier JN, Bishop AJ, Guadagnolo BA et al. Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy: rationale for combination neoadjuvant immune checkpoint inhibition and radiotherapy. Oncoimmunology 2018;7:e1385689. [DOI] [PMC free article] [PubMed] [Google Scholar]
123. Callegaro D, Raut CP, Ng D, Strauss DC, Honoré C, Stoeckle E et al. Has the outcome for patients who undergo resection of primary retroperitoneal sarcoma changed over time? A study of time trends during the past 15 years. Ann Surg Oncol 2021;28:1700–1709 [DOI] [PubMed] [Google Scholar]
124. Dossa F, Swallow CJ. Defining resectability criteria for primary retroperitoneal sarcoma: a challenging imperative. Br J Surg 2025;112:znaf044 [DOI] [PubMed] [Google Scholar]
125. Perhavec A, Provenzano S, Baia M, Sangalli C, Morosi C, Barisella M et al. Inoperable primary retroperitoneal sarcomas: clinical characteristics and reasons against resection at a single referral institution. Ann Surg Oncol 2021;28:1151–1157 [DOI] [PubMed] [Google Scholar]
126. Ng D, Acidi B, Johnston W, Callegaro D, Brar S, Gladdy R et al. Why do some patients with non-metastatic primary retroperitoneal sarcoma (RPS) not undergo resection? Can J Surg 2022;65:S100
127. Stojadinovic A, Yeh A, Brennan MF. Completely resected recurrent soft tissue sarcoma: primary anatomic site governs outcomes. J Am Coll Surg 2002;194:436–447 [DOI] [PubMed] [Google Scholar]
128. Fairweather M, Wang J, Jo VY, Baldini EH, Bertagnolli MM, Raut CP. Surgical management of primary retroperitoneal sarcomas: rationale for selective organ resection. Ann Surg Oncol 2018;25:98–106 [DOI] [PubMed] [Google Scholar]
129. Improta L, Pasquali S, Iadecola S, Barisella M, Fiore M, Radaelli S et al. Organ infiltration and patient risk after multivisceral surgery for primary retroperitoneal liposarcomas. Ann Surg Oncol 2023;30:4500–4510 [DOI] [PubMed] [Google Scholar]
130. Gronchi A, Lo Vullo S, Fiore M, Mussi C, Stacchiotti S, Collini P et al. Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol 2009;27:24–30 [DOI] [PubMed] [Google Scholar]
131. Bonvalot S, Rivoire M, Castaing M, Stoeckle E, Le Cesne A, Blay JY et al. Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol 2009;27:31–37 [DOI] [PubMed] [Google Scholar]
132. Gronchi A, Miceli R, Colombo C, Stacchiotti S, Collini P, Mariani L et al. Frontline extended surgery is associated with improved survival in retroperitoneal low- to intermediate-grade soft tissue sarcomas. Ann Oncol 2012;23:1067–1073 [DOI] [PubMed] [Google Scholar]
133. Pisters PWT. Resection of some—but not all—clinically uninvolved adjacent viscera as part of surgery for retroperitoneal soft tissue sarcomas. J Clin Oncol 2009;27:6–8 [DOI] [PubMed] [Google Scholar]
134. Raut CP, Swallow CJ. Are radical compartmental resections for retroperitoneal sarcomas justified? Ann Surg Oncol 2010;17:1481–1484 [DOI] [PubMed] [Google Scholar]
135. Ikoma N, Roland CL, Torres KE, Chiang Y, Wang W, Somaiah N et al. Concomitant organ resection does not improve outcomes in primary retroperitoneal well-differentiated liposarcoma: a retrospective cohort study at a major sarcoma center. J Surg Oncol 2018;117:1188–1194 [DOI] [PMC free article] [PubMed] [Google Scholar]
136. Pasquali S, Vohra R, Tsimopoulou I, Vijayan D, Gourevitch D, Desai A. Outcomes following extended surgery for retroperitoneal sarcomas: results from a UK referral centre. Ann Surg Oncol 2015;22:3550–3556 [DOI] [PubMed] [Google Scholar]
137. Tseng WW, Madewell JE, Wei W, Somaiah N, Lazar AJ, Ghadimi MP et al. Locoregional disease patterns in well-differentiated and dedifferentiated retroperitoneal liposarcoma: implications for the extent of resection? Ann Surg Oncol 2014;21:2136–2143 [DOI] [PubMed] [Google Scholar]
138. Radaelli S, Baia M, Drohan A, Morosi C, Sangalli C, Colombo C et al. Six surgical stages in the resection of primary right retroperitoneal liposarcoma: a standardized comprehensive approach. Ann Surg Oncol 2023;30:6896–6897 [DOI] [PubMed] [Google Scholar]
139. Baia M, Dossa F, Radaelli S, Callegaro D, Colombo C, Borghi A et al. Six surgical stages in the resection of primary left retroperitoneal liposarcoma: a standardized comprehensive approach. Ann Surg Oncol 2025;32:7836–7837 [DOI] [PubMed] [Google Scholar]
140. MacNeill AJ, Gronchi A, Miceli R, Bonvalot S, Swallow CJ, Hohenberger P et al. Postoperative morbidity after radical resection of primary retroperitoneal sarcoma: a report from the transatlantic RPS working group. Ann Surg 2018;267:959–964 [DOI] [PubMed] [Google Scholar]
141. Fiore M, Brunelli C, Miceli R, Manara M, Lenna S, Rampello NN et al. A prospective observational study of multivisceral resection for retroperitoneal sarcoma: clinical and patient-reported outcomes 1 year after surgery. Ann Surg Oncol 2021;28:3904–3916 [DOI] [PubMed] [Google Scholar]
142. Bonvalot S, Miceli R, Berselli M, Causeret S, Colombo C, Mariani L et al. Aggressive surgery in retroperitoneal soft tissue sarcoma carried out at high-volume centers is safe and is associated with improved local control. Ann Surg Oncol 2010;17:1507–1514 [DOI] [PubMed] [Google Scholar]
143. Fairweather M, Jolissaint JS, Fiore M, Strauss D, Bonvalot S, Ford SJ et al. Development of a surgical complexity score to predict postoperative morbidity following primary retroperitoneal sarcoma resection: a collaborative study from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG). Br J Surg 2025;112:znaf029. [DOI] [PubMed] [Google Scholar]
144. Previtali P, Fiore M, Colombo J, Arendar I, Fumagalli L, Pizzocri M et al. Malnutrition and perioperative nutritional support in retroperitoneal sarcoma patients: results from a prospective study. Ann Surg Oncol 2020;27:2025–2032 [DOI] [PubMed] [Google Scholar]
145. Kirov KM, Xu HP, Crenn P, Goater P, Tzanis D, Bouhadiba MT et al. Role of nutritional status in the early postoperative prognosis of patients operated for retroperitoneal liposarcoma (RLS): a single center experience. Eur J Surg Oncol 2019;45:261–267 [DOI] [PubMed] [Google Scholar]
146. Samà L, Kumar S, Covello E, D’Orazio F, Pindilli S, Levi R et al. Nutritional status in retroperitoneal sarcoma: implication of prognostic nutritional index (PNI) and skeletal muscle index (SMI) on postoperative and oncological outcomes. Clin Nutr ESPEN 2025;69:167–176 [DOI] [PubMed] [Google Scholar]
147. Baia M, Zanframundo C, Ljevar S, Della Valle S, Misotti A, Rampello NN et al. Preoperative nutritional support to tackle morbidity in multivisceral resection for retroperitoneal sarcoma. Early outcomes from a novel nutritional prehabilitation program in a prospective cohort. Eur J Surg Oncol 2024;50:108663. [DOI] [PubMed] [Google Scholar]
148. Tirotta F, Fiore M, Bonvalot S, Strauss D, Rutkowski P, Gyorki DE et al. Defining benchmark values for outcomes of comprehensive resection of primary retroperitoneal liposarcoma: a retrospective multicenter study. EClinicalMedicine 2025;84:103280. [DOI] [PMC free article] [PubMed] [Google Scholar]
149. Hull MA, Niemierko A, Haynes AB, Jacobson A, Chen Y-L, DeLaney TF et al. Post-operative renal function following nephrectomy as part of en bloc resection of retroperitoneal sarcoma (RPS). J Surg Oncol 2015;112:98–102 [DOI] [PubMed] [Google Scholar]
150. Callegaro D, Miceli R, Brunelli C, Colombo C, Sanfilippo R, Radaelli S et al. Long-term morbidity after multivisceral resection for retroperitoneal sarcoma. Br J Surg 2015;102:1079–1087 [DOI] [PubMed] [Google Scholar]
151. Baia M, Drohan A, Radaelli S, Callegaro D, Colombo C, Borghi A et al. Resection of primary leiomyosarcoma of the inferior vena cava and reconstruction with a cadaveric homograft. Ann Surg Oncol 2025;32:2979–2980 [DOI] [PubMed] [Google Scholar]
152. Seidensaal K, Dostal M, Kudak A, Jaekel C, Meixner E, Liermann J et al. Preoperative dose-escalated intensity-modulated radiotherapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft-tissue sarcoma: final results of a clinical phase I/II trial. Cancers (Basel) 2023;15:2747. [DOI] [PMC free article] [PubMed] [Google Scholar]
153. Sindelar WF, Kinsella TJ, Chen PW, Delaney TF, Tepper JE, Rosenberg SA et al. Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Arch Surg 1993;128:402–410 [DOI] [PubMed] [Google Scholar]
154. Pisters Pwt, Ballo MT, Fenstermacher MJ, Feig BW, Hunt KK, Raymond KA et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol 2003;21:3092–3097 [DOI] [PubMed] [Google Scholar]
155. Jones JJ, Catton CN, Sullivan O’, Couture B, Heisler J, Kandel RL et al. Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 2002;9:346–354 [DOI] [PubMed] [Google Scholar]
156. Smith Mjf, Ridgway PF, Catton CN, Cannell AJ, Sullivan O’, Mikula B et al. Combined management of retroperitoneal sarcoma with dose intensification radiotherapy and resection: long-term results of a prospective trial. Radiother Oncol 2014;110:165–171 [DOI] [PubMed] [Google Scholar]
157. Fairweather M, Wang J, Devlin PM, Hansen J, Baldini EH, Ready JE et al. Safety and efficacy of radiation dose delivered via iodine-125 brachytherapy mesh implantation for deep cavity sarcomas. Ann Surg Oncol 2015;22:1455–1463 [DOI] [PubMed] [Google Scholar]
158. Dziewirski W, Rutkowski P, Nowecki ZI, Sałamacha M, Morysiński T, Kulik A et al. Surgery combined with intraoperative brachytherapy in the treatment of retroperitoneal sarcomas. Ann Surg Oncol 2006;13:245–252 [DOI] [PubMed] [Google Scholar]
159. Paryani NN, Zlotecki RA, Swanson EL, Morris CG, Grobmyer SR, Hochwald SN et al. Multimodality local therapy for retroperitoneal sarcoma. Int J Radiat Oncol Biol Phys 2012;82:1128–1134 [DOI] [PubMed] [Google Scholar]
160. Ballo MT, Zagars GK, Pollock RE, Benjamin RS, Feig BW, Cormier JN et al. Retroperitoneal soft tissue sarcoma: an analysis of radiation and surgical treatment. Int J Radiat Oncol Biol Phys 2007;67:158–163 [DOI] [PubMed] [Google Scholar]
161. Bishop AJ, Zagars GK, Torres KE, Hunt KK, Cormier JN, Feig BW et al. Combined modality management of retroperitoneal sarcomas: a single-institution series of 121 patients. Int J Radiat Oncol Biol Phys 2015;93:158–165 [DOI] [PMC free article] [PubMed] [Google Scholar]
162. Zlotecki RA, Katz TS, Morris CG, Lind DS, Hochwald SN. Adjuvant radiation therapy for resectable retroperitoneal soft tissue sarcoma: the University of Florida experience. Am J Clin Oncol 2005;28:310–316 [DOI] [PubMed] [Google Scholar]
163. Le Péchoux C, Musat E, Baey C, Al Mokhles H, Terrier P, Domont J et al. Should adjuvant radiotherapy be administered in addition to front-line aggressive surgery (FAS) in patients with primary retroperitoneal sarcoma? Ann Oncol 2013;24:832–837 [DOI] [PubMed] [Google Scholar]
164. Pezner RD, Liu A, Chen Y-J, Smith DD, Paz IB. Full-dose adjuvant postoperative radiation therapy for retroperitoneal sarcomas. Am J Clin Oncol 2011;34:511–516 [DOI] [PubMed] [Google Scholar]
165. Gilbeau L, Kantor G, Stoeckle E, Lagarde P, Thomas L, Kind M et al. Surgical resection and radiotherapy for primary retroperitoneal soft tissue sarcoma. Radiother Oncol 2002;65:137–143 [DOI] [PubMed] [Google Scholar]
166. Bonvalot S, Gronchi A, Le Péchoux C, Swallow CJ, Strauss D, Meeus P et al. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2020;21:1366–1377 [DOI] [PubMed] [Google Scholar]
167. Callegaro D, Raut CP, Ajayi T, Strauss D, Bonvalot S, Ng D et al. Preoperative radiotherapy in patients with primary retroperitoneal sarcoma: EORTC-62092 trial (STRASS) versus off-trial (STREXIT) results. Ann Surg 2023;278:127–134 [DOI] [PubMed] [Google Scholar]
168. Lambdin J, Ryan C, Gregory S, Cardona K, Hernandez JM, van Houdt WJ et al. A randomized phase III study of neoadjuvant chemotherapy followed by surgery versus surgery alone for patients with high-risk retroperitoneal sarcoma (STRASS2). Ann Surg Oncol 2023;30:4573–4575 [DOI] [PMC free article] [PubMed] [Google Scholar]
169. Kedra A, Dohan A, Biau D, Belbachir A, Dautry R, Lucas A et al. Preoperative arterial embolization of musculoskeletal tumors: a tertiary center experience. Cancers (Basel) 2023;15:2657. [DOI] [PMC free article] [PubMed] [Google Scholar]
170. Reijers SJM, Davies E, Grünhagen DJ, Fiore M, Honore C, Rastrelli M et al. Variation in response rates to isolated limb perfusion in different soft-tissue tumour subtypes: an international multi-centre study. Eur J Cancer 2023;190:112949. [DOI] [PubMed] [Google Scholar]
171. Hayes AJ, Coker DJ, Been L, Boecxstaens VW, Bonvalot S, De Cian F et al. Technical considerations for isolated limb perfusion: a consensus paper. Eur J Surg Oncol 2024;50:108050. [DOI] [PubMed] [Google Scholar]
172. Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem B-C 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;11:561–570 [DOI] [PMC free article] [PubMed] [Google Scholar]
173. Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P et al. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncol 2018;4:483–492 [DOI] [PMC free article] [PubMed] [Google Scholar]
174. Angele MK, Albertsmeier M, Prix NJ, Hohenberger P, Abdel-Rahman S, Dieterle N et al. Effectiveness of regional hyperthermia with chemotherapy for high-risk retroperitoneal and abdominal soft-tissue sarcoma after complete surgical resection: a subgroup analysis of a randomized phase-III multicenter study. Ann Surg 2014;260:749–754. discussion 754-746 [DOI] [PMC free article] [PubMed] [Google Scholar]
175. Campana LG, Kis E, Bottyán K, Orlando A, de Terlizzi F, Mitsala G et al. Electrochemotherapy for advanced cutaneous angiosarcoma: a European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT). Int J Surg 2019;72:34–42 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Not applicable.

[zraf177-B1] 1. Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg 2014;260:416–421. discussion 421-412 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B2] 2. Gronchi A, Strauss DC, Miceli R, Bonvalot S, Swallow CJ, Hohenberger P et al. Variability in patterns of recurrence after resection of primary retroperitoneal sarcoma (RPS): a report on 1007 patients from the multi-institutional collaborative RPS working group. Ann Surg 2016;263:1002–1009 [DOI] [PubMed] [Google Scholar]

[zraf177-B3] 3. Tan MCB, Brennan MF, Kuk D, Agaram NP, Antonescu CR, Qin L-X et al. Histology-based classification predicts pattern of recurrence and improves risk stratification in primary retroperitoneal sarcoma. Ann Surg 2016;263:593–600 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B4] 4. National Comprehensive Cancer Network . Soft Tissue Sarcoma (Version 1.2025). https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf (accessed 25 October 2025)

[zraf177-B5] 5. Gronchi A, Miah AB, Dei Tos AP, Abecassis N, Bajpai J, Bauer S et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS clinical practice guidelines for diagnosis, treatment and follow-up(⋆). Ann Oncol 2021;32:1348–1365 [DOI] [PubMed] [Google Scholar]

[zraf177-B6] 6. Hayes AJ, Nixon IF, Strauss DC, Seddon BM, Desai A, Benson C et al. UK guidelines for the management of soft tissue sarcomas. Br J Cancer 2025;132:11–31 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B7] 7. Swallow CJ, Strauss DC, Bonvalot S, Rutkowski P, Desai A, Gladdy RA et al. Management of primary retroperitoneal sarcoma (RPS) in the adult: an updated consensus approach from the Transatlantic Australasian RPS Working Group. Ann Surg Oncol 2021;28:7873–7888 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B8] 8. Moulin B, Messiou C, Crombe A, Kind M, Hohenberger P, Rutkowski P et al. Diagnosis strategy of adipocytic soft-tissue tumors in adults: a consensus from European experts. Eur J Surg Oncol 2022;48:518–525 [DOI] [PubMed] [Google Scholar]

[zraf177-B9] 9. Morosi C, Stacchiotti S, Marchianò A, Bianchi A, Radaelli S, Sanfilippo R et al. Correlation between radiological assessment and histopathological diagnosis in retroperitoneal tumors: analysis of 291 consecutive patients at a tertiary reference sarcoma center. Eur J Surg Oncol 2014;40:1662–1670 [DOI] [PubMed] [Google Scholar]

[zraf177-B10] 10. Berger-Richardson D, Burtenshaw SM, Ibrahim AM, Gladdy RA, Auer R, Beecroft R et al. Early and late complications of percutaneous core needle biopsy of retroperitoneal tumors at two tertiary sarcoma centers. Ann Surg Oncol 2019;26:4692–4698 [DOI] [PubMed] [Google Scholar]

[zraf177-B11] 11. Nardi W, Nicolas N, El Zein S, Tzanis D, Bouhadiba T, Helfre S et al. Diagnostic accuracy and safety of percutaneous core needle biopsy of retroperitoneal tumours. Eur J Surg Oncol 2024;50:107298. [DOI] [PubMed] [Google Scholar]

[zraf177-B12] 12. Strauss DC, Qureshi YA, Hayes AJ, Thway K, Fisher C, Thomas JM. The role of core needle biopsy in the diagnosis of suspected soft tissue tumours. J Surg Oncol 2010;102:523–529 [DOI] [PubMed] [Google Scholar]

[zraf177-B13] 13. Heslin MJ, Lewis JJ, Woodruff JM, Brennan MF. Core needle biopsy for diagnosis of extremity soft tissue sarcoma. Ann Surg Oncol 1997;4:425–431 [DOI] [PubMed] [Google Scholar]

[zraf177-B14] 14. Hoeber I, Spillane AJ, Fisher C, Thomas JM. Accuracy of biopsy techniques for limb and limb girdle soft tissue tumors. Ann Surg Oncol 2001;8:80–87 [DOI] [PubMed] [Google Scholar]

[zraf177-B15] 15. Almond LM, Tirotta F, Tattersall H, Hodson J, Cascella T, Barisella M et al. Diagnostic accuracy of percutaneous biopsy in retroperitoneal sarcoma. Br J Surg 2019;106:395–403 [DOI] [PubMed] [Google Scholar]

[zraf177-B16] 16. Ikoma N, Torres KE, Somaiah N, Hunt KK, Cormier JN, Tseng W et al. Accuracy of preoperative percutaneous biopsy for the diagnosis of retroperitoneal liposarcoma subtypes. Ann Surg Oncol 2015;22:1068–1072 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B17] 17. Schneider N, Strauss DC, Smith MJ, Miah AB, Zaidi S, Benson C et al. The adequacy of core biopsy in the assessment of smooth muscle neoplasms of soft tissues: implications for treatment and prognosis. Am J Surg Pathol 2017;41:923–931 [DOI] [PubMed] [Google Scholar]

[zraf177-B18] 18. Borghi A, Fiore M, Tiné G, Strauss DC, Bonvalot S, Raut CP et al. Accuracy of Histology and Malignancy Grade between Preoperative Biopsy and Surgical Specimens in Primary Retroperitoneal Sarcoma. A Study from the Prospective Retroperitoneal Sarcoma Registry (Resar). Ann Surg 2025. 10.1097/SLA.0000000000007001. Epub ahead of print [DOI] [PubMed] [Google Scholar]

[zraf177-B19] 19. Tirotta F, Morosi C, Hodson J, Desai A, Barisella M, Ford SJ et al. Improved biopsy accuracy in retroperitoneal dedifferentiated liposarcoma. Ann Surg Oncol 2020;27:4574–4581 [DOI] [PubMed] [Google Scholar]

[zraf177-B20] 20. Berger-Richardson D, Swallow CJ. Needle tract seeding after percutaneous biopsy of sarcoma: risk/benefit considerations. Cancer 2017;123:560–567 [DOI] [PubMed] [Google Scholar]

[zraf177-B21] 21. Oliveira MP, de Lima PMA, de Mello RJV. Tumor contamination in the biopsy path of primary malignant bone tumors. Rev Bras Ortop 2012;47:631–637 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B22] 22. Ribeiro MB, de Oliveira CRGCM, Filippi RZ, Baptista AM, Caiero MT, Saito CF et al. Estudo histopatológico do trajeto de biópsia de tumores musculoesqueléticos malignos. Acta Ortopédica Bras 2009;17:279–281 [Google Scholar]

[zraf177-B23] 23. Mohana R, Faisham WI, Zulmi W, Nawfar AS, Effat O, Salzihan MS. The incidence of malignant infiltration in the biopsy tract of osteosarcoma. Malays Orthop J 2007;1:7–10 [Google Scholar]

[zraf177-B24] 24. Kaffenberger BH, Wakely PE Jr, Mayerson JL. Local recurrence rate of fine-needle aspiration biopsy in primary high-grade sarcomas. J Surg Oncol 2010;101:618–621 [DOI] [PubMed] [Google Scholar]

[zraf177-B25] 25. Saghieh S, Masrouha KZ, Musallam KM, Mahfouz R, Abboud M, Khoury NJ et al. The risk of local recurrence along the core-needle biopsy tract in patients with bone sarcomas. Iowa Orthop J 2010;30:80–83 [PMC free article] [PubMed] [Google Scholar]

[zraf177-B26] 26. Wilkinson MJ, Martin JL, Khan AA, Hayes AJ, Thomas JM, Strauss DC. Percutaneous core needle biopsy in retroperitoneal sarcomas does not influence local recurrence or overall survival. Ann Surg Oncol 2015;22:853–858 [DOI] [PubMed] [Google Scholar]

[zraf177-B27] 27. Hwang SY, Warrier S, Thompson S, Davidson T, Yang JL, Crowe P. Safety and accuracy of core biopsy in retroperitoneal sarcomas. Asia Pac J Clin Oncol 2016;12:e174–e178 [DOI] [PubMed] [Google Scholar]

[zraf177-B28] 28. Van Houdt WJ, Schrijver AM, Cohen-Hallaleh RB, Memos N, Fotiadis N, Smith MJ et al. Needle tract seeding following core biopsies in retroperitoneal sarcoma. Eur J Surg Oncol 2017;43:1740–1745 [DOI] [PubMed] [Google Scholar]

[zraf177-B29] 29. Tuttle R, Kane JM 3rd. Biopsy techniques for soft tissue and bowel sarcomas. J Surg Oncol 2015;111:504–512 [DOI] [PubMed] [Google Scholar]

[zraf177-B30] 30. Wu JS, Goldsmith JD, Horwich PJ, Shetty SK, Hochman MG. Bone and soft-tissue lesions: what factors affect diagnostic yield of image-guided core-needle biopsy? Radiology 2008;248:962–970 [DOI] [PubMed] [Google Scholar]

[zraf177-B31] 31. Bickels J, Jelinek JS, Shmookler BM, Neff RS, Malawer MM. Biopsy of musculoskeletal tumors. Current concepts. Clin Orthop Relat Res 1999;368:212–219 [PubMed] [Google Scholar]

[zraf177-B32] 32. Antonescu CR. The role of genetic testing in soft tissue sarcoma. Histopathology 2006;48:13–21 [DOI] [PubMed] [Google Scholar]

[zraf177-B33] 33. Thway K, Wang J, Swansbury J, Min T, Fisher C. Fluorescence in situ hybridization for MDM2 amplification as a routine ancillary diagnostic tool for suspected well-differentiated and dedifferentiated liposarcomas: experience at a tertiary center. Sarcoma 2015;2015:812089. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B34] 34. Italiano A, Di Mauro I, Rapp J, Pierron G, Auger N, Alberti L et al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol 2016;17:532–538 [DOI] [PubMed] [Google Scholar]

[zraf177-B35] 35. Schwab JH, Boland PJ, Antonescu C, Bilsky MH, Healey JH. Spinal metastases from myxoid liposarcoma warrant screening with magnetic resonance imaging. Cancer 2007;110:1815–1822 [DOI] [PubMed] [Google Scholar]

[zraf177-B36] 36. Fiore M, Grosso F, Lo Vullo S, Pennacchioli E, Stacchiotti S, Ferrari A et al. Myxoid/round cell and pleomorphic liposarcomas: prognostic factors and survival in a series of patients treated at a single institution. Cancer 2007;109:2522–2531 [DOI] [PubMed] [Google Scholar]

[zraf177-B37] 37. Bonvalot S, Gaignard E, Stoeckle E, Meeus P, Decanter G, Carrere S et al. Survival benefit of the surgical management of retroperitoneal sarcoma in a reference center: a nationwide study of the French Sarcoma Group from the NetSarc database. Ann Surg Oncol 2019;26:2286–2293 [DOI] [PubMed] [Google Scholar]

[zraf177-B38] 38. Bagaria SP, Chang Y-H, Gray RJ, Ashman JB, Attia S, Wasif N. Improving long-term outcomes for patients with extra-abdominal soft tissue sarcoma regionalization to high-volume centers, improved compliance with guidelines or both? Sarcoma 2018;2018::8141056. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B39] 39. Derbel O, Heudel PE, Cropet C, Meeus P, Vaz G, Biron P et al. Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort). PLoS One 2017;12:e0158406. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B40] 40. Berger NG, Silva JP, Mogal H, Clarke CN, Bedi M, Charlson J et al. Overall survival after resection of retroperitoneal sarcoma at academic cancer centers versus community cancer centers: an analysis of the National Cancer Data Base. Surgery 2018;163:318–323 [DOI] [PubMed] [Google Scholar]

[zraf177-B41] 41. Hoekstra HJ, Haas RLM, Verhoef C, Suurmeijer AJH, van Rijswijk CSP, Bongers BGH et al. Adherence to guidelines for adult (non-GIST) soft tissue sarcoma in The Netherlands: a plea for dedicated sarcoma centers. Ann Surg Oncol 2017;24:3279–3288 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B42] 42. Keung EZ, Chiang Y-J, Cormier JN, Torres KE, Hunt KK, Feig BW et al. Treatment at low-volume hospitals is associated with reduced short-term and long-term outcomes for patients with retroperitoneal sarcoma. Cancer 2018;124:4495–4503 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B43] 43. Maurice MJ, Yih JM, Ammori JB, Abouassaly R. Predictors of surgical quality for retroperitoneal sarcoma: volume matters. J Surg Oncol 2017;116:766–774 [DOI] [PubMed] [Google Scholar]

[zraf177-B44] 44. Blay J-Y, Honoré C, Stoeckle E, Meeus P, Jafari M, Gouin F et al. Surgery in reference centers improves survival of sarcoma patients: a nationwide study. Ann Oncol 2019;30:1143–1153 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B45] 45. Callegaro D, Barretta F, Raut CP, Johnston W, Strauss DC, Honoré C et al. New Sarculator prognostic nomograms for patients with primary retroperitoneal sarcoma: case volume does matter. Ann Surg 2024;279:857–865 [DOI] [PubMed] [Google Scholar]

[zraf177-B46] 46. 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 evaluation: results from the prospective registry of the Spanish group for research in sarcoma (GEIS). Oncologist 2019;24:e338–e346 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B47] 47. Tirotta F, Bacon A, Collins S, Desai A, Liu H, Paley L et al. Primary retroperitoneal sarcoma: a comparison of survival outcomes in specialist and non-specialist sarcoma centres. Eur J Cancer 2023;188:20–28 [DOI] [PubMed] [Google Scholar]

[zraf177-B48] 48. Vos M, Blaauwgeers HGT, Ho VKY, van Houdt WJ, van der Hage JA, Been LB et al. Increased survival of non low-grade and deep-seated soft tissue sarcoma after surgical management in high-volume hospitals: a nationwide study from The Netherlands. Eur J Cancer 2019;110:98–106 [DOI] [PubMed] [Google Scholar]

[zraf177-B49] 49. Villano AM, Zeymo A, Chan KS, Shara N, Al-Refaie WB. Identifying the minimum volume threshold for retroperitoneal soft tissue sarcoma resection: merging national data with consensus expert opinion. J Am Coll Surg 2020;230:151–160.e152 [DOI] [PubMed] [Google Scholar]

[zraf177-B50] 50. Villano AM, Zeymo A, McDermott J, Barrak D, Unger KR, Shara NM et al. Regionalization of retroperitoneal sarcoma surgery to high-volume hospitals: missed opportunities for outcome improvement. J Oncol Pract 2019;15:e247–e261 [DOI] [PubMed] [Google Scholar]

[zraf177-B51] 51. Villano AM, Zeymo A, Chan KS, Unger KR, Shara N, Al-Refaie WB. Variations in retroperitoneal soft tissue sarcoma outcomes by hospital type: a national cancer database analysis. JCO Oncol Pract 2020;16:e991–e1003 [DOI] [PubMed] [Google Scholar]

[zraf177-B52] 52. Andritsch E, Beishon M, Bielack S, Bonvalot S, Casali P, Crul M et al. ECCO essential requirements for quality cancer care: soft tissue sarcoma in adults and bone sarcoma. A critical review. Crit Rev Oncol Hematol 2017;110:94–105 [DOI] [PubMed] [Google Scholar]

[zraf177-B53] 53. Blay J-Y, Soibinet P, Penel N, Bompas E, Duffaud F, Stoeckle E et al. Improved survival using specialized multidisciplinary board in sarcoma patients. Ann Oncol 2017;28:2852–2859 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B54] 54. Sicklick JK, Swallow CJ, Raut CP, Callegaro D, Fiore M, Strauss DC et al. Creation and implementation of a monthly international tumor board: experience of the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG). Ann Surg Oncol 2023;30:6287–6289 [DOI] [PubMed] [Google Scholar]

[zraf177-B55] 55. Samà L, Kumar S, Ruspi L, Sicoli F, D’Amato V, Mintemur Ö et al. Learning curve in retroperitoneal sarcoma surgery. Eur J Surg Oncol 2024;50:108612. [DOI] [PubMed] [Google Scholar]

[zraf177-B56] 56. Hannan EL, Radzyner M, Rubin D, Dougherty J, Brennan MF. The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer. Surgery 2002;131:6–15 [DOI] [PubMed] [Google Scholar]

[zraf177-B57] 57. Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennam M et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B58] 58. Bowden L, Booher RJ. The principles and technique of resection of soft parts for sarcoma. Surgery 1958;44:963–977 [PubMed] [Google Scholar]

[zraf177-B59] 59. Gerrand CH, Wunder JS, Kandel RA, O’Sullivan B, Catton CN, Bell RS et al. Classification of positive margins after resection of soft-tissue sarcoma of the limb predicts the risk of local recurrence. J Bone Joint Surg Br 2001;83:1149–1155 [DOI] [PubMed] [Google Scholar]

[zraf177-B60] 60. Gundle KR, Kafchinski L, Gupta S, Griffin AM, Dickson BC, Chung PW et al. Analysis of margin classification systems for assessing the risk of local recurrence after soft tissue sarcoma resection. J Clin Oncol 2018;36:704–709 [DOI] [PubMed] [Google Scholar]

[zraf177-B61] 61. Bickels J, Wittig JC, Kollender Y, Kellar-Graney K, Malawer MM, Meller I. Sciatic nerve resection: is that truly an indication for amputation? Clin Orthop Relat Res 2002;399:201–204 [PubMed] [Google Scholar]

[zraf177-B62] 62. Brooks AD, Gold JS, Graham D, Boland P, Lewis JJ, Brennan MF et al. Resection of the sciatic, peroneal, or tibial nerves: assessment of functional status. Ann Surg Oncol 2002;9:41–47 [DOI] [PubMed] [Google Scholar]

[zraf177-B63] 63. Jones KB, Ferguson PC, Deheshi B, Riad S, Griffin A, Bell RS et al. Complete femoral nerve resection with soft tissue sarcoma: functional outcomes. Ann Surg Oncol 2010;17:401–406 [DOI] [PubMed] [Google Scholar]

[zraf177-B64] 64. Martin E, Dullaart MJ, Verhoef C, Coert JH. A systematic review of functional outcomes after nerve reconstruction in extremity soft tissue sarcomas: a need for general implementation in the armamentarium. J Plast Reconstr Aesthet Surg 2020;73:621–632 [DOI] [PubMed] [Google Scholar]

[zraf177-B65] 65. Conti L, Buriro F, Baia M, Pasquali S, Miceli R, De Rosa L et al. Contemporary role of amputation for patients with extremity soft tissue sarcoma. Eur J Surg Oncol 2023;49:934–940 [DOI] [PubMed] [Google Scholar]

[zraf177-B66] 66. Erstad DJ, Ready J, Abraham J, Ferrone ML, Bertagnolli MM, Baldini EH et al. Amputation for extremity sarcoma: contemporary indications and outcomes. Ann Surg Oncol 2018;25:394–403 [DOI] [PubMed] [Google Scholar]

[zraf177-B67] 67. Fiore M, Casali PG, Miceli R, Mariani L, Bertulli R, Lozza L et al. Prognostic effect of re-excision in adult soft tissue sarcoma of the extremity. Ann Surg Oncol 2006;13:110–117 [DOI] [PubMed] [Google Scholar]

[zraf177-B68] 68. Karakousis CP, Driscoll DL. Treatment and local control of primary extremity soft tissue sarcomas. J Surg Oncol 1999;71:155–161 [DOI] [PubMed] [Google Scholar]

[zraf177-B69] 69. Decanter G, Stoeckle E, Honore C, Meeus P, Mattei JC, Dubray-Longeras P et al. Watch and wait approach for re-excision after unplanned yet macroscopically complete excision of extremity and superficial truncal soft tissue sarcoma is safe and does not affect metastatic risk or amputation rate. Ann Surg Oncol 2019;26:3526–3534 [DOI] [PubMed] [Google Scholar]

[zraf177-B70] 70. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL 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;16:197–203 [DOI] [PubMed] [Google Scholar]

[zraf177-B71] 71. Beane JD, Yang JC, White D, Steinberg SM, Rosenberg SA, Rudloff U. Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial. Ann Surg Oncol 2014;21:2484–2489 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B72] 72. O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235–2241 [DOI] [PubMed] [Google Scholar]

[zraf177-B73] 73. Davis A, O’Sullivan B, Turcotte R, Bell R, Catton C, Chabot P et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48–53 [DOI] [PubMed] [Google Scholar]

[zraf177-B74] 74. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–868 [DOI] [PubMed] [Google Scholar]

[zraf177-B75] 75. Wang D, Zhang Q, Eisenberg BL, Kane JM, Li XA, Lucas D et al. Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: results of Radiation Therapy Oncology Group RTOG-0630 trial. J Clin Oncol 2015;33:2231–2238 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B76] 76. Guadagnolo BA, Bassett RL, Mitra D, Farooqi A, Hempel C, Dorber C et al. Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial. Lancet Oncol 2022;23:1547–1557 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B77] 77. Bishop AJ, Mitra D, Farooqi A, Swanson DM, Hempel C, Willis T et al. Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS): updated local control, late toxicities, and patient-reported outcomes. Cancer 2025;131:e35542. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B78] 78. Koseła-Paterczyk H, Szacht M, Morysiński T, Ługowska I, Dziewirski W, Falkowski S et al. Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol 2014;40:1641–1647 [DOI] [PubMed] [Google Scholar]

[zraf177-B79] 79. Kalbasi A, Kamrava M, Chu F-I, Telesca D, Van Dams R, Yang Y et al. A phase II trial of 5-day neoadjuvant radiotherapy for patients with high-risk primary soft tissue sarcoma. Clin Cancer Res 2020;26:1829–1836 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B80] 80. Leite ETT, Munhoz RR, de Camargo VP, Lima LGCAd, Rebolledo DCS, Maistro CEB et al. Neoadjuvant stereotactic ablative radiotherapy (SABR) for soft tissue sarcomas of the extremities. Radiother Oncol 2021;161:222–229 [DOI] [PubMed] [Google Scholar]

[zraf177-B81] 81. Bedi M, Singh R, Charlson JA, Kelly T, Johnstone C, Wooldridge A et al. Is 5 the new 25? Long-term oncologic outcomes from a phase II, prospective, 5-fraction preoperative radiation therapy trial in patients with localized soft tissue sarcoma. Adv Radiat Oncol 2022;7:100850. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B82] 82. Mayo ZS, Parsai S, Asha W, Dinh M, Mesko N, Nystrom L et al. Early outcomes of ultra-hypofractionated preoperative radiation therapy for soft tissue sarcoma followed by immediate surgical resection. Radiother Oncol 2023;180:109439. [DOI] [PubMed] [Google Scholar]

[zraf177-B83] 83. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008;113:573–581 [DOI] [PubMed] [Google Scholar]

[zraf177-B84] 84. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 2012;13:1045–1054 [DOI] [PubMed] [Google Scholar]

[zraf177-B85] 85. Pasquali S, Pizzamiglio S, Touati N, Litiere S, Marreaud S, Kasper B et al. The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial. Eur J Cancer 2019;109:51–60 [DOI] [PubMed] [Google Scholar]

[zraf177-B86] 86. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol 2017;18:812–822 [DOI] [PubMed] [Google Scholar]

[zraf177-B87] 87. Gronchi A, Palmerini E, Quagliuolo V, Martin Broto J, Lopez Pousa A, Grignani G et al. Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: final results of a randomized trial from Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups. J Clin Oncol 2020;38:2178–2186 [DOI] [PubMed] [Google Scholar]

[zraf177-B88] 88. Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 2017;18:1493–1501 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B89] 89. D’Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 2018;19:416–426 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B90] 90. Roland CL, Nassif Haddad EF, Keung EZ, Wang W-L, Lazar AJ, Lin H et al. A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma. Nat Cancer 2024;5:625–641 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B91] 91. Mowery YM, Ballman KV, Hong AM, Schuetze SM, Wagner AJ, Monga V et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. Lancet 2024;404:2053–2064 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B92] 92. Naghavi AO, Fernandez DC, Mesko N, Juloori A, Martinez A, Scott JG et al. American Brachytherapy Society consensus statement for soft tissue sarcoma brachytherapy. Brachytherapy 2017;16:466–489 [DOI] [PubMed] [Google Scholar]

[zraf177-B93] 93. Salerno KE, Alektiar KM, Baldini EH, Bedi M, Bishop AJ, Bradfield L et al. Radiation therapy for treatment of soft tissue sarcoma in adults: executive summary of an ASTRO clinical practice guideline. Pract Radiat Oncol 2021;11:339–351 [DOI] [PubMed] [Google Scholar]

[zraf177-B94] 94. le Grange F, Cassoni AM, Seddon BM. Tumour volume changes following pre-operative radiotherapy in borderline resectable limb and trunk soft tissue sarcoma. Eur J Surg Oncol 2014;40:394–401 [DOI] [PubMed] [Google Scholar]

[zraf177-B95] 95. Dagan R, Indelicato DJ, McGee L, Morris CG, Kirwan JM, Knapik J et al. The significance of a marginal excision after preoperative radiation therapy for soft tissue sarcoma of the extremity. Cancer 2012;118:3199–3207 [DOI] [PubMed] [Google Scholar]

[zraf177-B96] 96. Al-Absi E, Farrokhyar F, Sharma R, Whelan K, Corbett T, Patel M et al. A systematic review and meta-analysis of oncologic outcomes of pre- versus postoperative radiation in localized resectable soft-tissue sarcoma. Ann Surg Oncol 2010;17:1367–1374 [DOI] [PubMed] [Google Scholar]

[zraf177-B97] 97. Alektiar KM, Brennan MF, Healey JH, Singer S. Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity. J Clin Oncol 2008;26:3440–3444 [DOI] [PubMed] [Google Scholar]

[zraf177-B98] 98. Folkert MR, Singer S, Brennan MF, Kuk D, Qin L-X, Kobayashi WK et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol 2014;32:3236–3241 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B99] 99. Seddon B, Grange FL, Simões R, Stacey C, Shelly S, Forsyth S et al. The IMRiS trial: a phase 2 study of intensity modulated radiation therapy in extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2024;120:978–989 [DOI] [PubMed] [Google Scholar]

[zraf177-B100] 100. O’Sullivan B, Griffin AM, Dickie CI, Sharpe MB, Chung PWM, Catton CN et al. Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modality morbidities in lower extremity soft tissue sarcoma. Cancer 2013;119:1878–1884 [DOI] [PubMed] [Google Scholar]

[zraf177-B101] 101. Palassini E, Ferrari S, Verderio P, De Paoli A, Martin Broto J, Quagliuolo V et al. Feasibility of preoperative chemotherapy with or without radiation therapy in localized soft tissue sarcomas of limbs and superficial trunk in the Italian Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized Clinical Trial: three versus five cycles of full-dose epirubicin plus ifosfamide. J Clin Oncol 2015;33:3628–3634 [DOI] [PubMed] [Google Scholar]

[zraf177-B102] 102. Gronchi A, Verderio P, De Paoli A, Ferraro A, Tendero O, Majò J et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Ann Oncol 2013;24:817–823 [DOI] [PubMed] [Google Scholar]

[zraf177-B103] 103. Baldini EH, Goldberg J, Jenner C, Manola JB, Demetri GD, Fletcher CDM et al. Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol 1999;17:3252–3259 [DOI] [PubMed] [Google Scholar]

[zraf177-B104] 104. Pisters PWT, Pollock RE, Lewis VO, Yasko AW, Cormier JN, Respondek PM et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg 2007;246:675–681. discussion 681-672 [DOI] [PubMed] [Google Scholar]

[zraf177-B105] 105. Cahlon O, Brennan MF, Jia X, Qin L-X, Singer S, Alektiar KM. A postoperative nomogram for local recurrence risk in extremity soft tissue sarcomas after limb-sparing surgery without adjuvant radiation. Ann Surg 2012;255:343–347 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B106] 106. Rueten-Budde AJ, van Praag VM, van de Sande MAJ, Fiocco M. External validation and adaptation of a dynamic prediction model for patients with high-grade extremity soft tissue sarcoma. J Surg Oncol 2021;123:1050–1056 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B107] 107. Fiore M, Ford S, Callegaro D, Sangalli C, Colombo C, Radaelli S et al. Adequate local control in high-risk soft tissue sarcoma of the extremity treated with surgery alone at a reference centre: should radiotherapy still be a standard? Ann Surg Oncol 2018;25:1536–1543 [DOI] [PubMed] [Google Scholar]

[zraf177-B108] 108. Foppele GF, Fiocco M, Husson O, Kramer A, Retèl VP, van den Noort V et al. SCOPES: short course of preoperative radiotherapy in head and neck, trunk and extremity soft tissue sarcomas; a randomized phase II clinical trial. ESMO Rare Cancers 2025;4:100029 [Google Scholar]

[zraf177-B109] 109. Baldini EH, Guadagnolo BA, Salerno KE, Chung P, Bishop AJ, Kalbasi A et al. Hypofractionated preoperative radiation should not yet be used as standard of care for extremity and truncal soft tissue sarcoma. J Clin Oncol 2024;42:4240–4245 [DOI] [PubMed] [Google Scholar]

[zraf177-B110] 110. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma meta-analysis collaboration. Lancet 1997;350:1647–1654 [PubMed] [Google Scholar]

[zraf177-B111] 111. Callegaro D, Miceli R, Bonvalot S, Ferguson P, Strauss DC, Levy A et al. Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis. Lancet Oncol 2016;17:671–680 [DOI] [PubMed] [Google Scholar]

[zraf177-B112] 112. Acem I, van Houdt WJ, Grünhagen DJ, van der Graaf WTA, Rueten-Budde AJ, Gelderblom H et al. The role of perioperative chemotherapy in primary high-grade extremity soft tissue sarcoma: a risk-stratified analysis using PERSARC. Eur J Cancer 2022;165:71–80 [DOI] [PubMed] [Google Scholar]

[zraf177-B113] 113. Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol 2012;30:850–856 [DOI] [PubMed] [Google Scholar]

[zraf177-B114] 114. Gronchi A, Stacchiotti S, Verderio P, Ferrari S, Martin Broto J, Lopez-Pousa A et al. Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol 2016;27:2283–2288 [DOI] [PubMed] [Google Scholar]

[zraf177-B115] 115. Pasquali S, Palmerini E, Quagliuolo V, Martin-Broto J, Lopez-Pousa A, Grignani G et al. Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: a Sarculator-based risk stratification analysis of the ISG-STS 1001 randomized trial. Cancer 2022;128:85–93 [DOI] [PubMed] [Google Scholar]

[zraf177-B116] 116. Burgess MA, Bolejack V, Schuetze S, Van Tine BA, Attia S, Riedel RF et al. Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): final results of SARC028 expansion cohorts. J Clin Oncol 2019;37:11015 [Google Scholar]

[zraf177-B117] 117. Keung EZ, Burgess M, Salazar R, Parra ER, Rodrigues-Canales J, Bolejack V et al. Correlative analyses of the SARC028 trial reveal an association between sarcoma-associated immune infiltrate and response to pembrolizumab. Clin Cancer Res 2020;26:1258–1266 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B118] 118. Petitprez F, de Reyniès A, Keung EZ, Chen TW-W, Sun C-M, Calderaro J et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 2020;577:556–560 [DOI] [PubMed] [Google Scholar]

[zraf177-B119] 119. Italiano A, Bessede A, Pulido M, Bompas E, Piperno-Neumann S, Chevreau C et al. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nat Med 2022;28:1199–1206 [DOI] [PubMed] [Google Scholar]

[zraf177-B120] 120. Kasago IS, Chatila WK, Lezcano CM, Febres-Aldana CA, Schultz N, Vanderbilt C et al. Undifferentiated and dedifferentiated metastatic melanomas masquerading as soft tissue sarcomas: mutational signature analysis and immunotherapy response. Mod Pathol 2023;36:100165. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B121] 121. Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 2015;16:e498–e509 [DOI] [PubMed] [Google Scholar]

[zraf177-B122] 122. Keung EZ, Tsai J-W, Ali AM, Cormier JN, Bishop AJ, Guadagnolo BA et al. Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy: rationale for combination neoadjuvant immune checkpoint inhibition and radiotherapy. Oncoimmunology 2018;7:e1385689. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B123] 123. Callegaro D, Raut CP, Ng D, Strauss DC, Honoré C, Stoeckle E et al. Has the outcome for patients who undergo resection of primary retroperitoneal sarcoma changed over time? A study of time trends during the past 15 years. Ann Surg Oncol 2021;28:1700–1709 [DOI] [PubMed] [Google Scholar]

[zraf177-B124] 124. Dossa F, Swallow CJ. Defining resectability criteria for primary retroperitoneal sarcoma: a challenging imperative. Br J Surg 2025;112:znaf044 [DOI] [PubMed] [Google Scholar]

[zraf177-B125] 125. Perhavec A, Provenzano S, Baia M, Sangalli C, Morosi C, Barisella M et al. Inoperable primary retroperitoneal sarcomas: clinical characteristics and reasons against resection at a single referral institution. Ann Surg Oncol 2021;28:1151–1157 [DOI] [PubMed] [Google Scholar]

[zraf177-B126] 126. Ng D, Acidi B, Johnston W, Callegaro D, Brar S, Gladdy R et al. Why do some patients with non-metastatic primary retroperitoneal sarcoma (RPS) not undergo resection? Can J Surg 2022;65:S100

[zraf177-B127] 127. Stojadinovic A, Yeh A, Brennan MF. Completely resected recurrent soft tissue sarcoma: primary anatomic site governs outcomes. J Am Coll Surg 2002;194:436–447 [DOI] [PubMed] [Google Scholar]

[zraf177-B128] 128. Fairweather M, Wang J, Jo VY, Baldini EH, Bertagnolli MM, Raut CP. Surgical management of primary retroperitoneal sarcomas: rationale for selective organ resection. Ann Surg Oncol 2018;25:98–106 [DOI] [PubMed] [Google Scholar]

[zraf177-B129] 129. Improta L, Pasquali S, Iadecola S, Barisella M, Fiore M, Radaelli S et al. Organ infiltration and patient risk after multivisceral surgery for primary retroperitoneal liposarcomas. Ann Surg Oncol 2023;30:4500–4510 [DOI] [PubMed] [Google Scholar]

[zraf177-B130] 130. Gronchi A, Lo Vullo S, Fiore M, Mussi C, Stacchiotti S, Collini P et al. Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol 2009;27:24–30 [DOI] [PubMed] [Google Scholar]

[zraf177-B131] 131. Bonvalot S, Rivoire M, Castaing M, Stoeckle E, Le Cesne A, Blay JY et al. Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol 2009;27:31–37 [DOI] [PubMed] [Google Scholar]

[zraf177-B132] 132. Gronchi A, Miceli R, Colombo C, Stacchiotti S, Collini P, Mariani L et al. Frontline extended surgery is associated with improved survival in retroperitoneal low- to intermediate-grade soft tissue sarcomas. Ann Oncol 2012;23:1067–1073 [DOI] [PubMed] [Google Scholar]

[zraf177-B133] 133. Pisters PWT. Resection of some—but not all—clinically uninvolved adjacent viscera as part of surgery for retroperitoneal soft tissue sarcomas. J Clin Oncol 2009;27:6–8 [DOI] [PubMed] [Google Scholar]

[zraf177-B134] 134. Raut CP, Swallow CJ. Are radical compartmental resections for retroperitoneal sarcomas justified? Ann Surg Oncol 2010;17:1481–1484 [DOI] [PubMed] [Google Scholar]

[zraf177-B135] 135. Ikoma N, Roland CL, Torres KE, Chiang Y, Wang W, Somaiah N et al. Concomitant organ resection does not improve outcomes in primary retroperitoneal well-differentiated liposarcoma: a retrospective cohort study at a major sarcoma center. J Surg Oncol 2018;117:1188–1194 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B136] 136. Pasquali S, Vohra R, Tsimopoulou I, Vijayan D, Gourevitch D, Desai A. Outcomes following extended surgery for retroperitoneal sarcomas: results from a UK referral centre. Ann Surg Oncol 2015;22:3550–3556 [DOI] [PubMed] [Google Scholar]

[zraf177-B137] 137. Tseng WW, Madewell JE, Wei W, Somaiah N, Lazar AJ, Ghadimi MP et al. Locoregional disease patterns in well-differentiated and dedifferentiated retroperitoneal liposarcoma: implications for the extent of resection? Ann Surg Oncol 2014;21:2136–2143 [DOI] [PubMed] [Google Scholar]

[zraf177-B138] 138. Radaelli S, Baia M, Drohan A, Morosi C, Sangalli C, Colombo C et al. Six surgical stages in the resection of primary right retroperitoneal liposarcoma: a standardized comprehensive approach. Ann Surg Oncol 2023;30:6896–6897 [DOI] [PubMed] [Google Scholar]

[zraf177-B139] 139. Baia M, Dossa F, Radaelli S, Callegaro D, Colombo C, Borghi A et al. Six surgical stages in the resection of primary left retroperitoneal liposarcoma: a standardized comprehensive approach. Ann Surg Oncol 2025;32:7836–7837 [DOI] [PubMed] [Google Scholar]

[zraf177-B140] 140. MacNeill AJ, Gronchi A, Miceli R, Bonvalot S, Swallow CJ, Hohenberger P et al. Postoperative morbidity after radical resection of primary retroperitoneal sarcoma: a report from the transatlantic RPS working group. Ann Surg 2018;267:959–964 [DOI] [PubMed] [Google Scholar]

[zraf177-B141] 141. Fiore M, Brunelli C, Miceli R, Manara M, Lenna S, Rampello NN et al. A prospective observational study of multivisceral resection for retroperitoneal sarcoma: clinical and patient-reported outcomes 1 year after surgery. Ann Surg Oncol 2021;28:3904–3916 [DOI] [PubMed] [Google Scholar]

[zraf177-B142] 142. Bonvalot S, Miceli R, Berselli M, Causeret S, Colombo C, Mariani L et al. Aggressive surgery in retroperitoneal soft tissue sarcoma carried out at high-volume centers is safe and is associated with improved local control. Ann Surg Oncol 2010;17:1507–1514 [DOI] [PubMed] [Google Scholar]

[zraf177-B143] 143. Fairweather M, Jolissaint JS, Fiore M, Strauss D, Bonvalot S, Ford SJ et al. Development of a surgical complexity score to predict postoperative morbidity following primary retroperitoneal sarcoma resection: a collaborative study from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG). Br J Surg 2025;112:znaf029. [DOI] [PubMed] [Google Scholar]

[zraf177-B144] 144. Previtali P, Fiore M, Colombo J, Arendar I, Fumagalli L, Pizzocri M et al. Malnutrition and perioperative nutritional support in retroperitoneal sarcoma patients: results from a prospective study. Ann Surg Oncol 2020;27:2025–2032 [DOI] [PubMed] [Google Scholar]

[zraf177-B145] 145. Kirov KM, Xu HP, Crenn P, Goater P, Tzanis D, Bouhadiba MT et al. Role of nutritional status in the early postoperative prognosis of patients operated for retroperitoneal liposarcoma (RLS): a single center experience. Eur J Surg Oncol 2019;45:261–267 [DOI] [PubMed] [Google Scholar]

[zraf177-B146] 146. Samà L, Kumar S, Covello E, D’Orazio F, Pindilli S, Levi R et al. Nutritional status in retroperitoneal sarcoma: implication of prognostic nutritional index (PNI) and skeletal muscle index (SMI) on postoperative and oncological outcomes. Clin Nutr ESPEN 2025;69:167–176 [DOI] [PubMed] [Google Scholar]

[zraf177-B147] 147. Baia M, Zanframundo C, Ljevar S, Della Valle S, Misotti A, Rampello NN et al. Preoperative nutritional support to tackle morbidity in multivisceral resection for retroperitoneal sarcoma. Early outcomes from a novel nutritional prehabilitation program in a prospective cohort. Eur J Surg Oncol 2024;50:108663. [DOI] [PubMed] [Google Scholar]

[zraf177-B148] 148. Tirotta F, Fiore M, Bonvalot S, Strauss D, Rutkowski P, Gyorki DE et al. Defining benchmark values for outcomes of comprehensive resection of primary retroperitoneal liposarcoma: a retrospective multicenter study. EClinicalMedicine 2025;84:103280. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B149] 149. Hull MA, Niemierko A, Haynes AB, Jacobson A, Chen Y-L, DeLaney TF et al. Post-operative renal function following nephrectomy as part of en bloc resection of retroperitoneal sarcoma (RPS). J Surg Oncol 2015;112:98–102 [DOI] [PubMed] [Google Scholar]

[zraf177-B150] 150. Callegaro D, Miceli R, Brunelli C, Colombo C, Sanfilippo R, Radaelli S et al. Long-term morbidity after multivisceral resection for retroperitoneal sarcoma. Br J Surg 2015;102:1079–1087 [DOI] [PubMed] [Google Scholar]

[zraf177-B151] 151. Baia M, Drohan A, Radaelli S, Callegaro D, Colombo C, Borghi A et al. Resection of primary leiomyosarcoma of the inferior vena cava and reconstruction with a cadaveric homograft. Ann Surg Oncol 2025;32:2979–2980 [DOI] [PubMed] [Google Scholar]

[zraf177-B152] 152. Seidensaal K, Dostal M, Kudak A, Jaekel C, Meixner E, Liermann J et al. Preoperative dose-escalated intensity-modulated radiotherapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft-tissue sarcoma: final results of a clinical phase I/II trial. Cancers (Basel) 2023;15:2747. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B153] 153. Sindelar WF, Kinsella TJ, Chen PW, Delaney TF, Tepper JE, Rosenberg SA et al. Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Arch Surg 1993;128:402–410 [DOI] [PubMed] [Google Scholar]

[zraf177-B154] 154. Pisters Pwt, Ballo MT, Fenstermacher MJ, Feig BW, Hunt KK, Raymond KA et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol 2003;21:3092–3097 [DOI] [PubMed] [Google Scholar]

[zraf177-B155] 155. Jones JJ, Catton CN, Sullivan O’, Couture B, Heisler J, Kandel RL et al. Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 2002;9:346–354 [DOI] [PubMed] [Google Scholar]

[zraf177-B156] 156. Smith Mjf, Ridgway PF, Catton CN, Cannell AJ, Sullivan O’, Mikula B et al. Combined management of retroperitoneal sarcoma with dose intensification radiotherapy and resection: long-term results of a prospective trial. Radiother Oncol 2014;110:165–171 [DOI] [PubMed] [Google Scholar]

[zraf177-B157] 157. Fairweather M, Wang J, Devlin PM, Hansen J, Baldini EH, Ready JE et al. Safety and efficacy of radiation dose delivered via iodine-125 brachytherapy mesh implantation for deep cavity sarcomas. Ann Surg Oncol 2015;22:1455–1463 [DOI] [PubMed] [Google Scholar]

[zraf177-B158] 158. Dziewirski W, Rutkowski P, Nowecki ZI, Sałamacha M, Morysiński T, Kulik A et al. Surgery combined with intraoperative brachytherapy in the treatment of retroperitoneal sarcomas. Ann Surg Oncol 2006;13:245–252 [DOI] [PubMed] [Google Scholar]

[zraf177-B159] 159. Paryani NN, Zlotecki RA, Swanson EL, Morris CG, Grobmyer SR, Hochwald SN et al. Multimodality local therapy for retroperitoneal sarcoma. Int J Radiat Oncol Biol Phys 2012;82:1128–1134 [DOI] [PubMed] [Google Scholar]

[zraf177-B160] 160. Ballo MT, Zagars GK, Pollock RE, Benjamin RS, Feig BW, Cormier JN et al. Retroperitoneal soft tissue sarcoma: an analysis of radiation and surgical treatment. Int J Radiat Oncol Biol Phys 2007;67:158–163 [DOI] [PubMed] [Google Scholar]

[zraf177-B161] 161. Bishop AJ, Zagars GK, Torres KE, Hunt KK, Cormier JN, Feig BW et al. Combined modality management of retroperitoneal sarcomas: a single-institution series of 121 patients. Int J Radiat Oncol Biol Phys 2015;93:158–165 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B162] 162. Zlotecki RA, Katz TS, Morris CG, Lind DS, Hochwald SN. Adjuvant radiation therapy for resectable retroperitoneal soft tissue sarcoma: the University of Florida experience. Am J Clin Oncol 2005;28:310–316 [DOI] [PubMed] [Google Scholar]

[zraf177-B163] 163. Le Péchoux C, Musat E, Baey C, Al Mokhles H, Terrier P, Domont J et al. Should adjuvant radiotherapy be administered in addition to front-line aggressive surgery (FAS) in patients with primary retroperitoneal sarcoma? Ann Oncol 2013;24:832–837 [DOI] [PubMed] [Google Scholar]

[zraf177-B164] 164. Pezner RD, Liu A, Chen Y-J, Smith DD, Paz IB. Full-dose adjuvant postoperative radiation therapy for retroperitoneal sarcomas. Am J Clin Oncol 2011;34:511–516 [DOI] [PubMed] [Google Scholar]

[zraf177-B165] 165. Gilbeau L, Kantor G, Stoeckle E, Lagarde P, Thomas L, Kind M et al. Surgical resection and radiotherapy for primary retroperitoneal soft tissue sarcoma. Radiother Oncol 2002;65:137–143 [DOI] [PubMed] [Google Scholar]

[zraf177-B166] 166. Bonvalot S, Gronchi A, Le Péchoux C, Swallow CJ, Strauss D, Meeus P et al. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2020;21:1366–1377 [DOI] [PubMed] [Google Scholar]

[zraf177-B167] 167. Callegaro D, Raut CP, Ajayi T, Strauss D, Bonvalot S, Ng D et al. Preoperative radiotherapy in patients with primary retroperitoneal sarcoma: EORTC-62092 trial (STRASS) versus off-trial (STREXIT) results. Ann Surg 2023;278:127–134 [DOI] [PubMed] [Google Scholar]

[zraf177-B168] 168. Lambdin J, Ryan C, Gregory S, Cardona K, Hernandez JM, van Houdt WJ et al. A randomized phase III study of neoadjuvant chemotherapy followed by surgery versus surgery alone for patients with high-risk retroperitoneal sarcoma (STRASS2). Ann Surg Oncol 2023;30:4573–4575 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B169] 169. Kedra A, Dohan A, Biau D, Belbachir A, Dautry R, Lucas A et al. Preoperative arterial embolization of musculoskeletal tumors: a tertiary center experience. Cancers (Basel) 2023;15:2657. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B170] 170. Reijers SJM, Davies E, Grünhagen DJ, Fiore M, Honore C, Rastrelli M et al. Variation in response rates to isolated limb perfusion in different soft-tissue tumour subtypes: an international multi-centre study. Eur J Cancer 2023;190:112949. [DOI] [PubMed] [Google Scholar]

[zraf177-B171] 171. Hayes AJ, Coker DJ, Been L, Boecxstaens VW, Bonvalot S, De Cian F et al. Technical considerations for isolated limb perfusion: a consensus paper. Eur J Surg Oncol 2024;50:108050. [DOI] [PubMed] [Google Scholar]

[zraf177-B172] 172. Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem B-C 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;11:561–570 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B173] 173. Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P et al. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncol 2018;4:483–492 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B174] 174. Angele MK, Albertsmeier M, Prix NJ, Hohenberger P, Abdel-Rahman S, Dieterle N et al. Effectiveness of regional hyperthermia with chemotherapy for high-risk retroperitoneal and abdominal soft-tissue sarcoma after complete surgical resection: a subgroup analysis of a randomized phase-III multicenter study. Ann Surg 2014;260:749–754. discussion 754-746 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zraf177-B175] 175. Campana LG, Kis E, Bottyán K, Orlando A, de Terlizzi F, Mitsala G et al. Electrochemotherapy for advanced cutaneous angiosarcoma: a European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT). Int J Surg 2019;72:34–42 [DOI] [PubMed] [Google Scholar]

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Diagnosis and treatment of primary soft tissue sarcomas: comprehensive review

Fahima Dossa

Eldad Elnekave

Aisha B Miah

Catherine Mitchell

Sarah Watson

Alessandro Gronchi

Marco Fiore

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Results

STS guidelines

Table 1.

Diagnostic considerations for STS

Local staging

Biopsy and histopathological assessment

Fig. 1.

Distant staging

Importance of high-volume centres

Treatment of extremity STS

Surgery

Radiation

Table 2.

Chemotherapy

Immunotherapy

Treatment of retroperitoneal STS

Surgery

Fig. 2.

Fig. 3.

Radiation

Chemotherapy

Locoregional adjuncts for the treatment of STS

Transarterial embolization

Isolated limb perfusion

Regional hyperthermia

Electroporation

Future challenges

Conclusion

Contributor Information

Funding

Author contributions

Disclosures

Data availability

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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