Uterine Body Cancer and Uterine Sarcomas: Clinical Guidelines

List of Abbreviations

IV - Intravenous

WHO - World Health Organization

G-CSF - Colony-stimulating factors

EBRT - External beam radiation therapy

Malignant neoplasm

CT — computed tomography

RT - Radiation therapy

MRI — magnetic resonance imaging

PET - Positron emission tomography

PET-CT - Positron emission tomography-computed tomography

UCC - Uterine corpus cancer

CA-125 - Cancer antigen 125

Ultrasound — ultrasound examination

CT - Chemotherapy

dMMR - Deficient mismatch repair

ECOG - Eastern Cooperative Oncology Group

ESGO - European Society of Gynaecological Oncology

ESMO - European Society for Medical Oncology

ESTRO - European Society for Radiotherapy & Oncology

IMRT - Intensity Modulated Radiation Therapy

MMR - Mismatch repair

MSI-H - Microsatellite instability-high

PD-L1 (programmed cell death 1 ligand) - Programmed death-ligand 1

** - Vital and essential drugs

# - Off-label drug (used outside of the indications, contraindications, routes of administration, or dosages contained in the drug's package insert)

Terms and Definitions

Extrafascial hysterectomy – hysterectomy with minimal vaginal resection, without excision of the pubocervical ligament; the cardinal ligament is transected close to the uterus (Type I operation according to the classification of M.S. Piver, 1974).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Uterine corpus cancer (UCC) – a malignant tumor originating from the mucous membrane of the uterine corpus (endometrium).

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

In the majority of patients, UCC is sporadic. In approximately 5% of cases, UCC is associated with hereditary syndromes, notably Lynch syndrome [1]. Risk factors for this pathology include hyperestrogenism, early menarche, nulliparity, late menopause, age over 55 years, and tamoxifen use [2, 3]. Two pathogenetic types of UCC are distinguished [4].

Type I (more common). The tumor develops at a younger age compared to patients with the type II pathogenetic variant, against the background of prolonged hyperestrogenism and endometrial hyperplasia. Patients with type I pathogenetic UCC frequently present with obesity, diabetes mellitus, and hypertension; estrogen-secreting ovarian tumors or polycystic ovary syndrome are possible. Tumors of the type I pathogenetic variant are typically high-grade (well-differentiated) and have a more favorable prognosis.

Type II. Endometrial tumors are usually low-grade (poorly differentiated) and have a less favorable prognosis. Tumors of the type II pathogenetic variant occur at an older age, in the absence of hyperestrogenism, against the background of endometrial atrophy.

Approximately 80% of patients with UCC are diagnosed with endometrioid adenocarcinoma.

Uterine sarcomas include mesenchymal tumors, as well as mixed epithelial and mesenchymal tumors. The group of malignant mesenchymal tumors comprises leiomyosarcoma, endometrial stromal and related tumors. Mixed epithelial and mesenchymal tumors include adenosarcoma and carcinosarcoma. Genetic and molecular studies have demonstrated similarities in the molecular profiles of uterine carcinosarcoma and low-grade UCC, indicating the epithelial origin of carcinosarcoma.

1.3 Epidemiology of the Disease or Condition

In 2021, 25,482 cases of malignant neoplasms (MN) of the uterine corpus were detected. The crude incidence rate in 2021 was 32.62 per 100,000 female population. Over 10 years, this rate increased by 21.93%, with an average annual growth rate of about 1.96%. Over the same period, the age-standardized incidence rate (standardized to the world population age distribution) increased by 9.52%, reaching 17.34 per 100,000 population in 2021, with an average annual growth rate of 0.9%.

In the 65–69 age group, the highest incidence rate is observed—91.3 cases per 100,000 female population of the corresponding age. In the 60–64 and 70–74 age groups, malignant neoplasms of the uterine corpus rank 2nd in the structure of cancer incidence (86.4 and 88.7, respectively); in the 55–59 and 75–79 age groups, they rank 3rd; in the 50–54 and 80–84 age groups, they rank 4th; and in other age groups, 6th and below.

In 2021, 6,734 women died from malignant neoplasms of the uterine corpus. In the structure of female cancer mortality causes, malignant neoplasms of the uterine corpus rank 8th (5.2%).

Over a 10-year trend, the crude mortality rate from malignant neoplasms of the uterine corpus increased insignificantly by 0.68%, amounting to 8.62 per 100,000 female population in 2021, whereas the age-standardized mortality rate for women from malignant neoplasms of the uterine corpus is decreasing: in 2011 it was 4.32, and in 2021 it was 3.86 per 100,000 female population; a decrease of 13.2%, which indicates a true decline in mortality from this pathology. The highest mortality rates are noted in the age groups of 75 years and older—from 31.5 to 32.94 per 100,000 female population of the corresponding age [5].

1.4 Features of Coding the Disease or Condition

D07.0 – Endometrial carcinoma in situ

C54 Malignant neoplasm of uterine corpus:

C54.0 Isthmus uteri (lower uterine segment)

C54.1 Endometrium

C54.2 Myometrium

C54.3 Fundus uteri

C54.8 Overlapping lesion of uterine corpus

C54.9 Malignant neoplasm of uterine corpus, unspecified

C55 Malignant neoplasm of uterus, part unspecified

1.5 Classification of the disease or condition

International Histological Classification of UCC (World Health Organization (WHO) Classification, 5th Edition, 2020) [6 - 8]

There are 3 degrees of differentiation of endometrial adenocarcinoma:

G₁ – well-differentiated

G₂ – moderately differentiated

G₃ – poorly differentiated

According to the 2020 WHO classification, endometrioid carcinoma should be categorized into low-grade and high-grade; low-grade tumors include G1 and G2, while high-grade tumors include G3.

Staging

Staging of endometrial cancer and uterine sarcomas is performed according to the TNM (8th edition, 2017) and FIGO (2009) classifications (Tables 1, 2).

Table 1 presents the staging classification for endometrial cancer and carcinosarcoma, and Table 2 presents the staging classification for uterine leiomyosarcoma and endometrial stromal sarcoma.

Table 1. Stages of endometrial cancer and uterine carcinosarcoma according to the TNM system (8th edition, 2017) and FIGO classification (2009)

Table 2. Stages of uterine leiomyosarcoma and endometrial stromal sarcoma according to the TNM system (8th edition, 2017) and FIGO classification (2009)*

Simultaneous involvement of the uterine corpus and ovaries/pelvis in the setting of endometriosis should be interpreted as synchronous primary malignancies.

1.6 Clinical presentation of the disease or condition

The main clinical manifestations of malignant neoplasms of the uterine corpus are acyclic uterine bleeding during the reproductive period or postmenopausal bleeding. Sometimes malignant neoplasms of the uterine corpus are asymptomatic and detected in asymptomatic women during pelvic ultrasound (ultrasound examination). Malignant neoplasms of the uterine corpus may be accompanied by chronic anemia, as well as rapid growth of myomatous nodes and enlargement of the uterus.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of the disease or condition:

1) anamnesis data;

2) physical examination findings;

3) pathomorphological examination data of biopsy and/or surgical material from the uterine cavity;

4) diagnostic imaging findings.

2.1 Complaints and Anamnesis

Comment: the main symptom of endometrial cancer is acyclic uterine bleeding in the reproductive period or bleeding in the postmenopausal period. The intensity of bleeding does not correlate with the risk of endometrial cancer. Sometimes endometrial cancer is detected in asymptomatic women during pelvic ultrasound and subsequent examination or during cytological screening for cervical cancer. Special attention should be paid to long-standing anemia syndrome, as well as rapid growth of myomatous nodes.

2.2 Physical Examination

Comment:

- Special attention should be paid to assessing the patient's performance status according to the WHO/ECOG scale and/or the Karnofsky scale (see Appendix G1-2), and assessing nutritional status.

- During a vaginal (gynecological) examination, the mucous membrane of the cervix and vagina is visually inspected to detect potential tumor extension to the ectocervix or metastases in the vaginal wall. Bimanual gynecological examination assesses the condition of the parametria.

- Physical examination must include palpation of the inguinal, supraclavicular, and infraclavicular lymph nodes to rule out potential metastatic enlargement.

2.3 Laboratory Diagnostics

Comment:

Laboratory tests determine the functional state of various organs and systems to establish the feasibility of a particular type of treatment.

In a complete blood count (CBC), it is advisable to assess the following parameters: hemoglobin, red blood cells, platelets, white blood cells, hematocrit, mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC), differential white blood cell count (leukocyte formula), and erythrocyte sedimentation rate (ESR);

- a complete blood count (CBC) is performed (repeated) at least 5 days before the start of the next cycle of chemotherapy, radiation therapy, or targeted therapy, if administered [10].

- in the general biochemical blood test with evaluation of liver and kidney function parameters: study of total protein, glucose, total bilirubin, creatinine, blood urea, determination of the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) in the blood, study of

total bilirubin level in the blood; in some cases, plasma electrolytes (blood potassium, sodium, and chloride levels), etc.;

- in urinalysis: visual examination of urine (color and clarity), specific gravity (relative density), urine protein, hydrogen ion concentration (pH), urine glucose, ketone bodies, and microscopic examination of urine sediment.

- as part of the blood coagulation study, a coagulogram (exploratory hemostasis test) is evaluated (blood fibrinogen, prothrombin time by Quick, international normalized ratio (INR), prothrombin time (PT) in blood or plasma, activated partial thromboplastin time (APTT), and thrombin time (TT)). As indicated, additional tests include D-dimer concentration, antithrombin III activity, etc.

Comment: An elevated CA125 level is an indirect sign of tumor spread beyond the uterus.

2.4 Instrumental Diagnostics

Comment:

- Ultrasound is the simplest and most accessible method for visualizing the spread of the tumor process in the pelvic cavity, abdominal cavity, retroperitoneal space, as well as regional and distant lymph nodes.

- For pelvic ultrasound, transabdominal and transvaginal (TVUS) approaches should be used; if TVUS is not feasible, transrectal ultrasound should be performed.

- For patients of reproductive age, the endometrial thickness (M-echo) in the proliferative phase of the menstrual cycle is no more than 12 mm. For postmenopausal patients, the M-echo thickness is no more than 5 mm. If these M-echo thickness values are exceeded, neoplastic endometrial processes must be ruled out. [12, 128, 129]

- The use of color Doppler mapping (CDM), power Doppler imaging (PDI), elastography, and contrast-enhanced ultrasound (CEUS) increases the diagnostic value of the method in the differential diagnosis of malignant tumors of the uterine body and the assessment of primary tumor extent [130].

Comment:

- The diagnosis is established based on the results of endometrial aspiration biopsy and/or fractional diagnostic curettage of the cervical canal and uterine cavity with or without hysteroscopy, based on pathomorphological examination of the biopsy (surgical) material, with mandatory indication of the histological type and grade of the tumor differentiation.

- Hysteroscopy is essential when extension of the tumor process to the cervical canal is suspected or to determine the feasibility of standalone hormone therapy.

Comment:

- Pelvic MRI with intravenous contrast is the most informative method for assessing the depth of myometrial tumor invasion [128, 133]. The MRI protocol for assessing myometrial invasion in endometrial cancer should include: high-resolution T2-weighted images (WI) obtained in a plane perpendicular to the uterine cavity; diffusion-weighted imaging (DWI); dynamic contrast-enhanced (DCE) MRI with images obtained in the post-contrast phases at 30-60 sec, 120-180 sec, and 4-5 min [128, 134, 135].

- Pelvic MRI with intravenous contrast is a mandatory method when planning fertility-sparing treatment (in early stages of the disease) [136, 137].

- Contrast-enhanced pelvic computed tomography (CT) in women may be performed, if MRI is not feasible, in patients with malignant tumors of the uterine body to assess extrauterine invasion. Pelvic CT is not recommended for assessing the depth of myometrial invasion due to its low diagnostic accuracy, which is inherent to the physical principles of the method [14, 15, 16].

Comment:

– It should be borne in mind that at the time of surgery, metastatic lymph nodes are enlarged in fewer than 10% of patients with early-stage endometrial cancer. Further diagnostic evaluation of metastatic lymph node involvement is necessary to determine the extent of the surgical intervention.

– If a patient has contraindications to intravenous contrast enhancement during CT, the diagnostic accuracy of the method in assessing tumor spread is reduced; [18F]fluorodeoxyglucose ([18F]-FDG) PET-CT may be prescribed as an alternative imaging modality [18].

– In cases of histologically verified high-grade or undifferentiated uterine sarcomas, whole-body [18F]-FDG PET-CT using a tumor-tropic radiopharmaceutical is recommended when the results of other imaging modalities (ultrasound, MRI, CT) used to diagnose distant metastasis and lymph node status are inconclusive [138, 139].

– If chest CT is not feasible, targeted chest radiography is recommended for diagnosing metastatic lung lesions [9, 10, 19].

Comment: if MRI is not feasible and/or if there are contraindications, contrast-enhanced brain CT may be performed.

2.5 Other Procedures

reflecting the following parameters in the report [4]:

- histological type of the tumor;

- tumor grade;

- tumor size;

- depth of tumor invasion;

- myometrial thickness at the site of maximum tumor invasion;

- tumor invasion of the uterine serosa;

- presence or absence of tumor emboli in blood and lymphatic vessels ( lymphovascular invasion). If lymphovascular invasion is present, its grade must be specified (focal invasion – a single focus of invasion, substantial/marked invasion ≥5 vessels);

- extension of the tumor to the cervix, invasion into the cervical stroma;

- extension of the tumor into the parametrium;

- extension of the tumor to the vagina;

- total number of removed and affected pelvic lymph nodes on the right and left;

- total number of removed and affected para-aortic lymph nodes;

- metastatic involvement of the ovaries and fallopian tubes;

- tumor invasion into the wall of the urinary bladder or rectum (when pelvic exenteration or resection of adjacent organs is performed);

- degree of therapeutic pathomorphosis of the primary tumor and lymph node metastases in case of preoperative therapy.

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

Comment:

– In case of inconclusive results of the pathomorphological examination of biopsy material, patients with suspected malignant neoplasms of the uterus are indicated to undergo either a repeat biopsy or surgical intervention with pathomorphological examination of the biopsy (surgical) material, including intraoperative examination. In case of inconclusive results of the pathomorphological examination of biopsy (surgical) material in patients with suspected or confirmed malignant neoplasms of the uterus, pathomorphological examination of the biopsy (surgical) material using immunohistochemical methods is indicated for clarification purposes in order to determine further management tactics.

Comment:

– For endometrial malignancies, immunohistochemical testing for dMMR is the method of choice; it is advisable to assess the expression of 4 MMR proteins: MLH1, MSH2, MSH6, and PMS2. Alternative methods (PCR, NGS) can be used as an additional study method in case of inconclusive immunohistochemical testing results or when immunohistochemical testing is not feasible [184].

– In the serous subtype of endometrial cancer and in carcinosarcoma, it is advisable to determine HER2 expression, since in HER2-positive tumors, trastuzumab in combination with chemotherapy can be prescribed as early as the first line of therapy.

Comment: in the presence of somatic pathology and/or to clarify the extent of the tumor process, it is advisable to conduct additional examinations as indicated to select the optimal treatment tactics for the patient.

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

The prescription and use of medicinal products specified in the 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 may also be made taking into account the patient's condition.

3.1. Surgical treatment

• Surgical intervention is recommended as the most effective method of treatment for patients with endometrial cancer regardless of stage, either alone or in combination with other methods, provided that all manifestations of the tumor process can be completely removed [9, 17, 24–26].

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

Comment:

– Laparoscopic, laparotomic, laparoscopically assisted vaginal, and robot-assisted interventions are feasible for endometrial cancer, provided that the surgical access accomplishes the objectives of the surgical stage of treatment, including pelvic and para-aortic lymphadenectomy if indicated [24–27].

– Laparoscopic access is the primary approach in the surgical treatment of localized endometrial cancer [24, 28]. The advantage of this method lies in the reduction of peri- and postoperative complications, particularly in older patients and patients with overweight, while achieving comparable long-term treatment outcomes compared to laparotomic access [24, 28].

– In the presence of absolute contraindications to surgical treatment, radical radiation therapy (RT) or first-line chemotherapy (3–6 cycles) is performed, with the possibility of subsequently addressing the issue of surgical treatment for sanitation and prevention of bleeding risk. The scope of surgical treatment is determined depending on the stage of the disease and the patient's performance status.

• For patients with stage I endometrial cancer, surgical treatment is recommended as the most effective method [9, 17].

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

Comment:

- For high-grade stage IA endometrioid adenocarcinoma without myometrial invasion in reproductive-age patients with unfulfilled reproductive desires, standalone hormone therapy (HT) may be performed with the goal of fertility preservation [29 - 31]. This treatment option should be carried out in institutions with experience in treating such patients. Patients must be informed of the high recurrence rate after conservative treatment, as well as the necessity of surgical treatment after completing their reproductive plans. HT for endometrial cancer includes the use of a levonorgestrel-releasing intrauterine system (52 mg) and GnRH agonists. The duration of treatment is at least 9–12 months, provided that treatment efficacy is evaluated by endometrial histological examination every 3 months. In the absence of a complete histological response at 6–12 months from the start of treatment, hysterectomy is indicated. Upon achieving a complete response, pregnancy planning is possible. Realization of reproductive function is recommended as soon as possible after the end of treatment. Assisted reproductive technologies may be used. There is evidence of a marked increase in the risk of death in patients older than 40 years when using this treatment approach, and therefore its routine use in this age group is not recommended. for the purpose of diagnosis verification, determining the treatment strategy and algorithm, and assessing disease prognosis – preoperative radiotherapy is not advisable.

• The recommended scope of surgical intervention for patients with endometrial cancer is extrafascial hysterectomy with adnexectomy [9, 17].

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

Comment:

- In patients under 45 years of age with high-grade endometrial cancer with invasion of less than half the myometrial thickness and no signs of extrauterine tumor spread, ovarian preservation with hysterectomy and salpingectomy is possible [10, 26, 34]. Ovarian preservation is not advisable in the presence of BRCA1/2 gene mutations and Lynch syndrome.

- In the presence of ascites, it is necessary to collect fluid for cytological examination of the peritoneal fluid. The presence of tumor cells in the peritoneal effusion (based on cytological examination results) should be noted, but it does not affect the stage of the disease [3, 22].

- In the presence of a clinically significant pleural effusion, it is necessary to collect fluid for cytological examination of the pleural fluid [3, 22].

Comment:

- In the presence of indications for lymphadenectomy, lymph nodes of both regional zones are removed: pelvic and lumbar up to the renal vessels (level IV lymphadenectomy) in high risk. In intermediate risk – when clinical signs of lumbar lymph node involvement are present.

- In patients with intermediate risk of lymphogenic metastasis of stage I endometrioid endometrial cancer, sentinel lymph node mapping can be performed as an alternative to lymphadenectomy. In cases where mapping fails to identify sentinel lymph nodes, a full lymphadenectomy is recommended. If metastases are detected in sentinel lymph nodes, pelvic and lumbar lymphadenectomy up to the renal vessels (level IV) should be performed [141, 142, 143].

Table 3. Indications for lymphadenectomy in clinical stage I endometrial cancer (ESGO, ESMO, ESTRO consensus – European Societies of Gynaecological Oncology, Medical Oncology, and Radiotherapy and Oncology, respectively, 2014)

• For stage II endometrial cancer, surgical intervention followed by adjuvant treatment is recommended [92].

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

Comment: approximately 30% of patients with stage II endometrial cancer have pelvic lymph node metastases. The risk of para-aortic lymph node involvement, ovarian involvement, and peritoneal dissemination in clinical stage II endometrial cancer is higher than in stage I [22, 27].

• For stage III–IV endometrial cancer, it is recommended to start treatment with surgical intervention [27, 38, 39].

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

Comment:

- Surgery allows for the assessment of tumor spread and cytoreduction.

Comment:

- The greater omentum is removed in serous endometrial cancer and carcinosarcoma. There is evidence that lymphadenectomy in uterine carcinosarcoma not only allows for accurate staging but also improves patient survival. Non-endometrioid subtypes of endometrial cancer (serous, clear cell carcinoma, mixed adenocarcinoma, carcinosarcoma, dedifferentiated carcinoma) have an unfavorable prognosis. The exception is mucinous carcinoma, which in the vast majority of cases is well-differentiated and clinically similar to well-differentiated endometrioid endometrial cancer.

• For uterine leiomyosarcoma, it is recommended to perform extrafascial hysterectomy with adnexectomy [19, 42].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: in patients under 45 years of age with early-stage uterine leiomyosarcoma, ovarian preservation is permissible as it does not affect survival. Removal of pelvic and lumbar lymph nodes is not advisable because their involvement is extremely rare.

• For low-grade endometrial stromal sarcoma of the uterus, it is recommended to perform extrafascial hysterectomy and removal of macroscopically visible tumors. Pelvic and para-aortic lymphadenectomy may be advisable, but lymph node metastases do not affect overall survival [19].

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

Comment:

- Low-grade endometrial stromal sarcoma of the uterus is a hormone-dependent tumor. In stage I disease, ovarian metastases are extremely rare. Ovarian preservation in this case increases the risk of recurrence but does not affect overall survival; therefore, in young patients, ovarian preservation should be discussed individually at a multidisciplinary tumor board [43, 44].

• For high-grade endometrial stromal sarcoma of the uterus, it is recommended to perform extrafascial hysterectomy [45].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: given the extremely unfavorable prognosis, the role of lymphadenectomy and cytoreductive surgery is questionable. High-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma are extremely aggressive tumors with a tendency toward rapid hematogenous metastasis.

3.2. Adjuvant treatment

• The strategy of adjuvant therapy in patients with stage I endometrial cancer is recommended to be determined based on the scope of the performed surgical intervention [9, 46].

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

Comment:

- Indications for adjuvant external beam radiotherapy (EBRT) are determined primarily by risk factors for lymphogenous metastasis of endometrial cancer, which are completely negated by adequate lymphadenectomy. Despite the fact that none of the published randomized trials of pelvic lymphadenectomy in endometrial cancer have demonstrated an increase in survival with its performance, regional lymphadenectomy in endometrial cancer serves the following purposes: staging refinement and determining further treatment strategy [37, 38]. From the perspective of preventing regional progression, lymphadenectomy in early-stage endometrial cancer can be considered an alternative to EBRT, which is safer in terms of long-term consequences (late complications, radio-induced tumors), which is especially important in young patients.

- Indications for adjuvant treatment depend on the risk group to which the patient belongs (Table 4) [38].

Table 4. Risk groups in endometrial cancer (ESGO/ESTRO/ESP consensus, 2021)

Comment: determining the mutation status in the exonuclease domain of the polymerase epsilon (POLE) gene, assessing microsatellite instability (dMMR), detecting mutations in the p53 gene, etc., using immunohistochemistry can help refine the disease prognosis and individualize treatment tactics, but is not mandatory when deciding on adjuvant therapy.

• Adjuvant treatment for stage I–II endometrioid endometrial cancer is recommended to be carried out in accordance with the ESGO, ESMO, ESTRO consensus recommendations (2020) (Tables 5, 6) [38].

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

Table 5. Adjuvant treatment for stage I endometrioid endometrial cancer (ESGO, ESMO, ESTRO consensus, 2020)

Table 6. Adjuvant treatment for stage II endometrioid endometrial cancer (ESGO, ESMO, ESTRO consensus, 2014)

• For patients with stage III–IV endometrial cancer after surgery, external beam radiation therapy (EBRT) with concurrent or adjuvant chemotherapy (ChT), or alternatively sequential ChT followed by radiation therapy (RT), is recommended [144].

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

• In carcinosarcoma, adjuvant treatment is administered as for high-risk progression carcinomas. Alternatively, chemotherapy alone is possible [24, 35, 36, 101, 145].

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

• In non-endometrioid endometrial cancer, chemotherapy combined with brachytherapy is recommended as adjuvant treatment [190].

GCR CLEL 3Grade of Recommendation — C (Level of Evidence — 3)

Comment: the exception is stage IA clear-cell endometrial cancer (provided pelvic and para-aortic lymphadenectomy is performed) in the absence of lymphovascular space invasion, in which adjuvant brachytherapy may be administered.

3.3. Radiation therapy

• For patients with malignant neoplasms of the uterine body in the intermediate-high and high risk groups (see Table 4), considering the stage, histological type of the tumor, and extent of surgical treatment performed, it is recommended to administer RT: EBRT and/or brachytherapy, with or without adjuvant chemotherapy [11, 27, 102]. For patients with malignant neoplasms of the uterine body in the intermediate risk group for disease progression after surgery, it is recommended to perform observation (primarily for patients under 60 years of age) or brachytherapy [189].

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

Comment:

- Adjuvant RT is initiated no later than 60 days from the date of surgery or upon detection of clinical manifestations of disease progression.

External beam RT and/or brachytherapy are planned. Conformal RT IMRT/VMAT with preliminary CT or MRI-based volumetry is used.

All principles of conformal RT are taken into account when planning the irradiation volume for the pelvic region and regional metastasis zones, with or without inclusion of the para-aortic region. Brachytherapy involves both irradiation of the uterus in the absence of a surgical treatment phase and irradiation of the vaginal cuff in the postoperative period.

The planned target volume should include directly the primary tumor (in the absence of surgery), common, external, and internal iliac lymph nodes, the parametrial region, the upper third of the vagina/paravaginal region, and presacral lymph nodes (in cases of cervical tumor invasion) [42]. Extended radiation fields, according to indications, should include the pelvic volume and the region of all groups of iliac and para-aortic lymph nodes. The upper boundary of the field depends on the clinical situation and should reach the level of the L1–L2 vertebrae (or 1–2 cm above the level of the renal vessels), and, taking into account the level of para-aortic lymph node involvement, the upper boundary of the field may reach the Th12 vertebra. The CTV volume should be adjusted individually in cases of a positive vaginal resection margin, peritoneal involvement, or vaginal metastases.

Organs at risk (bladder, bowel loops) can change in volume depending on their filling degree during CT/MRI simulation, especially in patients after hysterectomy. The internal target volume (ITV), which includes the range of motion and deformation of the organs, is considered the clinical target volume (CTV) and must be fully included in the planning treatment volume (PTV). Treatment with a comfortably filled bladder reduces the radiation dose to the bowel and bladder. Repeated volumetric imaging using cone-beam CT is preferred, as it allows for smaller CTV-PTV margins, thereby reducing toxicity to normal tissues.

Postoperative conformal radiotherapy using IMRT/VMAT technology following surgery is the preferred technique. Low toxicity rates combined with high local control have been reported [42, 43].

The prescribed doses for external beam radiotherapy (EBRT) are a total dose of 45.0–50.4 Gy with a fractionation schedule of 1.8–2.0 Gy 5 times per week (the fractionation standard used in the clinic). In the presence of residual tumor in the pelvic lymph nodes or parametria, postoperative conformal radiotherapy using an integrated or sequential stereotactic boost is administered to reach total doses of 55–60 Gy (EQD2) for microscopic residual tumor or up to 66 Gy (EQD2) for macroscopic residual tumor.

The timing of postoperative irradiation of the vaginal vault depends on its healing; it is preferably performed 6 to 8 weeks, but no later than 12 weeks, after surgery. When planning postoperative brachytherapy, irradiation of no more than the upper 2/3 of the vagina to a depth of 0.5 cm from the mucosa is recommended. In cases of lymphovascular invasion or positive resection margins, the irradiated length of the vaginal vault may be increased [43–46].

Radioactive sources 60Co and 192Ir are routinely used in Russia.

• Adjuvant radiotherapy doses depend on the EBRT technique used. When definitive brachytherapy is administered, 3 fractions of 7 Gy, 5 fractions of 6 Gy, or 4 fractions of 5.5 Gy are prescribed. The 3 fractions of 7 Gy regimen is the most frequently used in clinical practice. The use of lower doses per fraction can be considered as an option for further reducing toxicity in selected cases. When EBRT is followed by brachytherapy, 2–3 fractions of 4–6 Gy are usually recommended.

If surgery is contraindicated, definitive combined radiotherapy or definitive brachytherapy is performed depending on the risk of progression. Total radiation doses depend on the clinical situation. When technical capabilities permit, preference is given to techniques with image guidance

capabilities. For definitive brachytherapy, doses should reach 48 Gy (EQD2) to the body of the uterus, cervix, and upper third (1–2 cm) of the vagina, while for combined radiotherapy, they are increased to 65 Gy (EQD2). When MRI is used, the total dose to the GTV can be increased to ≥80 Gy (EQD2).

• Palliative radiotherapy (brachytherapy, EBRT) is recommended for debilitated patients with endometrial cancer, whose performance status is assessed using the WHO/ECOG scale >2 scores and/or the Karnofsky scale ≤70 scores (see Appendix G1-2), in cases where other treatment options are not feasible due to severe concomitant comorbidities [191].

GCP CLEL 4Level of Evidence – C (Level of Likelihood of Evidence – 4)

Comment: Total doses can reach 40–50 Gy. For small tumor volumes where radical radiotherapy is not feasible, a hypofractionation regimen may be used [146].

• In cases of endometrial cancer recurrence in the vaginal vault or the presence of a vaginal metastasis as the sole manifestation of the disease, brachytherapy and/or EBRT are recommended, taking into account prior radiotherapy [146].

LoE CGoR 5Level of evidence – C (grade of recommendation – 5)

Comment: the total dose is planned taking into account previous treatment, reaching 30–50 Gy (EQD2) for the planned tumor volume [84].

3.4. Medical treatment

• In patients with a history of pelvic radiotherapy, primary prophylaxis with colony-stimulating factors (G-CSF) is recommended: filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the therapy regimen and until neutrophil counts recover from their nadir, or pegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after completion of chemotherapy administration in platinum-based regimens, or dose reduction of the drugs (e.g., carboplatin** AUC 5) [123, 125, 131, 146].

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

• Adjuvant/systemic chemotherapy is recommended for stage III–IV endometrial cancer and for non-endometrioid endometrial cancer of all stages (except mucinous endometrial cancer) following cytoreductive surgery [17, 38, 60–66, 188].

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

Comment:

Chemotherapy should preferably be initiated no later than 4 weeks after surgery. Typically, 6 courses of chemotherapy are administered according to one of the following regimens (radiotherapy is administered according to indications; see corresponding section):

- #paclitaxel** 175 mg/m² on day 1 and carboplatin** AUC 5–6 on day 1 every 3 weeks [64, 146]. According to indications, primary or secondary prophylaxis with colony-stimulating factors (G-CSF) is performed: filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the therapy regimen and until neutrophil counts recover from their nadir, or pegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after completion of chemotherapy administration [193];

- #paclitaxel** 175 mg/m² on day 1 and #cisplatin** 60–75 mg/m² on day 1 every 3 weeks. According to indications, primary or secondary prophylaxis with colony-stimulating factors (G-CSF) is performed: filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the therapy regimen and until neutrophil counts recover from their nadir, or pegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after completion of chemotherapy administration [62, 65, 66, 146, 193];

• Chemotherapy is recommended as first-line treatment for progressive endometrial cancer (6 courses of chemotherapy are administered, or until disease progression, or until unacceptable toxicity occurs) [61–75]. The regimens of choice are platinum- and taxane-based combinations.

GCP CLEL 2Level of Evidence – C (Level of Likelihood of Evidence – 2).

Comment: the following regimens are used:

- #paclitaxel** 175 mg/m² IV over 3 hours on day 1 and #cisplatin** 60 or 75 mg/m² IV over 2 hours on day 1 every 3 weeks. According to indications, primary or secondary prophylaxis with colony-stimulating factors (G-CSF) is performed: filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the therapy regimen and until neutrophil counts recover from their nadir, or pegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after completion of chemotherapy administration [65, 66, 114];

- #paclitaxel** 175 mg/m² IV over 3 hours on day 1 and carboplatin** AUC 5–6 IV over 1 hour on day 1 every 3 weeks; according to indications, primary or secondary prophylaxis of febrile neutropenia with colony-stimulating factors (G-CSF) is performed: filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the therapy regimen and until neutrophil counts recover from their nadir, or pegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after completion of chemotherapy administration [64, 70, 114];

- doxorubicin** 50–60 mg/m² IV on day 1 and #cisplatin** 50–75 mg/m² IV on day 1 every 3 weeks [62, 63, 146];

- #paclitaxel** 175 mg/m² IV over 3 hours on day 1, carboplatin** AUC 5–6 IV over 1 hour on day 1 every 3 weeks, and #trastuzumab** 8 mg/kg for the first infusion, then 6 mg/kg IV over 30–90 minutes every 3 weeks; according to indications, primary or secondary prophylaxis with colony-stimulating factors (G-CSF) is performed: filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the therapy regimen and until neutrophil counts recover from their nadir, or pegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after completion of chemotherapy administration (for patients with HER2/neu-positive serous endometrial carcinoma) [61, 146];

- #paclitaxel** 175 mg/m² IV over 3 hours on day 1, carboplatin** AUC 5–6 IV over 1 hour on day 1 every 3 weeks, and #pembrolizumab 200 mg IV infusion over 30 minutes every 3 weeks or 400 mg IV every 6 weeks (in case of MSI/MMR deficiency in the tumor). Pembrolizumab is administered for 2 years or until disease progression or unacceptable toxicity. According to indications, primary or secondary prophylaxis with colony-stimulating factors (G-CSF) is performed: filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the therapy regimen and until neutrophil counts recover from their nadir, or pegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after completion of chemotherapy administration [186, 146, 193];

• In case of a late recurrence (≥2 years) of endometrial cancer, a repeated tumor biopsy is recommended [76]. For the serous subtype of endometrial cancer with a disseminated process and progression, an immunohistochemical pathological examination of the HER2/neu receptor protein (determination of HER2/neu status) in the tumor sample is recommended to decide on the advisability of hormone therapy. In case of recurrence of highly differentiated endometrioid adenocarcinoma, small tumor volumes, and indolent course, hormone therapy is recommended [77 - 82].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: the following hormone therapy regimens for endometrial cancer recurrence are used (administered until disease progression or unmanageable toxicity):

- medroxyprogesterone** 500 mg/day orally daily [146];

- #tamoxifen** 20 mg orally once daily [146];

- #letrozole 2.5 mg/day orally daily [81];

- #anastrozole** 1 mg/day orally daily [81];

- #exemestane 25 mg/day orally daily [82].

• For patients with stage I uterine leiomyosarcoma, follow-up is recommended after radical surgical treatment [83].

GCP CLEL 2Level of Evidence – C (Level of Likelihood of Evidence – 2).

• Chemotherapy is recommended for high-grade uterine leiomyosarcoma, high-grade endometrial stromal sarcoma of the uterus, and undifferentiated uterine sarcoma of all stages [84 - 90].

GCP CLEL 2Level of Evidence – C (Level of Likelihood of Evidence – 2).

Comment: the following regimens are used:

- doxorubicin** 60–75 mg/m² IV bolus every 3 weeks (this regimen is preferred for uterine leiomyosarcoma; administration to debilitated patients is possible) [89];

- #gemcitabine** 900 mg/m² IV over 90 minutes on days 1 and 8 and #docetaxel** 100 mg/m² IV over 1 hour on day 8 with primary or secondary prophylaxis using #filgrastim** 150 mcg/m³ subcutaneously from days 9 to 15 or empegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after the completion of chemotherapy administration (following external beam radiation therapy to the pelvis and/or prior chemotherapy, a starting dose reduction of #gemcitabine** to 675 mg/m² and #docetaxel** to 75 mg/m² is possible; a prolonged form of #filgrastim** may be used) [90];

- #doxorubicin** 75 mg/m² IV 72-hour infusion and ifosfamide** 2500 mg/m²/day IV 3-hour infusion on days 1–4 (+ #mesna** at a dose of 100% of the ifosfamide** dose IV simultaneously with it on days 1–4) every 3 weeks (with primary prophylaxis with colony-stimulating factors (G-CSF): filgrastim** 5 mcg/kg (rounding the single dose up to 300 mcg is permitted) subcutaneously 24–72 hours after the completion of the therapy regimen on days 5–15, or empegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after the completion of chemotherapy administration) [84, 146];

- doxorubicin** 60 mg/m² IV on day 1 and #dacarbazine** 750 mg/m², dissolved together with doxorubicin**, IV 96-hour infusion every 3 weeks [85];

• Hormone therapy is recommended for disseminated forms of low-grade endometrial stromal sarcoma of the uterus and hormone-positive uterine leiomyosarcoma [77, 78].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: the following regimens are used (administered until progression or unmanageable toxicity):

- #letrozole 2.5 mg/day orally daily [77];

- #anastrozole** 1 mg/day orally daily [77];

- #exemestane 25 mg/day orally daily [82];

- medroxyprogesterone** 500 mg/day orally daily [146];

-

- #goserelin** 3.6 mg intramuscularly once every 28 days [77];

- #buserelin** 3.75 mg intramuscularly once every 28 days [146];

- #leuprorelin** 3.75 mg intramuscularly once every 28 days [77].

• In case of endometrial cancer progression after 1st-line chemotherapy, the use of 2nd-line chemotherapy is recommended (6 cycles of chemotherapy or until progression or unmanageable toxicity) [9, 91 - 98].

GOR CLOE 3Grade of Recommendation – C (Level of Evidence – 3).

Comment: the following regimens are used:

- #pembrolizumab** 200 mg IV drip as a 30-minute infusion every 3 weeks or 400 mg IV drip as a 30-minute infusion every 6 weeks (in the presence of a high level of microsatellite instability (MSI-H), including DNA mismatch repair deficiency (dMMR) in the tumor) [99, 146];

- pembrolizumab** 200 mg IV drip as a 30-minute infusion every 3 weeks or 400 mg IV drip as a 30-minute infusion every 6 weeks and lenvatinib** 20 mg once daily orally (in the absence of high microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR) in the tumor across all histological types except carcinosarcoma) [100, 146];

- #topotecan 1.0–1.25 mg/m² IV on days 1–5 every 3 weeks with primary prophylaxis using colony-stimulating factors (G-CSF): filgrastim** 5 mcg/kg (rounding the single dose up to 300 mcg is permitted) subcutaneously 24–72 hours after the completion of the therapy regimen until neutrophil counts recover to normal levels following their nadir, or empegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after the completion of chemotherapy administration [91];

- #paclitaxel** 135 mg/m² IV on day 1 every 3 weeks or 60–80 mg/m² IV on days 1, 8, and 15 every 3 weeks [95 - 98, 146];

- #oxaliplatin** 130 mg/m² over 2 hours every 3 weeks [94];

- #doxorubicin** (pegylated liposomal) 40–50 mg/m² IV every 4 weeks [93, 102, 146];

- #doxorubicin** 50 mg/m² IV every 4 weeks [146];

- #docetaxel** 75 mg/m² IV every 3 weeks [146]

- #bevacizumab** 7.5 mg/kg or 15 mg/kg IV every 3 weeks [92, 146].

- #gemcitabine** 800 mg/m² on days 1, 8, and 15 every 4 weeks [146].

If recurrence occurs more than 6 months after the completion of primary treatment, repeating the 1st-line chemotherapy (including platinum-based chemotherapy agents in the regimen) is possible. If the patient has previously undergone external beam radiation therapy, it is advisable to reduce the doses of #paclitaxel**, #ifosfamide**, and #gemcitabine__, both as monotherapy and in combinations, by 20% [9].

• In case of progression of leiomyosarcoma, high-grade endometrial stromal sarcoma of the uterus, and undifferentiated uterine sarcoma, both monochemotherapy and unused 1st-line regimens are recommended [103 - 110].

GCP CLEL 2Level of Evidence – C (Level of Likelihood of Evidence – 2).

Comment: the following chemotherapy drugs and regimens are used:

- #dacarbazine** 1200 mg/m² IV over 20–30 minutes every 3 weeks (total of 8 cycles) [110];

- #gemcitabine** 1000 mg/m² on days 1, 8, and 15 every 4 weeks [86, 87, 111, 112];

- #gemcitabine** 1800 mg/m² (infusion rate 10 mg/m2/min or over 3 hours) on day 1 IV infusion + #dacarbazine 500 mg/m² IV infusion on day 1 every 14 days [188];

- epirubicin** 75 mg/m² IV bolus every 3 weeks [103, 112, 146];

- #doxorubicin** 50–60 mg/m² IV over 1 hour every 3 weeks [113];

- pazopanib** 800 mg/day orally daily [114, 146] (used in case of progression during cytostatic therapy).

- #temozolomide** 50-75 mg/m²/day orally for 6 of 8 weeks or 150-300 mg/m2/day orally on days 1-5 every 4 weeks [115];

- #eribulin** 1.4 mg/m² IV over 2–5 minutes on days 1 and 8 every 3 weeks [110];

- trabectedin 1.5 mg/m² IV 24-hour infusion every 3 weeks (for uterine leiomyosarcoma, anthracyclines must have been used previously) [114, 116, 117];

- #docetaxel** 36 mg/m² IV over 1 hour on days 1, 8, and 15 every 4 weeks [109, 146].

- #vinorelbine** 30 mg/m² IV on days 1 and 8 every 3 weeks [146, 147]

Pazopanib**, #temozolomide**, and #eribulin** are used in case of progression during cytostatic therapy [110, 115].

NTRK inhibitors (L01E protein kinase inhibitors) are indicated for sarcomas upon confirmation of a pan-TRK gene rearrangement NTRK

3.5. Treatment of progressive uterine corpus cancer

• In case of endometrial cancer recurrence in the vaginal stump or a solitary vaginal metastasis without prior radiation therapy, combined radiation therapy or tumor excision followed by combined radiation therapy is recommended [118, 119].

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

• In case of endometrial cancer recurrence in the vaginal stump after brachytherapy, tumor excision followed by external beam radiation therapy is recommended [118, 119].

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

• In case of recurrence in the vaginal stump after combined radiation therapy, tumor excision or interstitial radiation therapy under image guidance is recommended. If conditions for surgical treatment and radiation therapy are lacking, chemotherapy is an option [119, 120].

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

Comment: hormone therapy is advisable only for endometrioid endometrial cancer expressing steroid hormone receptors. It should be borne in mind that systemic drug therapy has low efficacy when progression occurs within the irradiated area.

• In case of regional metastases of endometrial cancer, radiation therapy or lymphadenectomy followed by radiation therapy is recommended [121, 122].

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

• In case of regional metastases of endometrial cancer, it is recommended to consider additional systemic chemotherapy [123].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

• For solitary late distant metastases of uterine body cancer, it is recommended to consider local (surgical or radiation) treatment [9, 17].

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

Comment: hormone therapy is possible for distant metastases of highly differentiated uterine body cancer, as well as for small distant non-visceral metastases of endometrial uterine body cancer expressing steroid hormone receptors, in the absence of clinical manifestations (chemotherapy is indicated upon subsequent progression). For distant metastases of moderately and poorly differentiated uterine body cancer, large distant metastases, and in the presence of clinical manifestations, chemotherapy is advisable, combined with palliative radiation therapy if necessary. Palliative care is indicated in case of further progression.

3.6. Pain management

Pain management procedures and recommendations for malignant neoplasms of the uterine body comply with the recommendations presented in the guidelines «Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care» [http://cr.rosminzdrav.ru/#!/recomend/708].

3.7. Diet therapy

• To date, there is evidence of an increased risk of developing oncological diseases, including malignant neoplasms of the uterine body, in overweight (obese) female patients [3]. In this regard, it is recommended to implement measures aimed at reducing the patients' excess body weight to normal values. Modifying the usual dietary intake in such patients will help prevent complications of ongoing treatment (surgical, drug, or radiation therapy) [124].

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Pre-rehabilitation significantly accelerates functional recovery, shortens hospital stay after surgery, and reduces the incidence of complications and mortality during cancer treatment. Pre-rehabilitation includes therapeutic exercises (physiotherapy) for female reproductive system diseases, psychological and nutritional support, and patient education [148].

• Psychological support is recommended for all female patients with malignant neoplasms of the uterine body as part of pre-rehabilitation – it improves mood and reduces levels of anxiety and depression. Patients who have undergone a course of psychological pre-rehabilitation adapt better to daily life after surgical treatment [148].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: Psychological pre-rehabilitation using techniques aimed at stress management (relaxation techniques, positive mindset formation), starting 5 days before surgery and continuing for 30 days after, is performed for 40–60 minutes 6 days a week [148].

• All female patients with malignant neoplasms of the uterine body are recommended fast-track rehabilitation and ERAS (early rehabilitation after surgery) tactics, including complex analgesia, early enteral nutrition, avoidance of routine use of tubes and drains, and early mobilization (activation and verticalization) of patients as early as 1–2 days after surgery to reduce the risk of early postoperative complications and readmission rates [154].

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

• Early initiation of a therapeutic exercise complex incorporating aerobic and strength training, as well as stretching exercises, is recommended for all patients with malignant neoplasms of the uterine body to improve their quality of life [148].

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

• The use of breathing exercises, elevating the head of the bed, and early mobilization are recommended for female patients with malignant neoplasms of the uterine body to prevent the development of pulmonary congestion in the postoperative period [155].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• Early mobilization, prophylactic administration of anticoagulants (antithrombotic agents), and wearing compression stockings are recommended for all female patients with malignant neoplasms of the uterine body to prevent thrombotic complications in the postoperative period [158].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• For the treatment of pain syndrome in the postoperative period – which is interdisciplinary in nature – in addition to drug correction, it is recommended to use therapeutic exercises for female reproductive system diseases, positioning, psychological pain management methods (relaxation), transcutaneous electrical nerve stimulation, and acupuncture (stimulation of acupuncture points by other physical factors) [159].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

— intermittent pneumatic compression of the limbs combined with complete decongestive therapy [164, 166].

— low-intensity laser therapy (intravenous blood irradiation) combined with complete decongestive therapy;

— bioelectric therapy combined with complete decongestive therapy;

— deep oscillation (massage with an alternating electric field) combined with complete decongestive therapy [155, 160].

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

5. Prevention and Dispensary Observation

• physical examination, including gynecological examination, every 3 months for 3 years, then every 6 months for another 2 years;

• cytological examination of micro-specimens from scrapings of the vaginal tissues (vault) in non-irradiated patients every 3 months for 2 years, then every 6 months for another 3 years; once every 12 months or if recurrence is suspected;

• targeted chest radiography once a year;

• complex pelvic ultrasound (transvaginal and transabdominal), complex abdominal ultrasound, and retroperitoneal ultrasound every 3 months for 2 years, then every 6 months for another 3 years;

• in patients with serous uterine body cancer, late-stage uterine body cancer, as well as with initially elevated serum CA-125 levels, testing for serum cancer antigen CA 125 levels before each doctor's visit;

• MRI and CT of the pelvis and abdominal cavity, whole-body PET-CT with a tumor-tropic radiopharmaceutical – as clinically indicated [9].

GPR CLOE 5Grade of Recommendations – 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, "On the Basics of Protecting the Health of Citizens 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 Authority;

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 Authority.

Primary specialized health care is provided by an oncologist and other specialist physicians at an outpatient oncological care center or in a primary oncological office, or in the outpatient department of an oncological dispensary (oncological hospital).

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

Consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

In the event of the impossibility of acquiring biopsy (surgical) material or performing other diagnostic tests within the medical organization that incorporates the outpatient oncological care center (primary oncological office), the attending physician shall refer the patient to an oncological dispensary (oncological hospital) or to a medical organization providing medical care to patients with oncological diseases.

The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

The diagnosis of an oncological disease is established by an oncologist, and in the case of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96, also by a hematologist.

An oncologist from an outpatient oncological care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to cancer patients, including one subordinate to a federal executive body (hereinafter referred to as a federal medical organization), to clarify the diagnosis (if establishing the diagnosis is impossible, including the extent of the oncological process and disease stage), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as those corresponding to the codes of the International Classification of Diseases for Oncology (ICD-O), 3rd Edition 8936, 906-909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, an oncologist at an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall organize a consultation or a medical board (consilium), including via telemedicine technologies, at federal state budgetary institutions subordinate to the Russian Ministry of Health that provide medical care (hereinafter referred to as national medical research centers for the purposes of this Procedure), in order to determine the treatment tactics.

In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of:

of digital images obtained from pathomorphological examinations to the pathomorphological bureau (department) of the fourth group (reference center)^[1] via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

of digital images obtained from diagnostic imaging methods to the remote diagnostic imaging consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

biopsy (surgical) material for repeated pathomorphological, immunohistochemical, and molecular genetic studies: to the pathoanatomical bureau (department) of the fourth group (reference center), as well as to molecular genetic laboratories for molecular genetic testing.

Treatment tactics are established by a medical board (consilium) comprising oncologists, a radiation therapist, and a neurosurgeon (in cases of nervous system tumors) of the medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians when necessary.

Dispensary follow-up by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological diseases.

For record-keeping purposes, information about a newly diagnosed case of an oncological disease shall be sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of the subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.

Specialized medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated by paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as provided in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care shall not exceed the timeframes established in the program of state guarantees of free medical care to citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the regulations on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations and other non-profit organizations operating in the field of health protection.

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

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

1) the presence of complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form;

2) presence of complications of treatment (surgical intervention, RT, drug therapy, etc.) of the oncological disease.

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) the presence of indications for specialized antitumor treatment (surgical intervention, RT, including contact, EBRD and other types of RT, drug therapy, etc.) requiring monitoring in an inpatient or day hospital setting.

Indications for discharging a patient from a medical organization are:

1) completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in an inpatient 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) in cases of non-compliance by the patient with prescriptions or the internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

4) the need to transfer the patient to another medical organization according to the relevant medical specialty profile.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

7. Additional Information

Factors influencing the prognosis of the disease include:

- tumor size and extent;

- depth of invasion of the primary tumor;

- tumor grade;

- status of regional and peripheral lymph nodes;

- extent of cytoreductive surgery.

Patients diagnosed with endometrial cancer, especially of the 1st pathogenetic type, frequently present with obesity, diabetes mellitus, hypertension, and a number of other comorbid conditions that can worsen their general somatic status and limit the feasibility of radical treatment. Such patients may be offered palliative therapy based on medical indications, which has a less favorable impact on life expectancy and disease outcome [13].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ashrafyan L.A., Academician of the RAS, MD, PhD, Professor, Deputy Director of the V.I. Kulakovo National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Director of the Institute of Oncogynecology and Mammology.

2. Novikova E.G., MD, PhD, Professor, Head of the Oncogynecology Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Khokhlova S.V., MD, PhD, Head of the Oncological Department of Antitumor Drug Therapy, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

4. Urmancheeva A.F., MD, PhD, Professor, Leading Researcher at the Department of Oncogynecology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

5. Berlev I.V., MD, PhD, Professor, Head of the Scientific Department of Oncogynecology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

6. Antonova I.B., MD, PhD, Head of the Laboratory for Prevention, Early Diagnosis and Combined Treatment of Oncological Diseases, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.

7. Babaeva N.A., MD, PhD, Leading Researcher at the Institute of Oncogynecology and Mammology, Oncologist at the Oncological Department of Surgical Treatment Methods, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

8. Aleshikova O.I., Candidate of Medical Sciences, Senior Researcher at the Institute of Oncogynecology and Mammology, Oncologist at the Oncological Department of Surgical Treatment Methods, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

9. Orlov A.E., MD, PhD, Chief Physician of the Samara Regional Clinical Oncology Dispensary, Chief Freelance Oncologist of the Ministry of Health of the Samara Region, Head of the Department of Public Health and Healthcare of the Institute of Professional Education, Samara State Medical University of the Russian Ministry of Health.

10. Shchukin V.Yu., Head of the Oncological Department (Oncogynecology), Samara Regional Clinical Oncology Dispensary

11. Mukhtarullina S.V., MD, PhD, Head of the Department of Oncogynecology, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

12. Verenikina E.V., Candidate of Medical Sciences, Head of the Department of Oncogynecology, Rostov Research Oncology Institute of the Russian Ministry of Health.

13. Demidova L.V., MD, PhD, Leading Researcher at the Department of Radiation Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

14. Shevchuk A.S., Candidate of Medical Sciences, Head of the Department of Combined and Radiation Treatment Methods for Oncogynecological Diseases, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

15. Ulrikh E.A., MD, PhD, Professor, Chief Researcher at the Research Laboratory of Reproductive Technologies, Head of the "Oncofertility" Competence Center, V.A. Almazov National Medical Research Center.

16. Krasilnikov S.E., MD, PhD, Professor, Director of the Institute of Oncology and Neurosurgery, Oncologist, E.N. Meshalkin National Medical Research Center of the Russian Ministry of Health

17. Davydova I.Yu., MD, PhD, Leading Researcher at the Department of Pelvic Floor Oncosurgery, Moscow Clinical Scientific Center named after A.S. Loginov of the Moscow Healthcare Department

18. Krikunova L.I., MD, PhD, Professor, Head of the Department of Radiation and Combined Treatment Methods for Gynecological Diseases, National Medical Research Radiological Center of the Russian Ministry of Health.

19. Kolomiets L.A., MD, PhD, Professor, Head of the Gynecological Department, Research Institute of Oncology, Tomsk National Research Medical Center of the RAS.

20. Kreynina Yu.M., MD, PhD, Leading Researcher at the Laboratory of Innovative Technologies of Radiotherapy and Chemoradiation Treatment of Malignant Neoplasms, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.

21. Dubinina A.V., Candidate of Medical Sciences, Senior Researcher at the Radiotherapy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

22. Karseladze A.I., Professor, MD, PhD, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

23. Rubtsova N.A., MD, PhD, Head of the Department of Diagnostic Radiology, Radiologist, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

24. Bychenko V.G., Candidate of Medical Sciences, Head of the Department of Diagnostic Radiology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

25. Solopova A.E., MD, PhD, Associate Professor, Radiologist at the Department of Diagnostic Radiology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

26. Ryzhkova D.V., MD, PhD, Professor of the RAS, Head of the Department of Nuclear Medicine and Radiation Technologies with Clinic, Chief Researcher at the Research Laboratory of Nuclear Medicine and Theranostics, V.A. Almazov National Medical Research Center of the Russian Ministry of Health. Ovodenko D.L., MD, PhD, Head of the Department of Innovative Oncology and Gynecology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health. Grinevich V.N., Candidate of Medical Sciences, Head of the Department of Oncopathology, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

27. Snegovoy A.V., MD, PhD, Head of the Outpatient Chemotherapy Day Hospital Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

28. Meshcheryakova L.A., MD, PhD, Federal Research and Clinical Center of Physical-Chemical Medicine named after Yu.M. Lopukhin of the Federal Medical-Biological Agency

29. Slonov A.V., Candidate of Medical Sciences, Chief Physician of Clinical Hospital No. 123, Federal Research and Clinical Center of Physical-Chemical Medicine named after Yu.M. Lopukhin of the Federal Medical-Biological Agency

30. Rumyantsev A.A., Candidate of Medical Sciences, Head of the Antitumor Drug Therapy Department No. 4 of the Drug Treatment Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow

31. Yureneva S.V., Deputy Director for Science at the Institute of Oncogynecology and Mammology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, MD, PhD, Professor of the Department of Obstetrics and Gynecology.

Medical Rehabilitation Section:

1. Konchugova T.V., MD, PhD, Professor, Physiotherapist, Head of the Department of Preformed Physical Factors, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health.

2. Eremushkin M.A., MD, PhD, Professor, Head of the Department of Exercise Therapy and Clinical Biomechanics, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health.

3. Gilmutdinova I.R., Candidate of Medical Sciences, Head of the Department of Biomedical Technologies and Cell Technologies Laboratory, Transfusiologist, Dermatovenerologist, Cell Technology Specialist, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health.

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

5. Bulanov A.A., MD, PhD, Senior Researcher at the Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

6. Butenko A.V., MD, PhD, Professor, Chief Physician of the Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Chairman of the Scientific Council of the Association of Oncological Rehabilitation Specialists.

7. Nazarenko A.V., Candidate of Medical Sciences, Highest Qualification Category Physician, Head of the Radiology Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Russian Association of Therapeutic Radiation Oncologists (RATRO), European Society for Radiotherapy & Oncology (ESTRO), Russian-American Cancer Alliance (ARCA), Russian Representative to the IAEA.

8. Obukhova O.A., Candidate of Medical Sciences, Physiotherapist, Head of the Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the European Society for Clinical Nutrition and Metabolism (ESPEN), Russian Society for Parenteral and Enteral Nutrition (RESPEN).

9. Khulamkhanova M.M., Physiotherapist, Oncologist at the Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

10. Tkachenko G.A., Psychologist at the Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

11. Petrova T.A., Speech Therapist and Educator at the Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

12. Semiglazova T.Yu., MD, PhD, Leading Researcher at the 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 at the Department of Oncology, I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health.

13. Ponomarenko G.N., MD, PhD, Professor, Honored Scientist of the Russian Federation, Director General of the G.A. Albrecht Federal Scientific Center of Rehabilitation of the Disabled of the Russian Ministry of Labour, Head of the Department of Balneology and Physiotherapy, S.M. Kirov Military Medical Academy of the Russian Ministry of Defense.

14. Kovlen D.V., MD, PhD, Associate Professor at the Department of Balneology and Physiotherapy, S.M. Kirov Military Medical Academy of the Russian Ministry of Defense.

15. Kasparov B.S., Candidate of Medical Sciences, Deputy Chief Physician for Outpatient Care, Head of the Clinical and Diagnostic Department, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

16. Krutov A.A., Oncologist at the Clinical and Diagnostic Department, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health.

17. Zernova M.A., Exercise Therapy Instructor, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health.

18. Kondratyeva K.O., Medical Psychologist, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health.

19. Rumyantsev A.A., PhD, Head of the Antitumor Drug Therapy Department No. 4, Department of Drug Treatment, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health, Moscow.

20. Ivanova G.E., DSc, Chief Specialist in Medical Rehabilitation, Russian Ministry of Health; Head of the Department of Medical and Social Stroke Rehabilitation, Research Institute of Cerebrovascular Pathology and Rehabilitation, Pirogov Russian National Research Medical University, Russian Ministry of Health.

21. Romanov A.I., Academician of the Russian Academy of Sciences, DSc, Professor, Chief Physician, Rehabilitation Center, Administration of the President of the Russian Federation.

22. Stepanova A.M., Deputy Director for Science, Head of the Rehabilitation Department, Vosstanovlenie Private Multidisciplinary Diagnostic and Rehabilitation Center.

Healthcare Organization Section:

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

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

3. Ivanov S.A., DSc, Professor of the Russian Academy of Sciences, Director of the A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

4. Gevorkyan T.G., Deputy Director of the Research Institute of Clinical and Economic Radiology, N.N. Blokhin National Medical Research Center of Oncology.

No conflict of interest declared.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• medical students, resident physicians, clinical residents, and postgraduate students.

Methods used for collecting/selecting evidence: search in electronic databases; analysis of current scientific developments on the issue of uterine corpus cancer in Russia and abroad; generalization of practical experience of Russian and foreign specialists.

Table 1. Scale for grading the levels of evidence for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading the levels of evidence for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading the grades of recommendation for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative 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 draft of these recommendations was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Comments were received from primary care oncologists regarding the clarity of the presentation of the recommendations and their assessment of 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 recommendations 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.

Updates of clinical guidelines: updating is carried out at least once every 3 years, taking into account new information on the diagnosis and management of patients with uterine corpus cancer, 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 non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicines 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

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

Appendix B. Physician Action Algorithms

Flowchart for the diagnosis and treatment of a patient diagnosed with uterine corpus cancer

Appendix C. Patient Information

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

• consult an oncologist.

2. In case of stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• consult an oncologist.

3. In case of diarrhea:

• diet – exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meats, flour products, fermented dairy products, and rice water are permitted. Drink plenty of fluids.

• consult an oncologist.

4. In case of nausea:

• consult an oncologist.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO/ECOG performance status scale [82]

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

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

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655

Type: rating scale

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

Contents:

Key (interpretation): provided within the scale itself

Appendix G2. Karnofsky Performance Scale

Russian title: Karnofsky scale [83]

Original title (if applicable): KARNOFSKY PERFORMANCE STATUS

Source (official developer website, validation publication): Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of chemotherapeutic agents. edn. Edited by MacLeod C. New York: Columbia University Press; 1949: 191-205

Type: rating scale

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

Content (template):

Key (interpretation): provided within the scale itself