Soft tissue sarcomas: clinical guidelines

List of Abbreviations

AJCC – American Joint Committee on Cancer

Choi – Choi Criteria for Solid Tumor Response to Therapy

ECOG – Eastern Cooperative Oncology Group

IMRT – Intensity-Modulated Radiation Therapy

IORT – Intraoperative Radiation Therapy

RECIST – Response Evaluation Criteria in Solid Tumors

ASTS – alveolar soft tissue sarcoma

IV – intravenous

IMT – inflammatory myofibroblastic tumor

WHO – World Health Organization

CT – computed tomography

PT – physical therapy

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

PEComa – perivascular epithelioid cell tumor

PET/CT – Positron Emission Tomography combined with Computed Tomography using tumor-tropic radiopharmaceuticals

STS – soft tissue sarcoma

CCSS – clear cell soft tissue sarcoma

SFT – solitary fibrous tumor

US – ultrasound examination

VAC – Vincristine**+Doxorubicin**+Cyclophosphamide**

IE – Ifosfamide**+Etoposide**

GemTax – #Gemcitabine**+#Docetaxel**

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Locally advanced soft tissue sarcoma soft tissue sarcoma of any stage (up to IV) that occupies > 1 fascial compartment (anatomical zone) and/pyridazinally extends to vital structures.

Assessment of resectability may be influenced by factors such as the relationship with major vessels, bone structures, nerve plexuses, pelvic organs, abdominal cavity, mediastinum, and lungs. Evaluation of tumor resectability is highly subjective and may vary from institution to institution and from surgeon to surgeon

Open biopsy excisional biopsy

Primary unresectable soft tissue sarcoma – stage I–III soft tissue sarcoma that cannot be subjected to radical R0 surgical resection.

Primary resectable soft tissue sarcoma – stage I–III soft tissue sarcoma involving one or > 1 fascial compartment or one or > 1 anatomical zones, which can be subjected to radical R0 surgical resection.

Radiological response evaluation – evaluation of treatment response using the results of radiological examinations (computed tomography, magnetic resonance imaging, positron emission tomography, radiography, etc.) in comparison with the results of previous radiological examinations in accordance with one or more response evaluation systems (such as RECIST, WHO, or Choi).

Core-needle biopsy – percutaneous thick-needle biopsy

Fascial compartment – a term from topographic anatomy. An anatomical zone containing muscles, bounded from adjacent or other structures by a distinct fascia.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Soft tissue sarcomas (STS) are connective tissue tumors – tumors of ligaments, tendons, muscles, and adipose tissue originating from the primitive mesoderm. This group also includes tumors derived from primitive ectodermal cells (schwannoma) and endothelial cells lining blood vessels. This heterogeneous group of tumors is grouped together due to similarities in morphological presentation and clinical manifestations. Visceral sarcomas are rare and occur in the kidneys, prostate, lungs, and heart. Breast and uterine sarcomas are considered separately. Microscopic appearance, grade, and, in some cases, organ of origin play a decisive role in diagnosis, classification, and treatment planning. However, it should be understood that in the case of leiomyosarcoma, the tumor most likely arose from smooth muscle, whereas synovial sarcoma typically does not arise from the synovial capsule of joints.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

There is no single etiological factor for the development of soft tissue sarcomas. Genetic predisposition plays a role in some cases.

Malignant transformation of neurofibromas is frequently observed in neurofibromatosis (von Recklinghausen's disease). This is an autosomal dominant disorder characterized by multiple neurofibromas, giant nevi, and neurilemomas. Peripheral nerve sheath tumors – malignant peripheral nerve sheath tumors (10–15%) and malignant neurilemoma (5%) – frequently develop in the setting of neurofibromatosis [20].

Lymphedema increases the risk of developing certain forms of soft tissue sarcomas. Specifically, Stewart-Treves syndrome (angiosarcoma arising in the setting of post-mastectomy lymphedema of the upper extremity) has been described in women following breast cancer treatment [21, 22].

The impact of known carcinogens on the development of soft tissue sarcomas is insufficiently studied. The possibility of soft tissue sarcoma development following radiation therapy should be noted. Radio-induced sarcomas occur 6 to 30 or more years after irradiation (median 10 years). Total radiation dose, fractionation regimen, and type of radiation affect the incidence. Alkylating agents (cyclophosphamide**, etc.) combined with radiation therapy also increase the risk of secondary malignancies [23, 24].

Kaposi sarcoma arising in the setting of human herpesvirus type 8 infection in HIV-positive patients has an aggressive clinical course in both classical and endemic (African) variants [25, 26].

1.3 Epidemiology of the Disease or Condition

In 2023, a total of 3,214 individuals were diagnosed with soft tissue sarcomas in the Russian Federation [27]. In 2023, the crude incidence rate (both sexes) was 2.52 per 100,000 population (a 10-year change of "-9.75%"), and the age-standardized rate was 1.47 per 100,000 population (a 10-year change of "-14.32%"). The cumulative risk of developing soft tissue sarcomas was 0.15% [27].

In 2018, 1,477 men and 1,479 women died from soft tissue sarcomas in Russia. The crude mortality rate (both sexes) was 2.02 per 100,000 population, and the age-standardized mortality rate was 1.42 per 100,000 population (1.40 in women and 1.48 in men) [27].

In 2023, the distribution of newly diagnosed cases by stage was as follows: stage I–II – 55.5%, stage III – 24.3%, stage IV – 16.2%. Among newly diagnosed patients, the disease was detected actively in 12.3%. One-year mortality was 18.4% [28]. At the end of 2023, there were 31,429 patients under active follow-up (21.4 per 100,000 population), of whom 21,486 patients had been followed for 5 years or more. The caseload accumulation index was 11.2, and the mortality rate among registered patients was 4.0% [28].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems (hereinafter referred to as ICD-10), such tumors are classified according to the organ of primary origin; for example, retroperitoneal sarcoma has code C48, and breast sarcoma has code C50 [29].

C49 Malignant neoplasm of other types of connective and soft tissue

C49.0 Connective and soft tissue of head, face and neck

C49.1 Connective and soft tissue of upper limb, including shoulder region

C49.2 Connective and soft tissue of lower limb, including hip region

C49.3 Connective and soft tissue of thorax

C49.4 Connective and soft tissue of abdomen

C49.5 Connective and soft tissue of pelvis

C49.6 Connective and soft tissue of trunk, unspecified

C49.8 Overlapping lesion of connective and soft tissue

C49.9 Connective and soft tissue, unspecified

All neoplasms of uncertain or unspecified behavior (ICD-10 code D48) are considered potentially malignant. Such patients should be referred to oncologists in specialized (including federal) centers. Evaluation and treatment in a specialized institution minimize the likelihood of diagnostic errors and allow for timely initiation of appropriate therapy.

Thus, patients with code D48 are referred to federal oncological centers to ensure the most accurate diagnosis and adequate treatment, taking into account the potential risk of development or detection of malignant properties of the tumor.

D48 Neoplasm of uncertain or unknown behavior of other and unspecified sites

D48.1 Connective and other soft tissue

Excludes:

connective tissue of breast (D48.6)

cartilage:

- larynx (D38.0)

- nose (D38.5)

- joints (D48.0)

D48.2 Peripheral nerves and autonomic nervous system

1.5 Classification of the disease or condition

1.5.1 International Histological Classification

World Health Organization (WHO) Classification of Tumours of Soft Tissue (5th edition, 2020) [233]:

1.5.2 Staging

The working TNM classification approved in 2010 (AJCC, 7^th ed. 2010) is based on the tumor size and its depth relative to the superficial fascia for extremity sarcomas (a – superficial; b – deep, as well as all tumors of the abdominal cavity, pelvic cavity, thoracic cavity, and retroperitoneum):

T – Primary tumor:

T1 – Tumor 5 cm or less in greatest dimension

T1a – Superficial tumor

T1b – Deep tumor

T2 – Tumor more than 5 cm in greatest dimension

T2a – Superficial tumor

T2b – Deep tumor

N – Regional lymph nodes:

N0 – No histologically verified lymph node involvement

N1 – Regional lymph node metastases

M – Distant metastasis:

M0 – No distant metastasis

M1 – Distant metastasis present

Stage grouping

Stage I

T1a, bN0 M0, G1-2 (G1 by 3-grade system)

T2a, bN0 M0, G1-2 (G1 by 3-grade system)

Stage II

T1a, 1bN0 M0, G3-4 (G2-3-grade system)

T2aN0 M0, G3-4 (G2-3-grade system)

Stage III

T2b N0 M0, G3-4 (G3-3-grade system)

Any T N1 M0 (Any G)

Stage IV

Any T Any N M1, Any G

Currently, the 8th edition of the classification is available. Changes affect the size of the primary tumor depending on the site.

Below is the 8th edition of 2017 (AJCC, 8^th ed 2017) classification of soft tissue sarcomas (excluding GIST) [182]:

Soft tissue sarcomas of the trunk and extremities

T – Primary tumor

Tx Primary tumor cannot be assessed

T0 – No evidence of primary tumor

T1 – < 5 cm in greatest dimension

T2 – > 5 cm to 10 cm in greatest dimension

T3 – Tumor more than 10 cm, but less than 15 cm in greatest dimension

T4 – Tumor more than 15 cm in greatest dimension

N – Regional lymph nodes:

N0 – No histologically verified lymph node involvement

N1 – Regional lymph node metastases

M – Distant metastasis:

M0 – No distant metastasis

M1 – Distant metastasis present

Stage grouping

Stage I

T1 N0 M0 G1, Gx

Stage IB

T2 N0 M0 G1, Gx

T3 N0 M0, G1, Gx

T4 N0 M0 G1, Gx

Stage II

T1 N0 M0, G2, G3

Stage IIIA

T2 N0 M0 G2, G3

Stage IIIB

T3 N0 M0 G2, G3

T4 N0 M0 G2, G3

Stage IV

Any T N1 M0 Any G

Any T Any N M1 Any G

Soft tissue sarcomas of the abdominal cavity, thoracic cavity, and visceral organs

T – Primary tumor

T-x Primary tumor cannot be assessed

T1 – confined to the organ

T2 – tumor extends beyond the organ

T2a – invades the serosa or visceral peritoneum

T2b – extends beyond the serosa

T3 – invades a contiguous organ

T4 – multifocal growth

T4a – 2 involved zones

T4b – 3-5 involved zones

T4c – more than 5 involved zones

N – Regional lymph nodes:

N0 – No histologically verified lymph node involvement

N1 – Regional lymph node metastases

M – Distant metastasis:

M0 – No distant metastasis

M1 – Distant metastasis present

Stage

Currently, there are no recommendations for staging categorization

Soft tissue sarcomas of the head and neck

T – Primary tumor

Tx – Primary tumor cannot be assessed

T1 – < 2 cm in greatest dimension

T2 – > 2 cm to 4 cm in greatest dimension

T3 – Tumor greater than 4 cm

T4 – tumor with extension to adjacent organs/structures

T4a – extension to the orbit, skull base/dura, facial skeleton, etc.

T4b – extension to the brain, carotid artery, prevertebral muscles, or perineural growth into the central nervous system

N – Regional lymph nodes:

N0 – No histologically verified lymph node involvement

N1 – Regional lymph node metastases

M – Distant metastasis:

M0 – No distant metastasis

M1 – Distant metastasis present

Stage grouping

This is a new classification; data collection is required for proper staging.

Comments: The 8th TNM classification should be considered the sole working version after its Russian-language version is approved by professional societies and regulatory authorities.

1.5.2.1 Determination of grade.

This parameter characterizes a given subtype of soft tissue sarcomas most accurately and plays a crucial role in disease prognosis. Naturally, this factor plays a critical role in determining the scope of treatment.

Tumor grade is also one of the 3 factors determining the stage of the disease. The AJCC classification is the most widely used, in which histopathologic tumor grading (G) is included within the traditional TNM (tumor-node-metastases) staging system. Primary tumor extent categories T1 (< 5 cm) and T2 (≥ 5 cm) are subdivided into "a" and "b" depending on the location of the neoplasm relative to the muscular fascia ("a" – tumor is located superficially, above the fascia; "b" – tumor is located deep to the fascia or invades it). Regional lymph node status is taken into account (N0 – uninvolved nodes, N1 – regional lymph node metastases). Four degrees of tumor differentiation are distinguished: G1 – well-differentiated, G2 – moderately differentiated, G3 and G4 – poorly differentiated or undifferentiated sarcomas. However, in a number of scientific studies, authors consider three – G1, G2, G3 (G3+G4) and frequently even two G HI (G3+G4) and Glow (G1+G2) histopathologic grades, designating them as low- and high-grade tumors.

There are currently no uniform morphological criteria for assessing the grade of soft tissue sarcomas. The two most common systems of histopathologic tumor grading are:

1) NCI (National Cancer Institute, USA);

2) FNCLCC (Federation Nationale des Centres de Lutte Contre le Cancer Sarcoma Group) or, as it is also designated in English-language literature, FFCC (French Federation of Cancer Centers) [30].

The former takes into account the histological type of the tumor, its location, and the amount of necrosis; in certain situations, tumor cellularity, nuclear pleomorphism, and mitotic index are taken into account. The latter, in turn, is based on the calculation of three main parameters of sarcomas: tumor differentiation, mitotic activity, and amount of necrosis. Retrospective comparison of these two systems has shown that the FNCLCC system allows more accurate prediction of distant metastasis development and patient death from disease manifestations. The grade of soft tissue sarcomas using this method is determined by the sum of the following three parameters:

1) tumor differentiation:

1 point – sarcomas structurally close to normal tissue, e.g., well-differentiated liposarcoma;

2 points – sarcomas in which the histological type can be determined, e.g., biphasic synovial sarcoma;

3 points – embryonal sarcomas, undifferentiated sarcomas, and sarcomas of uncertain type;

2) mitotic count:

1 point – 0-9 in 10 fields (field 0.1734 mm²);

2 points – 10-19 in 10 fields;

3 points – more than 20 in 10 fields;

3) number of necrotic tumor cells:

0 points – no necrosis;

2 points – necrosis in less than 50% of tumor cells

3 points – necrosis in more than 50% of tumor cells

The total sum of all three parameters amounting to 2–3 points corresponds to G1, 4–5 points to G2, and 6–8 points to G3.

Mitotic rate, morphological characteristics of the cell nucleus, cellularity, cellular anaplasia or polymorphism, and the presence of necrosis are the most important factors for grading malignancy. Determining the malignancy grade is a subjective procedure, which is why some pathologists prefer to classify sarcomas into 2 types: high-grade or low-grade. Immunohistochemistry plays an extremely important role in the differential diagnosis of soft tissue sarcomas (STS) and should be performed in all cases where a mesenchymal tumor is suspected.

1.6 Clinical presentation of the disease or condition

Most patients present with complaints of an asymptomatic tumor mass. Symptoms appear as a result of advanced disease progression, secondary to the involvement of vital structures. Impaired limb function, pain from nerve compression, edema resulting from large vein compression, lymphedema, inflammation, tumor breakdown, etc., are not diagnostic symptoms per se, but rather the consequence of a long-standing problem.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Modern and accurate tumor imaging combined with histological examination is a critical factor determining staging, scope, and treatment strategy for primary, recurrent, and metastatic soft tissue sarcomas. Imaging encompasses a whole range of parameters: determining size, topography, relation to surrounding structures and blood vessels, degree of blood supply, presence of necrotic zones, response to prior therapy, and presence of treatment-induced necrosis. To answer all these questions, the full arsenal of modern oncological diagnostics should be utilized.

Criteria for establishing the diagnosis/condition:

1. anamnestic data

2. physical examination data

3. pathological anatomy examination data of biopsy (surgical) material.

• If soft tissue sarcoma is suspected, it is strongly recommended to refer the patient to a specialized oncological medical institution focused on the diagnosis and treatment of this disease [173].

GPP CLevel of Consensus of Recommendations – C (Level of Evidence – 5).

2.1 Complaints and Anamnesis

Comments: most often, patients seek medical attention due to the appearance of a "swelling", pain, edema in various anatomical areas, soft tissue deformation, or restricted range of motion in a nearby joint. When taking an anamnesis, information from close contacts (family, relatives) is important, as the latter may detect tumor growth in anatomical areas inaccessible to visual control by the patient. The onset of the disease, presence of pain syndrome, functional changes, and the impact of clinical manifestations on the patient's quality of life are specified. The presence of immunosuppression, viral infection, and a history of radiotherapy are recorded. Potential symptoms of genetically predetermined pathology in the family are also documented.

2.2 Physical Examination

Comment: there is significant variation and uncertainty regarding the diagnostic accuracy of physical examination; the rate of errors during physical examination is quite high, and other diagnostic methods must also be used to ensure an accurate diagnosis of malignant neoplasms.

Comments: it should be noted that palpation of lymph nodes in patients does not rule out the need for ultrasound examination (ultrasound) of lymph nodes in patients with an established diagnosis, since physical examination of lymph nodes lacks sufficient accuracy.

2.3 Laboratory Diagnostics

• In patients with a confirmed diagnosis of STS, when preparing for the next stage of treatment, it is recommended to perform a general clinical and general therapeutic biochemical blood test, as well as a coagulogram (preliminary assessment of the hemostatic system) in order to assess the prognosis of the disease and plan the treatment algorithm [174, 175, 176, 177, 178, 180].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comments: also, as part of selecting the optimal treatment algorithm for a patient with an established diagnosis, laboratory diagnostics are necessary to an extent that allows identifying contraindications to various types of therapy.

2.4 Instrumental Diagnostics

A tumor mass detected on palpation requires further diagnostic workup, i.e., clarification of anatomical localization using ultrasound, CT, and MRI, with the latter being the most informative method. Each of these techniques has its advantages and disadvantages, and their combination provides a complete imaging picture.

During MRI, vascular and nerve involvement by the tumor is visualized in 80% of cases, compared to only 60% with CT. The diagnostic capabilities of MRI surpass those of CT, except for cases involving bone structures and lung tissue. Information obtained via MRI regarding the state of major blood vessels is sufficiently comprehensive to avoid angiography. In addition to information about the primary tumor, MRI allows for a proper assessment of regional lymph nodes and a highly reliable estimation of their potential metastatic involvement.

Comments: all of the following studies can be used in the diagnosis and therapy of STS:

— Computed tomography (of the abdominal and retroperitoneal organs, chest organs, pelvic organs in men or pelvic organs in women), with contrast enhancement if necessary.

— Magnetic resonance imaging (of the chest organs, soft tissues, pelvic organs, abdominal organs, upper extremity, lower extremity, neck, or soft tissues of the head), with contrast enhancement if necessary.

— Dynamic MRI, diffusion-weighted MRI, MR spectroscopy – as indicated, according to the multidisciplinary tumor board decision.

— Ultrasound examination of soft tissues of the affected area (+ color Doppler mapping).

— Angiography, as indicated, according to the multidisciplinary tumor board decision (upper extremity arteries, femoral artery, internal carotid artery, thoracic aorta, pulmonary artery, external carotid artery, common carotid artery, vertebral artery, or carotid artery), or computed tomography angiography (of one anatomical region, upper extremity vessels, lower extremity vessels, pelvic vessels, or one zone).

— Radioisotope bone scan for myxoid liposarcomas (which metastasize to bones more frequently than other sarcomas). Scintigraphy with ²⁰¹Tl-chloride, ⁶⁷Ga-citrate, and ^99mTc-sestamibi.

— Brain MRI (if CT is not feasible) for alveolar soft part sarcoma and hemangiopericytoma (brain involvement is most frequently detected).

— Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (PET and PET/CT) – as indicated [39,40,41,42,43,44].

Comment: if brain MRI with IV contrast cannot be performed, brain CT with IV contrast is permissible [45].

Comments: The biopsy must be performed under the guidance of a certified oncologist, orthopedic traumatologist, or surgeon. Core-needle biopsy is the preferred method for obtaining tumor tissue for pathomorphological examination. Open (incisional) biopsy is performed when core-needle biopsy is not feasible. Endoscopic techniques may be used for lesions localized in the pelvic cavity, chest, or abdominal cavity.

2.5 Other Procedures

Histological verification / histological diagnosis

Comments: cytological examination is not routinely used to determine the histological subtype of STS [31]. The pathomorphological examination must be performed by a pathologist experienced in working within a multidisciplinary sarcoma treatment team. If the pathologist lacks experience/internship/training in a major reference laboratory, a "second opinion" must be arranged.

The role of molecular genetic testing in the differential diagnosis of soft tissue sarcomas

Immunohistochemical testing is mandatory for the first stage of establishing/differential diagnosis of certain soft tissue sarcoma subtypes.

The necessity of molecular genetic testing in the differential diagnosis of soft tissue sarcomas is determined by the pathologist.

Comments: for the differential diagnosis of certain soft tissue sarcoma subtypes, such as Ewing family tumors/PNET, synovial sarcoma, myxoid liposarcoma, alveolar sarcoma, and clear cell sarcoma, it is necessary to use (the need is determined by the pathomorphologist after IHC testing) cytogenetic analysis to study specific translocations/transcripts. The need to study the molecular genetic profile for the differential diagnosis of the above subtypes is due to fundamentally different approaches to the therapy of these forms of soft tissue sarcomas. Detection of SSX1/SSX2 chimeric transcripts with the specific chromosome 18 translocation t(X;18)(p11;q11) is found in synovial sarcoma. EWSR1 is found in Ewing family tumors/PNET and desmoplastic small round cell tumor [32,33,34,35,36,37,38]. Determining specific translocations/transcripts is also important in drug therapy. In the near future, cytogenetic analysis will expand the possibilities of targeted personalized therapy in the treatment of various soft tissue sarcoma subtypes [222].

Comments: FUS-CHOP gene rearrangement is an aberrant transcriptional regulator that affects adipocyte differentiation, stimulates their proliferation and tumor transformation – the fusion of CHOP and TLS genes with the synthesis of the FUS-CHOP protein [32,33,34,35,36,37,38,188,222].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Surgical Treatment

Comments: Wide excision of the tumor within healthy tissues, taking into account the principles of compartmentalization and zoning, is the standard surgical procedure. A one-centimeter margin from the neoplasm is considered the minimum; removal of the tumor within a muscle fascia or sleeve implies a margin of > 1-5 cm. The margin may be minimal in the case of a persistent anatomical barrier, such as muscle fascia, periosteum, or a tendon insertion. Marginal excision may be considered in exceptional cases. Resection margins are the primary method for assessing the quality of the surgical procedure, determined jointly by the surgeon and the pathologist. The biopsy site and tract must be included in the scope of the final surgery [95].

Comments: The presence of a microscopically positive margin is an indication for re-excision and/or postoperative radiation therapy. Marking of the tumor bed by the surgeon should be performed to determine the fields for subsequent radiotherapy. Wide organ-preserving surgeries with pre- and/or postoperative radiation therapy yield good outcomes in high-grade extremity sarcomas.

Comments: Performing radical surgery in the treatment of primary soft tissue sarcomas reduces the local recurrence rate to 15%. Requirements for radical surgery involve performing various scopes of interventions, such as removal of one or two myofascial compartments, resection of the major vascular bundle, bone resection, extensive chest and abdominal wall resections, spinal column resections, pelvic bone resections, etc. Each intervention must be planned in advance with the participation of an onco-orthopedist, neurosurgeon, plastic surgeon, microsurgeon, abdominal and thoracic surgeons, radiologist, and chemotherapist. The full scope of onco-orthopedic surgery is feasible only in major sarcoma centers.

Comments: Removal of a large mass of tissue requiring a reconstructive-plastic phase, blood loss exceeding 1000 ml, prolonged wound drainage, prior courses of chemotherapy, and radiotherapy are risk factors for infectious complications of > 12–15%. According to various authors, the mandatory use of antibiotics for up to 5–7 days after surgery can reduce the risk of complications [186,187]. Patients after implantation of metal structures and synthetic materials (vascular grafts, meshes, or plates) are considered a separate group. In cases of a high risk of infectious complications in patients who underwent surgeries with implant placement, high-risk prophylactic antibiotic therapy is recommended [185]. Risk factors include high-grade tumors, deep tumor location, immunosuppression from neoadjuvant chemotherapy, prior radiation therapy, inadequate antibiotic prophylaxis, corticosteroid use, large wound surface area, prolonged surgery time (more than 3 hours), massive blood loss exceeding 0.5 of the circulating blood volume (CBV), secondary wound healing, skin necrosis, additional surgical manipulations, and comorbid conditions (anemia, diabetes mellitus, etc.).

3.2 Radiation Therapy

3.2.1 Various Radiotherapy Options

3.2.1.1 Intensity-Modulated Radiation Therapy (IMRT)

Comments: a comparison of brachytherapy and IMRT (Intensity-Modulated Radiation Therapy) based on a randomized study demonstrated a reduction in the local recurrence rate with IMRT (8%/17%) with similar long-term control outcomes.

3.2.1.2 Brachytherapy.

Comments: the method is applicable if technical resources are available; it is recommended for use in medical organizations specializing in the care of patients with musculoskeletal system malignancies, provided they have the necessary equipment and trained personnel (surgeon, radiation oncologist, medical physicist).

3.2.1.3 Intraoperative radiotherapy

Comments: the use of intraoperative interstitial radiotherapy is feasible in clinics equipped with the necessary facilities and staffed by specially trained personnel. Indications for this type of therapy must be determined in specialized onco-orthopedic clinics through a multidisciplinary tumor board involving an onco-orthopedist, a radiation oncologist, and a chemotherapy specialist. If preoperative IMRT+IORT is not feasible, preoperative external beam radiotherapy with standard fractionation is recommended for patients with high-grade sarcomas in order to reduce the extent of surgery (limb-salvage) followed by postoperative therapy [48,207].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comment: the appropriateness of preoperative radiotherapy must be determined in specialized onco-orthopedic clinics by a multidisciplinary team including an onco-orthopedist, a radiation oncologist, and a chemotherapy specialist. Induction chemotherapy cycles should be initiated prior to radiotherapy. The preoperative radiotherapy regimen (fractionation, intervals, timing, etc.) must be determined in onco-orthopedic settings.

Use of postoperative external beam radiotherapy (3D and intensity-modulated radiotherapy [IMRT] techniques). Irradiation of the tumor bed (low-grade STS) according to intraoperative marking – margin of 2–3 cm from the edges, FX = 1.8–2 Gy, TDD = 50 Gy. In case of a positive resection margin, TDD = 65–70 Gy.

Irradiation of the tumor bed of the excised tumor according to intraoperative marking (high-grade STS) – margin of 5 cm from the tumor edges, FX = 1.8–2 Gy, TDD = 50 Gy. Subsequently, a local boost is delivered to the tumor bed up to 10–26 Gy depending on the resection margin status (negative – 10–16 Gy, 16–18 Gy – minimal residual tumor, 20–26 Gy – positive) [172].

Comments: published data on the efficacy of proton therapy in the treatment of soft tissue sarcomas are based on small case series (8 patients). Treatment may be recommended by a multidisciplinary tumor board decision, provided the technical capabilities for therapy are available.

3.3 Chemotherapy

Systemic treatment for disseminated soft tissue sarcomas may include cytotoxic chemotherapy, targeted therapy, and/or immunotherapy. The treatment of disseminated STSs may involve either monotherapy or combination chemotherapy. The choice of the optimal chemotherapy regimen to initiate (or continue) treatment largely depends on the activity spectrum of chemotherapeutic agents against the STS subtype. During treatment, patients generally manage to receive all available drugs, although complete responses are rare. Therapy selection should be based on ultimate goals, as shown below, with special attention paid to the histological subtype and the patient's performance status.

3.3.1 Neoadjuvant Chemotherapy

Comments: the preoperative treatment phase provides an opportunity to assess tumor response to the therapy administered and, if necessary, to modify the treatment regimen. Patients with a minor response to preoperative CT have a less favorable prognosis regarding long-term efficacy and increased survival. Therefore, they should undergo surgery at earlier stages of treatment or receive alternative systemic treatment regimens based on clinical data [85]. MRI and PET/CT enable early assessment of responses to neoadjuvant chemotherapy.

3.3.2 Adjuvant Chemotherapy

3.3.3 Isolated Perfusion / Regional Hyperthermia with Chemotherapy

Comments: indications are determined by a multidisciplinary tumor board. Treatment should be carried out in specialized musculoskeletal oncology centers.

3.3.4 Chemotherapy for Advanced Disease

Comments: doxorubicin**, ifosfamide**, and dacarbazine** are most frequently used. The standard first-line chemotherapy regimen for disseminated soft tissue sarcomas is the combination of doxorubicin** + ifosfamide**. For patients over 65 years of age, anthracycline monotherapy is the method of choice. In patients with a good general condition, combination chemotherapy is preferred when a pronounced tumor response is anticipated (highly chemotherapy-sensitive sarcomas). Therapy selection must be based on a number of factors, primarily the morphological structure of the tumor. The localization of the process, patient age, and the timing and scope of prior treatment must be taken into account [6]. Synovial sarcoma and myxoid liposarcoma are the most sensitive to chemotherapy: myxoid liposarcoma to doxorubicin**, and synovial sarcoma to alkylating agents such as ifosfamide**.

Uterine leiomyosarcomas, endometrial stromal sarcomas, myxofibrosarcomas, dedifferentiated liposarcomas, and malignant peripheral nerve sheath tumors exhibit individual variability in sensitivity to chemotherapy. Objective responses in these tumors are also possible with two-drug regimens of anthracycline/trabectedin, anthracycline/ifosfamide**, and #gemcitabine**/#docetaxel** [142].

Comments: data on the impact of surgical treatment of extrapulmonary metastases on long-term outcomes are lacking. The feasibility of surgical interventions for extrapulmonary metastases requires mandatory discussion by a multidisciplinary tumor board.

3.3.5 Drugs and Regimens

Comments: AI regimens

- HD AI:

Doxorubicin** 25 mg/m² on days 1–3 intravenously as a 72-hour continuous infusion; (when indicated, doxorubicin** dose reduction to 60 mg/m² on day 1 intravenously is permitted)

Ifosfamide** 2500 mg/m² on days 1–4 intravenously with mesna** 1000 mg/m² 3 times a day on days 1–4 per protocol;

Empegfilgrastim**/pegfilgrastim according to instructions on day 5, or filgrastim 5 mcg/kg/day subcutaneously according to instructions on days 5–14;

Cycle duration – 3 weeks [194]

- AI:

Doxorubicin** 60 mg/m² on day 1 intravenously

Ifosfamide** total dose 7500 mg/m², single dose 2500 mg/m² on days 1–3 intravenously with mesna** 1000 mg/m² 3 times a day on days 1–3 per protocol;

Cycle duration – 3 weeks [70,214,215]

The superiority of the doxorubicin** and ifosfamide** combination over doxorubicin** monotherapy has been demonstrated in randomized trials [70]. Dose escalation of the drugs: doxorubicin** 75–90 mg/m² and ifosfamide** 10 g/m² with CSF support leads to a higher rate of complete responses (9%) and overall responses (64%) [71]. A phase III randomized trial comparing the efficacy of doxorubicin** 75 mg/m² with the combination of doxorubicin** 75 mg/m² and ifosfamide** 10 g/m² demonstrated a statistically significant increase in progression-free survival (4.6 and 7.4 months, respectively) [72]. Based on these data, patients with soft tissue sarcomas younger than 65 years and with an ECOG score of 0–2 receive treatment with the HD AI combination followed by surgery, if feasible [194].

Comments: recommended combination regimens:

- ADIC is most frequently used for leiomyosarcomas:

Doxorubicin** 90 mg/m² as a 96-hour intravenous infusion

Dacarbazine** 900 mg/m² as a 96-hour infusion, dissolved together with doxorubicin**

Filgrastim** 5 mcg/kg/day subcutaneously on days 5–14 or empegfilgrastim**/pegfilgrastim according to instructions on day 5

Cycle duration – 4 weeks [209]

- doxorubicin + trabectedin for leiomyosarcomas:

Doxorubicin** 60–75 mg/m² on day 1 intravenously

#Trabectedin** 1.1 mg/m² as a 24-hour infusion

Empegfilgrastim**/pegfilgrastim according to instructions on day 3

Cycle duration – 3 weeks [234]

Comments: for patients who have previously received chemotherapy with episodes of grade 3–4 hematological toxicity, following pelvic radiation therapy, dose reduction of #gemcitabine** to 675 mg/m² on days 1 and 8 and #docetaxel** to 75 mg/m² is possible, also administered with colony-stimulating factors (CSFs) [231].

Comments: recommended single-agent chemotherapy regimens:

- doxorubicin** 60–75 mg/m² on day 1; 21-day cycle [6,7,50,210,214,215,218,219]. There is a correlation between doxorubicin** dose and treatment efficacy: doxorubicin** at doses of 25 mg/m² achieves 12% responses, whereas at doses of 60–75 mg/m² it demonstrates a response rate of 25–27% [50].

- ifosfamide** 1.6 g/m²/day or 2 g/m²/day – 2.5 g/m²/day for 5 days with mesna** at 120% of the ifosfamide** dose administered concurrently. There is a correlation between dose and treatment efficacy (from 6 g/m² to 8 g/m² and 10 g/m²) [51]. Data on the efficacy of high-dose ifosfamide** were obtained in two consecutive prospective studies: 19%–45% responses depending on dose and infusion rate [6,52,204]. Ifosfamide** monotherapy achieves the same results in the treatment of soft tissue sarcomas as doxorubicin** monotherapy, with no statistically significant differences in progression-free survival (PFS), overall survival (OS), and response rates. The high-dose regimen helps overcome resistance and allows for the re-administration of ifosfamide** after standard doses [6,53,55,204].

Comments: given the inflammatory nature of the disease, viral etiology, and increased incidence in immunocompromised individuals, immune checkpoint inhibitors are hypothesized to be highly effective in the treatment of Kaposi's sarcoma. In a single-arm phase II study of 17 patients with Kaposi's sarcoma treated with #pembrolizumab** 200 mg i.v. once every 21 days, the objective response rate was 71%, including a complete response in two patients (12%) [235]. Based on these data, #pembrolizumab** is recommended in second and subsequent lines for advanced forms of Kaposi's sarcoma, or in the presence of contraindications to pegylated doxorubicin [235].

Comments: #paclitaxel** is active against angiosarcomas of the head and neck skin; a retrospective review of 117 patients with metastatic angiosarcoma demonstrated a 53% overall response rate (stable disease in 29.5%) [63].

Comments: trabectedin is active against myxoid liposarcomas and leiomyosarcomas in second and subsequent lines. There are data on the efficacy of the drug in synovial sarcoma / Ewing's family / PNET / undifferentiated pleomorphic sarcoma. Tumor growth control is 62%, two-year survival is 32% [64,65,66].

Comments: the efficacy of eribulin** in soft tissue sarcomas has been confirmed in two phase II trials and one randomized phase III trial in patients with unresectable and/or metastatic soft tissue sarcomas [67,68,69]. An increase in overall survival up to 13.5 months (9.6 control) has been demonstrated in liposarcoma. The drug is recommended in second and subsequent lines of treatment for liposarcomas.

Comments: recommended regimens:

- HD VAI:

Vincristine 2 mg i.v. on day 1

Doxorubicin** – 25 mg/m² on days 1–3 i.v. as a 72-hour continuous infusion (if indicated, dose reduction of doxorubicin** to 60 mg/m² on day 1 i.v. is possible);

Ifosfamide** 2500 mg/m² on days 1–4 i.v. with mesna** 1000 mg/m² 3 times a day on days 1–4 per protocol;

Filgrastim** 5 mcg/kg/day s.c. on days 5–14 or empegfilgrastim**/pegfilgrastim per instructions on day 5;

Cycle duration – 21 days [211]

- alternating VAC-IE regimen:

VAC:

Vincristine** 2 mg i.v. on day 1;

Doxorubicin** 75 mg/m² i.v. on day 1

Cyclophosphamide** 1200 mg/m² i.v. on day 1;

Filgrastim** 5 mcg/kg/day s.c. on days 2–11 or until neutrophil recovery (or empegfilgrastim**/pegfilgrastim per instructions on day 2).

Cycle duration – 14–21 days.

IE:

Ifosfamide** 1800 mg/m² i.v. on days 1–5 with mesna** 720 mg/m² i.v. 3 times a day on days 1–5 per protocol;

Etoposide** 100 mg/m² on days 1–5 (total dose 500 mg/m²)

Cycle duration – 14–21 days [193,211,221,226,232,77,78].

- #temozolomide** 100 mg/m² on days 1–5 + #irinotecan** 40 mg/m² (total dose 200 mg/m²) on days 1–5 at 40 mg/m² (for Ewing's sarcoma). Cycle duration – 28 days [200].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: as a first-line therapy regimen for extraosseous Ewing's sarcoma / PNET, it is advisable to use the VAC/IE regimen – alternating courses of combinations of cyclophosphamide**, doxorubicin**, vincristine**, ifosfamide**, and etoposide**.

Ifosfamide** and etoposide**. The combination of ifosfamide** and etoposide** achieves a 40% response rate and a median time to progression of 8 months [77]. This combination demonstrates high activity in the treatment of small cell sarcomas. The combination of ifosfamide** and etoposide** is used in the treatment of Ewing's sarcomas either as a standalone regimen or in an alternating regimen with vincristine**, doxorubicin**, and cyclophosphamide** [78].

3.3.6 Targeted Agents

Comments: pazopanib** is a multityrosine kinase inhibitor targeting VEGFR-1, -2, and -3, PDGFR-α and -β, and c-Kit. The randomized, multicenter, double-blind phase III PALETTE trial demonstrated the efficacy of pazopanib** compared with placebo in patients with advanced soft tissue sarcoma (excluding GIST and liposarcoma) who had previously received chemotherapy. The pazopanib** group showed a threefold increase in progression-free survival compared with placebo (median PFS 20 weeks vs 7 weeks; p < 0.0001), with a 65% reduction in the risk of disease progression. The efficacy of pazopanib** was more than twice as high as that in the placebo group, at 73% (6% partial response plus 67% stable disease) vs 38% (0% objective response plus 38% stable disease), respectively. The phase III trial demonstrated that pazopanib** is an effective agent for the treatment of soft tissue sarcomas (excluding liposarcomas and GIST) as a 2nd-line and later therapy.

Comments: Data on the activity of #sorafenib**—a multitargeted tyrosine kinase inhibitor that inhibits RAF kinase and blocks the intracellular domain of VEGF receptors—support recommending the drug as a 4th–5th line therapy (for insensitive 2nd–3rd line subtypes) of sarcomas

3.3.7 Features of Therapy for Rare Histological Subtypes of Soft Tissue Sarcomas

This group of tumors includes: inflammatory myofibroblastic tumor (IMT), alveolar soft part sarcoma (ASPS), solitary fibrous tumor (SFT), perivascular epithelioid cell tumor (PEComa), and clear cell sarcoma of soft tissue (CCSST). These tumors are the rarest of all sarcomas, with an incidence not exceeding 1 case per 1,000,000 population per year [41,147], and all feature characteristic genetic translocations. These rare histological subtypes are characterized by low sensitivity to standard cytotoxic chemotherapy, but a relatively well-understood oncogenic mechanism opens new perspectives for targeted therapy.

Comments: the majority of IMTs harbor a recurrent clonal aberration involving the ALK locus on chromosome 2p23 [148]. It is classified as a low-grade sarcoma, typically localized in the lung, intestinal mesentery, retroperitoneum, or pelvis in children and adolescents. Among targeted therapy agents, the ALK/MET inhibitor #crizotinib** is the only effective therapeutic option for IMT.

Comments: alveolar soft part sarcoma predominantly affects young patients and is characterized by a typical morphological pattern and the presence of the t(X;17)(p11;q25) translocation [46]. It is distinguished by complete resistance to standard cytotoxic therapy. Cases of efficacy with antiangiogenic drugs such as #interferon alfa**, #sunitinib**, and pazopanib** have been described.

The administration of interferons, sunitinib**, and standard cytotoxic therapy requires a personalized decision due to the extremely rare occurrence of this subtype.

Comments: a number of studies have described pronounced responses of ASPS to immunotherapy. Even in a small cohort of four patients, half achieved a partial response bordering on a complete response. In the other two cases – stable disease [241]. The efficacy of the combination of #pembrolizumab** with #axitinib** (a tyrosine kinase inhibitor, 5 mg orally twice daily) has been described, with a 3-month progression-free survival (PFS) rate of 72.7%. PD-L1 expression was detected in all cases, although it did not correlate with a PFS of more than 6 months or the achievement of a partial response [242].

Comments: The standard of care for SFT is radical surgical resection. The use of standard chemotherapy regimens for disseminated forms is not justified. Anthracycline-based regimens have low efficacy [156]. Currently, cases of efficacy are reported for the combination of #temozolomide** and #bevacizumab**, #sorafenib**, #sunitinib**, and pazopanib** [157–162]. The administration of #bevacizumab**, #sorafenib**, #sunitinib**, and standard cytotoxic therapy requires a personalized decision due to the extremely rare occurrence of this subtype.

Comments: malignant PEComas can be localized in any anatomical site. The standard of care for localized processes is wide local excision, although tumors can locally recur and metastasize. Standard therapy is inappropriate due to a lack of efficacy [163].

Comments: according to literature reviews, #sirolimus demonstrates superior efficacy (ORR 41%, mPFS 9 months) compared to #gemcitabine** (ORR 20%, mPFS 3.4 months), anthracyclines (ORR 13%, mPFS 3.2 months), or antiangiogenic agents (ORR 8.3%, mPFS 5.4 months) in patients with disseminated PEComa [243].

Comments: in the largest retrospective study of patients with epithelioid hemangioendothelioma including 38 patients, the best responses according to RECIST were a partial response in 4 patients (10.8%) and stable disease in 28 patients (75.7%). With a median follow-up of 41.5 months, the mPFS was 13 months, and the median OS was 18.8 months. Based on these results, #sirolimus therapy is recommended for epithelioid hemangioendothelioma [244].

Comments: Alveolar soft part sarcomas (ASPS) are rare soft tissue sarcomas that can affect any anatomical region [46]. The standard of treatment is wide tumor excision; ASPS is resistant to standard doses of radiotherapy.

3.3.8. Specifics of aggressive fibromatosis therapy.

Aggressive fibromatosis is a rare form of soft tissue lesion. Treatment tactics always require a multidisciplinary team discussion. It is necessary to conduct a final workup and select therapy in specialized onco-orthopedic clinics of federal-level cancer institutions and national medical centers.

Comments: when the tumor is localized in the soft tissues of the anterior abdominal wall (abdominal desmoid), surgical treatment is recommended. For localizations in anatomical areas where tumor growth cannot lead to the rapid onset of life-threatening complications (pain, functional impairment, breakdown, severe neurological symptoms), it is recommended to begin treatment with a period of active surveillance with MRI/CT monitoring. In case of slow tumor growth, the use of nonsteroidal anti-inflammatory drugs (indoleacetic acid derivatives, phenylacetic acid derivatives, oxicams, propionic acid derivatives, COX-2 inhibitors) is recommended. The use of local treatment methods (surgery, ablation, radiotherapy with local hyperthermia) is recommended for localization in an unfavorable anatomical zone, as well as upon tumor progression. Surgical intervention should be performed according to the principles accepted in onco-orthopedics. Systemic drug treatment is recommended in cases of unresectable tumor process, expected mutilating extent of surgery, or prior radiotherapy.

3.4 Pain Management

The principles of analgesia and optimal selection of pain management therapy in patients with chronic pain syndrome comply with the analgesia principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients in Need of Palliative Medical Care".

3.5 Supportive Care

The principles of treatment and prevention of nausea and vomiting in patients comply with the principles outlined in the guidelines "Prevention and Treatment of Nausea and Vomiting" [86].

The principles of treatment and prevention of bone complications in patients comply with the principles outlined in the guidelines "Use of Bone-Modifying Agents for the Prevention and Treatment of Bone Pathology in Malignant Neoplasms" [87].

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients comply with the principles outlined in the guidelines "Treatment of Infectious Complications of Febrile Neutropenia and Administration of CSFs" [88], and the Clinical Guidelines of the Russian Ministry of Health "Acquired Neutropenias".

The principles of prevention and treatment of hepatotoxicity in patients comply with the principles outlined in the guidelines "Management of Hepatotoxicity" [89].

The principles of prevention and treatment of cardiovascular complications in patients correspond to the principles set out in the guidelines "Practical Guidelines for the Management of Cardiovascular Toxicity of Antineoplastic Drug Therapy" [90].

The principles of prevention and treatment of dermatological complications in patients correspond to the principles set out in the guidelines "Practical Guidelines for the Medical Management of Dermatological Reactions in Patients Receiving Antineoplastic Drug Therapy" [92].

The principles of nutritional support in patients correspond to the principles set out in the guidelines "Practical Guidelines for Nutritional Support in Cancer Patients" [93].

The principles of prevention and treatment of nephrotoxicity in patients correspond to the principles set out in the guidelines "Practical Guidelines for the Management of Antineoplastic Drug-Induced Nephrotoxicity" [93].

The principles of prevention and treatment of thromboembolic complications in patients correspond to the principles set out in the guidelines "Practical Guidelines for the Prevention of Thromboembolic Complications in Cancer Patients" [94].

The principles of prevention and management of drug extravasation consequences in patients correspond to the principles set out in the guidelines "Recommendations for the Management of Antineoplastic Drug Extravasation Consequences" [99].

3.6 Nutritional Therapy

No information available

Comments: To date, no reliable evidence has been obtained regarding the effect of dietary habits on the risk of developing soft tissue sarcoma (STS), or on the risk of recurrence or progression of this disease in individuals with an established diagnosis.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, for most types of medical rehabilitation, there are no clinical studies involving patients with soft tissue sarcomas. General principles of rehabilitation in orthopedics/traumatology are applicable to this patient group. It is also recommended to use the rehabilitation principles outlined in the RSA clinical guidelines "Clinical Guidelines for Rehabilitation".

5. Prevention and Dispensary Observation

5.1 Follow-up Schedule for STS Patients

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting Public Health in the Russian Federation", is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, which is approved by the authorized federal executive body;

2) in accordance with the procedure for providing care in the profile "oncology", mandatory for implementation on the territory of the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological care center or in a primary oncological office, primary oncological department, or outpatient department of an oncological dispensary.

If STS is suspected or detected in a patient, general practitioners, district general practitioners, general family practitioners, medical specialists, and mid-level medical personnel shall refer the patient for a consultation to an outpatient oncological care center or a primary oncological office or primary oncological department of a medical organization in the established manner for the provision of primary specialized health care.

Consultation at an outpatient oncological care center or a primary oncological office/department of a medical organization must be carried out no later than 5 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological care center (or the oncologist of the primary oncological office/department, if no such center exists) shall organize the collection of biopsy (surgical) material, as well as the execution of other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to collect biopsy (surgical) material or perform other diagnostic tests at the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

The timeframe for performing pathological anatomical examinations necessary for the histological verification of a malignant neoplasm shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material at the department of pathological anatomy (pathology bureau).

If a malignant solid tumor is suspected or detected during the provision of emergency medical care, patients shall be transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional specialized anti-tumor treatment methods.

The oncologist of the outpatient oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (if the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department is unable to establish the diagnosis, including the extent of the oncological process and the stage of the disease) and to receive specialized, including high-tech, medical care.

The timeframe for initiating specialized, excluding high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to patients with oncological diseases shall not exceed 14 calendar days from the date of histological verification of the malignant neoplasm or 14 calendar days from the date of establishing a preliminary diagnosis of a malignant neoplasm (in the absence of medical indications for outpatient pathological anatomical examinations).

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or in medical organizations providing medical care to patients with oncological diseases that hold a license, have the necessary material and technical base and certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, and treatment of oncological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with oncological diseases, the tactics of medical examination and treatment are determined by a medical council of oncologists and radiation therapists, with the involvement of other medical specialists if necessary. The decision of the medical council is drawn up in a protocol, signed by the participating physicians, and entered into the patient's medical documentation. According to the procedures for providing medical care to the adult population with oncological diseases included in ICD-10 categories C40-C41, C45-C49, an oncologist at an oncological dispensary (oncological hospital) or another medical organization providing care to cancer patients is recommended to arrange a consultation or medical council—including via telemedicine technologies—at federal medical organizations (National Medical Research Centers) to determine treatment tactics.

Indications for hospitalization in a 24-hour inpatient unit or day hospital of a medical organization providing specialized, including high-tech, medical care in the profile of «oncology» are determined by a medical council of oncologists and radiation therapists, with the involvement of other medical specialists if necessary.

6.1 Indications for Hospitalization

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1) the presence of complications requiring specialized medical care in an emergency or urgent form;

2) the presence of complications from treatment (surgical intervention, radiation therapy, drug therapy, etc.).

Indications for hospitalization in a medical organization in a planned form are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent observation in a 24-hour inpatient unit or day hospital;

2) the presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy—including contact, external beam, and other types of radiation therapy—drug therapy, etc.) requiring observation in a 24-hour inpatient unit or day hospital.

6.2 Indications for Discharge

Indications for discharging a patient from a medical organization are:

1) completion of the course of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour inpatient unit or day hospital, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal by the patient or their legal representative of specialized, including high-tech, medical care in a 24-hour inpatient unit or day hospital prescribed by the medical council of the oncological care organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) the need to transfer the patient to another medical organization in the relevant medical care profile. The conclusion on the feasibility of transferring the patient to a specialized medical organization is made after a preliminary consultation based on the provided medical documents and/or preliminary examination data by specialists of the medical organization to which the transfer is planned.

6.3 Outpatient Procedures

Medical procedures that can be provided as part of primary specialized medical care (i.e., on an outpatient basis) under the supervision of an oncologist:

1) core needle biopsy

2) obtaining tumor touch preps;

3) fine-needle aspiration biopsy of superficially located organs (lymph nodes, soft tissue neoplasms);

4) core biopsy of superficially located organs (lymph nodes, soft tissue neoplasms);

5) chemotherapy courses that do not require prolonged infusions and/or administration of supportive medications 1–4–6 hours after the infusion.

6.4 Indications for Referral to Another Medical Organization

Indications for referring a patient to another medical organization:

- clinical guidelines are designed to maximize the quality of medical care provided to patients in various clinical situations. If a medical organization lacks the capability to provide the recommended volume of medical care (e.g., lacks the capability to perform a biopsy with high-quality pathomorphological analysis), it is recommended to use the routing system to other medical organizations, including outside the federal subject and to federal centers with appropriate equipment and personnel;

clinical guidelines cannot describe the entire diversity of real clinical practice and cover only the most frequent and typical clinical situations. If a practicing physician or medical organization encounters a clinical situation not reflected in these clinical guidelines (atypical disease course, the need to initiate anti-tumor therapy in the presence of contraindications, progression during recommended treatments, etc.), it is recommended to use the telemedicine consultation system or routing to National Medical Research Centers to clarify treatment tactics;

detection or exacerbation of comorbid pathology unrelated to the profile of a cancer center, which prevents this stage of treatment (e.g., acute myocardial infarction, acute cerebrovascular accident, etc.), requires referral to specialized medical organizations.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1) Mamed D. Aliev, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Advisor to the Director General of the National Medical Research Center for Radiology of the Russian Ministry of Health, President of the Eastern European Sarcoma Group

2) Ilya I. Anisenia, PhD, Senior Researcher, Cancer Research Institute of the Tomsk National Research Medical Center, expert of the Eastern European Sarcoma Group

3) Artem V. Bukharov, MD, PhD, Senior Researcher, National Medical Research Center for Radiology of the Russian Ministry of Health

4) Beniamin Yu. Bokhyan, PhD, Senior Researcher, Department of Musculoskeletal Tumors, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, coordinator of the Eastern European Sarcoma Group

5) Aslan K. Valiev, MD, PhD, Head of the Department of General Oncology, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, expert of the Eastern European Sarcoma Group

6) Georgy I. Gafton, MD, PhD, Professor, Head of Scientific Department / Leading Researcher, N.P. Napalkov St. Petersburg Clinical Scientific and Practical Center for Specialized Medical Care (Oncology), expert of the Eastern European Sarcoma Group

7) Vitaly V. Egorenkov, PhD, Deputy Director for Medical Affairs, St. Petersburg Clinical Scientific and Practical Center for Specialized Medical Care (Oncology), expert of the Eastern European Sarcoma Group

8) Alexander A. Zheravin, PhD, Head of the Oncology and Radiotherapy Center, Academician E.N. Meshalkin National Medical Research Center of the Russian Ministry of Health, expert of the Eastern European Sarcoma Group

9) Stanislav M. Ivanov, PhD, Senior Researcher, Department of Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

10) Alexander A. Kurilchik, PhD, Leading Researcher, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, expert of the Eastern European Sarcoma Group

11) Ildar R. Safin, PhD, Senior Researcher, Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan, expert of the Eastern European Sarcoma Group

12) Evgeny A. Sushentsov, MD, PhD, Senior Researcher, Department of Musculoskeletal Tumors, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Scientific Secretary of the Eastern European Sarcoma Group

13) Anastasia A. Tararykova, PhD, Oncologist, Department of General Oncology, Research Institute of Clinical Oncology named after Academician of the Russian Academy of Sciences and RAMS N.N. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, expert of the Eastern European Sarcoma Group.

14) Valery V. Teplyakov, MD, PhD, Professor, Head of the Department of Oncological Orthopedics and Combined Treatment Methods, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health, expert of the Eastern European Sarcoma Group.

15) Alexander A. Fedenko, MD, PhD, Professor, Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Executive Director of the Eastern European Sarcoma Group.

Healthcare Organization Section:

1) A.A. Nevolskikh, MD, PhD, Professor, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health;

2) Zh.V. Khaylova, PhD, Chief Physician of the Clinic, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

3) S.A. Ivanov, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Honored Doctor of the Russian Federation, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Chief Freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

4) T.G. Gevorkyan, Deputy Director for the Implementation of Federal Projects, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

5) Yu.I. Komarov, PhD, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• medical geneticists;

• trauma and orthopedic surgeons;

• obstetricians and gynecologists;

• pathologists;

• medical students, residents, and graduate students.

Levels of Evidence Scale for Diagnostic Methods (Diagnostic Interventions)

Levels of Evidence Scale for Prevention, Treatment, and Rehabilitation Methods (Preventive, Therapeutic, Rehabilitation Interventions)

Grades of Recommendation Scale for Prevention, Diagnostic, Treatment, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, Rehabilitation Interventions)

Procedure for updating clinical guidelines

The guideline updating mechanism provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Specifics of Tumor Response Evaluation to Treatment

Differences between WHO criteria, RECIST 1.0, and RECIST 1.1

*Comments – it is necessary to take into account differences in the methodology of measuring target lesions

Current instructions for medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Figure 1. Flowchart for the diagnosis and treatment of patients with soft tissue sarcomas

Appendix C. Patient Information

Recommendations for self-detection of soft tissue sarcomas and primary prevention of STS

The main and first manifestation of STS is a swelling, edema, or induration. Most often, these signs are first discovered by the patient themselves or their relatives. The lack of oncological alertness prevents the patient from realizing the need to see a doctor. Self-diagnosis ranging from "lipoma" to "myositis" provides time and opportunity for STS growth. Consulting a doctor upon the appearance of even a minor and asymptomatic induration in the skin, subcutaneous tissue, or muscles will dramatically increase the detection rate of early-stage STS.

Consulting physicians and avoiding self-medication are key factors in primary prevention.

Recommendations for chemotherapy complications

In case of chemotherapy complications, it is necessary to contact an oncologist (chemotherapist).

1. If body temperature rises to +38°C or higher, start taking antibiotics as prescribed by the oncologist.

2. For stomatitis:

   • diet – soft and non-hot food;

   • frequently (every hour) rinse the oral cavity with decoctions of chamomile, oak bark, sage, and lubricate the gums with sea buckthorn (peach) oil;

   • treat the oral cavity as recommended by the oncologist.

3. For diarrhea:

   • diet – exclude fatty, spicy, smoked, sweet, dairy products, and fiber. Lean meat, flour products, fermented milk products, and rice water are allowed. Drink plenty of fluids;

   • take medications as prescribed by the oncologist.

4. For nausea, take medications as prescribed by the oncologist.

Information for the patient after surgical treatment

Timely communication with your attending physician and nurse regarding your health status is an important component of helping the medical team protect you during treatment.

Complications related to the surgery may also occur after discharge from the hospital. Any change in your well-being that you associate with the surgery must be discussed with the surgeon or oncologist. Various complaints – pain, edema, hyperemia, hyperthermia, sensory disturbances, joint dysfunction, etc. – may appear even at late post-operative periods and require a surgeon's examination.

Complications that you may experience usually occur within the first 2 weeks after surgery, but can also appear later.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO Patient Performance Status Scale/ECOG

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS)

Source (official developers' website, publication with validation): https://ecog-acrin.org/resources/ecog-performance-status [135]

Type: assessment scale

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content:

Key (interpretation): provided within the scale itself

Appendix G2. Karnofsky Performance Scale

Russian title: Karnofsky Performance Scale

Original title (if applicable): KARNOFSKY PERFORMANCE STATUS

Source (official developers' website, validation publication): [134]

Type: rating scale

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Key (interpretation): provided within the scale itself