Retroperitoneal soft tissue sarcomas: clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase

ACT – adjuvant polychemotherapy

AST – aspartate aminotransferase

AFP – alpha-fetoprotein

NOS – not otherwise specified

RFS – relapse-free survival

VAS – Visual Analog Scale for pain assessment

PFS – progression-free survival

i.v. – intravenous

WHO – World Health Organization

rhG-CSF – recombinant human granulocyte colony-stimulating factor [rhG-CSF]

CI – confidence interval

GI – gastrointestinal tract

Malignant neoplasms – malignant neoplasms

RPS – retroperitoneal sarcoma

IHC – immunohistochemistry / immunohistochemical examination

CT – computed tomography

LDH – lactate dehydrogenase

LMS – leiomyosarcoma

LPS – liposarcoma

RT – radiation therapy (radiotherapy)

PT – physical therapy

ICD-10 – International Classification of Diseases, 10th Revision

ICD-O – International Classification of Diseases for Oncology

mOS – median overall survival

MRI – magnetic resonance imaging

NACT – neoadjuvant polychemotherapy

IVC – inferior vena cava

OS – overall survival

OR – overall response

OR – odds ratio

PET – positron emission tomography

PET-CT – positron emission tomography combined with computed tomography

FSD – fraction single dose

HPF – high-power fields

CEA – carcinoembryonic antigen

TD – total dose

STS – soft tissue sarcoma

TFD – total focal dose

SFT – solitary fibrous tumor

Ultrasound – ultrasound examination

ACD – adequacy of evidence level

グレード – strength of recommendation level

hCG – human chorionic gonadotropin

ChT – chemotherapy

EGD – esophagogastroduodenoscopy

ECG – electrocardiography

EUS – endoscopic ultrasound

ECOG – Eastern Cooperative Oncology Group

FDA – Food and Drug Administration

FISH – fluorescence in situ hybridization (in situ fluorescence hybridization)

MSI – microsatellite instability (microsatellite instability)

mTOR – mammalian target of rapamycin

NGS – next-generation sequencing

RECIST – Response Evaluation Criteria in Solid Tumors

TMB-H – high tumor mutational burden

** – vital and essential drugs

# – drug used off-label (outside the indications, contraindications, routes of administration, or dosages specified in the approved product labeling)

Terms and Definitions

Adjuvant chemotherapy – a type of chemotherapy administered after complete surgical removal of the primary tumor to eliminate potential micrometastases.

Relapse-free survival (RFS) – the time interval from the start of treatment to disease progression, development of a second tumor, or patient death from any cause. Determined in cases of radical treatment for localized disease.

Time to progression (TTP) – the time interval from the start of treatment (or randomization date in clinical trials) to the date of disease progression, excluding patient death from causes unrelated to disease progression.

Second stage of rehabilitation – rehabilitation in inpatient medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period, late rehabilitation period, or the period of residual effects of the disease.

Progression-free survival (PFS) – the time interval from the start of treatment (or randomization date in clinical trials) to the date of disease progression or patient death from any cause.

Conformal radiotherapy – a high-precision external beam radiotherapy technique based on the three-dimensional determination of tumor volume and the anatomy of critical organs.

Chemotherapy course (cycle) – the period of time calculated from the first to the last day of cytostatic administration.

Neoadjuvant chemotherapy – a type of chemotherapy administered immediately before surgical removal of the primary tumor to improve the outcomes of surgery/radiation therapy and prevent metastasis.

Suboptimal cytoreductive surgery – hysterectomy with adnexectomy, removal of the greater omentum, and removal of tumor manifestations with macroscopically visible residual nodules, at least one of which is greater than 10 mm in diameter.

Overall survival (OS) – the time interval from the start of treatment to the patient's death from any cause.

R1 resection – removal of the affected organ within healthy tissue margins along with regional metastasis zones with the presence of microscopically detectable residual tumor (at the resection margins).

Optimal cytoreductive surgery – performance of hysterectomy with adnexectomy, removal of the greater omentum, as well as visible manifestations of the tumor process with macroscopically detectable residual tumor nodules, each not exceeding 10 mm in diameter.

Complete cytoreductive surgery – performance of hysterectomy with adnexectomy, removal of the greater omentum, as well as all visible manifestations of the tumor process without macroscopically detectable residual tumor masses.

Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgical treatment / chemotherapy / radiation therapy).

Full effect (FE), or complete tumor regression (CR, complete response) – disappearance of all lesions for a period of at least 4 weeks.

Disease progression (DP) – an increase in the sum of measurable lesions by 20% or more compared to the smallest sum recorded during treatment and/or follow-up, or the appearance of at least one new lesion.

Stage I rehabilitation – rehabilitation during the period of specialized treatment of the underlying disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the underlying disease;

Stage II rehabilitation – rehabilitation in inpatient settings of medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual effects of the disease.

Stage III rehabilitation – rehabilitation in the early and late rehabilitation periods, and the period of residual effects of the disease in departments (offices) of rehabilitation, physiotherapy, therapeutic exercise, reflexology, manual therapy, psychotherapy, medical psychology, speech therapy (defectology) offices providing outpatient medical care, day hospitals, as well as by mobile teams at home (including sanatorium-resort organizations).

Radical surgery (R0) – removal of the affected organ within healthy tissue margins along with regional metastasis zones without residual manifestations of the tumor process.

Symptomatic treatment – a set of therapeutic measures aimed at eliminating the most distressing manifestations of the tumor process, or treating complications, or correcting consequences associated with antitumor treatment.

Disease stabilization (SD) – a decrease in the sum of measurable lesions by less than 30% or an increase in the sum of measurable lesions by less than 20%, in the absence of new lesions or clear progression of non-measurable lesions.

Targeted therapy – a type of antitumor therapy that blocks the growth of cancer cells by interfering with the mechanism of action of specific target molecules necessary for carcinogenesis and tumor growth.

Levels of evidence – reflect the degree of certainty that the found effect of applying a medical technology is true. According to epidemiological principles, the certainty of evidence is determined by 3 main criteria: qualitative and quantitative characteristics, and consistency of evidence.

Grades of recommendation – unlike levels of evidence, they reflect the degree of certainty not only in the validity of the intervention effect, but also in the fact that following the recommendations will bring more benefit than negative consequences in a specific situation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Retroperitoneal non-organ sarcomas (RNOS) – a group of non-organ mesenchymal tumors with various differentiation lineages and variable malignant potential.

This group of neoplasms does not include:

• adrenal cortex tumors (adrenocortical adenoma/carcinoma);

• adrenal medulla tumors (pheochromocytoma, neuroblastoma);

• tumors of retroperitoneal paraganglia (paragangliomas, ganglioneuroma);

• mesenchymal tumors of the pelvic organs.

Regardless of anatomical location, mesenchymal neoplasms can be classified according to:

• differentiation lineage;

• biological potential;

• driver genetic abnormalities;

• malignancy grade (FNCLCC grading system).

Comment: due to the fact that for certain mesenchymal tumors a normal cellular counterpart has still not been established, it is more correct to speak of the differentiation lineage rather than histogenesis, if known [119].

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

To date, etiological factors for the development of retroperitoneal sarcomas have not been established. Liposarcomas are malignant mesenchymal tumors originating from neoplastic lipocytes/lipoblasts of varying degrees of differentiation. Their histogenetic source of development is most often the adipose tissue of the perirenal space, the mesentery of the colon, or the small intestine. Leiomyosarcomas are the second most common group of retroperitoneal tumors after liposarcomas [1]. These are malignant mesenchymal tumors originating from smooth muscle cells. They have two histogenetic sources of development in the retroperitoneal location: myocytes of the small intestine mesentery and muscle cells of the wall of the inferior vena cava and its visceral branches. Accordingly, retroperitoneal non-organ leiomyosarcomas and leiomyosarcomas of the inferior vena cava and renal veins are distinguished. Malignant peripheral nerve sheath tumors (malignant schwannomas) are the third most prevalent group of retroperitoneal non-organ tumors. These are tumors of neuroectodermal origin that form from Schwann cells and perineural fibroblasts (neurofibrosarcomas). Other histological types are significantly less common.

1.3 Epidemiology of the Disease or Condition

There are no epidemiological data on the incidence of RNOS in Russia.

Patients with retroperitoneal non-organ sarcomas account for about 15% of patients with soft tissue sarcomas [156]. Etiological factors and pathogenesis of retroperitoneal sarcomas remain incompletely understood. The main genetic abnormalities detected in retroperitoneal non-organ sarcomas are presented in Section 1.4.3.

The occurrence of certain types of sarcomas is associated with hereditary syndromes. Approximately 5% of patients with neurofibromatosis develop soft tissue sarcomas, and the most frequent neoplasms are malignant peripheral nerve sheath tumors. Desmoid tumors occur in 7.5%–16% of patients with familial polyposis [157].

1.4 Features of Coding the Disease or Condition

A specific feature of coding RNOS is the fact that these tumors belong to soft tissue sarcomas. Many histological forms of soft tissue sarcomas are extremely rarely diagnosed retroperitoneally in adult patients. According to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10), RNOS have the code: C48.0 [119].

1.5 Classification of the disease or condition

1.5.1. International Histological Classification

Table 1 shows the histological types of mesenchymal tumors that can be located retroperitoneally [119].

Table 1. Histological types of mesenchymal neoplasms with primary retroperitoneal location

In accordance with the criteria of the WHO Classification of Soft Tissue and Bone Tumors [2, 120], it is customary to distinguish 4 clinical and prognostic groups of mesenchymal neoplasms (see Table 2).

Table 2. Clinical and prognostic groups of mesenchymal neoplasms

` – metastasis rate in this group does not exceed 2% of cases.

``– true sarcomas with a metastasis rate of 20–100%.

1.5.2. Staging

Currently, retroperitoneal extraorgan sarcomas are staged according to the TNM soft tissue sarcoma staging system (8th edition, 2017).

The staging is based on tumor size, grade, and the presence (absence) of distant metastases.

Tumor size

T1 – tumor ≤5 cm;

T2 – tumor >5 cm and ≤10 cm;

T3 – tumor >10 cm and ≤15 cm;

T4 – tumor >15 cm.

Histological grade (G)

G1 – low grade;

G2, G3 – high grade.

Table 3. TNM staging of retroperitoneal extraorgan sarcomas (8th edition, 2017).

1.5.3. Genetic Abnormalities of Retroperitoneal Sarcomas

In general, all mesenchymal tumors, depending on the genetic abnormality underlying their development, can be broadly divided into two large groups: sarcomas with a simple ("translocation-associated") and a complex karyotype ("non-translocation-associated" sarcomas). Specifically, for the first group, translocations are a typical type of driver mutations, while for the second, other mutations are typical.

In complex diagnostic cases, the assessment of genetic abnormalities can help clarify the histological type of the tumor.

Comment: it is advisable to perform molecular genetic testing to clarify the tumor subtype.

Table 4 lists the diagnostically significant genetic abnormalities of retroperitoneal mesenchymal neoplasms that can provide substantial assistance in verifying the histological type of the tumor [2, 119].

Table 4. Main genetic abnormalities of retroperitoneal mesenchymal neoplasms

1.5.4. Sarcoma Grading

In accordance with the WHO Classification guidelines [2, 120], the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system should be used by the pathologist to determine the histological grade of sarcoma when examining biopsy and surgical specimens.

All mesenchymal neoplasms belonging to clinical and prognostic groups 2 and 3 in terms of their biological potential (i.e., not true sarcomas) are not subject to FNCLCC grading: atypical lipomatous tumor (synonym: well-differentiated liposarcoma), inflammatory myofibroblastic tumor, solitary fibrous tumor (SFT).

The FNCLCC system is based on the semiquantitative evaluation of morphological parameters such as tumor cell differentiation, mitotic count per 10 high-power fields (×400 magnification), and the extent of tumor necrosis (Table 5).

For the most common histological types of sarcomas, Table 6 provides a scoring system for evaluating the level of tumor differentiation.

As noted in section 1.4.2, the three-tier FNCLCC grading system is comparable to the binary sarcoma grading system [2, 119], which divides them into low grade (equivalent to G1 by FNCLCC) and high grade (equivalent to G2–G3 by FNCLCC) tumors.

Table 5. FNCLCC histological grading system

Table 6. Scoring system for evaluating sarcoma differentiation (FNCLCC)

Comment: it should be noted that, like any prognostic scale, the FNCLCC system has limited applicability and cannot predict the clinical course of absolutely all sarcomas, regardless of their anatomical location [2, 119].

Thus, in a number of sarcomas, the grade may increase as the disease progresses (leiomyosarcoma, myxoid liposarcoma, angiosarcoma, malignant peripheral nerve sheath tumor): G1 → G2 → G3. Therefore, the pathology report following the examination of a biopsy or surgical specimen must note the increase in the malignant potential of the tumor.

Conversely, in other sarcomas, a high grade (G3) remains invariably unchanged regardless of the histological variant of the tumor or progression status (synovial sarcoma, epithelioid sarcoma, all pleomorphic sarcomas, rhabdoid tumor, Ewing sarcoma family of tumors).

It should be noted that a decrease in grade, i.e., an increase in cellular differentiation, is not typical for any sarcoma.

Due to the ineffectiveness of the FNCLCC system, neoplasms such as malignant SFT and extrarenal PEComa do not require grading [2, 119].

Comment: the assessment of metastatic risk in SFT has specific features.

Over the years, the WHO expert committee's understanding of the clinical and histological features reflecting the biological potential of SFT has changed repeatedly. Thus, the previous WHO Classification of Tumours of Soft Tissue and Bone noted that "malignant SFT is usually a hypercellular tumor with a mitotic rate of >4/10 HPF, variable cellular atypia, foci of necrosis, and/or infiltrative growth; of all these features, only the mitotic rate is most strongly associated with prognosis" [2].

In turn, in the latest edition of the Classification [119], the expert panel proposed replacing the long-standing division of SFT into "benign" and "malignant" forms with stratification into low-, intermediate-, and high-risk metastatic groups. In addition, this stratification scheme is recommended by WHO to assess metastatic risk instead of traditional anatomical site-based staging. Table 7 shows the WHO-approved SFT metastatic risk assessment scale developed by Demicco E.G. et al. [119, 120].

Table 7. Modified metastatic risk assessment scale for solitary fibrous tumor (2017)

1.5.5. Assessment of Morphological Regression of Sarcomas

In accordance with the recommendations of the College of American Pathologists (CAP, 2021) [131] and the International Collaboration on Cancer Reporting (ICCR, 2021) [132], pathomorphological assessment of treatment-induced changes in soft tissue sarcoma is performed by calculating the proportion of viable tumor cells in the residual tumor. This indicator must be reflected by the pathologist in the histological report upon examination of the surgical specimen of a radically resected sarcoma as a continuous scale (from 0 to 100%).

Taking into account the large size of most sarcomas, assessment of the volume of massive necrotic foci is recommended to be carried out in 2 stages:

• macroscopically — during grossing of the surgical specimen,

• microscopically — during examination of histological slides.

Assessment of treatment-induced changes in sarcomas after neoadjuvant therapy is not performed on core needle biopsy or incisional biopsy specimens [131, 132].

1.6 Clinical presentation of the disease or condition

Retroperitoneal soft tissue sarcomas (RSTS) represent a heterogeneous group of diseases. One of their features is slow expansive growth with minimal clinical manifestations. The absence of pain "allows" tumors to reach large (>20–30 cm in diameter) sizes. Depending on the type and rate of growth, and histological structure, such tumors may either invade adjacent organs or, conversely, displace them, which in some cases allows for organ-sparing surgery. Liposarcomas more often develop without pain and are more difficult to diagnose by ultrasound. Leiomyosarcomas may arise from small or large veins (the inferior vena cava), have a greater malignant potential and a tendency toward hematogenous metastasis. Malignant peripheral nerve sheath tumors are most often located paravertebrally or along major nerve trunks, and their growth (when nerves are involved) may be accompanied by pain. In cases of pelvic localization, a diagnostic workup is necessary to rule out organ origin of the tumor (uterine, ovarian, rectal, prostatic, or bladder masses).

Thus, obtaining maximum information before surgery not only about the formal size of the tumor, but also about its biological nature is a priority in the treatment of RPS.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1. history data;

2. physical examination data;

3. imaging data (CT, MRI);

4. data from vital morphological examination of biopsy/surgical specimens and/or immunohistochemical study.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

• All patients with suspected RPS are recommended to undergo a standard workup, including a complete blood count, urinalysis, general clinical blood chemistry, and coagulography (screening coagulation test). Since there are no pathognomonic laboratory signs of RPS, further examination depends on the differential diagnosis formulated by the clinician [151, 153].

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

Comment: in the case of differential diagnosis with germ cell tumor metastases or lymphoma involving retroperitoneal lymph nodes, it is advisable to determine blood lactate dehydrogenase (LDH) activity, serum alpha-fetoprotein (AFP) level, and serum human chorionic gonadotropin (free beta-subunit) level. A significant increase in LDH suggests a lymphoproliferative disorder (if enlarged lymph nodes are suspected), while elevated AFP and hCG levels suggest germ cell tumors involving retroperitoneal lymph nodes, especially in young patients. Elevated blood or urinary catecholamine levels may indicate chromaffin tissue tumors (extra-adrenal pheochromocytoma) [7, 9, 12, 14–18, 31, 34, 35, 38, 103, 112].

2.4 Instrumental Diagnostics

Comment: it is necessary to discuss in advance with relevant specialists the possibility of high-flux intermittent hemodialysis sessions, either at the surgical facility or at the patient's place of residence.

Comment: biopsy can be performed under ultrasound guidance, CT guidance, or EGD + EUS. Percutaneous biopsy under US/CT guidance should be performed using a 14–18G needle, taking at least 4 core fragments of material; the most solid area should be punctured. If the obtained material is uninformative, a repeat biopsy must be performed [31].

Comment: performing an open or laparoscopic biopsy may lead to dissemination of the tumor process. Laparotomy/laparoscopy and intraoperative core biopsy may be performed if US-guided puncture is technically impossible [31].

2.5 Other Procedures

Comment: it is most important to rule out lymphoproliferative involvement of retroperitoneal lymph nodes, germ cell tumor metastases in retroperitoneal lymph nodes, and metastases of other epithelial tumors in retroperitoneal lymph nodes.

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

Retroperitoneal sarcomas (RPS) are a histologically heterogeneous and rare type of malignant tumors; therefore, every clinical case must be reviewed at a multidisciplinary tumor board involving specialists from high-profile medical institutions that accumulate patients with RPS.

• Patients with RPS are recommended to undergo a multidisciplinary tumor board consisting of a surgeon, oncologist, radiation oncologist, radiologist, and pathologist to develop a treatment plan [10, 14, 19, 31, 112, 124].

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

3.1. Surgical Treatment of Patients with Retroperitoneal Soft Tissue Sarcomas

Surgical resection of the tumor is the main method to achieve a cure. The goal of surgical treatment is complete ("en-bloc") tumor removal—an R0/R1 operation [14, 31, 103, 112]. To perform an R0 resection, combined procedures are justified. A sign of RPS unresectability is, as a rule, sleeve-like involvement of the mesenteric vessels (arteries and/or veins). At the same time, close adjacency to a vessel does not always indicate tumor invasion.

The asymptomatic course of the early stages of the tumor process, as well as the anatomical complexity of the region, cause frequent local recurrence. Locoregional recurrence should be operated on according to the principles of primary tumor removal. Multifocal recurrence (especially with spread to other anatomical zones) generally indicates progression, in which multivisceral resections do not increase the radicality of the operation [1, 6, 7, 9, 14, 16–18, 29–31, 34].

• Treatment of patients with RPS is recommended to be carried out in highly specialized federal cancer centers (at least 13 patients per year), which ensures optimal survival rates [14, 31, 99, 104, 112, 124].

  Comment: it is advisable to perform computed tomography of the abdominal cavity and retroperitoneum with intravenous bolus contrast enhancement 1 month after surgical treatment in order to objectify treatment outcomes and for subsequent follow-up.

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• In case of detecting an unresectable retroperitoneal non-organ-specific sarcoma based on preoperative examination or intraoperative exploration, consultation in a highly specialized cancer center is recommended [113].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: in case of distant metastases (1–4 metastases) within a single organ, the issue of their surgical removal should be discussed at a tumor board [31, 34, 98].

When determining treatment tactics, the following favorable prognostic factors should be considered: metachronous appearance of metastases, involvement of only a single organ, a recurrence-free interval of more than 12 months, absence of local recurrence if radical surgery for the primary tumor was previously performed, good patient functional status, and absence of progression during systemic chemotherapy for 6 months or more in patients with oligometastases of retroperitoneal lipo- and leiomyosarcomas starting from the moment the chemotherapy course began [31, 121–145].

3.2. Chemotherapy in the Treatment of Patients with Operable Retroperitoneal Soft Tissue Sarcomas

Resectable RPS

Comment: there are currently no separate prospective randomized studies assessing the role of chemotherapy in patients with resectable RPS. Data from studies evaluating the efficacy of treatment regimens for soft tissue sarcomas (STS) and their subgroup analyses are presented. Discussing the algorithm for choosing treatment tactics during a multidisciplinary tumor board with the participation of a surgeon, radiation oncologist, and medical oncologist is preferred. Consideration may be given to neoadjuvant chemotherapy in myxoid liposarcoma, pleomorphic liposarcoma, and synovial sarcoma.

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Drug therapy for unresectable and disseminated RPS

• All patients with RPS receiving therapy are recommended to undergo follow-up evaluations every 2–3 cycles with response assessment according to RECIST 1.1 criteria (Appendix G2. Response Evaluation Criteria in Solid Tumors RECIST 1.1) [19].

GGR CLevels of Evidence – C (harvester of evidence – 5).

Algorithm for selecting a drug therapy regimen in patients with locally advanced and disseminated RPS

First-line drug therapy

Few studies evaluate the results of systemic drug therapy in patients with RPS. The presented data are extrapolated from studies investigating the efficacy of chemotherapy in STS.

Principles of first-line systemic drug therapy

• In the first-line treatment of patients with G2–G3 RPS, it is recommended to prescribe doxorubicin**-based regimens [38, 39].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

When choosing a chemotherapy regimen, it is necessary to take into account the patient's general condition, the toxicity profile of the regimen, and the number and severity of comorbid conditions.

1. In patients with ECOG 0–1 and chemotherapy-sensitive subtypes of RPS, it is recommended to prescribe doxorubicin** in combination with ifosfamide** (AI or HD AI regimens, presented in Table 8) [44, 45].

GCR ALEL 2Grade of Recommendation – A (Level of Evidence – 2)

2. The HD AI regimen (presented in Table 8) is recommended for patients in a generally satisfactory condition (ECOG 0), without clinically significant comorbidities, and without impaired internal organ function; a mandatory condition is the possibility of weekly monitoring of side effects and timely administration of supportive care [44].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: a phase III study comparing doxorubicin** at a dose of 75 mg/m² and the combination of doxorubicin** 75 mg/m² with ifosfamide** 10 g/m² included 228 patients with locally advanced and disseminated STS. Progression-free survival (PFS) median was higher in the combination group (7.4 vs. 4.6 months) (HR 0.74; 95% CI 0.60–0.90; p = 0.003), and overall response was also in favor of the combination (60% vs. 31%); overall survival (OS), although not achieving a statistically significant advantage, was higher in the HD AI group (14.3 vs. 12.8 months) (HR 0.83; 95% CI 0.67–1.03; p = 0.076) [7, 44, 45].

3. It is recommended, as one of the treatment options, to consider prescribing the GemTax regimen (presented in Table 8) for G2–3 leiomyosarcomas in the first-line setting [42, 47].

GGR ALoE 2Levels of Evidence – A (Level of Evidence – 2).

4. It is recommended, as one of the treatment options, to consider the combination of doxorubicin** with #dacarbazine** (ADIC regimen, presented in Table 8) in the first-line treatment of G2–3 leiomyosarcomas if there are contraindications to the AI or GemTax regimens [41].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: the EORTC-STBSG 18 study evaluated the efficacy of the ADIC regimen compared to doxorubicin** monotherapy and doxorubicin** (A) in combination with ifosfamide** (AI) as first-line therapy for disseminated leiomyosarcoma. In the treatment groups, median PFS reached 9.2, 4.8, and 8.2 months (p = 0.0723), respectively, with overall response rates (ORR) of 30.9%, 19.5%, and 25.6%. Median OS in the cohort of patients receiving ADIC chemotherapy reached 35.4 months versus 29.3 months with the AI regimen and 21.4 months with single-agent doxorubicin** [125]. A small study showed that administering the GemTax regimen in the first-line setting for disseminated leiomyosarcomas allows achieving an ORR in 53% of patients [126].

5. It is recommended to use doxorubicin** monochemotherapy if there are contraindications to the combination regimen [61, 62].

GGR ALoE 2Level of Evidence – A (Level of Evidence – 2).

6. Pazopanib** is recommended in first-line treatment for chemoresistant histotypes (clear cell STS, PEComa), with the regimen presented in Table 8 [48].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

7. It is recommended to use #everolimus** 10 mg daily in the treatment of unresectable forms of malignant PEComa (the regimen is presented in Table 8) [64]

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

Comment: studies have shown that mTOR inhibitors (L01EG: Mammalian target of rapamycin (mTOR) kinase inhibitors) normalize cellular proliferation and angiogenesis. Retrospective studies of mTOR inhibitors (L01EG: Mammalian target of rapamycin (mTOR) kinase inhibitors) have demonstrated a therapeutic effect in the form of stabilization. A partial response was achieved in a number of patients (the regimen is presented in Table 8) [59, 64].

8. For ECOG 3 and the presence of severe comorbid conditions, symptomatic therapy is recommended. It may be advisable to discuss the issue of systemic treatment at a multidisciplinary tumor board in patients with chemotherapy-sensitive soft tissue sarcomas (synovial sarcoma, Ewing sarcoma, myxoid liposarcoma) [19, 98].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

9. #Paclitaxel** is recommended for patients with unresectable angiosarcomas in the 1st line of therapy (the regimen is presented in Table 8) [57].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Drug therapy in the 2nd and subsequent lines of treatment

1. 2nd-line chemotherapy is recommended for patients with an ECOG performance status of 0–2. In the absence of contraindications, combination regimens can be used [55, 63, 100, 101, 51, 52, 111].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: the choice of preferred regimen in metastatic soft tissue sarcoma depends primarily on the patient's condition and the histological subtype of the tumor [98].

2. Ifosfamide** monotherapy is recommended for dedifferentiated liposarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor (the regimen is presented in Table 8) [36, 39, 90, 98, 154].

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

3. In patients with synovial sarcoma and ECOG 0, it is recommended to consider high-dose ifosfamide (HD I) (the regimen is presented in Table 8). A prerequisite is the possibility of weekly monitoring of side effects and timely administration of supportive care [39, 90, 117].

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

4. Trabectedin in the 2nd and subsequent lines of therapy may be recommended for the treatment of leiomyosarcomas (the regimen is presented in Table 8) [51, 52, 111].

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

Comment: a phase II study investigated trabectedin at a dose of 1.5 mg/m2 as a 24-hour infusion in patients with unresectable disseminated soft tissue sarcoma following progression on ifosfamide** and doxorubicin**. With a median follow-up of 34 months, the overall response rate (ORR) reached 8.1% (partial response was recorded in patients with leiomyosarcoma (56%), synovial sarcoma (61%), liposarcoma (40%), and malignant fibrous histiocytoma /MFH/ (83%)).

The phase II study included only patients with lipo- and leiomyosarcomas. Randomization was performed into two groups with different administration regimens of trabectedin: group 1 received a 24-hour continuous infusion at a dose of 1.5 mg/m² once every 3 weeks, while group 2 used a weekly regimen of a 3-hour infusion at a dose of 0.58 mg/m² for 3 consecutive weeks with a 2-week interval. Median progression-free survival (PFS) was statistically significantly higher in the 24-hour infusion group at 3.7 months versus 2.3 months (p = 0.0302, HR 0.0734; 95% CI 0.554–0.970, p = 0.0028). One-year survival reached 60% with the 24-hour infusion and 50% with the 3-hour infusion (p = 0.09), but no significant differences in median overall survival (OS) were achieved — 13.9 and 11.8 months, respectively (HR 0.843; 95% CI 0.635–1.090, p = 0.192) [51, 52].

5. Eribulin** is recommended for patients with liposarcomas in the 2nd and subsequent lines of therapy (the regimen is presented in Table 8) [63, 99, 100].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: a randomized phase III study included patients with unresectable or metastatic lipo- or leiomyosarcoma who had received at least two lines of therapy, one of which was anthracycline-based (L01DB: Anthracyclines and related substances). The first group of patients received eribulin** (1.4 mg/m² on days 1 and 8) every 3 weeks, and the second group received #dacarbazine** (850–1200 mg/m² on day 1) every 3 weeks. Median overall survival (mOS) in the overall eribulin** group reached 13.5 months, and with #dacarbazine** — 11.3 months (HR 0.75; 95% CI: 0.61–0.94; p = 0.011). Analysis showed that in patients with liposarcoma, eribulin** therapy achieved an mOS of 15.6 months, compared to 8.4 months with #dacarbazine** (HR 0.51; 95% CI 0.35–0.75). A similar benefit was found for median progression-free survival (2.9 vs. 1.7 months) (HR 0.52; 95% CI: 0.35–0.78). Subgroup analysis in patients with leiomyosarcoma revealed no differences in median OS and PFS [63].

6. Pazopanib** is recommended [can be prescribed to patients with G1 in chemoresistant histotypes (alveolar and clear cell soft tissue sarcoma, solitary fibrous tumor / hemangiopericytoma)] for patients with soft tissue sarcoma, except for patients with liposarcomas, with efficacy monitoring after 2 months of administration (the regimen is presented in Table 8) [48].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: in the randomized phase III PALETTE study, patients with disseminated soft tissue sarcoma after progression on standard therapy received pazopanib** at a dose of 800 mg daily or placebo. A significant increase in median PFS was found in the pazopanib** group compared to the placebo group — 4.6 and 1.6 months, respectively (HR 0.31; 95% CI 0.24–0.40, p < 0.0001). However, no statistically significant benefit in mOS was achieved — 12.5 and 10.7 months, respectively (HR 0.86; 95% CI 0.67–1.11, p = 0.25). Adverse prognostic factors for PFS were ECOG 1 (p = 0.03), 2 or more prior lines of polychemotherapy (p = 0.04), and Grade 3 (p = 0.004) [48].

7. For patients with ECOG 0–1 with leiomyosarcoma and dedifferentiated pleomorphic sarcoma, the administration of #gemcitabine** in combination with #docetaxel** or #dacarbazine** is recommended (the regimen is presented in Table 8) [53, 54].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: in a randomized phase II study comparing the GemTax combination and #gemcitabine** monotherapy in patients with disseminated soft tissue sarcoma (n = 122), the superiority of the combination regimen was demonstrated: median PFS and OS were 3.0 and 11.5 months in the monotherapy group, and 6.2 and 17.9 months in the GemTax group. Attention should be drawn to the high hematological toxicity: grade 3 anemia was observed in 13% of patients in the #gemcitabine** group and 7% in the GemTax group, grade 3–4 thrombocytopenia in 35% and 40%, and febrile neutropenia in 7% and 5 of cases, respectively (despite prophylactic administration of rhG-CSF). Subgroup analysis revealed maximum activity of the combination in leiomyosarcoma and dedifferentiated pleomorphic sarcoma [53, 55].

8. For patients with an ECOG performance status of 2, monochemotherapy with #dacarbazine** is recommended (the regimen is presented in Table 8) [53, 55].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

9. #Palbociclib** [can be prescribed to patients with G1 liposarcomas] is recommended for patients with liposarcomas in the 3rd and subsequent lines of therapy (the regimen is presented in Table 8) [56].

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

Comment: #palbociclib** is a reversible oral cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (L01EF: Cyclin-dependent kinase (CDK) inhibitors). A phase II study showed that the administration of #palbociclib** to patients with well-differentiated and dedifferentiated liposarcomas achieves a 12-week PFS of 66% with a median PFS of 18 weeks [56].

10. #Abemaciclib** is recommended for patients with dedifferentiated liposarcomas in the 3rd and subsequent lines of therapy (the regimen is presented in Table 8) [128, 150].

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

Comment: #abemaciclib** is a reversible oral cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (L01EF: Cyclin-dependent kinase (CDK) inhibitors). A phase II study showed that the administration of #abemaciclib** to patients with well-differentiated and dedifferentiated liposarcomas achieves a 12-week PFS of 76% with a median PFS of 30.4 weeks [128].

11. #Gemcitabine** is recommended as the 3rd and subsequent lines of treatment for angiosarcomas (the regimen is presented in Table 8) [58].

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

12. #Pembrolizumab** may be recommended as a line of therapy for TMB-H ≥10 in undifferentiated pleomorphic sarcoma (the regimen is presented in Table 8) [130].

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

13. #Crizotinib** may be recommended as the 1st line of therapy for inflammatory myofibroblastic tumor with ALK translocation [133].

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

Chemotherapy regimens for soft tissue sarcomas

Table 8. Recommended chemotherapy regimens in the treatment of patients with soft tissue sarcomas

Table No. 9. Sensitivity of various soft tissue sarcoma subtypes to drug therapy

3.3. Radiation Therapy for Patients with Retroperitoneal Soft Tissue Sarcomas

• Neoadjuvant radiotherapy for retroperitoneal sarcomas is not routinely recommended [31, 103].

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

Comment: consider neoadjuvant radiotherapy in patients with primary G1 liposarcomas [31, 103]. Preoperative radiotherapy may be administered at a total dose of 50 Gy using standard fractionation of 1.8–2.0 Gy per fraction (134). Conformal radiotherapy using IMRT is preferred for all patients, provided the department has appropriate technical equipment (135).

Comment: radiotherapy is not performed in the presence of multifocal recurrence involving multiple non-contiguous anatomical regions.

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

3.4. Pain Management

Principles of analgesia and optimal choice of pain management in patients with malignant soft tissue neoplasms experiencing chronic pain syndrome correspond to the principles of analgesia set forth in the clinical guidelines "Chronic Pain Syndrome in Adult Palliative Care Patients" [155]. Pain intensity is assessed using various scales; the most commonly used is the visual analogue scale (VAS), represented by a 10 cm uncalibrated line reflecting pain intensity in millimeters from 0 to 100 mm (see Appendix G3, Visual Analogue Scale for Pain Assessment). [140]

3.5. Supportive Care in Patients with RSTS

Principles of treatment and prevention of nausea and vomiting in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Prevention and Treatment of Nausea and Vomiting" [141]

Principles of prevention and treatment of infectious complications and febrile neutropenia in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Management of Infectious Complications of Febrile Neutropenia and Administration of Colony-Stimulating Factors" [142]

Principles of prevention and treatment of hepatotoxicity in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Management of Hepatotoxicity" [143]

Principles of prevention and treatment of cardiovascular complications in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Practical Guidelines for the Management of Cardiovascular Toxicity of Antineoplastic Drug Therapy" [144]

Principles of nutritional support in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Practical Guidelines for Nutritional Support in Cancer Patients" [145]

Principles of prevention and treatment of nephrotoxicity in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Practical Guidelines for the Management of Antineoplastic Drug-Induced Nephrotoxicity" [146]

Principles of prevention and treatment of thromboembolic complications in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" [147]

Principles of prevention and treatment of drug extravasation sequelae in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Guidelines for the Management of Antineoplastic Drug Extravasation Sequelae" [148]

Principles of prevention and treatment of immune-mediated adverse events in patients with malignant soft tissue neoplasms correspond to the principles set forth in the methodological guidelines "Practical Guidelines for the Management of Immune-Mediated Adverse Events" [149]

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, clinical trials involving patients with malignant soft tissue neoplasms are lacking for most types of medical rehabilitation. These recommendations are based on numerous studies, including meta-analyses (Steffens D. et al., 2018, etc.) and systematic reviews (Stout N.L. et al., 2017; Segal R. et al., 2017, etc.), which have demonstrated that various types of medical rehabilitation significantly accelerate functional recovery, shorten postoperative hospital stays, and reduce complication and mortality rates in patients with other malignant neoplasms.

4.1. Pre-rehabilitation

Comment: patients are advised to increase physical activity 2 weeks prior to surgery to reduce hospital stay and the risk of postoperative complications, as well as to improve postoperative quality of life [73].

4.2. Rehabilitation Following Surgical Treatment

4.3. Rehabilitation During Chemotherapy

• This recommendation is based on the results of systematic reviews (Stout N.L. et al., 2017; Segal R. et al., 2017, etc.) on the effects of physical exercise in patients with other malignant neoplasms – recommended is the use of aerobic exercise during chemotherapy, which increases hemoglobin and erythrocyte levels, reduces the duration of leukopenia and thrombocytopenia, and increases the likelihood of completing the planned chemotherapy course [79, 80].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

4.4. Rehabilitation During Radiation Therapy

4.5. Principles of Psychological Rehabilitation for Patients with RSTS

5. Prevention and Dispensary Observation

Comment: performing a CT scan within 2 weeks post-surgery is recommended to detect residual tumor and evaluate the dynamics of suspicious tumor nodules.

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

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, approved by the authorized federal executive body;

2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution 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.

When a malignant neoplasm 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 in the established manner for a consultation at an outpatient cancer center, primary oncology office, or primary oncology department of a medical organization to receive primary specialized health care.

Consultation at an outpatient cancer center, primary oncology office, or primary oncology department of a medical organization must be conducted no later than 5 working days from the date the referral for consultation is issued. The oncologist at the outpatient cancer center (or, in the absence of such a center, the oncologist at the primary oncology office or primary oncology department) shall organize the collection of biopsy (surgical) material, as well as the performance of other diagnostic tests necessary to establish a diagnosis, including determining 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 neoplasm is suspected or detected during the provision of emergency medical care, patients shall be transferred or referred to medical organizations that provide medical care to patients with oncological diseases in order 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 care to cancer patients, the tactics of medical examination and treatment shall be determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium shall be drawn up in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.

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.

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

1. the need to perform complex interventional diagnostic medical interventions requiring subsequent monitoring in an inpatient or day-inpatient setting;

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 monitoring in an inpatient or day-inpatient setting.

Indications for discharging a patient from a medical organization are:

• completion of a course of treatment or a stage of specialized (including high-tech) medical care in an inpatient or day-inpatient setting, provided there are no complications of treatment requiring drug correction and/or inpatient medical interventions;

• refusal by the patient or their legal representative of specialized (including high-tech) medical care in an inpatient or day-inpatient setting prescribed by the concilium of the cancer-care medical organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or inpatient medical interventions;

• the need to transfer the patient to another medical organization of the appropriate medical profile. The conclusion regarding the feasibility of transferring the patient to a specialized medical organization shall be made after a preliminary consultation based on the provided medical documents and/or preliminary examination data by specialists of the receiving 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 capacity to deliver the recommended scope of medical care (for example, the inability to perform sentinel lymph node biopsy), it is recommended to use the routing system to refer patients to other medical organizations, including those outside the federal subject, such as federal centers with appropriate equipment and personnel;

• clinical guidelines cannot describe the full diversity of real-world 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, need to initiate anti-tumor therapy despite contraindications, progression during recommended treatments, etc.), it is recommended to use telemedicine consultations 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.

7. Additional Information

Prognostic factors in malignant neoplasms include: histological tumor type, grade, stage, and the radicality of surgery.

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of specialized medical care for adult patients with malignant neoplasms are specified in Table 10.

Table 10. Criteria for evaluating the quality of medical care

References

Appendix A1. Working Group Composition

1. Stylidi I.S., Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences, Professor, Director of the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Head of the Department of Abdominal Oncology at the N.I. Trapeznikov Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health. i.stilidi@front.ru,

2. Nered S.N., Doctor of Medical Sciences, Leading Researcher, Surgical Department No. 6 of Abdominal Oncology, Thoracoabdominal Division, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health., nered@mail.ru

3. Nikulin M.P., Candidate of Medical Sciences, Senior Researcher, Surgical Department No. 6 of Abdominal Oncology, Thoracoabdominal Division, Research Institute of Clinical Oncology named after N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health., maximpetrovich@mai.ru

4. Abgaryan M.G., Candidate of Medical Sciences, Senior Researcher, Surgical Department No. 6 of Abdominal Oncology, Thoracoabdominal Division, Research Institute of Clinical Oncology named after N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health., abgaryan.mikael@gmail.ru

5. Arkhiri P.P., Surgeon, Surgical Department No. 6 of Abdominal Oncology, Thoracoabdominal Division, Research Institute of Clinical Oncology named after N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health., arhiri@mail.ru

6. Kalinin A.E., Candidate of Medical Sciences, Senior Researcher, Surgical Department No. 6 of Abdominal Oncology, Thoracoabdominal Division, Research Institute of Clinical Oncology named after N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health main2001@inbox.ru

7. Khomyakov V.M., Candidate of Medical Sciences, Head of the Thoracoabdominal Surgical Department, Department of Thoracoabdominal Oncosurgery, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Ministry of Health of Russia, vladimirkhom@mail.ru

8. Zinoviev G.V., Candidate of Medical Sciences, Head of the Surgical Department of Bone, Soft Tissue and Skin Tumors, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, zinovevgrigory@gmail.com

9. Kozlov N.A., Pathologist, Department of Pathology, Division of Morphological and Molecular Genetic Diagnostics, Research Institute of Clinical Oncology named after N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, newbox13@mail.ru

10. Savelov N.A., Head of the Department of Pathology, Moscow City Oncology Hospital No. 62 of the Moscow Healthcare Department.

11. Stroganova A.M., Head of the Molecular Biology Laboratory, Medical Geneticist, Department of Morphological and Molecular Genetic Diagnostics of Tumors, Research Institute of Clinical Oncology named after N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, stroganova_am@mail.ru

12. Artamonova E.V., Doctor of Medical Sciences, Head of the Department of Drug Treatment (Chemotherapy) No. 1, Research Institute of Clinical Oncology named after Academician of RAS and RAMS N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, artamonovae@mail.ru

13. Titova T.A., Candidate of Medical Sciences, Researcher, Department of Drug Treatment (Chemotherapy) No. 1, Research Institute of Clinical Oncology named after Academician of RAS and RAMS N.I. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, tatiana.titovadoc@gmail.com

14. Chernykh M.V., PhD in Medical Sciences, Deputy Director for Clinical Work, Research Institute of Clinical and Experimental Radiology, Head of the Radiotherapy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, dr.chernich@mail.ru

15. Vladimirova L.Yu., MD, Prof., Head of the Department of Drug Treatment of Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, lubovurievna@gmail.com

    Medical Rehabilitation Section:

    1. Obukhova O.A., PhD in Medical Sciences, Physical and Rehabilitation Medicine Physician, Head of the Medical Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Russian Association for Clinical Nutrition and Metabolism (RSPEN). Tkachenko G.A., Candidate of Psychological Sciences, Medical Psychologist at the Rehabilitation Center, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation; Associate Professor at the Department of Psychiatry, Central State Medical Academy of the Administration of the President of the Russian Federation, Moscow, obukhova0404@yandex.ru

    2. Semiglazova T.Yu., MD, Leading Researcher, Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor, Department of Oncology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, St. Petersburg, tsemiglazova@mail.ru

    3. Ivanova G.E., Professor, MD, Chief Specialist in Medical Rehabilitation of the Russian Ministry of Health, Head of the Department of Medical and Social Stroke Rehabilitation, Research Institute of Cerebrovascular Pathology and Stroke, Head of the Department of Medical Rehabilitation, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow, g.ivanova@rehabrus.ru

    4. Filonenko E.V., MD, Professor, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Oncologist, Moscow, derkul23@yandex.ru

    Healthcare Organization Section:

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

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

    3. Ivanov S.A., MD, Professor of the RAS, Director, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

    4. Gevorkyan T.G., Deputy Director, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health. t.gevorkian@ronc.ru

    Conflict of Interest:

    None of the working group members had any conflict of interest during the development of these clinical guidelines, specifically personal interest in obtaining, personally or through a company representative, material gain or other advantage that affects or may affect the proper performance of their professional duties and other obligations, including those related to the development and review of clinical guidelines, due to a contradiction between the personal interest of said persons and the interests of patients.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. radiotherapists;

2. oncologists;

3. radiologists;

4. radiologists;

5. surgeons;

6. anesthesiologists-resuscitologists;

7. general practitioners (internal medicine);

8. general practitioners (family medicine);

9. medical geneticists;

10. pathologists;

11. healthcare organization and public health physicians;

12. physical and rehabilitation medicine physicians;

13. clinical pharmacologists;

14. medical students, residents, and postgraduate students.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Methods used for collecting/selecting evidence: search in electronic databases; analysis of modern scientific developments on the problem of ovarian cancer in Russia and abroad; synthesis of practical experience of Russian and foreign specialists.

Table A1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table A2. Levels of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table A3. Grades of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Good Practice Points (GPPs): best practice recommendations are based on the qualification and clinical experience of the authoring group.

Methods used for formulating recommendations – expert consensus.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review

• Internal expert review.

Description of the guideline validation method:

The preliminary version of these guidelines has been reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is accessible and understandable.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

Consultations and peer review:

The draft guidelines were also reviewed by independent experts, who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Procedure for updating clinical guidelines

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

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its reliability. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Federal Law No. 323-FZ of November 21, 2011 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

2. Order of the Russian Ministry of Health No. 116n of February 19, 2021 "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases"

3. Order of the Russian Ministry of Health No. 804n of October 13, 2017 "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808).

4. Letter of the Federal Compulsory Medical Insurance Fund No. 5071/26-2/i of April 23, 2019. http://www.ffoms.ru/documents/the-orders-oms/.

5. Order of the Ministry of Health and Social Development of Russia No. 541n of July 23, 2010 "On Approval of the Unified Qualification Reference Book of Positions of Managers, Specialists, and Employees, Section 'Qualification Characteristics of Employee Positions in Healthcare'".

6. Federal Law No. 489-FZ of December 25, 2018 "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Protecting the Health of Citizens in the Russian Federation' Regarding Clinical Guidelines".

7. Order of the Russian Ministry of Health No. 103n of February 28, 2019 "On Approval of the Procedure and Terms for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

8. State Register of Medicines: https://grls.rosminzdrav.ru.

   Current package inserts for the medicinal products mentioned in these clinical guidelines can be found in the State Register of Medicines hosted on the website of the Russian Ministry of Health: http://grls.rosminzdrav.ru, as well as on the RUSSCO website.

Appendix B. Physician Action Algorithms

Fig. 1. Treatment algorithm for patients with localized retroperitoneal non-organ-specific sarcomas.

Fig. 2. Treatment algorithm for patients with recurrent localized retroperitoneal non-organ-specific sarcomas.

Fig. 3. Treatment algorithm for patients with unresectable/metastatic retroperitoneal non-organ-specific sarcomas.

Appendix C. Patient Information

The patient is informed about the clinical presentation and diagnostic/staging methods for retroperitoneal sarcomas, and is introduced to various treatment methods and their potential outcomes/complications. The choice of treatment method should be made as a result of such a discussion after the patient has had the opportunity to ask all questions of interest.

It is necessary to reassure the patient and help them overcome psychological discomfort related to the disease.

The patient should be informed about the nature of post-treatment follow-up and the importance of regular examinations.

Patients should also be informed about clinical trials being conducted in the Russian Federation for patients with relevant nosologies.

Independent self-monitoring of the disease course by the patient is not possible; the frequency of physician visits is determined individually in each specific case.

Benefits of quitting smoking and alcohol consumption:

• Higher survival rates

• Greater treatment efficacy

• Fewer and less severe side effects of antineoplastic treatment (cardiopulmonary complications, fatigue, weight loss, mucositis, loss of taste)

• Accelerated recovery of general condition after treatment

• Lower risk of recurrence

• Lower risk of second primary tumors

• Lower risk of infections

• Higher quality of life

Recommendations for chemotherapy/radiation therapy complications: contact your oncologist/chemotherapy specialist/radiation oncologist!

1) If body temperature rises to 38 °C or higher:

2) For stomatitis:

• Diet – mechanical and thermal sparing;

• Frequent mouth rinsing (every hour) with chamomile, oak bark, or sage decoction; apply sea buckthorn (or peach) oil to the oral mucosa;

• Treat the oral cavity as recommended by your oncologist/chemotherapy specialist.

3) For diarrhea:

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

• Take medications as recommended by your oncologist/chemotherapy specialist.

4) For nausea:

• Take medications as recommended by the oncologist (chemotherapy specialist).

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

Appendix G1. WHO/ECOG Patient Performance Status Scale

Russian title: WHO/ECOG Patient Performance Status Scale.

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

Source (official developer website, publication with validation): https://ecogacrin.org/resources/ecog-performance-status.

Original publication: Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649−55 [102].

Type: rating scale.

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

Content (template):

Scoring key (interpretation): provided within the scale itself.

Appendix G2. Response Evaluation Criteria in Solid Tumors

RECIST 1.1 (Response Evaluation Criteria In Solid Tumors 1.1)

Russian title: Response Evaluation Criteria in Solid Tumors 1.1.

Original title (if applicable): Response Evaluation Criteria In Solid Tumors 1.1 (RECIST).

Source (official developer website, publication with validation): Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026 [136].

Type: rating scale.

Purpose: standardization of response evaluation in solid tumors to treatment.

Content (template):

Scoring key (interpretation): provided within the scale itself.

The content is presented in methodological guidelines No. 46 of the State Budgetary Healthcare Institution "Scientific and Practical Center of Medical Radiology" of the Moscow Healthcare Department and is available on the website: http://medradiology.moscow/d/1364488/d/no46_2018_recist_11.pdf.

Appendix G3. Visual Analog Scale

for Pain Assessment

Russian title: Visual Analog Scale for Pain Assessment.

Original title: Visual Analog Scale for Pain (VAS Pain).

Source (official developer website, publication with validation): Hawker G.A., Mian S., Kendzerska T., French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res. (Hoboken) 2011;63(Suppl 11):S240–52 [137].

Type: rating scale.

Purpose: intended for quantitative assessment of pain intensity considering the patient's subjective sensations and for selecting analgesic therapy.

Content (template):

"Rate your pain severity on the scale, where 0 is no pain and 10 is the most severe, unbearable pain."

Instructions: the patient is asked to mark the severity of pain on a 10-centimeter line from 0 to 10.

Key: 1–3 scores – mild pain; 4–7 scores – moderate pain; 8 or more scores – severe pain.

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