Non-epithelial ovarian tumors: clinical guidelines

List of Abbreviations

β-hCG – beta-subunit of human chorionic gonadotropin

AFP – alpha-fetoprotein

aPTT – activated partial thromboplastin time

OGCT – ovarian germ cell tumor

GnRH – gonadotropin-releasing hormone

HT – hormone therapy

CT – computed tomography

LDH – lactate dehydrogenase

RT – radiation therapy

PT – physical therapy

INR – international normalized ratio

MRI – magnetic resonance imaging

NEOT – non-epithelial ovarian tumors

PET-CT – positron emission tomography combined with computed tomography

RP – radiopharmaceutical

CA125 – tumor antigen 125

CDU – color duplex ultrasonography

US – ultrasound examination

CT – chemotherapy

EGD – esophagogastroduodenoscopy

HE4 – human epididymis protein 4

Terms and Definitions

Non-epithelial ovarian tumors – a heterogeneous group of malignant ovarian tumors originating from cells other than the ovarian surface epithelium.

Germ cell tumors of the ovary – rare forms of non-epithelial ovarian tumors representing a heterogeneous group of neoplasms developing from so-called "germ cells", i.e., cells involved in the formation of gonads and gametogenesis.

Dysgerminoma – the most common histological variant of malignant ovarian germ cell tumors, representing the female analogue of seminoma in males.

Non-dysgerminoma – germ cell tumors, which include yolk sac tumors, embryonal carcinoma, choriocarcinoma, polyembryoma, immature teratoma, and mixed germ cell tumor.

Sex cord-stromal tumors – constitute a heterogeneous group of tumors and differ in their ability to produce steroid hormones.

Granulosa cell tumor of the ovary – a hormone-active type of ovarian tumor originating from granulosa stromal cells.

Sertoli-Leydig cell tumors – malignant androgen-producing ovarian neoplasms composed of Sertoli cells, sex cord elements, and stromal cells structurally similar to Leydig cells of the male gonads. Most commonly seen in women of reproductive age.

Neuroendocrine tumors of the ovary – rare ovarian tumors arising from cells of the neuroendocrine system directly involved in the regulation of homeostasis via paracrine and endocrine mechanisms.

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

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

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

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Non-epithelial ovarian tumors (NEOT) – a heterogeneous group of malignant ovarian tumors originating from cells other than the ovarian surface epithelium.

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

The exact etiology of NEOT remains unclear. The majority of NEOT develop from specific ovarian cells (germ cells, granulosa cells, theca cells, stromal fibroblasts, and steroid cells) [1].

1.3 Epidemiology of the Disease or Condition

NEOT account for approximately 10% of all malignant ovarian neoplasms. Annually in Europe, 3.7 cases of ovarian germ cell tumors (OGCT) per 100,000 women and 2.1 cases of granulosa cell tumors per 1 million are registered [1, 2]. Statistical tracking of NEOT incidence is not maintained in the Russian Federation. Germ cell tumors are usually diagnosed in the first 20 years of life, whereas sex cord-stromal tumors typically occur at age 40–50 [1, 2]. Neuroendocrine tumors of the ovary occur in no more than 1% of cases, with the peak incidence in the peri- and postmenopausal period [3].

1.4 Features of Coding the Disease or Condition

Malignant neoplasm of ovary (C56)

1.5 Classification of the disease or condition

1.5.1. International Histological Classification (WHO, 5th edition, 2020)

Stromal tumors.

Fibroma

8810/1 Cellular fibroma

8600/0 Thecoma

8601/0 Luteinized thecoma

8810/3 Fibrosarcoma

8602/0 Sclerosing stromal tumor

8590/0 Signet-ring cell stromal tumor

8590/0 Microcystic stromal tumor

8650/0 Leydig cell tumor

8760/0 Steroid cell tumor, benign

8760/3 Steroid cell tumor, malignant

Sex cord-stromal tumors:

8620/3 Adult granulosa cell tumor

8622/1 Juvenile granulosa cell tumor

8640/1 Sertoli cell tumor

8623/1 Sex cord tumor with annular tubules

Mixed sex cord-stromal tumors

8631/0 Well-differentiated Sertoli-Leydig cell tumor

8631/1 Sertoli-Leydig cell tumor

8631/1 Moderately differentiated Sertoli-Leydig cell tumor

8631/3 Poorly differentiated Sertoli-Leydig cell tumor

8633/1 Retiform Sertoli-Leydig cell tumor

8590/1 Sex cord-stromal tumors, 8632/1 Gynandroblastoma

Germ cell tumors

9060/3 Dysgerminoma

9071/3 Yolk sac tumor

9070/3 Embryonal carcinoma

9100/3 Choriocarcinoma

9080/0 Benign mature teratoma

9080/3 Immature teratoma

9085/3 Mixed malignant germ cell tumor

Monodermal teratoma / Somatic type

Tumors originating from a dermoid cyst

9090/0 Struma ovarii, benign

9090/3 Struma ovarii, malignant

9091/1 Strumal carcinoid

9084/3 Teratoma with malignant transformation

9080/0 Cystic teratoma

Germ cell tumors combined with sex cord-stromal tumors

9073/1 Gonadoblastoma

8594/1 Mixed germ cell and sex cord-stromal tumor

Neuroendocrine carcinoma

8041/3 Small cell neuroendocrine carcinoma

1.5.2. Staging

Staging of ovarian tumors is performed similarly to epithelial ovarian tumors based on the results of pathological examination of surgical (biopsy) material and intraoperative surgical staging according to the FIGO (2014) and TNM (8th edition, 2017) classifications (Table 1).

Table 1. Staging of ovarian cancer according to TNM (8th edition, 2017) and FIGO (2014)

1.6 Clinical presentation of the disease or condition

In early stages, the disease may be asymptomatic or present with minor discomfort. Symptoms at all stages may also include pelvic pain, dysmenorrhea. In advanced disease, it manifests with nonspecific symptoms: abdominal distension, weight loss, abdominal pain, dyspnea, general fatigue.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the disease or condition

The diagnosis is established based on:

anamnestic data;

physical and instrumental examination data;

morphological verification;

data obtained from diagnostic imaging of patients,

other confirmatory studies performed according to indications.

2.1 Complaints and Anamnesis

Comment: In early stages, the disease may be asymptomatic or present with minor discomfort. Initial symptoms may include pelvic pain and dysmenorrhea [4]. Special attention should be paid to age, menstrual irregularities, and family history, as germ cell tumors are predominantly diagnosed in adolescents and young women. In some cases, OGT presents with symptoms associated with atypical hormonal activity.

2.2 Physical Examination

Comment: special attention should be paid to the patient's general appearance during examination and assessment of the patient's performance status according to WHO/ECOG and/or Karnofsky scale (see Appendix G1-2), as well as nutritional status assessment. Body temperature, pain syndrome, and the presence of pleurisy or ascites must also be noted. In case of menstrual irregularities, consultation with several specialists is required: gynecologist, endocrinologist, geneticist.

2.3 Laboratory Diagnostics

• During initial diagnosis, it is recommended that all patients with OGT and suspected OGT undergo:

- complete blood count (CBC) with differential (hemoglobin, hematocrit, erythrocytes, mean corpuscular volume [MCV], red cell distribution width [RDW], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], platelets, leukocytes, leukocyte differential, erythrocyte sedimentation rate [ESR]);

- general clinical biochemical blood test assessing liver and kidney function (total protein, glucose, creatinine, urea, iron, alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, lactate dehydrogenase [LDH], alkaline phosphatase [ALP], plasma electrolytes [potassium, sodium, chloride]);

- urinalysis (color, transparency, specific gravity, protein, pH, glucose, ketone bodies, urobilinogen, leukocyte esterase, automated microscopy for epithelial cells, erythrocytes, casts, crystals, mucus, bacteria, and fungi);

- coagulogram (screening hemostasis assay) (blood fibrinogen level, International Normalized Ratio [INR], prothrombin time in blood or plasma, activated partial thromboplastin time [APTT], thrombin time, blood D-dimer concentration, and additionally—antithrombin III activity in blood and plasminogen activator inhibitor level in blood, as clinically indicated).

- tumor marker panel (alpha-fetoprotein [AFP] serum level, human chorionic gonadotropin [free beta-subunit] serum level, LDH, CA 125 cancer antigen serum level, human epididymis protein 4 [HE4] blood level, inhibin B blood level, anti-Müllerian hormone blood level) in all patients with suspected OGT [7-10, 45, 108, 115].

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

Comment: Elevated levels of AFP, β-hCG, and LDH above reference ranges are characteristic of GCT. AFP production is more consistent with yolk sac tumor manifestations, while β-hCG is characteristic of choriocarcinoma. Elevated AFP and β-hCG are typical of embryonal carcinoma and polyembryoma. About one-third of immature teratomas produce AFP [12].

The diagnosis of dysgerminoma is established not solely on the basis of the morphological report. This requires a normal AFP level and a β-hCG level not exceeding 200 IU/L. In other cases, the tumor should be classified as a non-dysgerminoma and treated accordingly. The presence of elevated AFP or β-hCG levels in patients with mature teratoma indicates the presence of a malignant component in the tumor. Such patients should be treated according to the non-dysgerminoma treatment principles.

CA-125 and HE4 levels may be slightly elevated in germ cell tumors and carcinosarcomas, and these markers have no diagnostic value in germ cell tumors, granulosa cell tumors, and sex cord-stromal tumors.

Inhibin B has high specificity as a tumor marker. In typical granulosa cell tumors, an elevated inhibin B level is observed in virtually all patients, and its serum concentration is directly dependent on tumor status. In rare cases, inhibin B may be undetectable, which is a sign of extreme malignancy. Anti-Müllerian hormone concentration in granulosa cell tumor is less informative [4].

• All patients with suspected OGT are recommended to have total testosterone and total estradiol blood levels measured to verify the diagnosis and determine further treatment tactics [12, 13, 119, 107].

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

Comment: sex cord-stromal tumors are frequently characterized by the presence of testicular structures that produce sex hormones [12, 13]. In Sertoli-Leydig cell tumors and other hormonally active tumors, blood levels of total testosterone and estradiol may be elevated (virilization is observed in 70–85% of patients) [106, 107].

• All patients with suspected OGT are recommended to have total blood calcium levels measured to verify the diagnosis and determine further treatment tactics [124, 125, 126].

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

Comment: Hypercalcemia occurs in 70% of cases of small cell carcinoma of the ovary, hypercalcemic type, which allows this tumor to be suspected already at the comprehensive examination stage [13].

• All patients with OGT after surgical intervention are recommended to undergo a repeat blood AFP and β-hCG test, if they were initially elevated, to determine further management tactics and disease prognosis [7, 32, 108, 118].

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

Comment: Persistently elevated marker levels indicate the presence of residual tumor.

Comment: in patients with non-dysgerminoma, an increase in size or the appearance of new lesions while tumor markers (AFP and β-hCG) are decreasing or normal during therapy is not always a manifestation of progression (growing teratoma syndrome). In these situations, the initially planned chemotherapy regimen must be completed, followed by surgical removal of the tumor.

2.4 Instrumental Diagnostics

Comment: Ultrasound – is the simplest imaging method for masses in the abdominal cavity, pelvic cavity, and retroperitoneal space, but it is significantly inferior to CT/MRI in assessing the extent of the process; therefore, CT/MRI may be performed instead of or after ultrasound for diagnostic clarification purposes.

Comment:

- CT of the chest, abdomen, kidneys and upper urinary tract, and retroperitoneal space with intravenous bolus contrast enhancement is the most accurate diagnostic method for determining the extent of the tumor process and the efficacy of ongoing treatment.

- If there are contraindications to the use of iodine-containing radiocontrast agents (RCA), CT of the chest may be performed without contrast enhancement. If CT of the chest cannot be performed, targeted chest radiography is recommended. CT of the chest has higher sensitivity and specificity in detecting metastatic lesions of the lungs, pleura, and intrathoracic lymph nodes (LNs).

- If it is impossible to perform CT of the abdomen with intravenous contrast (contraindications to iodine-containing RCAs, pregnancy, etc.), MRI of the abdomen with or without intravenous contrast (during pregnancy) is recommended.

- MRI of the pelvis with intravenous contrast is more informative than MRI without contrast and is preferred over pelvic CT; MRI of the abdomen, kidneys, and retroperitoneal space can be used as an adjunct in case of ambiguous CT results

- In ongoing pregnancy, MRI of any localization is performed without the administration of RCAs.

• In case of suspected distant metastasis in patients with ovarian germ cell tumors, it is recommended to perform whole-body positron emission tomography with tumorotropic radiopharmaceuticals (PET-CT) [108, 45].

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

Comment: PET-CT may be useful in patients with ovarian germ cell tumors to determine process dissemination.

• In case of a high β-hCG level (above 50,000 mIU/mL) or multiple lung metastases due to the high risk of metastatic brain involvement, brain MRI with contrast is recommended [108, 115].

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

Comments: MRI with intravenous contrast is more informative than MRI without contrast (performed in the presence of contraindications to RCAs, including pregnancy)

• All patients with ovarian germ cell tumors or suspected ovarian germ cell tumors are recommended to undergo esophagogastroduodenoscopy (EGD) to rule out a primary gastrointestinal (GI) tract tumor and assess for concomitant GI diseases [108, 115].

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

Comment: EGD is a mandatory examination method for patients with suspected ovarian germ cell tumors, allowing to rule out secondary (metastatic) ovarian involvement in malignant neoplasms (MNs) of the GI tract.

• All patients with ovarian germ cell tumors or suspected ovarian germ cell tumors are recommended to undergo colonoscopy for differential diagnosis with GI tract MNs and to assess for concomitant GI diseases [108, 115].

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

2.5 Other Procedures

• Due to the rarity and complexity of morphological verification, it is recommended to review glass slides and blocks in a medical organization providing medical care in the field of oncology and having experience in treating patients with ovarian germ cell tumors to confirm the morphological diagnosis [45].

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

- tumor dimensions, capsule damage, or tumor extension onto the capsule;

- histological structure of the tumor;

- tumor grade;

- presence of malignant cells in each individual peritoneal biopsy specimen, as well as the greater omentum;

- indication of the total number of examined and affected lymph nodes;

- degree of therapeutic pathomorphosis in the case of administered chemotherapy [3, 10].

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

Comment:

- Frequently, patients with germ cell tumors undergo emergency surgery in gynecological hospitals due to severe pain syndrome resulting from capsule rupture, hemorrhage, or tumor pedicle torsion. In most cases, morphological verification of the diagnosis can be obtained during the surgical stage of treatment or diagnostic laparoscopy.

- In the case of advanced tumor process and initiation of systemic treatment according to vital indications in patients with germ cell tumors, the presence of high AFP and/or β-hCG marker levels is sufficient for diagnosis.

- In certain situations, ovarian tumors may have an extragonadal location; in this case, ultrasound/CT-guided biopsy of the primary lesion is recommended.

- If morphological verification of the diagnosis is necessary, the pathomorphological examination of biopsy (surgical) material can be supplemented by immunohistochemical typing, especially in germ cell tumors and sex cord-stromal tumors.

Comment: to standardize the evaluation of systemic treatment efficacy, it is effective to use RECIST – Response Evaluation Criteria In Solid Tumors.

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

3.1. Germ cell tumors of the ovary

3.1.1. Surgical treatment of ovarian germ cell tumors (OGCT)

• In patients wishing to preserve fertility, regardless of the extent of the process, unilateral salpingo-oophorectomy is recommended [7-10, 16, 18, 22, 23, 27-31, 110].

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

• In patients not wishing to preserve fertility, regardless of the extent of germ cell tumors, hysterectomy with adnexectomy (total hysterectomy with adnexectomy) via laparoscopic (using video endoscopic techniques) or laparotomic approach depending on the clinical situation is recommended [7-10, 16, 18, 22, 23, 27-31, 110].

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

Comments: Surgical staging is of great importance in determining subsequent treatment tactics. Surgical treatment includes midline or lower midline laparotomy. A laparoscopic approach is possible in early-stage disease and small-sized ovarian tumors.

- Urgent intraoperative histological examination of the removed ovary is mandatory to determine the adequate surgical volume.

- Unilateral salpingo-oophorectomy is the recommended volume of surgical intervention regardless of the extent of the process in patients wishing to preserve fertility.

- In patients without reproductive potential or not wishing to preserve fertility, hysterectomy with adnexectomy is recommended.

- Resection of the contralateral ovary is performed only in the presence of macroscopic signs of involvement.

- In gonadal dysgenesis (XY karyotype, determined during genetic evaluation), bilateral adnexectomy (salpingo-oophorectomy) is performed.

Performing an omentectomy (resection of the greater omentum) along the transverse colon is recommended for staging purposes.

- To determine the stage of the disease, it is also mandatory to collect peritoneal washings from the parietal peritoneum of the diaphragm, paracolic gutters, and pelvis for subsequent cytologic examination, and biopsies of suspicious peritoneal lesions are performed. Iliac and/or para-aortic lymphadenectomy (retroperitoneal lymphadenectomy) is performed only in patients with enlarged lymph nodes. The principle of surgical treatment includes the removal of all visible metastatic lesions without resection of adjacent organs.

Given the high chemosensitivity of the tumor, the extent of cytoreductive surgery should not be mutilating or lead to a potential increase in postoperative complications that could delay the start of chemotherapy.

In case of inadequate staging, repeat cytoreduction for restaging is recommended only if subsequent active surveillance is not considered as an option.

3.1.2. Post-surgical staging treatment tactics

Further treatment tactics depend on the histological type and stage of the disease. All ovarian germ cell tumors (OGCTs) are divided into two subtypes: "dysgerminoma," diagnosed based on morphological findings and tumor markers (AFP within normal limits, β-hCG should not exceed 200 mIU/mL). "Non-dysgerminoma" includes immature teratoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma, polyembryoma, and mixed germ cell tumor. The treatment of other types of non-dysgerminoma, with the exception of immature teratoma, is similar to that of yolk sac tumor. In cases of mixed OGCT, treatment is planned according to the most unfavorable component [17, 21]. Table 2 presents the treatment strategy after staging in patients with OGCTs.

The rarity of germ cell tumors complicates large-scale clinical trials; therefore, all evidence regarding chemotherapy (CT) is extrapolated from clinical trials in male germ cell tumors, as these tumors share a common histogenetic origin, but occur more frequently in men than in women, and their management is based on a more extensive evidence base.

Table 2. Treatment strategy for OGCT patients after surgical staging

*In the absence of residual tumor, 3 cycles of chemotherapy (CT) according to the BEP regimen are indicated; in the presence of residual tumor, 4 cycles of CT according to the BEP regimen are recommended (see Table 3).

• Stage IA. With adequate staging and confirmation of stage IA ovarian dysgerminoma, active surveillance is recommended (for the follow-up schedule, see section 3.1.3) [32, 33, 111].

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

• Stages IB–IC. Active surveillance is possible if adequate surgical staging has been performed. In the absence of adequate surgical staging or if active surveillance is declined, it is recommended to administer 3 cycles of adjuvant CT according to the BEP regimen (see Table 3) or 2 cycles of single-agent carboplatin** AUC7 [45].

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

• Stages IIA–IV. It is recommended to administer 3 cycles of CT according to the BEP regimen (see Table 3) [7, 45].

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

Comment: if LDH levels are elevated above 2 times the upper limit of normal or if visceral metastases are present, 4 cycles of BEP are recommended (see Table 3) [7].

In patients older than 40 years, as well as in those with concomitant interstitial lung disease, 4 cycles of the EP regimen are recommended (see Table 3). [45]

• Stage IA G1. With adequate staging and confirmation of stage IA G1 immature ovarian teratoma, active surveillance is recommended (for the follow-up schedule, see section 3.1.3) [4, 36, 45].

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

• Stages IA G2–IC. It is recommended to administer CT according to the BEP regimen (3 cycles) (see Table 3) [4, 45].

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

• Stages IIA–IV. It is recommended to administer CT according to the BEP regimen (see Table 3) [6, 7, 11, 17, 35, 45].

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

Comment: the number of chemotherapy cycles depends on the presence of residual tumor after surgical treatment: in the absence of residual tumor, 3 cycles of CT according to the BEP regimen are indicated (see Table 3); in the presence of residual tumor, 4 cycles of CT according to the BEP regimen are recommended (see Table 3). Elevated levels of tumor markers AFP or hCG indicate the presence of residual tumor.

Yolk sac tumor belongs to the unfavorable prognosis subtype.

• Patients with yolk sac tumor are recommended to receive chemotherapy regardless of the disease stage [36, 113].

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

• Patients with early stages and/or absence of residual tumor are recommended to receive 3 cycles of CT according to the BEP regimen (see Table 3) [113].

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

• Patients with early stages in the presence of residual disease are recommended to receive 4 cycles of CT according to the BEP regimen (see Table 3) [113].

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

3.1.3. Principles of active surveillance after surgical treatment for stage IA in patients with dysgerminoma and immature teratoma

• Patients are recommended to undergo close active surveillance according to the schedule, provided that surgical staging has been performed [45].

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

Comment: follow-up schedule for dysgerminoma (conducted in an outpatient setting at a regional oncological dispensary or by a district oncologist). Physical and gynecological examination, AFP, β-hCG, and LDH levels; abdominal and pelvic ultrasound every 3 months for the 1st year; every 4 months for the 2nd and 3rd years; every 6 months for the 4th year; and annually thereafter (up to 10 years). Chest X-ray or CT is performed every 6 months for the first two years, and annually thereafter (up to 5 years).

Follow-up schedule for immature teratoma: physical and gynecological examination, AFP and β-hCG levels every 1–2 months; abdominal and pelvic ultrasound every 2 months for the 1st year; every 3 months for the 2nd and 3rd years; every 6 months for the 4th year; and annually thereafter (up to 10 years). Chest X-ray or CT is performed every 6 months for the first two years, and annually thereafter (up to 5 years).

3.1.4. Principles of chemotherapy

CT after surgery and intraoperative staging should ideally be initiated as soon as possible, within 10–14 days [16, 40], according to the regimens specified in Table 3.

• If there are contraindications to bleomycin**, CT according to the EP program (see Table 3) is recommended, consisting of 3 cycles in the absence of residual tumor and 4 cycles in the presence of residual tumor [6, 18, 23, 45, 114].

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

Comment: due to the development of late bleomycin** toxicity in the form of pneumonitis, it is recommended to exclude bleomycin** from the treatment regimen in patients older than 40 years or with a prior history of pulmonary disease. In patients with advanced non-dysgerminoma, an equally effective but more myelotoxic alternative to the BEP regimen is the PEI combination (etoposide**, cisplatin**, ifosfamide**) (see Table 3).

Table 3. Main first-line chemotherapy regimens for germ cell tumors [109].

Bleomycin may be presented as bleomycin hydrochloride (isomer A5) and bleomycin sulfate (a mixture of isomers A2 and B2), which have different pharmacological activities. When using bleomycin sulfate in the BEP regimen, doses of 30 mg are used on days 1, 3, 5 (or days 1, 8, 15). When using the less studied bleomycin hydrochloride, cycle doses are 30–40% lower, for example, 30 mg on days 1 and 5;

^§ administration of cisplatin** is carried out against the background of intravenous hydration with normal saline** (total daily volume 2.5 L), necessary to maintain diuresis >100 mL/hour during cisplatin** administration and for the subsequent 3 hours;

^§ mesna** is used at a daily dose of 100% of the ifosfamide** dose, divided into three administrations throughout the day: immediately before ifosfamide** and then 4 and 8 hours after the start of its infusion.

All chemotherapy cycles are administered every 3 weeks (calculated from the start of the previous chemotherapy course). A delay of the scheduled treatment course is possible in the presence of infection, neutropenia less than 500/µL, or thrombocytopenia less than 50,000/µL on the first day of the planned course (see the drug dose reduction table). If febrile neutropenia, grade IV neutropenia lasting more than 7 days, or neutropenia complicated by infection was noted during the previous chemotherapy course, prophylactic administration of colony-stimulating factors (G-CSF) is justified for all subsequent chemotherapy courses. In patients in poor general condition due to the extent of the tumor process, the first course may be administered in a 40–60% reduced dose (e.g., etoposide** and cisplatin** for two days) [4, 11, 21, 24, 35, 40-44, 121]. The dose reduction algorithm is presented in Table 4.

Table 4. Algorithm for dose reduction of chemotherapy drugs in the VIP regimen depending on hematological toxicity* [6]

*determined by laboratory tests on the day of the start of the next chemotherapy course; the percentage of the drug dose is indicated.

- Before each 1st-line chemotherapy course, it is necessary to determine tumor markers; upon completion of chemotherapy, repeat CT of the baseline affected areas to determine further treatment tactics [18, 19, 22, 23, 30-32, 37].

- In patients with non-seminoma, an increase in size or the appearance of new lesions against the background of decreasing or normal tumor markers (AFP and hCG) during therapy is not always a manifestation of progression (growing teratoma syndrome). In such situations, it is necessary to complete the initiated planned volume of chemotherapy followed by surgical removal of the tumor.

3.1.5. Treatment of residual tumor after chemotherapy

• In the presence of a residual tumor in seminoma (peritoneum, retroperitoneal lymph nodes, lungs, mediastinal lymph nodes, etc.) after completion of chemotherapy and normalization of tumor markers, further treatment is not recommended; active surveillance is recommended [11].

Level of recommendations-based evidence – 5 (level of data reliability – C).

Comment: if the residual tumor size is >3 cm, PET/CT can be performed. If there is pathological uptake of the radiopharmaceutical in the residual tumor, its removal is advisable. If the patient refuses or surgical treatment is technically impossible, a repeat PET/CT is recommended after 2-3 months. If the increased uptake persists, the issue of surgical treatment or active surveillance should be reconsidered.

• In the presence of a residual tumor in non-seminoma (peritoneum, retroperitoneal lymph nodes, lungs, mediastinal lymph nodes, etc.) <1 cm after completion of chemotherapy and normalization of tumor markers, further treatment is not recommended; active surveillance is recommended [11].

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

Comment: if the residual tumor size is >1 cm, its removal is indicated. In case of involvement of multiple anatomical regions, surgical treatment begins with the zone of maximum involvement. Patients with a complete regression, or those in whom necrosis or teratoma is found in the resected residual tumor, are subject to surveillance. In questionable cases with a small tumor and a normal marker level, consultation at an expert center is recommended.

• If elements of a malignant germ cell tumor are detected in the residual tumor, second-line chemotherapy (TIP or VeIP regimens) is recommended: 2 cycles in case of radical surgery, 4 cycles in case of non-radical surgery [21, 29, 35, 45–48, 115, 109].

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

• Before starting chemotherapy for a recurrence, it is recommended to exclude growing teratoma syndrome—the appearance or increase in size of metastases against the background of decreasing/normal tumor markers [109].

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

• If growing teratoma syndrome is confirmed, surgical treatment—complete removal of recurrent tumor nodes, which may be represented by glial tissue (peritoneal gliomatosis), cartilage tissue (chondromatosis), or elements of a mature teratoma—is recommended for all patients [115]. In case of multiple recurrences, repeated surgical interventions are recommended until complete cure.

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

Comment: Repeated recurrences of growing teratoma syndrome and peritoneal gliomatosis are quite likely, especially if the nodules were not completely excised. When this syndrome is confirmed, chemotherapy is not indicated.

• In case of recurrence of germ cell tumors, chemotherapy based on a combination of #ifosfamide** and cisplatin** is recommended (Table 5) [6, 42–44].

GOR BLOE 3Grade of Recommendation – B (Level of Evidence – 3).

Comments:

The optimal chemotherapy regimen is TIP, which allows achieving long-term survival in 25% of patients. The VeIP regimen can serve as an alternative. Usually, 4 cycles are administered [45, 47]. No superiority of one regimen over the other as second-line therapy has been shown.

Table 5. Chemotherapy regimens used in the treatment of GCT recurrences

^¶cisplatin** administration is carried out against the background of intravenous hydration with normal saline (total daily volume 2.5 L) required to maintain diuresis >100 mL/hour during the administration of cisplatin** and for the subsequent 3 hours;

^§mesna** is used in a daily dose equal to 100% of the ifosfamide** dose and divided into three administrations during the day: immediately before ifosfamide** and then 4 and 8 hours after the start of its infusion.

• After completion of chemotherapy for germ cell tumor recurrence, surgical removal of all residual tumor is recommended for patients [45].

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

• In case of AFP and/or β-hCG elevation despite ongoing therapy, exhaustion of chemotherapy options, and localization of the tumor within a single anatomical region, its removal is recommended [21, 24, 42, 45].

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

Comments: this approach offers a cure rate of about 25% in patients, particularly those with late relapses, moderately elevated AFP levels, and retroperitoneal localization of the residual tumor. In case of rapid progression with rising β-hCG, surgical treatment is futile [46].

• In the treatment of late relapses of germ cell tumors (after 2 years from the end of prior chemotherapy), surgical treatment is recommended [15, 42, 45, 54, 106].

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

Comments: the proportion of late relapses among all relapses does not exceed 5%. A characteristic feature of late relapses is low sensitivity to chemotherapy, which makes it advisable to perform radical surgery as a first step for potentially resectable tumors, even in the presence of elevated markers. If radical tumor removal is not feasible and markers are elevated, second-line chemotherapy should be initiated, followed by surgery.

3.2. Sex cord-stromal tumors

3.2.1. Surgical treatment of sex cord-stromal tumors

Comments: laparoscopic access is appropriate in early stages (IA-IB) for small tumors. Biopsy of the contralateral ovary is not advisable if it appears visually normal.

• In young patients with sex cord-stromal tumors and unfulfilled reproductive potential who present with early-stage disease (unilateral ovarian involvement), fertility-sparing surgery is recommended, consisting of unilateral salpingo-oophorectomy (on the affected side) with biopsy of the contralateral ovary (if pathologically altered) and subtotal greater omentectomy (via video-endoscopic or open laparotomy approach depending on the clinical situation), adhering to surgical staging principles [40].

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

Comment: given the high probability of unilateral ovarian involvement and the young age of patients with sex cord-stromal tumors, preference is given to fertility-sparing surgical approaches. Endometrial status should be evaluated. If ultrasound signs suggest potential endometrial pathology, endometrial aspiration biopsy or diagnostic curettage is recommended.

Performing a biopsy of the contralateral ovary in young patients with unfulfilled reproductive potential at an early stage is not advisable if it appears visually normal.

3.2.2. Sex cord tumors (granulosa cell tumor)

• In stage IA–B with adequate staging of sex cord-stromal tumors, follow-up after surgery is recommended [45]; for tumor sizes greater than 10–15 cm, adjuvant chemotherapy is indicated [13, 17, 26, 45, 54, 56].

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

• In stage I with high-risk recurrence factors, adjuvant chemotherapy is recommended [13, 17, 45].

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

Comment: For patients with stage IC, indications for adjuvant chemotherapy are not yet fully established. High-risk factors in stage I include: tumor rupture, stage IC, low tumor differentiation, and tumor size exceeding 10–15 cm.

• Adjuvant or first-line therapy for stages IC–IV in sex cord-stromal tumors includes 3–4 cycles of BEP chemotherapy or 6 cycles of chemotherapy with #carboplatin** and #paclitaxel** [45] (see Table 6).

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

• The possibility of treating local relapses must be discussed at a multidisciplinary tumor board involving a radiation oncologist.

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

3.2.3. Treatment of ovarian stromal tumors (Sertoli-Leydig cell tumors)

• For stage IA ovarian stromal tumors, active surveillance is recommended; in young patients with poorly differentiated tumors or heterologous elements in the tumor, adjuvant chemotherapy with BEP (3 cycles), EP (4 cycles), or 6 cycles of #paclitaxel** and #carboplatin** (Table 6) is recommended [13, 45, 57].

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

Table 6. Chemotherapy regimens for sex cord-stromal tumors

^§The dose of #bleomycin may be reduced in patients older than 40 years (e.g., omitting #bleomycin in the 4th cycle). When using domestic bleomycin hydrochloride instead of bleomycin sulfate, cumulative doses must be reduced by one-third (e.g., 30 mg on days 1 and 5).

• In patients with stage IB–IV disease, adjuvant chemotherapy is recommended: 3–4 cycles of BEP or 6 cycles of chemotherapy with #paclitaxel** and #carboplatin** (see Table 6) [12, 45, 57].

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

3.2.4. Treatment of advanced stages and recurrences of sex cord-stromal tumors

• Due to the low sensitivity of the tumor to cytostatic agents, patients with advanced stages and relapses of sex cord-stromal tumors are recommended to consider the feasibility of surgical treatment followed by chemotherapy [2, 14, 45].

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

Comment: optimal cytoreductive surgeries are the most effective. In advanced stages and disease relapse, surgery is performed as the first step, followed by 3–4 cycles of BEP chemotherapy or 6 cycles of the ovarian cancer regimen – #paclitaxel** + #carboplatin** (see Table 6). If prior therapy included the BEP regimen, the following ovarian cancer drug combinations are possible: "#paclitaxel** + #carboplatin**" or "#cyclophosphamide** + #doxorubicin** + #cisplatin**" (see Table 6). There is evidence of the efficacy of hormone therapy (gonadotropin-releasing hormone (GnRH) analogues, antiestrogens, aromatase inhibitors) in granulosa cell tumors of the ovary [55]. Granulosa cell tumors can recur years later, up to 20 years, which necessitates long-term patient follow-up.

• For patients who are not candidates for surgical treatment followed by chemotherapy, presenting with massive or residual tumors, or in cases of disease recurrence, it is recommended to consult a radiation oncologist to determine the feasibility of palliative radiotherapy [128, 129].

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

3.2.5. Neuroendocrine tumors (small cell carcinoma of the ovary, hypercalcemic type)

This is a rare, highly aggressive type of non-epithelial ovarian tumor [24] that requires an individualized clinical approach for each patient; therefore, treatment should preferably be carried out in a medical center with experience in managing such patients [24].

• For all patients with stages IC–IV, it is recommended to administer adjuvant or 1st-line chemotherapy containing platinum-based drugs, such as the EP regimen (see Table 6 for dosing) [59].

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

• For patients with small cell ovarian cancer experiencing disease progression, it is recommended to administer treatment similar to that for small cell lung cancer due to their shared histogenesis [24, 26, 59].

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

3.3 Pain management

The procedures and recommendations for pain management in epithelial ovarian cancer correspond to the guidelines presented in the clinical practice recommendations «Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Care» [http://cr.rosminzdrav.ru/#!/recomend/708].

3.4. Diet therapy

• Currently, there is evidence of an increased risk of cancer in overweight and obese patients; therefore, measures aimed at reducing patients' excess weight to normal values are recommended. Adjusting the usual diet in such patients will help prevent complications from ongoing treatment (surgical, drug, or radiation therapy) [1].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1. Prehabilitation

Pre-rehabilitation significantly accelerates functional recovery, shortens hospital stays after surgery, and reduces the rate of complications and mortality during cancer treatment. Pre-rehabilitation includes physical conditioning (therapeutic exercise/physical therapy), psychological and nutritional support, and patient education [63].

Physical pre-rehabilitation consists of a combination of aerobic and anaerobic loads. Such a combination improves exercise tolerance, enhances quality of life, and increases muscle tone.

Increasing physical activity 2 weeks before surgery improves postoperative quality of life, allowing a return to full daily activities as early as 3 weeks post-surgery [64].

An increased level of physical activity significantly improves the quality of life and survival of patients with ovarian cancer [77].

• For all patients with epithelial ovarian cancer, it is recommended to perform physical therapy in the preoperative period in order to reduce the frequency and probability of postoperative complications [65].

GCR ALEL 3Grade of Recommendation – A (Level of Evidence – 3).

• For all patients, it is recommended to provide psychological support as part of pre-rehabilitation to reduce postoperative pulmonary complications and hospital stay duration [65].

GCR ALEL 3Grade of Recommendation – A (Level of Evidence – 3).

Comment: psychological support improves mood and reduces anxiety and depression in patients. Patients who have undergone a course of psychological pre-rehabilitation adapt better to everyday life after surgical treatment

4.2. Stage I rehabilitation in surgical treatment

• In order to reduce the duration of hospital stay and the rate of postoperative complications, it is recommended to manage surgical patients using fast-track rehabilitation and ERAS («early rehabilitation after surgery») programs. These include multimodal pain control, early enteral nutrition, avoidance of routine nasogastric tubes and drains, and early mobilization (activation and verticalization) of patients as early as 1–2 days post-surgery without increasing the risks of early postoperative complications or hospital readmission rates [67, 68].

GUR CLOE 4Grading of Recommendations Assessment, Development, and Evaluation (GRADE) – C (Level of Evidence – 4).

Comment: Early initiation of physical therapy does not increase the rate of postoperative complications and improves quality of life.

Comment: in the postoperative period, more than 75% of patients develop it more than 7 days after surgery; furthermore, ovarian cancer patients with prolonged hospitalization and a history of venous thromboembolism have an increased risk of developing it.

• For all patients, it is recommended to manage postoperative pain using an interdisciplinary approach, and in addition to drug therapy, to use the following methods: physical rehabilitation (physical therapy), positioning, psychological pain relief methods (relaxation), transcutaneous electrical nerve stimulation, and acupuncture [72].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence – 5).

• For all patients, it is recommended to conduct general medical massage sessions starting from the 2nd day after surgery to reduce pain intensity, anxiety, and tension, and to improve the patient's quality of life [73].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence – 5).

• For all patients, it is recommended to conduct psychological counseling and relaxation techniques in the postoperative period, which helps reduce patient anxiety and tension, decreases the frequency of analgesic use, and improves the quality of life in gynecological cancer patients [74].

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

4.3. Stage II of rehabilitation in surgical treatment

• All patients are recommended to maintain an active lifestyle after completing treatment [75].

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

Comment: obesity and a sedentary lifestyle following multimodal treatment for ovarian cancer are independent factors that worsen patients' quality of life and lead to distress

• All patients are recommended to engage in physical activity—a combination of strength training, aerobic exercise, and stretching—which significantly improves patients' quality of life and helps control weight [76].

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

• For all patients who develop lower limb lymphedema, it is recommended to perform complete decongestive therapy, including manual lymphatic drainage, wearing compression garments, performing a complex of physical exercises, and skin care [78, 79].

GCR BLEL 3Grade of Recommendation – B (Level of Evidence – 3).

• For all patients who develop lower limb lymphedema, it is also recommended to prescribe:

- Intermittent pneumatic compression of the lower extremities in combination with complete decongestive therapy [79]

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5);

- Electrotherapy in combination with complete decongestive therapy [81]

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2);

- Pulsed low-frequency electromagnetic therapy (low-frequency magnetotherapy) in combination with complete decongestive therapy [82].

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5);

- Pulsed oscillometry (alternating electric field massage) in combination with complete decongestive therapy [83].

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

• All patients are recommended to have acupuncture sessions, as it significantly reduces fatigue and improves quality of life [84].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

4.4. Stage III of rehabilitation in surgical treatment

Functional pelvic floor disorders significantly impair the social adaptation of patients with female reproductive system tumors, leading to physical and psychological disability [89].

A healthy lifestyle and daily physical activity help control clinical manifestations of menopause such as depression and fatigue, and provide prevention of cardiovascular and osteoporosis-related complications in patients after combined treatment for malignancies [85, 86]. Increased physical activity has a positive effect on sexual function in patients with gynecological cancer [88].

• All patients with gynecological cancer experiencing menopause are recommended psychological support and patient education to improve quality of life [86].

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

• All patients are recommended to undergo periodic courses of medical massage, as they significantly improve quality of life by reducing fatigue, depression, and clinical manifestations of menopause [95].

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

4.5. Rehabilitation during chemotherapy

Comments: Dosed, gradually increasing physical activity improves tolerance to chemotherapy in patients with gynaecologic malignancies [92].

• To reduce fatigue, asthenia, and depression during chemotherapy, it is recommended to perform exercise therapy (LFK). Combining exercise therapy with psychological support in treating chemotherapy-induced fatigue and depression is more effective than pharmacotherapy alone [94].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comment: this recommendation is based on the results of a study evaluating the effects of massage on breast cancer patients; there is no reason to assume this therapy would be ineffective in ovarian cancer patients.

• Patients receiving chemotherapy are recommended a 6-week course of terrain cure (walking therapy) to control the clinical manifestations of polyneuropathy [98].

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

• All patients are recommended to perform a set of exercise therapy (LFK) to reduce the incidence of cardiac complications during chemotherapy [105].

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

5. Prevention and Dispensary Observation

Given the high curability of germ cell tumors and the long life expectancy of patients, prevention and early diagnosis of late chemotherapy complications (cardiovascular diseases, metabolic syndrome, hypogonadism, infertility, pulmonary toxicity, etc.) involving relevant specialists are required.

• For patients with stage I nondysgerminoma under active surveillance (no chemotherapy administered), the following is recommended [45, 115]:

- physical examination and tumor markers monthly in the first year, every 2 months in the second year, every 3 months in the third year, every 4 months in the fourth year, every 6 months in the fifth year, and annually thereafter;

- comprehensive abdominal ultrasound, comprehensive pelvic ultrasound (transvaginal and transabdominal), regional and distant lymph node ultrasound every 2 months in the first year, every 3 months in the second year, every 4 months in the third and fourth years, and annually thereafter;

- chest X-ray performed at every second visit [45, 115] for early detection of disease progression or recurrence.

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

• For patients with stage I germinoma after completed chemotherapy, active surveillance is recommended:

- physical examination, tumor markers, comprehensive abdominal ultrasound, comprehensive pelvic ultrasound (vaginal and transabdominal), ultrasound of regional and distant lymph nodes, and the retroperitoneal space every 2–3 months in the first year, every 3 months in the second year, then every 4 months in the third and fourth years, every 6 months in the fifth year, and annually thereafter;

- chest X-ray performed at every second visit [45, 115] for early detection of disease progression or recurrence.

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

Sex cord-stromal tumors

• Patients with early-stage, low-risk sex cord-stromal tumors after completion of treatment are recommended to undergo follow-up care with an oncologist for early detection of disease progression or recurrence, consisting of: physical examination, determination of tumor marker levels (inhibin, anti-Müllerian hormone, estradiol, testosterone depending on the histological type of the tumor), comprehensive abdominal ultrasound, comprehensive pelvic ultrasound (transvaginal and transabdominal), retroperitoneal ultrasound, and regional and distant lymph node ultrasound every 6–12 months for 10 years or more [14, 45].

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

• Patients with early-stage, high-risk and advanced-stage sex cord-stromal tumors after completion of treatment are recommended to undergo follow-up care with an oncologist for early detection of disease progression or recurrence, consisting of: physical examination, determination of tumor marker levels (inhibin, anti-Müllerian hormone, estradiol, testosterone depending on the histological type of the tumor), comprehensive abdominal ultrasound, comprehensive pelvic ultrasound (transvaginal and transabdominal), and regional and distant lymph node ultrasound every 4–6 months for 10 years or more. Chest X-ray once a year. Contrast-enhanced CT of the abdomen and/or chest as clinically indicated [14, 45].

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, "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 procedures for the provision of medical care approved by the authorized federal executive authority and mandatory for implementation across 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 medical specialists at an ambulatory cancer care center, or, in its absence, at a primary oncology office or the outpatient department of an oncological dispensary (cancer hospital).

In case of suspicion or detection of an oncological disease in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient oncological care center, or, in its absence, to 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, primary oncological office, or outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 3 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of such a center, the oncologist of the primary oncological office or outpatient department of the oncological dispensary/hospital) arranges for the acquisition of biopsy (surgical) material, as well as the performance 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 obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that includes the ambulatory cancer care center (primary oncology office), the patient is referred by the oncologist to an oncological dispensary (cancer 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 timeframe 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, which is 7 working days from the date of prescribing the examinations.

The diagnosis of an oncological disease is established by a medical specialist based on the results of diagnostic examinations, including cytological and/or histological verification of the diagnosis, except for cases where obtaining biopsy and/or puncture material is not feasible.

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:

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

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 accounting purposes, information about a newly diagnosed case of an oncological disease is sent within 3 working days by the oncologist of the medical organization where the corresponding diagnosis was established to the oncological dispensary or the organization of a constituent entity of the Russian Federation that performs the registration of patients with newly diagnosed malignant neoplasms, including through the use of the Unified State Health Information System. If the presence of an oncological disease is confirmed in a patient, information about the refined diagnosis is sent from the oncological dispensary or the organization of the constituent entity of the Russian Federation that performs the registration of patients with newly diagnosed malignant neoplasms to the medical organization providing clinical follow-up of the patient.

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 medical care, in medical organizations subordinate to federal executive authorities is provided based on medical indications provided for in clause 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities to provide specialized (excluding high-tech) medical care, stipulated in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care. (Clause 5: to receive specialized medical care on a planned basis, the federal medical organization is chosen upon the referral of the attending physician.) If several federal medical organizations participating in the implementation of the Program provide specialized medical care for diseases and conditions (group of diseases and conditions) corresponding to the patient's diseases and conditions (group of diseases and conditions), the attending physician is obliged to inform the patient (the patient's legal representative) about the possibility of choosing a federal medical organization, including the potential waiting times for specialized medical care, which may exceed the waiting times established by the program of state guarantees of free provision of medical care to citizens.

The waiting time for the provision of specialized (excluding high-tech) medical care must not exceed the timeframe established in the program of state guarantees of free medical care for citizens, approved by the Government of the Russian Federation, which is 7 working days.

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 oncological disease treatment (surgery, radiotherapy, drug therapy, etc.) requiring the provision of specialized medical care in an emergency and urgent form

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

1) the need to perform complex interventional diagnostic medical procedures, as well as endoscopic examinations when they cannot be performed on an outpatient basis, 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 by the patient or their legal representative of specialized, including high-tech, medical care in an inpatient or day hospital setting established by the concilium of the medical organization providing cancer care

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

No additional information available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ashrafyan L.A., Academician of the RAS, Dr. of Med. Sci., Professor, Deputy Director of the V.I. Kulakovskiy 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., Dr. of Med. Sci., Professor, Head of the Department of Oncogynecology at the 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., Dr. of Med. Sci., Head of the Department of Antineoplastic Drug Therapy, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

4. Urmancheeva A.F., Dr. of Med. Sci., 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., Dr. of Med. Sci., 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., Dr. of Med. Sci., 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., Dr. of Med. Sci., 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., Cand. of Med. Sci., 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. Mukhtarullina S.V., Dr. of Med. Sci., 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.

10. Verenikina E.V., Cand. of Med. Sci., Head of the Department of Oncogynecology, Rostov Research Institute of Oncology of the Russian Ministry of Health.

11. Demidova L.V., Dr. of Med. Sci., 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.

12. Shevchuk A.S., Cand. of Med. Sci., 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.

13. Ulrich E.A., Dr. of Med. Sci., Professor, Chief Researcher at the Research Laboratory of Reproductive Technologies, Head of the "Oncofertility" Competence Center, V.A. Almazov National Medical Research Center.

14. Krasilnikov S.E., Dr. of Med. Sci., Professor, Director of the Institute of Oncology and Neurosurgery, Oncologist, E.N. Meshalkin National Medical Research Center of the Russian Ministry of Health.

15. Davydova I.Yu., Dr. of Med. Sci., Leading Researcher at the Department of Pelvic Floor Oncosurgery, A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department.

16. Krikunova L.I., Dr. of Med. Sci., 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.

17. Kolomiets L.A., Dr. of Med. Sci., Professor, Head of the Gynecological Department, Research Institute of Oncology, Tomsk National Research Medical Center of the RAS.

18. Kreynina Yu.M., Dr. of Med. Sci., Leading Researcher at the Laboratory of Innovative Technologies in Radiotherapy and Chemoradiation Treatment of Malignant Neoplasms, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.

19. Dubinina A.V., Cand. of Med. Sci., Senior Researcher at the Department of Radiotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

20. Karseladze A.I., Professor, Dr. of Med. Sci., V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

21. Rubtsova N.A., Dr. of Med. Sci., 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.

22. Bychenko V.G., Cand. of Med. Sci., 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.

23. Solopova A.E., Dr. of Med. Sci., 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.

24. Ryzhkova D.V., Dr. of Med. Sci., 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.

25. Ovodenko D.L., Dr. of Med. Sci., 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.

26. Grinevich V.N., Cand. of Med. Sci., 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., Dr. of Med. Sci., 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., Oncogynaecologist, Dr. of Med. Sci., Federal Research and Clinical Center of Physical-Chemical Medicine named after Yu.M. Lopukhin of the Federal Medical-Biological Agency.

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

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

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

5. 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.

6. 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.

7. 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).

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

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

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

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

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

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

18. 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.

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

20. 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.

21. 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 conflicts of interest.

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.

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

Table A2. Levels of Evidence (LoE) rating scale for prevention, treatment, and medical rehabilitation methods, including those based on natural healing factors (preventive, therapeutic, and rehabilitative interventions)

Table A3. Grades of Recommendation (GoR) rating scale for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural healing factors (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: revision is carried out at least once every 3 years taking into account new information on the diagnosis and management of patients with endometrial 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 professional medical non-profit organizations. The generated proposals must take into account the results of comprehensive evaluation 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

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

Appendix B. Physician Action Algorithms

Figure 1. Flowchart for the diagnosis and treatment of patients with sex cord-stromal tumors

Figure 2. Flowchart for the diagnosis and treatment of female patients with ovarian germ cell tumors

Appendix C. Patient Information

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

- Consult an oncologist to determine the advisability of starting antibiotic therapy

2. In case of stomatitis:

- diet: mechanically sparing,

- Consult a physician

- treat the oral cavity as recommended by the oncologist.

3. In case of diarrhea:

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

- Consult a physician

4. In case of nausea:

Consult a physician

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO/ECOG Performance Status Scale.

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

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

Name in Russian: Karnofsky Scale.

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