Soft Tissue Sarcoma Guidelines

The consideration of soft tissue sarcoma (STS) as a single entity is a matter of necessity to enable clinical study of these exceedingly rare diseases. Their wide range of natural history and biologic behavior makes it exceedingly difficult to establish management guidelines that account for the nuances of individual clinical presentations. With over 50 distinct histologic subtypes, STS requires physicians to adapt guidelines to fit the clinical features of each patient’s disease. However, certain principles serve as cornerstones for multimodality management of STS when applied in the context of a highly individualized patient and tumor assessment.

While the overwhelming majority of STS cases are sporadic, rare cases involve a genetic predisposition. The National Comprehensive Cancer Network (NCCN) Soft Tissue Sarcoma Panel specifically identifies Li-Fraumeni syndrome and familial adenomatous polyposis (FAP) as genetic cancer syndromes with a predisposition for the development of STS, along with Carney-Stratakis syndrome, which is associated with gastrointestinal stromal tumors (GISTs) and paragangliomas. Patients with hereditary retinoblastoma and neurofibromatosis (NF1 and NF2) are also at increased risk of developing STS. NCCN recommendations for genetic testing include the following ^[1] :

• Patients with a personal or family history of Li-Fraumeni syndrome or FAP should be considered for genetic testing and assessment
• Patients diagnosed with desmoid tumors (aggressive fibromatoses) should be evaluated for family history of FAP or Gardner syndrome
• In patients with GISTs lacking  KIT or  PDGFRA mutations (wild-type GISTs), succinate dehydrogenase ( SDH) gene mutational analysis should be considered; loss of SDHB protein expression by immunohistochemistry is a useful screen to identify patients who would be candidates for germline mutation testing, but it is not diagnostic of a germline mutation

Li-Fraumeni syndrome most commonly results from mutations in the TP53 gene. European Society for Medical Oncology (ESMO) guidelines, developed in partnership with EURACAN (European Reference Network for Rare Adult Solid Cancers) and GENTURIS (European Reference Network for Genetic Tumour Risk Syndromes), recommend performing germline TP53 testing—if possible, before initiation of treatment—in the following ^[6] :

• Patients < 46 years of age with STS and at least one first- or second-degree relative < 56 years of age with a  TP53 core tumor (breast cancer, STS, bone sarcoma, central nervous system tumour, adrenocortical carcinoma)
• Patients with STS (especially in radiation therapy fields) and with another  TP53 core tumor < 46 years of age

ESMO advises that radiation therapy should be avoided if possible in TP53 mutations carriers, after multidisciplinary discussion, and annual whole-body magnetic resonance imaging (MRI) is recommended. ^[6]

WHO Classification of Tumors

The World Health Organization classification system for tumors of the soft tissue and bone incorporates detailed cytogenetic and molecular data into the classifications. ^[2] Tumors are further classified as benign, intermediate, or malignant, and intermediate tumors are designated as either locally aggressive or rarely metastasizing.

Gastrointestinal stromal tumors (GISTs) are included, with three subtypes:

• Benign
• Uncertain malignant potential
• Malignant

A chapter on undifferentiated/unclassified sarcomas includes the following subtypes:

• Undifferentiated spindle cell sarcoma
• Undifferentiated pleomorphic sarcoma (previously classified as malignant fibrous histiocytoma)
• Undifferentiated round cell sarcoma
• Undifferentiated epithelioid sarcoma
• Undifferentiated sarcoma not otherwise specified

Tumor Grading Systems

The French Federation of Cancer Centers Sarcoma Group (FNCLCC) system ^[3] and the National Cancer Institute system are most commonly used for grading STS. ^[4] Both are three-grade systems. The FNCLCC is based on tumor differentiation, tumor necrosis, and mitotic activity, while the NCI system bases the evaluation on histology, location, and tumor necrosis. In comparison studies, the FNCLCC has shown slightly better ability to predict metastasis development and mortality.

Tumor Staging

The NCCN follows the tumor-node-metastasis (TNM) classification of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) for staging of STS. ^[1] The European Society for Medical Oncology (ESMO) considers the AJCC/UICC classifications of limited clinical value and recommends the use of validated nomograms ^{[13, 14, 15]} to personalize risk assessment and aid clinical decision making, especially regarding the benefit of adjuvant/neoadjuvant treatment. ^[6]

Anatomic stage/prognostic groupings for STS are detailed in Tables 1 and 2, below. ^[5]

 

Table 1. Staging of Soft Tissue Sarcomas of the Trunk and Extremities (Open Table in a new window)

For description of TNM designations, see Soft Tissue Sarcoma Staging.

Table 2. Staging of Retroperitoneal Sarcomas (Open Table in a new window)

GISTs are staged separately from other sarcomas. Primary T stage is determined by tumor size. Histologic grade is replaced by mitotic activity and a cutoff of 5 mitoses per 5 mm² stratifies low vs high mitotic rate (low mitotic rate, ≤5 mitoses per 5 mm²; high mitotic rate: > 5 mitoses per 5 mm²). GISTs arising primarily from the omentum should be staged according to the gastric GIST staging, while GISTs arising from all other sites should be staged according to the small intestinal group staging. Anatomic stage/prognostic groupings for GIST are detailed in Tables 3 and 4, below. ^[5]

 

Table 3. Staging of Gastric and Omental Gastrointestinal Stromal Tumors (Open Table in a new window)

Table 4. Staging of Small Intestine, Esophageal, Colorectal, Mesenteric, and Peritoneal Gastrointestinal Stromal Tumors (Open Table in a new window)

For description of GIST TNM designations, see Gastrointestinal Stromal Tumors (GISTs) Staging.

Diagnosis

The National Comprehensive Cancer Network (NCCN) workup for STS of the extremities, superficial trunk, or head and neck includes evaluation and management prior to initiation of therapy by a multidisciplinary team with expertise and experience in sarcoma. ^[1] The European Society for Medical Oncology (ESMO) guidelines concur and recommend referral of all patients with any unexplained deep soft tissue mass, or any superficial soft tissue lesion larger than 5 cm, to a center that specializes in the treatment of STS. ^[6]

The NCCN guidelines recommend the following as essential aspects of the workup ^[1] :

• History and physical examination (H&P) 
• Adequate imaging of primary tumor for all lesions with a reasonable chance of being malignant
• Carefully planned core needle (preferred) or open incisional biopsy (may be considered by an experienced surgeon) after adequate imaging; biopsy should be placed along future resection axis with minimal dissection and careful attention to hemostasis, and should establish grade and histologic subtype
• Imaging studies that include cross-sectional imaging MRI, with or without CT scanning for tumor details, including size and contiguity to nearby visceral structures; additional studies may be warranted in individual situations
• Ancillary diagnostic methodologies (eg, immunohistochemistry, classical cytogenetics, electron microscopy, molecular genetic testing) as appropriate
• Chest imaging

Overall, the ESMO guidelines are in agreement with NCCN. ESMO recommendations for imaging in diagnosis of primary STS in the extremities, pelvis, and trunk include the following ^[6] :

• MRI is the main imaging modality.
• Standard radiographs may be useful to rule out a bone tumor, detect bone erosion with a risk of fracture, and show calcifications.
• CT has a role in calcified lesions; to rule out a myositis ossificans; in pleuropulmonary sarcomas; and in retroperitoneal sarcomas, where its performance is identical to that of MRI.
• Ultrasound may be used as first-line imaging, but if there is any suspicion for STS it should be followed by CT or MRI.

Treatment

NCCN treatment recommendations for localized low-grade disease (stage IA, IB) are as follows ^[1] :

• Surgical resection is definitive treatment if margins are >1 cm or the fascial plane is intact.
• Re-resection may be necessary when margins are ≤1 cm and are without an intact fascial plane.
• Postoperative radiation therapy should be considered if final surgical margins are ≤1 cm and without an intact fascial plane (category 2B  for stage IA; category 1 for stage B tumors).
• Radiation therapy may be unnecessary with low-grade lesions ≤5 cm because local recurrence is infrequent and observation is an option.
• The patient should undergo evaluation for rehabilitation therapy to achieve maximal function.
• Follow-up includes a history and physical examination every 3-6 months for 2-3 years and then annually thereafter. After 10 years, likelihood of recurrence is small and follow-up should be individualized by subtype.
• Consider chest imaging and baseline/follow-up imaging of the primary site, based on histology.

Initial resection margins and decisions concerning re-resection should be tailored to individual subtype biologic features. For example, a well-differentiated liposarcoma or atypical lipomatous tumor may be adequately treated with a 1 cm margin or less. In contrast, a widely infiltrative dermatofibrosarcoma protuberans, myxofibrosarcoma, or angiosarcoma would require far wider resection margins to ensure adequate treatment, due to the locally infiltrative nature of these subtypes.

For extremity STS, the goal should be preservation of limb function to the extent that is possible without compromising appropriate oncologic resection. Prior to considering an amputation, patients should be evaluated by a multidisciplinary team with expertise in STS. Dissection should be through grossly normal tissue planes not involved with tumor. Radical compartmental approaches are not routinely required and offer no benefit in overall or disease-free survival. Close margins may be necessary to preserve critical structures and hence function and quality of life.

For stage II-III disease, the NCCN recommends that treatment options should be decided on the basis of the patient’s age, performance status, and comorbidities, as well as the location and histologic subtype of the tumor. NCCN treatment recommendations for these cases (with acceptable functional outcomes) are as follows ^[1] :

• Surgical resection and preoperative and postoperative radiation therapy (category 1 for stage IIA)
• Adjuvant chemotherapy in addition to postoperative radiation therapy may be considered for stage IIB/III
• Stage IIA: Preoperative radiation therapy and surgical resection is an alternative treatment option, depending on the location and resectability of the tumor, as well as histologic subtype
• Stage IIB/III: Preoperative radiation therapy or chemoradiation are options; postoperative radiation therapy boost with or without adjuvant chemotherapy may also be considered; Preoperative chemotherapy and postoperative radiation therapy with or without adjuvant chemotherapy is also an option
• For high-grade resectable tumors > 8 cm, preoperative and postoperative therapy may be considered
• Regional lymph node dissection for patients with stage III tumors with lymph node involvement
• Evaluation for rehabilitation therapy to achieve maximal function
• H&P every 3-6 months for 2-3 years and then annually thereafter; after 10 years, likelihood of recurrence is small and follow-up should be individualized by subtype
• Consider chest imaging and baseline/follow-up imaging of primary site based on histology

NCCN treatment recommendations for stage II-III disease and select stage IV disease (any T, N1, M0) that is resectable with adverse functional outcomes, and unresectable primary disease, are as follows ^[1] :

• Radiation therapy, chemoradiation, or chemotherapy
• Surgical resection for tumors that become resectable with acceptable functional outcome after neoadjuvant treatment and postoperative radiation therapy (if radiation therapy is not given preoperatively), with or without postoperative chemotherapy
• Positron emission tomography/computed tomography (PET/CT) may be useful for large (> 3 cm), deep tumors of certain histologic subtypes to assess response to neoadjuvant chemotherapy; patients with a change in the maximum standardized uptake value (SUVmax) in response to neoadjuvant therapy are at lower risk of recurrence and death following resection
• For tumors that remain unresectable or without acceptable functional outcome following primary treatment, observation is an option for asymptomatic patients; symptomatic patients may be treated with chemotherapy, palliative surgery, amputation/radical resection, or best supportive care
• Limb-sparing regional limb infusion therapy may be considered as an option for unresectable tumors only if treated at a center with experience in isolated limb perfusion or infusion
• Evaluation for rehabilitation therapy to achieve maximal function
• H&P every 3-6 months for 2-3 years and then annually thereafter; after 10 years, likelihood of recurrence is small and follow-up should be individualized by subtype.
• Consider chest imaging and baseline/follow-up imaging of primary site based on histology

The ESMO guidelines state that surgery is the standard treatment for all patients with an adult-type, localized STS. It must be carried out by a surgeon specifically trained in the treatment of this disease within a sarcoma center/network. The standard surgical procedure is an en bloc excision with R0 margins, but R1 excision can be acceptable in carefully selected cases; in particular, marginal excisions along the pseudocapsule are advised for atypical lipomatous tumors. ^[6]

The ESMO guidelines provide treatment recommendations for localized, clinically resectable STS of the extremity and superficial trunk on the basis of STS grade, as follows ^[6] :

• Grade 1 – Surgery, with R0 resection if feasible; radiation therapy (RT) is optional, depending upon histology and anatomic location, and may be administered either preoperatively or postoperatively.
• Grade 2-3, high risk – Optional RT, with or without chemotherapy; surgery; postoperative RT (if not given preoperatively) and/or chemotherapy are optional; in cases of R1 resection where R0 re-resection not feasible, RT is indicated if not given preoperatively

For localized extremity and superficial trunk STS that is clinically unresectable, ESMO guidelines recommend chemotherapy with or without RT, or RT; if R0/R1 resection becomes feasible, surgery with or without RT is recommended; if not, treatment is as for advanced disease.

NCCN treatment recommendations for stage IV/metastatic disease and unresectable disease are as follows ^[1] :

• Patients should be referred to a multidisciplinary team with extensive experience in the treatment of STS.
• Treatment options should be based on performance status, patient preferences, specific clinical problems from the metastases and treatment availability.
• Enrollment in a clinical trial is recommended.
• For patients with single-organ or resectable stage IV disease, metastasectomy may be considered in conjunction with preoperative or postoperative chemotherapy with or without radiation. Ablative and intra-arterial modalities may be considered, depending on disease anatomy and tumor burden and patient comorbidities.
• Symptomatic patients with disseminated disease may be treated with palliative measures, including radiation, surgery, or chemotherapy.

ESMO recommendations for advanced or metastatic, clinically resectable STS with isolated metastases are as follows ^[6] :

• Complete resection feasible: Surgery, with postoperative chemotherapy optional
• Complete resection feasible, and high risk: Optional preoperative chemotherapy, surgery, optional postoperative chemotherapy

For advanced or metastatic, clinically unresectable STS (eg, with multiple metastases), ESMO guidelines recommend chemotherapy with doxorubicin, alone or in combination with ifosfamide or dacarbazine. In patients with partial response or stable disease, chemotherapy is continued until maximum dose progression or unacceptable toxicity; patients with unresponsive disease should receive histology-driven chemotherapy

Systemic therapy regimens

The NCCN and ESMO guidelines provide similar recommendations for chemotherapy regimens. ^{[1, 6]}

ESMO recommendations regarding chemotherapy regimens include the following:

• Standard chemotherapy is based on anthracyclines as first-line treatment. Multi-agent chemotherapy with either adequate-dose anthracycline plus ifosfamide or dacarbazine may be the treatment of choice, particularly in subtypes sensitive to ifosfamide or dacarbazine, when a tumor response is felt to be potentially advantageous and patient performance status is good.
• Gemcitabine-docetaxel is not generally recommended as a first-line therapy for advanced STS.
• Imatinib is standard medical therapy for patients with dermatofibrosarcoma protuberans.
• NTRK inhibitors (eg, larotrectinib, entrectinib) are standard treatment for advanced NTRK-rearranged sarcomas and can be considered also in the preoperative setting, when cytoreduction can improve morbidity and function.
• Trabectedin is an option in advanced STS for second-line and subsequent treatment (category 1 recommendation for liposarcoma and leiomyosarcoma, category 2A for other subtypes.
• Pazopanib is an option in non-adipogenic STS in second-line and subsequent treatment (patients ineligible for IV systemic therapy or patients who are not candidates for anthracycline-based therapy).
• Eribulin is a category 1 option in patients with liposarcomas and category 2A for other subtypes.
• Dacarbazine plus gemcitabine, or gemcitabine plus docetaxel, is an option in doxorubicin-pretreated patients.

Similarly, the NCCN recommends the following anthracycline-based regimens as first-line agents for advanced or metastatic STS ^[1] :

• Doxorubicin
• Epirubicin
• Liposomal doxorubicin
• AD (doxorubicin, dacarbazine
• AIM (doxorubicin, ifosfamide,mesna)
• Ifosfamide, epirubicin, mesna

For NTRK gene fusion–positive STS only, the NCCN recommends larotrectinib or entrectinib.

Diagnosis

The National Comprehensive Cancer Network (NCCN) guidelines for intra-abdominal sarcomas recommend evaluation and management prior to initiation of therapy by a multidisciplinary team with expertise and experience in sarcoma. A pretreatment chest/abdominal/pelvic CT scan with intravenous contrast, with or without MRI, is also indicated.

Pre-resection biopsy is not necessarily required, based on degree of suspicion of other malignancies. Image-guided core needle biopsy is required for patients receiving preoperative radiation therapy (RT) or chemotherapy, because the treatment regimen is selected on the basis of the histologic subtype. ^[1]

The ESMO guidelines also include a recommendation for functional assessment of the contralateral kidney. In addition, ESMO considers a pretreatment core biopsy to be required but cautions against open or laparoscopic biopsy. ^[6]

Treatment

For resectable disease, NCCN recommends surgery with or without intraoperative RT; preoperative therapy with RT (in patients at high risk for recurrence) and chemotherapy as options. ^[1] Dissection should be through grossly normal tissue planes not involved with tumor. Radical compartmental approaches are not routinely required. Close margins may be necessary to preserve critical structures and hence function and quality of life.

Patients with clinical pathologic findings shown below should receive appropriate adjuvant therapy per NCCN guidelines. However, the follow-up recommendations remain the same which are:

• R0: Consider adjuvant systemic therapy in patients at high risk for metastatic disease
• R1: Adjuvant RT should not be administered routinely, except in highly selected patients and unless local recurrence would cause undue morbidity
• R2: As per R1, but consider re-resection if it can be done safely

Recommended follow-up includes a physical exam with imaging every 3-6 months for 2-3 years then every 6 months for the next 2 years then annually.

For unresectable or stage IV disease, the NCCN recommends the following as options:

• Observation, if the patient is asymptomatic and the tumor biology is indolent
• Systemic therapy (eg, doxorubicin/ifosfamide/mesna) and/or RT
• Surgery for symptom control

Patients who receive chemotherapy and/or RT should undergo imaging to assess treatment response, followed by resection if feasible. The NCCN advises always considering the resection of resectable metastatic disease if the primary tumor can be controlled. If the disease is still unresectable after neoadjuvant therapy or is progressive, the NCCN recommends palliative or best supportive care. ^[1]

ESMO recommendations are as follows ^[6] :

• Standard treatment of retroperitoneal sarcoma consists of surgical resection en bloc with adherent organs.
• Neoadjuvant treatment can be considered in technically unresectable/borderline resectable cases that could be converted to resectability by downsizing, and in chemosensitive histologies such as synovial sarcoma. Neoadjuvant treatment may take the form of chemotherapy, external beam RT (EBRT), regional hyperthermia or combinations thereof.
• Neoadjuvant RT has shown signs of efficacy in primary low-intermediate-grade retroperitoneal liposarcoma however, preoperative RT should not be considered standard of care treatment in primary retroperitoneal sarcoma ^[16] .
• Intraoperative/postoperative RT is of no proven value in retroperitoneal sarcoma. The role of adjuvant/neoadjuvant chemotherapy is not yet established.

Decisions concerning adjuvant RT and re-resection must be tailored to specific histologic subtypes. Intraoperative placement of radio-opaque markers may assist adjuvant RT planning.

Diagnosis

The NCCN guidelines for gastrointestinal stromal tumors (GISTs) recommend evaluation and management, prior to initiation of therapy, by a multidisplinary team with expertise and experience in sarcoma. Abdominal/pelvic CT scan with contrast, with or without MRI, is also indicated and chest imaging should be considered. Very small GISTs (< 2 cm) may be evaluated with endoscopic ultrasound (EUS)-guided fine-needle aspiration; for GISTs 2 cm or larger, endoscopy with or without ultrasound may also be indicated in select patients. ^[1]

Genetic testing for KIT and PDGFRA is a strong recommendation, and in the absence of KIT or PDGFRA mutations, testing for loss of SDHB protein expression by immunohistochemistry should be considered.  If SDHB expression is lost, then genetic counseling and germline mutation testing in SDH genes should be considered. In patients with advanced GISTs, identification of specific KIT and PDGFRA mutations helps predict responsiveness to imatinib and the possible benefit of a higher imatinib dose. ^[1]

SDH-deficient GISTs represent approximately 10% of gastric GISTs and 5-7.5% of all GISTs overall. Wild-type GISTs, including SDH-deficient GISTs, occur more often in children than in adults. The prognosis and biological behavior of SDH-deficient GISTs differ from that of KIT and PDGFRA GISTs, and their management should therefore vary accordingly. Given that these tumors lack the tyrosine kinase mutation, their response to imatinib is poor, and surgery is the mainstay of treatment. ^{[7, 8]}

ESMO guidelines include the following recommendations ^[9] :

• EUS assessment is the standard approach for patients with esophagogastric or duodenal nodules < 2 cm.
• If a GIST is diagnosed on biopsy, resection is performed unless the clinician expects major morbidity. If a biopsy is not feasible, active surveillance is a valid alternative.
• Biopsy/excision is the standard approach to tumors ≥ 2 cm in size.
• Mutational analysis should be considered a standard part of the diagnostic work-up of all GISTs (with the possible exclusion of < 2 cm nonrectal GISTs).

Treatment

NCCN treatment recommendations for localized resectable disease include the following ^[6] :

• Surgical resection is the primary treatment.
• For tumors < 2 cm with no high-risk features, consider periodic endoscopic surveillance.
• Preoperative treatment with imatinib may prevent accurate assessment of recurrence risk; consider preoperative imatinib only for marginally resectable or initially unresectable tumors, where surgical morbidity could be reduced by downstaging the tumor preoperatively.
• Testing the tumor to ensure it has a mutation that is likely to respond to imatinib (especially  KIT exon 11) is recommended prior to starting preoperative imatinib.
• Consider postoperative imatinib for at least 36 months for high-risk tumors.

ESMO guidelines include the following treatment recommendations ^[9] :

• The standard treatment of localized GISTs is complete surgical excision of the lesion, with no dissection of clinically negative lymph nodes. R0 excision is the goal (ie, margins are clear of tumor cells at least at the site of origin in the GI tract).
• If laparoscopic excision is planned, the technique needs to follow the principles of oncological surgery.
• In low-risk GISTs located in unfavorable locations, the decision can be made with the patient to accept possibly R1 (microscopically positive) margins.
• Adjuvant therapy with imatinib 400 mg/day for 3 years is the standard treatment for patients with a significant risk of relapse.
• In the case of  KIT exon 9 mutation, adjuvant imatinib at a higher dose of 800 mg daily for 3 years may be considered.
• PDGFRA exon 18  D842V–mutated GISTs show poor response to imatinib.
• Adjuvant treatment should be avoided in NF1-related and SDH expression–negative GISTs.
• Patients at a very high risk of relapse due to tumor rupture at the time of surgery should be considered for adjuvant imatinib therapy.
• If R0 surgery is not feasible or implies major sequelae and the tumor harbors a sensitive mutation, preoperative treatment with imatinib is standard. In cases of  PDGFRA-D842V mutation, neoadjuvant avapritinib may be considered.

NCCN treatment recommendations for unresectable or metastatic disease include the following ^[6] :

• Imatinib (category 1); initial standard dosage is 400 mg/day; this may be increased to 800 md/day if progression is observed ^[1]
• After assessment of therapeutic effect, resection may be considered or imatinib may be continued if resection is not feasible. Treatment for more than 6 months may be required to elicit maximal response to imatinib.
• Continuous daily dosing of sunitinib for patients with imatinib-resistant GIST
• Regorafenib (category 1) for patients with disease progression on imatinib and sunitinib
• Tyrosine kinase inhibitor (TKI) therapy should be continued as long as patients are receiving clinical benefit (response or stable disease)
• Palliative RT (category 2B) for symptomatic lesions.
• Continuation of TKI therapy lifelong for palliation of symptoms is an essential component of best supportive care
• Resection or ablative therapy may be considered in cases of focal or limited progression

ESMO treatment recommendations for advance or metastatic GISTs include the following ^[9] :

• Imatinib is the standard first-line treatment for locally advanced, inoperable, and metastatic cases, except for GIST without  KIT/PDGFRA mutations or with a  PDGFRA exon 18 D842V mutation. The standard dose of imatinib is 400 mg daily.
• Imatinib is also the standard treatment for patients with metastatic disease who have had all lesions removed surgically and whose tumor harbors a sensitive genotype, although surgery is not recommended as a primary approach in the metastatic setting.
• Standard first-line treatment for patients with  KIT exon 9 mutation is imatinib 800 mg daily.
• Standard first-line treatment for patients with  PDGFRA exon 18 D842V mutations is avapritinib 300 mg daily.
• In the metastatic setting, treatment should be continued indefinitely, unless intolerance or specific patient request to interrupt. Surgery of residual metastatic disease should be individualized.
• Surgical excision of progressing disease should be considered for individual patients with limited progression, while continuing imatinib. In the case of tumor progression on 400 mg of imatinib, the dose can be increased to 800 mg daily (with the exception of insensitive mutations).
• In the case of confirmed progression or rare intolerance on imatinib, standard second-line treatment is sunitinib 50 mg daily 4 weeks on/2 weeks off, or 37.5 mg once daily.
• Regorafenib, 160 mg daily for 3 out of every 4 weeks, is the standard third-line therapy for patients progressing on or failing to respond to imatinib and sunitinib.
• Ripretinib 150 mg daily is the standard fourth-line treatment in patients progressing on or intolerant to imatinib, sunitinib, regorafenib.
• SDH-deficient GISTs are insensitive to imatinib but can have some sensitivity to sunitinib and regorafenib.
• NTRK-rearranged GISTs are sensitive to treatment with NTRK inhibitors (eg, larotrectinib, entrectinib).
• BRAF-mutated GISTs benefit from BRAF inhibitors (including BRAF–MEK inhibitor combinations).
• Rechallenge with imatinib (if the patient has already been exposed with evidence of response) or continuation of treatment beyond progression is an option.
• RT may be considered as a palliative resource for selected patients.

Sarcoma specialists from the United Kingdom, including members of the British Sarcoma Group and NHS England Sarcoma Clinical Reference Group, issued guidelines on management of STS in 2016. ^[10]

Clinical presentation, referral, and assessment

Recommendations are as follows:

• Any patient with a soft tissue mass that is increasing in size or is >5 cm, whether or not painful, should be referred either for an urgent ultrasound scan or directly to a sarcoma diagnostic center.
• If the ultrasound scan does not definitively confirm benign pathology, the patient should be referred for further investigation on an urgent suspected cancer referral pathway.
• Any retroperitoneal or intra-abdominal mass with an imaging appearance suggestive of an STS should be referred to a specialist center before biopsy or surgical treatment.
• All patients with a suspected STS should be managed by a specialist sarcoma multidisciplinary team, as specified in the National Institute for Health and Clinical Excellence (NICE) guidance.
• Ultrasound scan by a musculoskeletal radiologist should be considered as the first-line investigation and may be supplemented by ultrasound-guided core biopsy.
• Magnetic resonance imaging and core needle biopsy are recommended prior to definitive surgery.
• Imaging of the thorax by computed tomography scan for lung metastases should be done before radical treatment; further staging may be considered depending on subtype and location of the sarcoma.

Management of localized disease

Recommendations are as follows:

• Surgery is the standard treatment for most patients with localized soft tissue sarcoma.
• For patients with resectable disease, a wide excision through normal uninvolved tissues is the surgical procedure of choice.
• The definition of what constitutes a wide margin is controversial, but with the addition of adjuvant radiation therapy (RT), a close but tumor-free margin (R0) may be adequate.
• Where a wide excision is not possible due to anatomic constraints, a planned marginal or microscopically positive margin 

The Trans-Atlantic Retroperitoneal Sarcoma Working Group was established in 2013 to address challenging management issues encountered when caring for patients with retroperitoneal soft tissue sarcomas (RPS). ^[11] The working group mainly addresses primary RPS that is non-visceral in origin. Desmoid tumors and gastrointestinal stromal tumors (GISTs) are not addressed by the working group.

Clinical presentation, referral, and assessment

Recommendations are as follows:

• Review of cross-sectional imaging by a dedicated tumor board is required.
• CT of the chest, abdomen, and pelvis with intravenous contrast is the preferred imaging modality. MRI is an option for patients with contrast allergy, for pelvic tumors, or for cases in which detailed anatomic information (eg, sciatic foramen) is required.
• Functional assessment of the contralateral kidney is generally required prior to resection.
• Image-guided core needle biopsy is recommended unless the imaging is definitive, such as in the case of well-differentiated/de-differentiated liposarcoma. Fine-needle aspiration biopsy should be avoided, as it is generally unhelpful.
• Open or laparoscopic surgical biopsy should be avoided. If an RPS is encountered unexpectedly at surgery, management should be deferred until proper imaging and tissue sampling can be performed by an expert soft tissue sarcoma (STS) team.

Management of localized disease

Recommendations are as follows:

• Surgical therapy of RPS should be undertaken with the primary goal of complete macroscopic (R0/R1) resection. Adherent structures and organs should be resected en bloc with the tumor.
• Organ and critical structure preservation (eg, kidney, bladder, duodenum, sciatic nerve) should be prioritized on the basis of on anatomic issues, histologic subtype biologic features, and patient physiology.
• Thorough preoperative planning is required to properly engage and prepare necessary subspecialists. RPS may require involvement of urology, vascular surgery, neurosurgery, and reconstructive surgery, in addition to a surgical oncologist with expertise in STS.
• The surgical team must be familiar with the consequences of major neurovascular structure sacrifice and patients should be thoroughly counseled about potential functional loss prior to intervention.
• Neoadjuvant chemotherapy or radiation therapy (RT) may be considered in patients with technically unresectable or borderline resectable disease. Intraoperative RT or brachytherapy are rarely useful.

Prognosis and follow-up for primary disease

For patients with intermediate- or high-grade sarcoma, the recommended follow-up schedule is as follows:

• Risk of recurrence persists beyond 15-20 years, so patients should be followed indefinitely.
• The median time to recurrence is less than 5 years; thus, more frequent imaging is indicated during this time frame.

Imaging and clinical follow-up for RPS is not strictly evidence based. A reasonable approach is to image patients every 3-6 months for the first 5 years after resection, and annually thereafter.