Bone sarcomas: Clinical Guidelines

List of Abbreviations

CT – computed tomography

MRI – magnetic resonance imaging

PNET – primitive neuroectodermal tumor

US – ultrasound examination

PCT – polychemotherapy

IMRT – intensity-modulatedradiationtherapy

ESR – erythrocyte sedimentation rate

MIC – minimum inhibitory concentration

Terms and Definitions

Relapse-free survival – from the onset of remission until the occurrence of a relapse.

Event-free survival – from the start of treatment until the end of remission regardless of the cause.

Overall survival – from the start of treatment until the end of the study or patient death.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Bone sarcoma is a tumor of non-epithelial origin. It develops from pluripotent cells of mesodermal derivatives, specifically mesenchyme (primary connective tissue)

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

Risk factors for bone sarcomas include prior radiation therapy, immunodeficiency states, Paget disease, Ollier disease; benign bone tumors can also lead to malignant transformation. However, in most cases, no specific etiological factors are identified, and the tumor develops de novo [1–3].

1.3 Epidemiology of the Disease or Condition

Primary malignant bone tumors account for 0.001% of all newly diagnosed malignancies. In Russia, the incidence of primary malignant bone tumors is 1.03 cases per 100,000 population, which is consistent with incidence data in other countries [4].

1.4 Features of Coding the Disease or Condition

Malignant neoplasm of bone and articular cartilage (C40):

C40.0 – scapula and long bones of the upper limb;

C40.1 – short bones of the upper limb;

C40.2 – long bones of the lower limb;

C40.3 – short bones of the lower limb;

C40.8 – lesion of bones and articular cartilage of limbs overlapping one or more of the above sites;

C40.9 – bone and articular cartilage of limb, unspecified.

Malignant neoplasm of bone and articular cartilage of other and unspecified sites (C41):

C41.0 – bones of skull and face;

C41.1 – mandible;

C41.2 – vertebral column;

C41.3 – ribs, sternum and clavicle;

C41.4 – pelvic bones, sacrum and coccyx;

C41.8 – lesion of bone and articular cartilage overlapping one or more of the above sites;

C41.9 – bone and articular cartilage, unspecified.

All neoplasms of uncertain or unknown 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 facility 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.

Neoplasm of uncertain or unknown behavior of other and unspecified sites (D48):

D48.0 – Neoplasm of uncertain or unknown behavior of bone and articular cartilage

1.5 Classification of the disease or condition

1.5.1. International Histological Classification

International Histological Classification of Tumors of Bone (World Health Organization (hereinafter – WHO) classification, 5th edition, 2020) [126]:

International Classification of Diseases for Oncology (WHO 2020)

1.5.2. Staging

The working TNM classification approved in 2017 (AJCC, 8^th ed 2017) applies to all primary malignant bone tumors, except malignant lymphoma, multiple myeloma, surface/juxtacortical osteosarcoma, and juxtacortical chondrosarcoma. Staging is not applicable when the primary tumor is located in the spine or pelvic bones.

The T criterion indicates the size of the primary tumor (Table 1).

Table 1. T criterion (primary tumor size)

The N criterion indicates the presence or absence of regional lymph node metastases (Table 2).

Table 2. N criterion (regional lymph node involvement)

The M criterion characterizes the presence or absence of distant metastases (Table 3).

Table 3. M criterion (distant metastases)

G – histological grade (determined based on the histological structure of the tumor, degree of differentiation, mitotic rate, and spontaneous necrosis) (Table 4).

Table 4. G – histological grade of the tumor

The grouping of criteria for staging bone tumors is presented in Table 5.

Table 5. Grouping of TNM and G criteria for staging bone tumors

1.6 Clinical presentation of the disease or condition

Clinical manifestations of the disease follow a certain staging pattern and largely depend on the tumor localization. The initial symptom is pain, which patients often attempt to attribute to recent trauma in the corresponding area. A low-grade fever may occur. The disease progresses rapidly, and after 2–3 months, swelling and skin hyperemia appear. If the tumor is localized near a joint, functional impairment develops. In the absence of radical treatment, pronounced intoxication symptoms (weakness, severe weight loss, fever, leukocytosis, increased ESR (erythrocyte sedimentation rate)) appear after 5–7 months and progressively worsen.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Differential diagnosis of bone sarcoma is carried out with benign and metastatic bone tumors, osteomyelitis, arthritis, and other degenerative and dystrophic joint disorders [2]. As a rule, an erroneous diagnosis of osteomyelitis, arthritis, and other degenerative-dystrophic joint disorders leads to misdiagnosis at the initial stage, inappropriate treatment, and consequently disease progression, often precluding limb-sparing treatment.

Diagnostic criteria:

The modern approach to the diagnosis of bone sarcomas should feature an optimized algorithm. It includes:

• analysis of patient complaints;

• physical examination;

• instrumental and laboratory test results;

• morphological verification of the diagnosis.

2.1 Complaints and Anamnesis

Comments: clarify the onset of the disease, presence of pain syndrome, and functional changes in order to assess the impact of clinical manifestations on the patient's quality of life.

2.2 Physical Examination

2.3 Laboratory Diagnostics

2.4 Instrumental Diagnostics

Comments: allows for primary diagnosis and planning of limb-sparing reconstruction if necessary.

Comments:The following medical services may be performed as computed tomography: A06.03.002 Computed tomography of the facial skull; A06.03.002.005 Computed tomography of the facial skull with intravenous bolus contrast enhancement; A06.03.002.006 Computed tomography of the facial skull with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction; A06.03.021.001 Computed tomography of the upper extremity; A06.03.021.002 Computed tomography of the upper extremity with intravenous bolus contrast enhancement; A06.03.021.003 Computed tomography of the upper extremity with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction; A06.03.036.001 Computed tomography of the lower extremity; A06.03.036.002 Computed tomography of the lower extremity with intravenous bolus contrast enhancement; A06.03.036.003 Computed tomography of the lower extremity with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction; A06.03.058 Computed tomography of the spine (one segment); A06.03.058.001 Computed tomography of the spine with multiplanar and three-dimensional reconstruction; A06.03.058.003 Computed tomography of the spine with intravenous contrast enhancement (one segment); A06.03.062 Computed tomography of bone; A06.03.067 Computed tomography of the sternum with multiplanar and three-dimensional reconstruction; A06.03.068 Computed tomography of the ribs with multiplanar and three-dimensional reconstruction; A06.03.069 Computed tomography of the pelvic bones; A06.04.017 Computed tomography of joint; A06.04.020 Computed tomography of temporomandibular joints; A06.07.013 Computed tomography of the maxillofacial region; A06.09.005 Computed tomography of chest organs; A06.09.005.002 Computed tomography of chest organs with intravenous bolus contrast enhancement; A06.20.002 Computed tomography of pelvic organs in women; A06.20.002.003 Computed tomography of pelvic organs in women with contrast enhancement; A06.21.003 Computed tomography of pelvic organs in men; A06.21.003.003 Computed tomography of pelvic organs in men with contrast enhancement; A06.23.004 Computed tomography of the brain; A06.23.004.006 Computed tomography of the brain with intravenous contrast enhancement; A06.30.005 Computed tomography of abdominal organs; A06.30.005.001 Computed tomography of abdominal and retroperitoneal organs; A06.30.005.002 Computed tomography of abdominal and retroperitoneal organs with intravenous bolus contrast enhancement; A06.30.005.003 Computed tomography of abdominal organs with intravenous bolus contrast enhancement

The following medical services may be performed as magnetic resonance imaging:

A05.03.001 Magnetic resonance imaging of bone tissue (one region); A05.03.002 Magnetic resonance imaging of the spine (one segment); A05.03.002.001 Magnetic resonance imaging of the spine with contrast enhancement (one segment); A05.03.003 Magnetic resonance imaging of the skull base; A05.03.003.001 Magnetic resonance imaging of the skull base with angiography; A05.03.004 Magnetic resonance imaging of the facial skull; A05.03.004.001 Magnetic resonance imaging of the facial skull with intravenous contrast enhancement; A05.04.001 Magnetic resonance imaging of joints (one joint); A05.04.001.001 Magnetic resonance imaging of joints (one joint) with contrast enhancement; A05.23.009 Magnetic resonance imaging of the brain; A05.23.009.001 Magnetic resonance imaging of the brain with contrast enhancement; A05.30.004 Magnetic resonance imaging of the pelvic organs; A05.30.004.001 Magnetic resonance imaging of the pelvic organs with intravenous contrast enhancement; A05.30.005 Magnetic resonance imaging of the abdominal cavity organs; A05.30.005.001 Magnetic resonance imaging of the abdominal cavity organs with intravenous contrast enhancement; A05.30.006 Magnetic resonance imaging of the chest organs; A05.30.006.001 Magnetic resonance imaging of the chest organs with intravenous contrast enhancement; A05.30.007 Magnetic resonance imaging of the retroperitoneal space; A05.30.007.001 Magnetic resonance imaging of the retroperitoneal space with intravenous contrast enhancement; A05.30.008 Magnetic resonance imaging of the neck; A05.30.008.001 Magnetic resonance imaging of the neck with intravenous contrast enhancement; A05.30.011 Magnetic resonance imaging of the upper extremity; A05.30.011.001 Magnetic resonance imaging of the upper extremity with intravenous contrast enhancement; A05.30.011.002 Magnetic resonance imaging of the hand; A05.30.012 Magnetic resonance imaging of the lower extremity; A05.30.012.001 Magnetic resonance imaging of the lower extremity with intravenous contrast enhancement; A05.30.012.002 Magnetic resonance imaging of the foot;

The following medical services may be performed as single-photon emission computed tomography of the bones: A07.03.003 Single-photon emission computed tomography of bones; A07.03.003.001 Whole-body single-photon emission computed tomography of bones; A07.03.004 Single-photon emission computed tomography combined with whole-body bone computed tomography [1, 19, 20].

Comments: The following medical services may be performed as an ultrasound examination: A04.01.001 Ultrasound examination of soft tissues (one anatomical zone); A04.03.001 Ultrasound examination of bones; A04.03.002 Ultrasound examination of the spine; A04.04.001 Ultrasound examination of a joint; A04.04.001.001 Ultrasound examination of the hip joint; A04.04.002 Ultrasound examination of tendons; A04.06.002 Ultrasound examination of lymph nodes (one anatomical zone); A04.09.001 Ultrasound examination of the pleural cavity; A04.09.002 Ultrasound examination of the lungs; A04.16.001 Ultrasound examination of abdominal organs (complex); A04.30.003 Ultrasound examination of the retroperitoneal space; A04.30.010 Complex ultrasound examination of pelvic organs (transvaginal and transabdominal);

The following medical services may be performed as computed tomography: A06.23.004 Computed tomography of the brain; A06.23.004.006 Computed tomography of the brain with intravenous contrast enhancement; A06.09.005 Computed tomography of the chest cavity organs; A06.09.005.002 Computed tomography of the chest cavity organs with intravenous bolus contrast enhancement; A06.30.005 Computed tomography of the abdominal cavity organs; A06.30.005.001 Computed tomography of the abdominal cavity and retroperitoneal space; A06.30.005.002 Computed tomography of the abdominal cavity and retroperitoneal space with intravenous bolus contrast enhancement; A06.30.005.003 Computed tomography of the abdominal cavity with intravenous bolus contrast enhancement; A06.20.002 Computed tomography of the pelvic organs in women; A06.20.002.003 Computed tomography of the pelvic organs in women with contrast enhancement; A06.21.003 Computed tomography of the pelvic organs in men; A06.21.003.003 Computed tomography of the pelvic organs in men with contrast enhancement.

The following medical services may be performed as whole-body PET/CT: A07.03.005 Positron emission tomography of bones; A07.03.006 Positron emission tomography of bones combined with whole-body computed tomography; A07.30.042 Whole-body positron emission tomography with tumorotropic radiopharmaceuticals; A07.30.043 Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals; A07.30.043.001 Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement [6, 20].

• Patients diagnosed with Ewing sarcoma are recommended to undergo bone marrow biopsy followed by pathomorphological examination and cytological examination of a bone marrow smear (myelogram) to assess metastatic involvement [8, 12, 15, 16].

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

Comments: patients with Ewing sarcoma and PNET, regardless of primary localization or tumor size, may have isolated bone marrow involvement in the absence of bone metastases. Such features of the tumor process make bilateral bone marrow trephine biopsy a prerequisite for complete disease staging.

2.5 Other Procedures

Comments: proper execution of a tumor biopsy allows for rapid diagnosis verification and initiation of treatment. Regardless of the biopsy method (core needle biopsy or surgical), tissue sampling must be performed with minimal trauma to the patient. When choosing the sampling site, the anticipated surgical approach for subsequent treatment must be considered, which will allow the biopsy scar to be excised later without altering the standard surgical approach. Given that disruption of bone integrity can provoke a pathological fracture, biopsy of an intraosseous tumor fragment should be performed only in cases where the extraosseous component of the tumor is absent or poorly defined.

Standards for tumor biopsy:

1. Biopsy must be performed under the supervision of a certified musculoskeletal oncologist or radiologist.

2. Morphological verification of the obtained biopsy material must be performed in major oncological institutions with a correspondingly trained pathologist.

3. The preferred method for obtaining tumor tissue for pathomorphological examination is core needle biopsy.

4. Open tumor biopsy is permissible: 1) in cases of anatomically difficult localization of the tumor lesion; 2) as a second stage in the event of a negative result after a prior core needle biopsy, or due to scanty and low-informative material obtained via core needle biopsy.

5. When performing an open tumor biopsy, the fundamental topographical criterion is the standard surgical approach of the upcoming surgical treatment, taking into account the tumor localization.

6. The determination of further treatment tactics must be carried out jointly by an orthopedic oncologist surgeon, a chemotherapy specialist, and, if necessary, a radiation therapist.

7. Incorrect selection of the biopsy site or violation of its technique compromises adequate local control, limits the choice of muscle flap reconstruction, and significantly increases the risk of recurrence following subsequent limb-sparing surgery. The following are performed: A11.03.001 Bone biopsy; A11.03.001.001 CT-guided core needle biopsy of long bones; A11.03.001.002 CT-guided core needle biopsy of spinal bones; A11.03.001.003 CT-guided core needle biopsy of pelvic bones; A11.04.001 Joint tissue biopsy; A11.06.002 Lymph node biopsy; A11.06.002.001 Ultrasound-guided lymph node biopsy; A11.06.002.002 Video-endoscopic lymph node biopsy; A11.06.002.003 Intraoperative lymph node biopsy.

Comments: this is a fundamental examination in the treatment of bone sarcomas, serving as the basis for determining treatment tactics and prognosis.

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

The prescription and use of medications specified in clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions presented in the instructions, and dose adjustments are also possible taking into account the patient's condition.

The choice of treatment tactics is determined based on the patient's age, disease stage, tumor size and localization, and the degree of tumor differentiation [1, 2, 6].

3.1. Surgical treatment

3.1.1. Surgical treatment of patients with bone osteosarcoma

Comments: the possibility of limb-sparing surgery should be considered first. The size of the primary tumor focus and the extent of the extraosseous component cannot be used as independent criteria when deciding on ablative surgery. Bone resection is performed with a minimum required margin of at least 3–5 cm from the expected tumor edge (provided there is no tumor spread into the medullary canal of the remaining part of the bone).

If limb-sparing surgery is impossible, radical ablative surgery must be performed. Amputation or disarticulation of a limb is performed in the following cases:

- extensive primary multiple tumor spread;

- involvement of the main neurovascular bundle in the tumor process, which technically precludes the reconstructive-plastic stage of the surgery;

- patient's refusal of limb-sparing surgery;

- vital indications for emergency surgery – tumor breakdown, bleeding.

In specialized centers, limb-salvage surgery is successfully performed in 80% of patients. Wide tumor margins are important for the prevention of local recurrences regardless of the tumor response.

Performed: A16.03.009 Facial bone resection; A16.03.010 Mandibular resection and reconstruction; A16.03.059 Marginal bone resection; A16.03.060 Tibial resection; A16.03.060.001 Segmental tibial resection; A16.03.061 Fibular resection; A16.03.061.001 Segmental fibular resection; A16.03.062 Leg bone resection; A16.03.062.001 Segmental leg bone resection; A16.03.063 Femoral resection; A16.03.063.001 Segmental femoral resection; A16.03.064 Humeral resection; A16.03.064.001 Segmental humeral resection; A16.03.065 Forearm bone resection; A16.03.065.001 Segmental forearm bone resection; A16.03.066 Pubic bone resection; A16.03.066.001 Pubic bone resection with reconstructive plastic component; A16.03.067 Iliac bone resection; A16.03.067.001 Iliac bone resection with reconstructive plastic component; A16.03.068 Pelvic bone resection; A16.03.068.001 Planar pelvic bone resection; A16.03.068.002 Combined pelvic bone resection; A16.03.068.003 Combined pelvic bone resection with reconstructive plastic component; A16.03.068.004 Pubic and ischial bone resection; A16.03.068.005 Pubic and ischial bone resection with reconstructive plastic component; A16.03.069 Sacral resection; A16.03.070 Interilioabdominal pelvic bone resection; A16.03.071 Interilioabdominal pelvic bone amputation; A16.03.072 Sternal resection; A16.03.073 Rib extirpation; A16.03.074 Sternal extirpation; A16.03.075 Resection of shoulder girdle bones; A16.03.075.001 Resection of shoulder girdle bones with reconstructive plastic component; A16.03.075.003 Scapular resection during surgery for malignant chest wall tumors; A16.03.075.004 Clavicular resection during surgery for malignant chest wall tumors; A16.03.075.005 Rib resection during surgery for malignant chest wall tumors; A16.03.075.006 Clavicular resection with reconstructive plastic component; A16.03.076 Extirpation of shoulder girdle bones; A16.03.076.001 Extirpation of shoulder girdle bones with reconstructive plastic component; A16.03.077 Chest wall resection; A16.03.077.001 Simultaneous chest wall resection; A16.03.077.002 Chest wall resection with reconstructive plastic component; A16.03.077.003 Chest wall resection with microsurgical plastic repair; A16.03.078 Interscapulothoracic amputation of shoulder girdle bones; A16.03.079 Interscapulothoracic resection of shoulder girdle bones; A16.03.080 Maxillary resection; A16.03.080.001 Maxillary resection with reconstructive plastic component; A16.03.080.002 Maxillary resection with microsurgical plastic repair; A16.03.080.003 Combined maxillary resection with microsurgical plastic repair; A16.03.080.004 Maxillary resection with microsurgical plastic repair using video-endoscopic technologies; A16.03.081 Mandibular resection; A16.03.081.001 Mandibular resection with reconstructive plastic component; A16.03.081.002 Mandibular resection with microsurgical plastic repair; A16.03.081.003 Mandibular resection with microsurgical plastic repair using video-endoscopic technologies; A16.03.082 Amputation of one or more fingers; A16.03.083 Rib resection; A16.03.083.001 Rib resection with reconstructive plastic component; A16.03.085 Costal arch resection; A16.03.092 Patellar resection; A16.03.092.001 Patellar resection with reconstructive plastic component; A16.03.093 Patellectomy; A16.03.093.001 Patellectomy with reconstructive plastic component; A16.03.091 Removal of neoplasm of the cranial vault bones; A16.04.007 Vertebral resection; A16.04.007.001 Simultaneous vertebral resection.

Comments: the following types of reconstructive surgeries involving endoprosthetics are distinguished:

1) standard primary surgeries in adults;

2) standard primary surgeries in children and adolescents;

3) endoprosthetics of rare anatomical zones;

4) revision endoprosthetics.

Requirements for the design of the endoprosthesis during primary endoprosthetics in adults:

1) modularity of the endoprosthesis design;

2) maximum reliability and maintainability of the endoprosthesis;

3) versatility of endoprosthesis components;

4) maximum service life;

5) stable endoprosthesis fixation;

6) good functional outcome;

7) short manufacturing time of the endoprosthesis.

Features of endoprosthetics in primary joint replacement in children and adolescents:

1) availability of a cementless method of endoprosthesis fixation;

2) expandable endoprosthesis mechanism (invasive and non-invasive).

Comments: in modern onco-orthopedics, the growing number of primary endoprosthetics procedures and successes in the treatment of bone sarcomas lead to an annual increase in the number of patients requiring repeat orthopedic surgeries associated with endoprosthesis instability or failure.

Each revision endoprosthesis is manufactured individually. The use of a modular endoprosthesis system simplifies subsequent revision surgeries and increases the biological bone reserve. The ability to manufacture custom endoprosthesis components for revision surgeries in the event of instability allows replacing part of the endoprosthesis without removing the entire structure.

Comments: in global onco-orthopedic and orthopedic practice, including in the Russian Federation, revision endoprosthetics is classified into a separate clinical-economic group due to the prolonged duration of procedures, labor-intensiveness of manipulations, and the need for high-tech instruments, innovative equipment, and a team of onco-orthopedists with over 10 years of experience.

Comments: a low risk of infectious complications in the early postoperative period following the placement of oncological endoprostheses is ensured by adhering to an adequate regimen of preventive antibiotic therapy [114].

Recommended regimen of preventive antibacterial therapy:

- Duration of preventive antibacterial therapy up to 5 days postoperatively [127, 128].

- Groups of drugs recommended for preventive antibacterial therapy when surgery duration is up to 6 hours: Cephalosporins, Penicillins.

- In case of allergy to beta-lactam antibiotics: Glycopeptide antibiotic [131, 132, 133].

If there is a high risk of wound colonization by anaerobic flora at the time of surgery, Metronidazole** should be added to the antibacterial regimen.

If there is a high risk of wound contamination with Gram-positive MRS infection: Glycopeptide antibiotic.

- Treatment may be continued for up to 10–14 days postoperatively.

- If there is a high risk of wound contamination with mixed infection (see risk factors for infectious complications in patients after oncological endoprosthetics):

- Vancomycin** 2 hours before skin incision combined with Cefoperazone 30 minutes before skin incision, with repeated administration of drugs after 12 hours. Therapy may be continued for up to 72 hours postoperatively [4, 100, 101].

Factors increasing the risk of infectious complications in patients after oncological arthroplasty:

– Immunosuppression after polychemotherapy;

– Prior radiation therapy;

– Prolonged systemic glucocorticoid therapy;

– Extensive wound surface;

– Surgery duration exceeding 6 hours;

– Blood loss exceeding 0.5 of circulating blood volume;

– Comorbidities (diabetes mellitus);

– Obesity (body mass index >30) or cachexia;

– Revision arthroplasty.

Comments: periprosthetic infection is a specific type of implant-associated infectious and inflammatory process characteristic of oncological arthroplasty due to the increased risk of endoprosthesis bed contamination during surgery and the postoperative period. This process is caused by the colonization of the skin by various infectious strains against the background of immunosuppression during chemotherapy, which is associated with the risk of their entry into the postoperative wound during surgical treatment.

– Two-stage revision arthroplasty is the most effective method for treating infectious complications in patients with established oncological endoprostheses.

– Verification of the infectious strain prior to initiating antibacterial therapy using microbiological culture of wound discharge for aerobic and facultative anaerobic microorganisms.

– The choice of treatment regimen is made according to the results of microbiological testing. Empirical selection of systemic antibacterial drugs (J01) is performed in the absence of a verified infection strain.

– Administration of systemic antibacterial therapy (J01) for 2 weeks, followed by a decision on whether to continue conservative treatment upon achieving remission or to proceed to the surgical stage of treatment.

Recommended combined treatment regimen for patients with infectious complications following oncological arthroplasty:

– Total (standard) duration of systemic antibacterial therapy (J01) after the 1st stage of revision arthroplasty (implant removal) is 6 weeks:

• 2 weeks of parenteral administration;

• 4 weeks of oral (per os) administration.

– If systemic antibacterial therapy (J01) yields a negative response, treatment is prolonged with a change in the regimen.

– Performing the second stage of revision arthroplasty no earlier than 2 weeks after discontinuing systemic antibacterial therapy (J01) in the absence of signs of an infectious-inflammatory process.

– Total duration of systemic antibiotic therapy (J01) after the 2nd stage of revision arthroplasty (implant insertion) is 4–6 weeks:

• 2 weeks – parenteral administration;

• 2–4 weeks – oral (per os) administration.

Comments: the administration of bisphosphonates together with calcium supplements immediately after oncological arthroplasty for the first year, in the absence of contraindications, significant side effects, and complications, helps to reverse osteopenia/osteoporosis developing within the first year after surgery and reduces the risk of early endoprosthesis instability [89, 90, 102].

Comments: rehabilitation of cancer patients is divided into two categories: the fullest restoration of functional potential and its maintenance. Rehabilitation after limb-salvage surgery aims at the fullest restoration of functional potential.

Comments: in cases where a patient is diagnosed with a tumor in the pelvic bones, spine, or other anatomically complex sites (bones of the wrist, ankle joints, sternum, etc.), custom oncological implants can be used to replace post-resection defects, manufactured using computer modeling and 3D printing (additive technologies). These technologies make it possible to anatomically replicate the segment of the bone defect that was resected as a result of the tumor lesion. To perform precise, radical resections, personalized instruments as well as prototyping models of the operated anatomical region created through additive technologies can be used [68, 72].

Comments: indications for mutilating surgeries are determined individually in each specific case, based on the principles of radicality [70, 71]. Indications for mutilating surgeries may include:

High-grade bone sarcomas not amenable to R0 limb-salvage treatment, extensive soft tissue involvement, massive involvement of vascular and neural structures, severe infectious process in soft tissues and bone structures, tumor breakdown, and tumor intoxication.

Procedures performed: A16.03.071 Interiliac-abdominal pelvic bone amputation; A16.03.078 Interscapulothoracic amputation of the shoulder girdle; A16.03.082 Amputation of one or more fingers; A16.30.017 Lower extremity amputation; A16.30.017.001 Lower leg amputation; A16.30.017.002 Foot amputation; A16.30.017.003 Toe amputation; A16.30.017.004 Thigh amputation; A16.30.018 Lower extremity disarticulation; A16.30.019 Upper extremity amputation; A16.30.019.001 Arm amputation; A16.30.019.002 Forearm amputation; A16.30.019.003 Hand amputation; A16.30.019.004 Finger amputation of the upper extremity; A16.30.020 Upper extremity disarticulation; A16.04.023 Disarticulation; A16.04.023.001 Finger disarticulation; A16.04.023.002 Toe disarticulation.

3.1.2. Surgical treatment of patients with Ewing sarcoma

The recommended surgical treatment tactics for patients with Ewing's sarcoma of the bone and osteosarcoma have no fundamental differences and are performed in compliance with the oncological and orthopedic rules for this type of surgery described in section 3.1.1.

3.2. Conservative treatment

3.2.1. Chemotherapy for patients with bone osteosarcoma

Comments: surgery alone is impractical, as 80–90% of patients are diagnosed with lung metastases and local recurrences within 1.5 years after surgery. Chemotherapy as part of complex treatment significantly improves 5-year survival in patients with localized disease (from 20% to 60%).

Comments: usually, 3–4 cycles of preoperative chemotherapy are administered. The degree of tumor necrosis after preoperative chemotherapy is a reliable independent prognostic factor. If there is a marked tumor response to treatment (tumor necrosis of 90% or more), there is a high probability of increased disease-free and overall survival. In non-responding patients, postoperative chemotherapy does not improve survival.

- for grade III–IV (more than 90% of the tumor tissue is necrotic as a result of preoperative chemotherapy), repeating the AP regimen postoperatively is recommended, also for 4 cycles of chemotherapy without replacing cytostatic agents [66-67],

- with a low therapeutic pathomorphosis response (less than 90% of the tumor tissue is necrotic as a result of preoperative chemotherapy), high-dose chemotherapy is recommended in the postoperative period:

- HD I: ifosfamide** 2000 mg/m² on days 1–7 IV with #mesna** 800 mg/m² 3 times a day on days 1–7, empegfilgrastim**/pegfilgrastim according to the instructions on day 8 or filgrastim** 5 mcg/kg/day subcutaneously according to the instructions on days 8–17 or until neutrophil recovery. A total of up to 4–6 courses, with a 3-week interval [12, 130];

- HD MTX after 3 weeks: methotrexate** 12 g/m² IV, followed by calcium folinate** infusion, 4 administrations at 14-day intervals only for young patients [12, 46, 130].

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

Comments: the evaluation of the degree of therapeutic pathomorphosis should be performed only by an experienced pathologist specializing in bone oncology in specialized centers. The use of methotrexate** is more justified in young patients; its efficacy in patients older than 25–30 years is considered questionable [1, 7]. High-dose chemotherapy can only be administered in specialized centers equipped with facilities for monitoring drug serum concentrations and in intensive care units. Aggressive chemotherapy is carried out under the cover of hematopoiesis-stimulating agents and antidotes, with prolonged drug infusion; methotrexate mass concentration in serum or blood plasma is determined (A09.05.035 Investigation of drug levels in blood).

A mandatory condition for chemotherapy is strict adherence to the administration technique for high doses of methotrexate**, ifosfamide**, and cisplatin**.

Chemotherapy regimens:

- HD I (used in case of low efficacy or in the adjuvant setting with low therapeutic pathomorphosis) according to the regimen: ifosfamide** 2000 mg/m² on days 1–7 IV with #mesna** 800 mg/m² 3 times a day on days 1–7, empegfilgrastim**/pegfilgrastim according to the instructions on day 8 or filgrastim** 5 mcg/kg/day subcutaneously according to the instructions on days 8–17 or until neutrophil recovery [8, 12];

- HD MTX: methotrexate** 12 g/m² IV infusion followed by calcium folinate** administration starting 24 hours after the start of the methotrexate** infusion and continuing until the serum methotrexate** level falls below 1×10 ^-7 mol/L (100 nmol/L), 4 administrations at 14-day intervals only for young patients; [46]

The use of methotrexate** is more justified in young patients; its efficacy in patients older than 25–30 years is considered questionable [1, 7]. High-dose chemotherapy can only be administered in specialized centers equipped with facilities for monitoring drug serum concentrations and in intensive care units.

— GemTax: #gemcitabine** 900 mg/m² IV on days 1 and 8 + #docetaxel** 100 mg/m² IV on day 8 + empegfilgrastim**/pegfilgrastim according to the instructions on day 9 or filgrastim** 5 mcg/kg/day subcutaneously according to the instructions on days 9–18 or until neutrophil recovery [12, 130]

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

— #sorafenib** 400 mg twice daily orally, daily with meals until disease progression or unacceptable toxicity [48, 49]

— #regorafenib** 160 mg once daily orally for 3 weeks; cycle repeated every 4 weeks [122]

— #cabozantinib** 60 mg once daily orally until disease progression or unacceptable toxicity [123]

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

• External beam radiation therapy for bone lesions using neutron, proton, and heavy ion beams (proton therapy) is recommended as an independent treatment method for skull and spine bone sarcomas, orbital sarcomas, and as part of multimodal and combined treatment approaches for R1 and R2 resection margins after surgical treatment [8, 19, 40, 41, 42, 43, 44, 45, 74, 75].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comments: proton therapy helps increase treatment efficacy by delivering higher radiation doses to the tumor. Proton therapy is the most preferred type of radiation treatment when critical structures are in close proximity and recommended radiation dose constraints cannot be met. Proton therapy can be effectively used when repeated courses of irradiation are necessary for recurrent chordomas and chondrosarcomas, demonstrating high local control and survival rates in situations where treatment options are limited [42].

3.2.2. Conservative treatment of patients with Ewing sarcoma

Ewing family sarcomas/PNET are rare tumors, predominantly affecting young individuals, characterized by high sensitivity to radiation and chemotherapy; their treatment requires a multidisciplinary approach and should be carried out in specialized centers.

Staging does not differ from the generally accepted classification for primary bone tumors described in detail in the osteosarcoma section. For extraosseous tumors, staging is performed according to the soft tissue tumor staging system [1, 2].

Given the high frequency of bone and bone marrow metastasis, recommended local treatment (surgery or radiation therapy) must be accompanied by combination chemotherapy, because in clinically localized disease, 90% of patients have micrometastases at the time of diagnosis. The combination of chemotherapy, surgery, and/or radiation therapy has increased the 5-year survival rate from 10% to 60%. Following tumor biopsy and thorough staging, up to 6 cycles of induction chemotherapy are administered over 12–24 weeks, followed by local treatment and subsequent administration of 6 to 10 cycles of chemotherapy at 3-week intervals. The total duration of treatment is 12 months. The most active cytostatic agents are doxorubicin**, cyclophosphamide**, ifosfamide**, vincristine**, dactinomycin, and etoposide**. Virtually all treatment regimens are based on combinations of 4–6 of the listed drugs. The most effective treatment regimens included at least one alkylating chemotherapy agent (ifosfamide** or cyclophosphamide**) and doxorubicin**. The addition of ifosfamide** and etoposide** to the treatment program significantly improved therapy outcomes in patients with non-metastatic Ewing sarcoma/PNET.

Radical surgery, when feasible, is considered the best opportunity for local control.

Radiation therapy is indicated when radical surgery is not feasible and is considered when histological examination of the resected specimen reveals an insufficient therapeutic pathomorphosis response (i.e., more than 10% viable tumor cells are detected). Non-radical surgery followed by radiation therapy is no more effective than radiation therapy alone. Radiation therapy is delivered at doses of 40–45 Gy for microscopic residual tumors and 50–60 Gy in the presence of macroscopic disease [16, 17].

• A consolidating course of external beam radiotherapy is recommended if radical surgical treatment is not feasible. Irradiation should be initiated at weeks 12–18 of chemotherapy. Radiation therapy is administered at a fractional dose (FD) of 2 Gy up to a cumulative dose (CD) of 44 Gy to the primary tumor site prior to medical treatment (maximum tumor size on baseline MRI), including 1–1.5 cm of surrounding tissue in the target volume, and up to a CD of 54 Gy to the primary tumor site following medical treatment (determined by MRI performed prior to radiotherapy), including 1–1.5 cm of surrounding tissue in the target volume [130].

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

• A preoperative course of external beam radiotherapy is recommended when there is a high probability of R1 or R2 resection. Radiotherapy is delivered using standard fractionation with an FD of 2 Gy up to a CD of 44 Gy to the site of initial tumor extent prior to medical treatment (maximum tumor size on MRI), including 2 cm of surrounding tissue in the target volume [130].

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

• A postoperative course of external beam radiotherapy is recommended to be initiated no later than 60 days after surgery. In the case of R0 resection, radiation therapy is administered in the event of an incomplete pathomorphological response. Radiotherapy is delivered with standard fractionation at an FD of 2 Gy up to a CD of 44 Gy to the site of initial tumor extent prior to medical treatment (maximum tumor size on MRI), including 1–1.5 cm of surrounding tissue in the target volume. For R1 resection, the target volume, FD, and CD are identical. For R2 resection, the CD should be further escalated up to 54 Gy for the residual tumor site and surrounding tissue within 1–1.5 cm [130].

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

• In the case of metastatic lung lesions, if a complete clinical response is achieved, it is recommended to consider whole-lung irradiation. Irradiation is administered at an FD of 1.5 Gy up to a CD of 18 Gy [130].

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

- cyclophosphamide** 250 mg/m² IV on days 1–5; #topotecan 0.75 mg/m² IV on days 1–5; cycle repeated every 3–4 weeks [12, 51, 52, 53, 54, 130]

- etoposide** 100 mg/m² IV on days 1–5; #topotecan 0.75 mg/m² IV on days 1–5; cycle repeated every 3–4 weeks [12, 130]

- #irinotecan** 250 mg/m² IV on day 6; #temozolomide** 150 mg/m² orally or IV on days 1–5; cycle repeated every 4 weeks [12, 130]

- GemTax: #gemcitabine** 900 mg/m² on days 1 and 8 as a 90-minute infusion; #docetaxel** 100 mg/m² on day 8; lipegfilgrastim**/pegfilgrastim per instructions on day 9, or filgrastim** 5 mcg/kg/day SC per instructions on days 9–18 or until neutrophil recovery [12, 130]

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

- vincristine** 2 mg on day 1 + #doxorubicin 25 mg/m²/day on days 1–3 as a continuous 24-hour infusion (total cumulative dose of 75 mg/m² over 72 hours) + #ifosfamide** 2.5 g/m² IV as a 3-hour infusion on days 1–4 IV with concomitant mesna**; lipeg/pegfilgrastim per instructions on day 5, or filgrastim** per instructions on days 5–14 or until neutrophil recovery. Cycle duration is 21 days [108, 130].

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

• In addition to standard regimens, as a third-line and subsequent therapy, it is recommended to use:

- #regorafenib** 160 mg once daily orally for 3 weeks; cycle repeated every 4 weeks until disease progression or unacceptable toxicity [122, 130]

- #cabozantinib** 60 mg once daily orally until disease progression or unacceptable toxicity [123, 130]

- #pazopanib** 800 mg once daily orally until disease progression or unacceptable toxicity [125, 130]

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

- HD I: #ifosfamide** 2000 mg/m² on days 1–7 IV with concomitant #mesna** 800 mg/m² 3 times daily on days 1–7, lipegfilgrastim**/pegfilgrastim per instructions on day 8, or filgrastim** 5 mcg/kg/day SC per instructions on days 8–17 or until neutrophil recovery [119, 130];

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

Comment: for patients with primary mesenchymal chondrosarcoma of bone, the same chemotherapy regimens in the same sequence are recommended as for the treatment of Ewing sarcoma [109, 130].

3.2.3. Conservative treatment of patients with giant cell tumor of bone

Giant cell tumor of bone is an osteolytic bone lesion of uncertain malignant potential, characterized by a locally aggressive nature and a high rate of local recurrence. Repeated and extended surgical interventions can lead to patient disability and a reduced quality of life. Conservative surgical management is preferred, but it is associated with a high risk of local recurrence. Furthermore, in anatomically complex locations of giant cell tumor of bone, potential surgical options are severely limited. Denosumab** reduces the need for disabling surgery, is associated with rapid and clinically significant pain relief, and in metastatic disease, is associated with regression and/or stabilization of lung metastases [12, 73, 74, 75, 130]. For operable giant cell tumor of bone, it is recommended to determine the scope of potential surgical treatment prior to initiating therapy.

• To prevent osteonecrosis and hypocalcemia, it is recommended to take daily prophylactic calcium supplements combined with vitamin D and/or other agents (A11CC, A12AX). The duration of therapy may be extended due to a continuing treatment response or in anatomically complex disease locations, taking into account the high risks of postoperative complications and disease recurrence [103–107, 130].

LoE AGoE 3Level of Evidence – A (Grade of Recommendation – 3).

3.3. Treatment of metastatic and recurrent tumor disease

Comments: IV ifosfamide** and high-dose IV methotrexate** are most commonly used. The use of etoposide** is unwarranted as its efficacy in the treatment of osteosarcomas has not been proven. If metastases appear more than 6 months after multimodal treatment, the previously used chemotherapy regimen may be repeated. In case of earlier progression, other cytostatic combinations should be used.

Comments: in lung metastases, complete surgical removal of metastases can achieve a 40% 5-year survival rate.

• In recurrent Ewing sarcoma, palliative therapy is recommended, except for patients with local recurrence following a prolonged disease-free interval [19, 20, 37, 38, 39].

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

Comments:

- The only significant prognostic factor in recurrence is the time of its onset: patients who experience recurrence later than 2 years after diagnosis have better outcomes.

- Patients with metastatic disease should receive the same standardized chemotherapy as patients with localized disease, combined with appropriate local treatment of metastases (primarily radiotherapy).

- In patients with pulmonary osteosarcoma metastases, increased survival can be achieved by resection of residual metastases only after effective chemotherapy.

- Patients with bone or bone marrow metastases have a poor prognosis (5-year survival rate of less than 20%). In the presence of bone metastases, radiotherapy is indicated.

Comments: giant cell tumor is characterized by a low metastatic potential not exceeding 6%. In case of negative dynamics during maintenance therapy, it is recommended to resume therapy once every 28 days or use alternative local control methods (radiotherapy, proton therapy, transarterial embolization of tumor-feeding vessels). Prior to treatment initiation, a prophylactic dental examination of the oral cavity and systematic daily oral hygiene are recommended during denosumab** therapy [111-113].

Comments: drug therapy options for advanced chordoma are limited. #imatinib**, #dasatinib**, and #sorafenib** are the agents with the highest level of evidence for efficacy in progressive chordoma and represent reasonable palliative treatment options to slow disease progression or alleviate symptoms [116, 117, 118, 130].

Comments: conventional chondrosarcoma is characterized by low sensitivity to drug therapy. Exceptions are mesenchymal and dedifferentiated chondrosarcomas, which have an unfavorable prognosis. For these subtypes, it is recommended to follow the same treatment principles as for Ewing sarcoma and osteosarcoma, respectively.

3.4. Supportive care

The principles of treatment and prevention of nausea and vomiting in patients correspond to the principles outlined in the clinical guidelines "Prevention and Treatment of Nausea and Vomiting" (Authors: Vladimirova L.Yu., Gladkov O.A., Kogonia L.M., Koroleva I.A., Semiglazova T.Yu. DOI: 10.18027/2224–5057–2018–8–3s2–502–511; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-35.pdf).

The principles of treatment and prevention of bone complications in patients correspond to the principles outlined in the clinical guidelines "Use of Bone-Modifying Agents for the Prevention and Treatment of Bone Pathology in Malignant Neoplasms" (Authors: Manzyuk L.V., Bagrova S.G., Kopp M.V., Kutukova S.I., Semiglazova T.Yu. DOI: 10.18027/2224–5057–2018–8–3s2–512–520; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-36.pdf).

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients correspond to the principles outlined in the clinical guidelines "Treatment of Infectious Complications of Febrile Neutropenia and Administration of Colony-Stimulating Factors" (Authors: Sakaeva D.D., Orlova R.V., Shabaeva M.M. DOI: 10.18027/2224–5057–2018–8–3s2–521–530; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-37.pdf).

The principles of prevention and treatment of hepatotoxicity in patients correspond to the principles outlined in the clinical guidelines "Management of Hepatotoxicity" (Authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V. DOI: 10.18027/2224–5057–2018–8–3s2–531–544; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-38.pdf).

The principles of prevention and treatment of cardiovascular complications in patients correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Management of Cardiovascular Toxicity Caused by Antineoplastic Drug Therapy" (Authors: Vitsenya M.V., Ageev F.T., Gilyarov M.Yu., Ovchinnikov A.G., Orlova R.V., Poltavskaya M.G., Sycheva E.A. DOI: 10.18027/2224–5057–2018–8–3s2–545–563; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-39.pdf).

The principles of prevention and treatment of dermatological complications in patients correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Drug Treatment of Dermatological Reactions in Patients Receiving Antineoplastic Drug Therapy" (Authors: Koroleva I.A., Bolotina L.V., Gladkov O.A., Gorbunova V.A., Kruglova L.S., Manzyuk L.V., Orlova R.V. DOI: 10.18027/2224–5057–2018–8–3s2–564–574; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-40.pdf).

The principles of nutritional support in patients correspond to the principles outlined in the clinical guidelines "Practical Guidelines for Nutritional Support in Cancer Patients" (Authors: Sytov A.V., Leiderman I.N., Lomidze S.V., Nekhaev I.V., Khoteev A.Zh. DOI: 10.18027/2224–5057–2018–8–3s2–575–583; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-41.pdf).

The principles of prevention and treatment of nephrotoxicity in patients correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Management of Antineoplastic Drug-Induced Nephrotoxicity" (Authors: Gromova E.G., Biryukova L.S., Dzhumabaeva B.T., Kurmukov I.A. DOI: 10.18027/2224–5057–2018–8–3s2–591–603; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-44.pdf).

The principles of prevention and treatment of thromboembolic complications in patients correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" (Authors: Somonova O.V., Antukh E.A., Elizarova A.L., Matveeva I.I., Selchuk V.Yu., Cherkasov V.A., DOI: 10.18027/2224–5057–2018–8–3s2–604–609; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-45.pdf)

The principles of prevention and treatment of drug extravasation sequelae in patients correspond to the principles outlined in the clinical guidelines "Guidelines for the Management of Antineoplastic Drug Extravasation Sequelae" (Author: Buydenok Yu.V. DOI: 10.18027/2224–5057–2018–8–3s2–610–616; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-46.pdf).

The principles of prevention and treatment of immune-mediated adverse events in patients correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Management of Immune-Mediated Adverse Events" (Authors: Protsenko S.A., Antimonik N.Yu., Bershtein L.M., Novik A.V., Nosov D.A., Petenko N.N., Semenova A.I., Chubenko V.A., Yudin D.I., DOI: 10.18027/2224–5057–2018–8–3s2–636–665; https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-48.pdf).

• To control nausea and vomiting induced by polychemotherapy, it is recommended to use serotonin antagonists (serotonin 5-HT₃ receptor blockers) [8, 28, 77].

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

• Medical nutrition therapy

The organization of medical nutrition therapy for patients with (name of clinical guidelines) during inpatient treatment in medical organizations is carried out in accordance with current orders of the Russian Ministry of Health

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

• For patients who have completed the combined treatment stage, follow-up is recommended (B04.027.001 Dispensary visit (examination, consultation) by an oncological specialist) with examinations every 3 months for the first 2 years, then every 6 months up to 5 years. The minimum diagnostic scope includes computed tomography of the chest cavity [19, 34].

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

Comments: the objective of monitoring is the early detection of disease progression for the prompt initiation of chemotherapy or surgical treatment of resectable metastatic lesions and recurrent tumors, prevention of orthopedic complications, and early detection of endoprosthesis instability.

• For patients with osteosarcoma, radiography of the affected skeletal bone is additionally recommended [1, 6, 8, 10, 12].

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 the provision of medical care in the profile "oncology", mandatory for implementation throughout 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 sarcoma is suspected or detected in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the prescribed manner for a consultation at an outpatient oncological care center, a primary oncological office, or a primary oncological department of a medical organization to receive 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 sarcoma is suspected or detected during the provision of emergency medical care, patients are transferred or referred to medical organizations providing medical care to cancer patients 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 an emergency or urgent form are:

1) presence of sarcoma complications requiring specialized medical care in an emergency and urgent form;

2) presence of treatment complications (surgery, radiotherapy, drug therapy, etc.) of sarcoma.

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

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

2) presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy, including brachytherapy, teletherapy, and other types of radiation therapy, drug therapy, etc.) requiring monitoring in a 24-hour or day hospital setting.

Indications for discharging a patient from a medical organization are:

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

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day hospital setting established by the multidisciplinary team of the medical organization providing cancer care, 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 of the appropriate medical profile. The conclusion on the feasibility of transferring a patient to a specialized medical organization is made after a prior consultation based on the provided medical documents and/or preliminary examination data by specialists of the receiving medical organization.

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

2) core needle biopsy of superficially located organs (lymph nodes, soft tissue neoplasms).

Indications for referring a patient to another medical organization:

— clinical guidelines are intended 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 scope of medical care, it is recommended to use the referral system to route patients to other medical organizations, including outside the federal subject, and to federal centers with the appropriate equipment and personnel;

— clinical guidelines cannot describe the full diversity of actual 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 despite contraindications, progression during recommended treatments, etc.), it is recommended to use telemedicine consultations or referral to national medical research centers to clarify management tactics;

— identification or exacerbation of a comorbid pathology unrelated to the profile of the oncological institution that hinders the current stage of treatment (e.g., acute myocardial infarction, acute cerebrovascular accident, etc.) requires routing the patient to specialized medical organizations.

7. Additional Information

Adverse factors affecting treatment outcomes:

1) development of infectious complications;

2) development of instability in arthroplasty;

3) presence of a pathological fracture;

4) development of anemia or thrombocytopenia syndromes requiring blood component transfusions;

5) prolongation of intervals between chemotherapy administrations;

6) dose reduction of chemotherapy drugs;

7) non-compliance of the patient with recommendations, both during treatment and during follow-up monitoring.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

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

2. Anisenya Ilya Ivanovich, PhD, Senior Researcher at the Cancer Research Institute, Tomsk National Research Medical Center, Expert of the Eastern European Sarcoma Group.

3. Bukharov Artem Viktorovich, PhD, Senior Researcher at the National Medical Research Center for Radiology of the Russian Ministry of Health.

4. Bokhyan Beniamin Yurikovich, PhD, Senior Researcher at the Department of Musculoskeletal Tumors, Scientific Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Coordinator of the Eastern European Sarcoma Group.

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

6. Gafton Georgy Ivanovich, MD, PhD, Professor, Head of Scientific Department, Leading Researcher at the N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Expert of the Eastern European Sarcoma Group.

7. Egorenkov Vitaly Viktorovich, PhD, Deputy Chief Medical Officer at the St. Petersburg Clinical Scientific and Practical Center for Specialized Medical Care (Oncological), Expert of the Eastern European Sarcoma Group.

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

9. Kurilchik Alexander Alexandrovich, PhD, Leading Researcher at the 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.

10. Musaev Elmar Rasimovich, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Vertebral Surgery Department, Scientific Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Expert of the Eastern European Sarcoma Group.

11. Safin Ildar Rafailovich, PhD, Senior Researcher at the Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan, Expert of the Eastern European Sarcoma Group.

12. Sokolovsky Anatoly Vladimirovich, MD, PhD, Researcher at the Department of Musculoskeletal Tumors, Scientific Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Expert of the Eastern European Sarcoma Group.

13. Sokolovsky Vladimir Alexandrovich, MD, PhD, Leading Researcher at the Department of Musculoskeletal Tumors, Scientific Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Expert of the Eastern European Sarcoma Group.

14. Denis I. Sofronov, Cand. of Sci. (Med.), Research Associate, Department of Musculoskeletal Tumors, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology; Expert, Eastern European Sarcoma Group.

15. Evgeny A. Sushentsov, Dr. of Sci. (Med.), Senior Research Associate, Department of Musculoskeletal Tumors, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology; Scientific Secretary, Eastern European Sarcoma Group.

16. Anastasia A. Tararykova, Cand. of Sci. (Med.), Oncologist, Department of Musculoskeletal Tumors, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology; Expert, Eastern European Sarcoma Group.

17. Valery V. Teplyakov, Dr. of Sci. (Med.), Professor, Head of the Department of Oncological Orthopedics with Combined Treatment Methods, Russian Scientific Center of Roentgenology and Radiology, Russian Ministry of Health; Expert, Eastern European Sarcoma Group.

18. Alexander A. Fedenko, Dr. of Sci. (Med.), Professor of the RAS, Head of the Chemotherapy Department, National Medical Research Center for Radiology, Russian Ministry of Health; Executive Director, Eastern European Sarcoma Group.

19. Yulia V. Gumenetskaya, Head of the Radiotherapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

20. Irina V. Bulycheva, Pathologist, Department of Pathology, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology.

21. Ilkin M. Mikayilov, Trauma Surgeon and Orthopedic Surgeon, Research Department of Neuroorthopedics with Bone Oncology, Vreden National Medical Research Center of Traumatology and Orthopedics, Russian Ministry of Health.

Medical Care Organization Section

1. Yuri A. Fomenko, Cand. of Sci. (Med.), Deputy General Director for Clinical and Expert Work, National Medical Research Center of Oncology, Russian Ministry of Health.

2. Sergey A. Ivanov, Dr. of Sci. (Med.), Professor, Corresponding Member of the RAS, Honored Physician of the RF, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology, Russian Ministry of Health; Chief freelance oncologist of the Central Federal District, Russian Ministry of Health.

3. Zhanna V. Khaylova, Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

4. Yuri I. Komarov, Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health.

Supportive Care Section

1. Oleg A. Gladkov, Professor, Dr. of Sci. (Med.), Director of EVIMED Medical Center LLC.

2. Vera V. Karaseva, Dr. of Sci. (Med.), Associate Professor, Professor, Department of Oncology, Institute of Professional Education, Pirogov Russian National Research Medical University, Russian Ministry of Health.

Conflict of interest. All working group members declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1) oncologists, orthopedic trauma surgeons, surgeons, general practitioners, radiologists, pediatricians;

2) faculty and students of medical educational institutions, residents and postgraduate students.

Methods used for evidence collection/selection: search in electronic databases; analysis of current scientific developments on the diagnosis and treatment of sarcomas 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 А2. Levels of evidence (LoE) rating scale for preventive, diagnostic, therapeutic, and rehabilitation methods (interventions)

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 expert review;

- internal expert review.

Description of the recommendation validation method. The preliminary version of these guidelines was peer-reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the guidelines is easily understandable.

Feedback was received from primary care oncologists regarding the clarity of the recommendations and their assessment of their importance as a working tool in daily practice.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and the resulting changes to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and Expert 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 guidelines.

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-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of patients with bone sarcomas, or if there are justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

The decision to update is made by the Russian Ministry of Health based on proposals submitted by medical professional associations. The formulated proposals must take into account the results of a comprehensive assessment of medicinal products and medical devices, as well as the results of clinical approbation.

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

1. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of the Criteria for Assessing the Quality of Medical Care".

2. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (ed. of January 15, 2025) <On Approval of the List of Vital and Essential Drugs, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care.>

3. Decree of the Government of the Russian Federation No. 588 dated April 5, 2022 "On Recognition of a Person as Disabled."

4. Order of the Ministry of Labor of Russia No. 374n dated July 26, 2024 "On Approval of Classifications and Criteria Used in Carrying Out Medical and Social Expertise of Citizens by Federal Medical and Social Expertise Institutions" (Registered with the Ministry of Justice of Russia on August 23, 2024, No. 79273)

5. Federal Law No. 351-FZ dated December 9, 2010, «On Amendments to the Federal Law „On Veterans“ and Articles 11 and 11.1 of the Federal Law „On Social Protection of Disabled Persons in the Russian Federation.“»

Appendix B. Physician Action Algorithms

Table App3. Flowchart for the diagnosis and treatment of a patient with bone sarcoma

Algorithm for the diagnosis and treatment of osteosarcoma

Appendix C. Patient Information

1. Patients with any form of bone sarcoma are not removed from clinical dispensary observation.

2. Recommendations for chemotherapy complications  contact an oncologist:

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

- consult the attending oncologist;

2) for stomatitis:

- diet – mechanical and thermal sparing;

- frequent mouth rinsing (every hour) – chamomile, oak bark, sage, lubricate the mouth with sea buckthorn (peach) oil;

- treat the oral cavity according to the oncologist's recommendation;

3) for diarrhea:

- diet – exclude fatty, spicy, smoked, sweet foods, dairy products, and fiber. Lean meat, flour products, fermented milk products, and rice decoction are permitted. Drink plenty of fluids;

- take medications as prescribed by the oncologist;

4) for nausea:

- take medications as prescribed by the oncologist.

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

No.