Ovarian cancer / fallopian tube cancer / primary peritoneal cancer: clinical guidelines

List of Abbreviations

AFP – alpha-fetoprotein

NOS – not otherwise specified

i.v. – intravenous

WHO – World Health Organization

GI – gastrointestinal tract

Malignant neoplasms – malignant neoplasms

IHC – immunohistochemistry

CT – computed tomography

RT – radiation therapy (radiotherapy)

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

MRI – magnetic resonance imaging

PET – positron emission tomography

PET-CT – positron emission tomography combined with computed tomography using a tumorotropic radiopharmaceutical

CEA – carcinoembryonic antigen

OC – ovarian cancer

Ultrasound – ultrasound examination

ACD – adequacy of evidence level

グレード – strength of recommendation level

ChT – chemotherapy

EGD – esophagogastroduodenoscopy

ECG – electrocardiography

CA19.9 – carbohydrate antigen 19.9

CA125 – carbohydrate antigen 125

CTCAE – Common Terminology Criteria for Adverse Events

ECOG – Eastern Cooperative Oncology Group

HE4 – human epididymis protein 4

HRD – homologous recombination deficiency

MSI – microsatellite instability (microsatellite instability)

PARP – poly(ADP-ribose)polymerase

PCI – Peritoneal cancer index

RECIST – Response Evaluation Criteria in Solid Tumors

ROMA – Risk of Ovarian Malignancy Algorithm

TRG – Tumor Regression Grade

** – vital and essential drugs

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

Terms and Definitions

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

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

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

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

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

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

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).

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

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

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Ovarian cancer, fallopian tube cancer and primary peritoneal cancer – a group of malignant tumors originating from the epithelium of the respective organs. The clinical course and treatment methods for primary peritoneal and fallopian tube cancer are practically identical to ovarian cancer, therefore these nosologies are considered together in these guidelines. Hereinafter, the term "ovarian cancer" (OC) will be used.

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

In 10% of patients diagnosed with OC, the development of the disease is associated with the presence of known hereditary syndromes. The most common hereditary breast and ovarian cancer syndrome is associated with BRCA gene mutations [1]. In the majority of patients, OC is sporadic. Risk factors for this pathology include: nulliparity, smoking, overweight, frequent use of fertility drugs (studies do not provide a clear conclusion on this risk factor), and the use of estrogen-only hormone replacement therapy for at least 10 years (studies do not provide a clear conclusion on this risk factor) [2].

1.3 Epidemiology of the Disease or Condition

In the structure of oncological diseases among the female population of Russia, OC ranks 9th, which accounted for 4.2% in 2021. The crude incidence rate of OC in Russia in 2021 was 17.05 per 100,000 female population, which in absolute terms amounted to 13,315 new cases. The average age of women at diagnosis was 59.1 years. The age-standardized incidence rate of OC was 10.46 cases per 100,000 female population. The change in the incidence rate of OC over the preceding 10 years (since 2011) was -1.85% [3].

In 2021, 7,213 women died from OC in Russia. In the structure of cancer mortality among women in Russia, OC ranks 7th (5.6%). The crude mortality rate from OC in Russia in 2021 was 9.23 per 100,000 female population. The age-standardized mortality rate from OC in Russia in 2021 was 4.65 per 100,000 population [3].

1.4 Features of Coding the Disease or Condition

Peritoneal cancer, ovarian cancer, and fallopian tube cancer are histologically identical. The treatment of these pathological processes is identical; therefore, these nosologies are combined into a single section.

Malignant neoplasm of retroperitoneum and peritoneum (C48):

C48.0 – Retroperitoneum

C48.1 – Specified parts of peritoneum

C48.2 – Peritoneum, unspecified

Malignant neoplasm of ovary (C56)

Malignant neoplasm of other and unspecified female genital organs (C57)

C57.0 – Fallopian tube

C57.1 – Broad ligament

C57.2 – Round ligament

C57.3 – Parametrium

C57.4 – Uterine adnexa, unspecified

C57.7 – Other specified female genital organs

C57.8 – Lesion of female genital organs overlapping more than one of the above sites

C57.9 – Female genital organs, unspecified

Neoplasms of uncertain or unknown behavior of female genital organs (D39)

D39.1 – Ovary

D39.7 – Other female genital organs

D39.9 – Female genital organ, unspecified

1.5 Classification of the disease or condition

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

· 8441/3 serous carcinoma:

· 8460/3 low-grade,

· 8461/3 high-grade;

· 8380/3 endometrioid carcinoma;

· 8474/3 seromucinous carcinoma;

· 8480/3 mucinous carcinoma;

· 8310/3 clear cell carcinoma;

· 9000/3 malignant Brenner tumor;

· 8020/3 undifferentiated carcinoma;

· 8323/3 mixed epithelial carcinoma.

1.5.2. Staging

Staging is currently performed according to the FIGO (2014) and TNM (8th edition, 2016) classifications (Table 1).

Table 1. TNM (8th edition, 2016) and FIGO (2014) staging of ovarian cancer.

1.5.3. Assessment of tumor spread and severity of peritoneal carcinomatosis.

Assessment of tumor spread and the severity of peritoneal carcinomatosis using the Peritoneal Cancer Index (PCI) via diagnostic imaging and video-endoscopic visualization can be used to plan treatment for patients with advanced ovarian cancer, thereby reducing the rate of suboptimal surgical interventions.

To calculate the PCI, the classification proposed in 1998 by P.H. Sugarbaker [202] and included in the assessment of spread in disseminated ovarian cancer by the European Society of Gynaecological Oncology (ESGO) in 2017 is used, according to which the abdominal cavity is divided into 13 regions:

• 0 – central region: mid-abdomen, entire greater omentum, transverse colon;

• 1 – right upper quadrant: capsule of the right lobe of the liver, surface of the right hemidiaphragm, right subhepatic space;

• 2 – epigastric region: left lobe of the liver, falciform ligament of the liver, lesser omentum;

• 3 – left upper quadrant: surface of the left hemidiaphragm, tail of the pancreas, stomach;

• 4 – left flank: descending colon, left paracolic gutter;

• 5 – left lower quadrant: left pelvic sidewall, sigmoid colon;

• 6 – pelvis: uterus, ovaries, fallopian tubes, urinary bladder, pouch of Douglas, rectum;

• 7 – right lower quadrant: right pelvic sidewall, cecum, appendix;

• 8 – right flank: ascending colon, right paracolic gutter;

• 9 – upper jejunum;

• 10 – lower jejunum;

• 11 – upper ileum;

• 12 – lower ileum.

Each region is assigned a specific score depending on the size of the tumor nodules (0 – no tumor, 1 – nodules up to 5 mm, 2 – nodules from 5 mm to 5 cm, 3 – nodules >5 cm or confluent invasive infiltrates), and the total PCI can range from 0 to 39 points. If infiltrative changes are present regardless of the nodule size, a score of 3 is assigned.

For an example of an intraoperative protocol for PCI calculation, see Appendix G6.

A high total PCI score is a prognostic factor indicating the impossibility of performing optimal cytoreductive surgery.

During intraoperative revision, with a total score of 0 to 15, the rate of optimal surgeries ranged from 62 to 99 %, whereas with an index >16 points it does not exceed 35 % [203].

Comment:

- There is no universally accepted gold standard examination method for assessing peritoneal carcinomatosis, and the results of magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) demonstrate similar efficacy with certain limitations.

- When performing pelvic MRI and abdominal CT, there is an overlap of intersection zones 7 and 8, 0 and 6, and 4 and 5. When calculating the final index, overlapping zones are not summed; instead, the highest score in each overlapping zone is taken into account.

1.6 Clinical presentation of the disease or condition

In early stages, the disease may be asymptomatic or present with minor discomfort. In advanced cases, the disease manifests with nonspecific symptoms: increased abdominal girth, dyspepsia, weight loss, loss of appetite, abdominal or pelvic pain, dyspnea, and general weakness.

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 data;

3) diagnostic imaging data;

4) morphological verification

5) Laboratory methods

Histological verification of the neoplasm is mandatory to establish a clinical diagnosis. The diagnosis of ovarian cancer is established based on the histological examination of material obtained during surgery or via preoperative biopsy. If surgery or biopsy cannot be performed at the first stage, treatment begins with preoperative chemotherapy; in this case, the diagnosis can be established based on cytological data, CA-125 levels, and the clinical presentation (e.g., in massive tumor spread requiring immediate initiation of chemotherapy). ³Pleural effusion should be verified using thoracentesis followed by cytological examination of the obtained material.

2.1 Complaints and Anamnesis

• All patients are recommended a thorough collection of complaints and anamnesis (including family cancer history). In early stages, ovarian cancer may be asymptomatic or present with minor discomfort. In advanced cases, the disease manifests with nonspecific symptoms: increased abdominal girth, dyspepsia, weight loss, loss of appetite, abdominal or pelvic pain, dyspnea, and general weakness [1, 4].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

Comment: Information on complaints and details of the anamnesis, including family history, is collected to identify factors that may influence the choice of treatment tactics.

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 Appendices G1–G2), assessment of nutritional status, presence of pain syndrome, body temperature, hemodynamics, enlargement of peripheral lymph nodes, and the presence of pleurisy and ascites.

2.3 Laboratory Diagnostics

Comments: The complete blood count is performed (repeated) no later than 5 days before the start of each chemotherapy cycle [5, 6–12]. In the complete blood count, it is advisable to assess the following parameters: hemoglobin, erythrocyte, platelet, and leukocyte levels, hematocrit, mean corpuscular volume and mean corpuscular hemoglobin concentration, differential leukocyte count (leukocyte formula), erythrocyte sedimentation rate; in the general clinical blood chemistry panel assessing liver and kidney function: total protein, glucose, total bilirubin, creatinine, blood urea, serum iron, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) activity in the blood, total bilirubin in the blood; in some cases, plasma electrolytes (potassium, sodium, and chloride levels in the blood); in the routine urinalysis: visual examination of urine (color, transparency), specific gravity (relative density) of urine, urine protein, hydrogen ion concentration (pH) of urine, urine glucose, detection of ketone bodies in urine, and microscopic examination of urine sediment.

As part of the evaluation of the blood coagulation system, a coagulogram is assessed (exploratory study of the hemostatic system) (testing blood levels of fibrinogen, prothrombin [Quick's method], determination of the international normalized ratio [INR], prothrombin time [PT], activated partial thromboplastin time [APTT], and thrombin time [TT] in the blood). According to clinical indications, additional tests include determining the blood concentration of D-dimer and antithrombin III activity in the blood.

• When ovarian cancer is suspected, it is recommended that all patients undergo blood testing for human epididymis secretory protein 4 (HE4) and calculation of the ROMA index to assess the probability of ovarian cancer [15–17].

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

Comment: Determination of HE4 in the blood and the ROMA index does not replace the need for morphological verification of the diagnosis; however, an elevated HE4 level increases the specificity of ovarian cancer diagnosis.

• When mucinous carcinoma is suspected, it is recommended—in addition to measuring blood levels of cancer antigen CA125—to assess blood levels of cancer antigen CA19.9 and serum carcinoembryonic antigen (CEA) for differential diagnosis [18].

GRC ALOE 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: CEA and CA19.9 may be elevated in mucinous ovarian cancer, which subsequently allows for monitoring the efficacy of therapy. Additionally, elevated concentrations of these markers may indicate a primary gastrointestinal tumor.

• For women under 40 years of age in whom the probability of non-epithelial tumors is high, it is recommended at the diagnostic stage to perform a serum alpha-fetoprotein (AFP) assay and a serum human chorionic gonadotropin (free beta-subunit) assay [19].

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

Comment: Non-epithelial ovarian tumors predominantly occur at a young age (detailed information is provided in the section «Non-epithelial ovarian tumors»).

• All patients with high-grade serous and endometrioid carcinomas are recommended to undergo molecular genetic testing for mutations in the BRCA1 and BRCA2 genes using blood, oral mucosa scrapings, and/or biopsy (surgical) material as predictors of treatment outcomes and for selecting the patient's treatment algorithm [1, 20, 21].

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

Comment: The frequency of BRCA1 and BRCA2 gene mutations in these histological tumor types is approximately 15%. Knowledge of BRCA mutation status is useful to determine the tumor's increased sensitivity to alkylating agents, platinum compounds, and poly (ADP-ribose) polymerase (PARP) inhibitors. If PCR testing yields negative results, full genome sequencing of the tumor sample is recommended to identify rare germline and somatic mutations in the BRCA1/2 genes. In patients with germline mutations, subsequent genetic counseling is advisable to determine the need for DNA testing in blood relatives.

In endometrioid and clear cell ovarian tumors, microsatellite instability (MSI) testing in biopsy (surgical) material by immunohistochemistry (IHC) and/or PCR and other methods may be performed to determine indications for immunotherapy¹.

Comprehensive genomic profiling is not recommended due to the extremely low probability of detecting therapeutically actionable mutations.

2.4 Instrumental Diagnostics

• All patients with a clinically suspected ovarian mass are recommended to undergo a comprehensive pelvic ultrasound (transvaginal and transabdominal) as the first-line imaging method for differential diagnosis and malignant risk stratification [167, 168].

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

Comment: Transvaginal ultrasound is an accessible and highly informative first-line imaging modality of choice when an ovarian mass is suspected. It is recommended to perform the assessment using malignancy risk stratification systems, among which O-RADS should be preferred, allowing for the accurate characterization of up to 80–93% of masses.

• When ovarian cancer is suspected, all patients are recommended to undergo contrast-enhanced pelvic MRI for diagnostic clarification (including when the interpretation of a pelvic mass detected on ultrasound is ambiguous) to determine organ origin, refine the risk of malignancy, and assess the extent of pelvic tumor spread for treatment planning [169].

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

Comment: The diagnostic efficacy of MRI in differentiating ovarian masses is 94–100% with a specificity ranging from 91% to 93%, making it the gold standard for refining the diagnosis of ovarian masses in accordance with ESUR, ACR, and NCCN guidelines [169, 170, 171].

In the presence of contraindications to gadolinium-based contrast agents, performing an unenhanced MRI is acceptable.

• All patients with diagnosed or suspected ovarian cancer based on ultrasound findings are recommended to undergo contrast-enhanced computed tomography (CT) of the chest and abdomen with intravenous bolus injection to assess the extent of tumor spread when planning treatment tactics [172, 173, 174].

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

Comment:

-In case of contraindications to iodine-containing radiocontrast agents, chest CT may be performed without contrast enhancement.

-If chest CT cannot be performed, targeted chest radiography is recommended. Chest CT has higher sensitivity and specificity in detecting metastatic lesions in the lungs, pleura, and intrathoracic lymph nodes.

-If contrast-enhanced abdominal CT cannot be performed (contraindications to iodine-based contrast agents, pregnancy, etc.), contrast-enhanced abdominal MRI is recommended.

-Contrast-enhanced abdominal MRI can also be used as an alternative to CT or as a supplement in cases of ambiguous CT results to assess the extent of peritoneal carcinomatosis and resectability: the method has higher diagnostic performance compared to CT, whose sensitivity drops significantly for small lesions <1 cm in size, as well as in specific anatomical regions (right subdiaphragmatic space, mesentery, and small bowel serosa) down to 22–50% compared to MRI (75–90%). This determines MRI's higher sensitivity in predicting suboptimal cytoreduction (91%) compared to 50% for CT, with similar specificity: 100% and 97% for MRI and CT, respectively [175, 176, 177].

• It is possible to perform whole-body positron emission tomography combined with computed tomography using a tumor-tropic radiopharmaceutical (PET-CT) to assess the extent of tumor involvement (supraclavicular, intrathoracic lymph nodes, pleura) in cases of ambiguous CT/MRI findings, particularly if they may alter treatment strategy, as well as in patients with stage IV ovarian cancer (FIGO) [178, 179, 180].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

Comment: The diagnostic performance of PET-CT in detecting lymph node metastasis and distant metastatic lesions is superior to CT, demonstrating a sensitivity of 69.4%, specificity of 97.5%, and diagnostic accuracy of 94.0% [181]

• If tomographic methods (CT, MRI, PET-CT) are unavailable, all patients with diagnosed or suspected ovarian cancer are recommended to undergo ultrasound of the cervical-supraclavicular, subclavian, axillary, and inguinal lymph nodes, as well as the abdominal and retroperitoneal spaces [206, 207, 208].

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

Comment: Ultrasound is the simplest and most accessible method for evaluating abdominal, retroperitoneal, and pelvic organs and structures, as well as the status of regional and peripheral lymph nodes. However, this method has limitations and cannot replace CT/MRI/PET-CT when assessing tumor dissemination at the clinical decision-making stage for treatment planning. Evaluating chemotherapy response using RECIST 1.1 criteria is also impossible via ultrasound, as it requires tomographic imaging techniques.

• All patients with or suspected of having ovarian cancer are recommended to undergo esophagogastroduodenoscopy (EGD) to rule out a primary gastrointestinal (GI) tract tumor and evaluate concurrent GI disorders [22].

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

Comment: EGD is a mandatory examination for patients with suspected ovarian cancer, allowing clinicians to rule out secondary (metastatic) ovarian involvement from gastrointestinal malignancies.

• All patients with or suspected of having ovarian cancer are recommended to undergo colonoscopy for differential diagnosis with gastrointestinal malignancies and evaluation of concurrent gastrointestinal disorders [22, 23].

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

Comment: Colonoscopy is a mandatory examination for patients with suspected ovarian cancer, allowing clinicians to rule out secondary (metastatic) ovarian involvement from gastrointestinal malignancies. If colonoscopy is not feasible, a barium enema or other radiographic examination of the large intestine should be performed.

• All female patients with suspected or confirmed ovarian cancer are recommended to undergo a breast examination to rule out secondary (metastatic) tumor involvement and multiple primary malignancies [27, 28–30].

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

Comments: Women under 40 years of age undergo breast ultrasound in the first phase of the menstrual cycle (if applicable); women over 40 years of age are recommended to undergo mammography in the first phase of the menstrual cycle (if applicable). Consultation with a breast specialist (mammologist) is performed if necessary based on the test results. Breast examination is carried out in accordance with the principles outlined in the clinical guidelines for breast malignancies.

• For diagnosed or suspected ovarian cancer during pregnancy, all patients are recommended to undergo ultrasound and/or MRI of the abdominal and pelvic organs (without paramagnetic contrast agents) to assess the extent of the tumor process and plan treatment tactics [182]

GCP CLOE 3Grade of Recommendation – C (Level of Evidence – 3)

Comment: In the first trimester of pregnancy, the preferred diagnostic method is comprehensive ultrasound of the abdominal and pelvic organs (transvaginal and transabdominal). When ordering an MRI of the abdominal and pelvic organs, the risk/clinical necessity ratio must be evaluated. When performing MRI in the second and third trimesters of pregnancy, there are no risks to the fetus; the administration of paramagnetic contrast agents during MRI is not recommended.

• All patients with confirmed ovarian cancer following neoadjuvant chemotherapy (ChT), during adjuvant and isolated ChT, are recommended to undergo chest CT, abdominal and pelvic CT/MRI with intravenous contrast to evaluate treatment efficacy. In case of ambiguous CT/MRI results, PET-CT is recommended as an auxiliary method. [183]

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

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

• Following anti-tumor treatment, to assess dynamics, it is recommended to perform chest CT, abdominal and pelvic CT/MRI with intravenous contrast if recurrence is suspected based on clinical examination and/or "marker" recurrence. In case of ambiguous CT/MRI results in patients with recurrent ovarian cancer or suspected recurrence, positron emission tomography combined with computed tomography using a tumor-tropic radiopharmaceutical (PET-CT) is recommended as an additional imaging modality. [184, 185, 186]

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

Comment:

- during follow-up after anti-tumor treatment, imaging methods are prescribed according to clinical indications. Routine use of MSCT or MRI in asymptomatic patients is not recommended; when clinical indications are present, the choice of modality is similar to that at the diagnostic stage.

- A prospective multicenter cohort study showed that the use of

PET-CT in recurrent ovarian cancer (elevated CA-125 levels, presence of

clinical symptoms) can influence treatment tactics in approximately 60% of patients and detect additional lesions undetectable by traditional imaging methods in 68% of patients. At the same time, 77% of the lesions were localized below the level of the diaphragm, presenting with peritoneal carcinomatosis in the majority of cases. However, routine PET-CT in asymptomatic patients is not recommended. Detection of ovarian cancer recurrence is limited in patients with low-grade tumors.

• Patients with confirmed or suspected ovarian cancer may be recommended diagnostic laparoscopy for morphological verification of the diagnosis (if less invasive methods appear ineffective), to clarify the extent of the tumor process or presence of recurrent tumor, for staging, and to assess resectability [20, 31].

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

Comment:

- Histological verification is mandatory to establish a clinical diagnosis of ovarian cancer.

- Exceptions include patients with a clinical presentation of advanced ovarian cancer (with ascites, peritoneal carcinomatosis, elevated CA-125 and HE4 levels, and CEA within normal limits or only slightly elevated, with no evidence of a primary malignancy of another site, including GI tract, breast, etc.) who, due to their severe condition, require urgent initiation of chemotherapy; in this case, morphological verification of the neoplasm can be performed using cytologic examination of material obtained from the patient via minimally invasive techniques (paracentesis, etc.).

2.5 Other Procedures

• Morphological verification of the diagnosis is strongly recommended for all patients with suspected ovarian cancer prior to treatment initiation. Material sampling can be performed during diagnostic laparoscopy or laparotomy with urgent intraoperative pathomorphological examination of biopsy (surgical) material [20].

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

Comment:

Histological verification of the neoplasm is mandatory to establish a clinical diagnosis and prescribe conservative treatment in most cases. Exceptions include patients with a clinical presentation of advanced ovarian cancer (with ascites, peritoneal carcinomatosis, elevated CA-125 and HE4 levels, and CEA within normal limits or only slightly elevated, with no evidence of a primary malignancy of another site, including GI tract, breast, etc.) who, due to their severe condition, require urgent initiation of chemotherapy; in this case, verification of the neoplasm can be performed using cytologic examination of material obtained from the patient via minimally invasive techniques (paracentesis, etc.).

Surgical intervention can in some cases be performed without morphological verification.

Pleural effusion should be verified via transthoracic puncture followed by cytologic examination of the obtained material.

Pleural effusion must be verified via transthoracic puncture followed by cytologic examination of the obtained material.

1) Dimensions of the primary tumor, capsule damage, or tumor extension onto the capsule;

2) Histological structure of the tumor;

3) Tumor grade (degree of malignancy);

4) Presence of malignant cells in each individual peritoneal biopsy and in the greater omentum;

5) Indication of the total number of examined and affected lymph nodes;

6) Degree of therapeutic pathomorphosis in the case of preoperative therapy.

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

Comment: In case of doubtful or negative biopsy results of a neoplasm based on pathomorphological examination, patients with suspected ovarian cancer are indicated for surgical intervention with urgent intraoperative pathomorphological examination of the biopsy (surgical) material;

- if necessary to morphologically verify the diagnosis of ovarian cancer, the pathomorphological examination of the biopsy (surgical) material may be supplemented by IHC typing;

7) the degree of therapeutic pathomorphosis in the case of preoperative therapy is evaluated in accordance with international recommendations using the Tumor Regression Grade (TRG) scale [34, 35]: TRG 0 – complete response, TRG 1 – near-complete response, TRG 2 – partial response, TRG 3 – poor morphological response; no response to treatment (see Appendix G3).

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 effective and safe medical care; therefore, their prescription and use in clinical practice are determined in accordance with the specific clinical situation, compliance with safety precautions during their use, and possible dose adjustments taking into account the patient's condition.

• Given the tumor spread and the patient's condition allowing for optimal cytoreductive surgery at the first stage, it is recommended to perform a surgical intervention in the scope of complete or optimal cytoreduction [1, 36–38].

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

Comment: For the definition of complete and optimal cytoreduction, see the section «Terms and Definitions».

3.1. Surgical treatment of stage I–II ovarian cancer

• In stages I–II of the disease, during the revision of the abdominal cavity organs, it is strongly recommended to perform all surgical staging procedures [32, 33, 39–41].

GCR ALOE 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: The following manipulations are performed for the surgical staging of ovarian cancer:

1. Midline laparotomy for a full revision of the abdominal and pelvic organs and to provide adequate access to the greater omentum. Laparoscopic surgery in early stages (stage I) for staging purposes can be used in major oncological centers if trained specialists and the appropriate level of technical equipment are available [5].

2. If there is no morphological verification of the diagnosis, laparotomy should be performed with urgent intraoperative pathomorphological examination of the biopsy (surgical) material.

3. If ascites is detected, the fluid is aspirated for cytological examination. In the absence of ascites, a cytological examination of peritoneal washings is performed (including from its diaphragmatic surface, lateral gutters, and small pelvis).

4. All regions of the abdominal cavity and small pelvis, including the subdiaphragmatic space, greater and lesser omentum, small and large intestine and their mesenteries, the surface of the parietal and visceral peritoneum, and the retroperitoneal space, are carefully and methodically inspected; all areas of the peritoneum and adhesions suspicious for metastases are biopsied. The entire peritoneal surface must be inspected. Adhesions preventing revision must be noted.

5. If the revision did not confirm the presence of metastases, biopsies of randomly selected areas of the peritoneum of the pelvic walls, rectouterine pouch, urinary bladder, lateral gutters, and the right and left domes of the diaphragm are performed (scrapings from the diaphragmatic surfaces may be performed).

6. Resection (removal) of the greater omentum is mandatory and is performed at the level of the greater curvature of the stomach in ovarian cancer.

7. Total pelvic and lumbar lymphadenectomy up to the level of the renal vessels is mandatory in stage I ovarian cancer (except for mucinous and endometrioid adenocarcinoma) to decide on the need for adjuvant chemotherapy; in all other cases, it is decided individually. [217]

8. Appendectomy (removal of the appendix) is advisable if its involvement is suspected.

Organ-preserving surgery (unilateral adnexectomy with resection of the contralateral ovary, resection of the greater omentum (omentectomy, pelvic and lumbar lymphadenectomy, and staging procedures) as an exception is possible in young patients wishing to preserve fertility, with low-grade serous carcinoma, endometrioid or mucinous carcinoma of stages IA and IC1, provided that careful follow-up is possible and the hereditary nature of the disease is proven to be absent. In the endometrioid histological variant of the tumor, a biopsy of the uterine tissues (endometrium) should be performed to rule out synchronous endometrial cancer.

Minimally invasive surgical interventions, in particular laparoscopic ones, can be used only for morphological verification of the diagnosis, staging, or for predicting the volume of cytoreductive surgery.

If staging procedures are not performed during the initial surgery, it is advisable to perform a second surgical intervention for restaging purposes [42–44].

3.2. Surgical treatment of stage III-IV ovarian cancer

• Given the tumor spread and the patient's condition allowing for optimal cytoreductive surgery at the first stage, it is recommended to perform surgical intervention in the scope of complete or optimal cytoreduction, i.e., removal of all visible manifestations of the disease [1, 45].

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

Comment: For the definition of complete and optimal cytoreduction, see the section «Terms and Definitions».

• If it is impossible to perform cytoreductive surgery at the first stage, it is recommended to start treatment with chemotherapy (CT) [46–48].

GGR ALEL 1Grade of Recommendation – A (Level of Evidence – 1).

Comment: Patients who are indicated for preoperative CT may include patients with a poor ECOG/WHO performance status, as well as patients with an extremely high dissemination of the tumor process that makes optimal cytoreduction impossible. These patients need interval cytoreductive surgery as soon as possible (after 2–3 courses of neoadjuvant CT). If conditions for complete cytoreduction are not met after 3 courses of chemotherapy, a decision is made individually to administer another 3 courses of chemotherapy, followed by an assessment of the feasibility of complete cytoreductive surgery. In case of progression after 3 courses of neoadjuvant CT, the patient is switched to 2nd-line CT.

The stages of surgical treatment and staging procedures are specified in section 3.1.

• Lymphadenectomy in stage III–IV ovarian cancer is recommended in case of complete cytoreduction when lymph nodes are enlarged and suspicious for metastatic involvement according to preoperative imaging or intraoperative revision [49, 50].

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

Comment: Internal, external, common iliac, obturator, pre- and para-aortic, aortocaval, pre- and para-caval lymph nodes up to the level of the renal vessels are subject to removal.

3.3. Adjuvant and first-line chemotherapy

The degree of therapeutic pathomorphosis based on the results of the pathomorphological examination of the surgical (biopsy) material after preoperative CT is not a reason for changing the CT line [51].

1) Stage Ia–Ib;

2) Low-grade carcinoma;

3) Non-clear cell histological type of tumor;

4) Surgical staging procedures have been fully performed [42–44, 51].

GGR ALEL 2Grade of Recommendation - A (Level of Evidence - 2).

• For patients with stages IA, IB with high-grade carcinomas or clear cell histological type, as well as those in whom surgical staging procedures were not performed, it is recommended to administer 4–6 courses of platinum-based CT (Table 2) [42–44, 51].

GOM ALOE 1Grade of Recommendation - A (Level of Evidence - 1).

Comment: The optimal timing for starting CT is up to 25 days from the moment of surgical intervention for patients with ovarian cancer. Up to 8–10% of patients may experience hypersensitivity reactions during therapy with platinum agents. The use of desensitization protocols can improve patient survival. Currently, there is no data demonstrating the superiority of any specific protocol over other possible desensitization regimens.

When treating female patients with a history of allergic reactions (hypersensitivity reactions) to platinum agents, it is recommended to evaluate the feasibility of continuing therapy with platinum-based drugs (ATC L01XA: Platinum compounds):

1. Assess the severity of the allergic reaction. In the event of a grade 1–3 allergic reaction according to the CTCAE (Common Terminology Criteria for Adverse Events), consideration should be given to continuing therapy using a desensitization protocol. In the event of a grade 4 allergic reaction (life-threatening hypersensitivity reaction) according to the international scale for assessing the severity of adverse events (CTCAE), the drug that caused it must be discontinued and not prescribed subsequently until consultation with a specialist experienced in desensitization therapy (an allergist-immunologist or an oncologist (chemotherapist)).

2. When choosing a desensitization protocol, one should be guided by specialized literature. The desensitization protocol must include fractional administration of the drug that caused the allergic reaction and the prophylactic use of drugs that reduce the risk of hypersensitivity (systemic antihistamines (H1-histamine receptor blockers), glucocorticoids). When treating female patients with hypersensitivity reactions, it is mandatory to follow the chosen desensitization protocol during each subsequent treatment course.

3. Before administering therapy using a desensitization schedule, it should be ensured that the staff of the medical organization are familiar with the symptoms of allergic reactions and the procedures to follow in the event of their occurrence. Rapid access to necessary medications (systemic antihistamines (H1-histamine receptor blockers), glucocorticoids, epinephrine**) and/or to the resuscitation service must be ensured.

4. In the event of recurrent hypersensitivity reactions despite adherence to the desensitization protocol, further decisions on treatment tactics should be made individually, taking into account the risk-benefit ratio of continuing therapy, as well as the severity of the hypersensitivity reaction;

5. In some cases, it may be advisable to replace the platinum agent that caused the hypersensitivity reaction with another drug of the same class (e.g., cisplatin** with carboplatin** or oxaliplatin**). When replacing the drug, the spectrum of its toxicity and efficacy within the used treatment regimen should be taken into account.

Table 2 presents the adjuvant/first-line chemotherapy regimens.[187]

The combination of CP (platinum compounds and cyclophosphamide**) is not recommended for use in patients with ovarian cancer due to lower clinical efficacy.

Table 2. Chemotherapy for primary ovarian cancer

¹ Perform for primary or secondary prophylaxis of neutropenia with #filgrastim** at 5 mcg/kg (rounding of a single dose to 300 mcg is possible) subcutaneously 24–72 hours after completion of the treatment regimen and until normalization of the neutrophil count after their maximum drop, or with #empegfilgrastim** 7.5 mg subcutaneously once, no earlier than 24 hours after the completion of chemotherapy administration.[214, 215]

• Intraperitoneal chemotherapy is recommended for stages II–IV in the event of primary debulking surgery with a maximum residual tumor nodule size of no more than 1 cm and requires prior implantation of an intraperitoneal port [42–44, 51, 213]

AGR ALEL 1Level of Evidence - A (level of data reliability - 1).

Comments: In patients receiving maintenance therapy with olaparib in combination with #bevacizumab**, in the event of signs of intolerable toxicity associated with #bevacizumab**, it is necessary to discontinue #bevacizumab** and continue therapy with olaparib** as monotherapy.

The addition of olaparib** in maintenance monotherapy or in combination with #bevacizumab** is possible upon achieving a complete or partial response following suboptimal debulking; in the case of complete/optimal debulking (i.e., in the absence of target lesions), the administration of a poly(ADP-ribose) polymerase (PARP) inhibitor is possible if disease progression after completion of chemotherapy is ruled out. Previously performed complete debulking should not be considered a contraindication to the prescription of olaparib**.

• In all patients with ovarian cancer, starting from stage IC, in the absence of contraindications, curative (first-line) platinum-based chemotherapy is recommended for 6 courses (see Table 2) [12, 33].

AGR BLEL 2Level of Evidence - B (level of data reliability - 2).

• In the case of low-grade serous ovarian cancer, maintenance endocrine therapy is recommended after the completion of chemotherapy [59, 60].

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

Comment: Aromatase inhibitors [60] or #tamoxifen** (20 mg twice daily, 28-day cycle) [60] until progression or for three years are recommended as drugs. The necessity of immunohistochemical typing to determine estrogen and progesterone receptor expression during pathomorphological examination of surgical (biopsy) material to determine sensitivity to endocrine therapy has not been proven and is optional.

Comment: If the tumor progresses during first-line chemotherapy (platinum-refractory cancer), monotherapy with a non-platinum agent may be attempted (Table 3). In all other cases, including partial treatment response with residual tumor, active surveillance until progression is recommended. Maintenance therapy, with the exception of bevacizumab** and endocrine therapy, is ineffective. "Second-look" surgery is also not recommended.

3.4. Treatment of ovarian cancer recurrence

Ovarian cancer progression is defined by the presence of any of the following criteria [62]:

(a) clinically or radiologically confirmed progression; (b) an increase in CA-125 to 2 times the upper limit of normal (if it was previously within the normal range) or an increase in CA-125 to 2 times the lowest value recorded during treatment (if normalization of CA-125 was not documented during treatment), confirmed by a repeat test at an interval of at least 1 week [63].

Ovarian cancer progression criteria are not an absolute indication to start a new line of chemotherapy, but serve to evaluate the efficacy of previous treatment, such as determining the duration of the platinum-free interval.

• Second- and subsequent-line chemotherapy, and/or targeted therapy, and/or hormone therapy is recommended to be initiated in patients with recurrent ovarian cancer if indicated (growth of tumor lesions and patient symptoms related to tumor progression, or presence of tumor lesions whose growth may lead to complications) and in the absence of medical contraindications [32, 62, 64].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

1) platinum-free interval duration of more than 6 months;

2) presence of one or more recurrent tumors in the absence of widespread carcinomatosis and ascites >500 ml;

3) WHO/ECOG performance status of 0 and a Karnofsky performance scale score of 80–100 (see Appendix G1–G2) [65–67].

GR ALEL 2Grade of Recommendations — A (Level of Evidence — 2).

Comment: Selected patients with recurrent ovarian cancer may be considered candidates for secondary cytoreductive surgery. Secondary cytoreduction is appropriate only if it can be performed with no macroscopic residual disease. Surgery should be planned before starting chemotherapy for recurrence.

Comment: Table 3 summarizes the recommended chemotherapy regimens for recurrent ovarian cancer.

• For disease recurrence with a platinum-free interval of 6 to 24 months, it is recommended to administer a combination of platinum compounds (cisplatin** or carboplatin**) combined with another antineoplastic agent not previously used in this patient (see Table 3) [68–70].

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

Table 3. Acceptable 2nd and subsequent-line chemotherapy regimens (average duration of 2nd-line chemotherapy is 4–6 cycles) [187]

² Alternatively, Cisplatin** 75 mg/m² / Carboplatin** AUC 5–6 may be used depending on medical indications.

¹ Administer with primary or secondary prophylaxis using #filgrastim** 5 mcg/kg (rounding the single dose to 300 mcg is permitted) subcutaneously 24–72 hours after completion of the chemotherapy regimen and until neutrophil counts recover after their nadir, or #empegfilgrastim** 7.5 mg subcutaneously as a single dose, at least 24 hours after the completion of chemotherapy administration [214, 215].

• For patients with ovarian cancer recurrence, regardless of BRCA1/2 mutation status, when the disease course indicates increased tumor cell sensitivity to DNA-damaging agents (e.g., patients with high-grade serous and endometrioid adenocarcinoma with a long platinum-free interval and/or high sensitivity to platinum compounds), maintenance monotherapy with olaparib** (tablets)¹ at a dose of 300 mg (two 150 mg tablets) twice daily (total daily dose 600 mg) is recommended until disease progression [20, 92, 216].

GR ALEL 2Grade of Recommendations — A (Level of Evidence — 2).

¹Repeat administration is possible after use in maintenance therapy of previous lines [93].

• In case of recurrence with a platinum-free interval of less than 6 months, if no progression occurred during platinum-based chemotherapy, platinum-free monochemotherapy is recommended, with re-administration of platinum-based chemotherapy as a potential option in the future (see Table 3) [68, 69].

GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).

Comment: If the platinum-free interval is less than 6 months and symptoms of the oncological process are mild, platinum-free monochemotherapy is recommended. If the tumor subsequently progresses, re-administration of platinum-based chemotherapy is preferred, provided that tumor progression was not previously documented during platinum-based chemotherapy. If there are severe symptoms associated with tumor progression or if a BRCA1/2 mutation is present, it is advisable to resume platinum-based chemotherapy immediately, provided that tumor progression was not previously documented during platinum-based chemotherapy.

• In case of inefficacy of 2 consecutive chemotherapy regimens, its further administration is questionable due to the predicted low efficacy; it is recommended to consider either symptomatic therapy or inclusion in clinical trials [28, 99].

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

• When a non-taxane-based combination is used as 1st-line chemotherapy, it is recommended to include taxanes as 2nd-line chemotherapy [71].

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

• As maintenance therapy for patients with pathogenic germline or somatic BRCA1/2 gene mutations, it is recommended to consider prescribing olaparib** provided that all of the following conditions are met:

1) high-grade serous carcinoma;

2) objective response after the last platinum-based chemotherapy administered for a platinum-sensitive relapse [97, 98].

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

Comment: Administration of olaparib** at a dose of 300 mg (two 150 mg capsules) twice daily (total daily dose of 600 mg) [92, 19–20] should be initiated within 8 weeks after the completion of platinum-based chemotherapy and continued until disease progression or intolerable toxicity [20, 92].

• In specific clinical situations in patients with relapsed disease, it is recommended to consider the use of radiation therapy on an individual basis for palliative purposes [99, 100].

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

Comment: Certain non-serous histological tumor types, such as clear cell, mucinous, or endometrioid, are in many cases localized to the pelvis, and metastasis may be limited to regional lymph nodes. Given the resistance of non-serous histotypes to drug therapy, radiation therapy targeting recurrent lesions and metastases may be used.

3.5. Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy

• When administering antitumor drug therapy with emetogenic side effects, it is recommended to provide prevention and treatment of nausea and vomiting [1, 2].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The principles of diagnosis, prevention, and treatment of nausea and vomiting during antitumor drug therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Vladimirova L.Yu. et al. Nausea and vomiting [3].

https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting

• In patients with bone metastases, it is recommended to provide prevention and treatment of bone complications [4].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The principles of diagnosis, prevention, and treatment of bone complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Bagrova S.G. et al. Bone tissue pathology [5].

https://rosoncoweb.ru/standarts/?chapter=bone_pathology

• Patients are recommended to receive prevention and treatment of venous thromboembolic complications [6-8].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The principles of diagnosis, prevention, and treatment of venous thromboembolic complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Somonova O.V. et al. Thromboembolic complications [9].

https://rosoncoweb.ru/standarts/?chapter=thromboembolism

• During antineoplastic drug therapy, patients are recommended to receive prophylaxis and treatment for febrile neutropenia and infectious complications [10-12].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, as well as the principles of antibacterial therapy, are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Sakaeva D.D. et al. Practical guidelines for the diagnosis and treatment of febrile neutropenia [13].

https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia

• During antitumor drug therapy, patients are recommended to receive management of hepatotoxicity [14, 15].

GCR CLOE 3Grade of Recommendation — C (Level of Evidence — 3).

Comments. The principles of diagnosis, prevention, and treatment of hepatotoxicity are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Tkachenko P.E. et al. Hepatotoxicity [16].

https://rosoncoweb.ru/standarts/?chapter=hepatotoxicity

• When patients receive antitumor drug therapy, it is recommended to provide prevention and treatment of cardiovascular complications [17-20].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The principles of diagnosis, prevention, and treatment of cardiovascular complications during antitumor therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Vitsenya M.V. et al. Cardiovascular toxicity [21].

https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of dermatological reactions [22].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The principles of diagnosis, prevention, and treatment of skin complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Koroleva I.A. et al. Dermatological reactions [23].

https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions

• To maintain the metabolic reserves of a cancer patient and increase their tolerance to treatment (surgical, drug, radiation), nutritional support is recommended. The choice of nutritional support method is determined by the patient's various types of nutritional disorders. Placement of a nasogastric, nasointestinal, percutaneous, endoscopic, laparoscopic, or laparotomy stoma, endoscopic stenting for tumor stenosis, or palliative radiation therapy may be recommended [24, 25].

LOE 1Grade of Recommendation — 1 (Level of Evidence — 1).

Comments. The principles of nutritional support are presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Sytov A.V. et al. Nutritional support [26].

https://rosoncoweb.ru/standarts/?chapter=nutritional_support

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of nephrotoxicity [27-29].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of nephrotoxicity is presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Gromova E.G. et al. Nephrotoxicity [30].

https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of immune-mediated adverse events [31-34].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of immune-mediated adverse events is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Protsenko S.A. et al. Immune-mediated adverse events [35]. https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of mucositis [36, 37].

GCR CLEL 5Grade of Recommendation — C (Level of Evidence — 5).

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of mucositis is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Semiglazova T.Yu. et al. Mucositis [38].

https://rosoncoweb.ru/standarts/?chapter=mucositis

• Patients are recommended to receive treatment for anemia occurring as a symptom of a malignant neoplasm and as an adverse event of antitumor drug therapy [39, 40].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The procedure and principles for the prevention and treatment of anemia comply with the principles outlined in the clinical guidelines "Anemia in Malignant Neoplasisms" (ID: KR624, approval year 2020, www.cr.rosminzdrav.ru) and in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Orlova R.V. et al. Anemia [41].

• During treatment, patients are recommended to receive treatment for anorexia-cachexia syndrome [42].

GCR CLOE 3Grade of Recommendation — C (Level of Evidence — 3).

Comments. A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A. V. et al. Practical guidelines for the treatment of anorexia-cachexia syndrome in cancer patients [43].

https://rosoncoweb.ru/standarts/?chapter=anorexia-cachexia

• When administering cyclic antineoplastic drug therapy involving continuous prolonged (exceeding 6 hours) infusions of antineoplastic agents (fluorouracil, doxorubicin, etc.) or in case of poor peripheral vein condition, it is recommended to use central venous access and infusion pumps [44].

GCR BLOE 2Grade of Clinical Recommendation — B (Level of Evidence — 2).

Comments. The choice of central access method is determined by the planned duration of the entire treatment course, patient preferences, and anatomical features. For prolonged courses of therapy (exceeding 3 months), implantation of a subcutaneous venous port system is most convenient. For shorter periods, a peripherally inserted central catheter may serve as an alternative. The principles of central venous access use are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Isyngulova A. Z. et al. Central venous access [45].

https://rosoncoweb.ru/standarts/?chapter=central_venous_access

• During antineoplastic drug therapy, it is recommended to provide prevention and treatment of antineoplastic drug extravasation. When planning antineoplastic drug therapy, the selection of vascular access is important for the prevention of antineoplastic agent extravasation [46].

GCR CLOE 3Grade of Clinical Recommendation — C (Level of Evidence — 3).

Comments. Algorithms for vascular access selection, prevention, diagnosis, and treatment of extravasation are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Buydenok Yu.V. et al. Extravasation of antineoplastic drugs [47].

 https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs

• During antineoplastic treatment, it is recommended to manage chronic pain syndrome [48].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Kogonia L.M. et al. Chronic pain syndrome [49].

https://rosoncoweb.ru/standarts/?chapter=chronic_pain_syndrome

• During antineoplastic drug therapy, it is recommended to provide prevention and treatment of infusion reactions [50].

GCR CLOE 3Grade of Clinical Recommendation — C (Level of Evidence — 3).

Comments. Algorithms for the prevention, diagnosis, and treatment of infusion reactions are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Orlova R.V. et al. Infusion reactions [51].

https://rosoncoweb.ru/standarts/?chapter=infusion_reactions

• During therapy, it is recommended to monitor and treat reactivation/exacerbation of chronic viral hepatitis [52].

GCP BLEL 3Grade of Recommendation — B (Level of Evidence — 3).

Comments. The principles of monitoring and management tactics in cancer patients with chronic viral hepatitis are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Feoktistova P.S. et al. Chronic viral hepatitis [53].

 https://rosoncoweb.ru/standarts/?chapter=chronic_viral_hepatitis

• During antineoplastic drug therapy, it is recommended to provide prevention and treatment of neurological complications [54].

GCR BLEL 2Grade of Recommendation — B (Level of Evidence — 2).

Comments. The principles of diagnosis, prevention, and treatment of neurological complications of antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Latipova D.Kh. et al. Neurological complications [55].

https://rosoncoweb.ru/standarts/?chapter=neurological_complication

• During antineoplastic hormone therapy, patients are recommended to undergo prevention and treatment of hormone-mediated adverse events [56].

GCR BLEL 2Grade of Recommendation — B (Level of Evidence — 2).

Comments. The principles of diagnosis, prevention, and treatment of hormone-mediated adverse events are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Stenina M.B. et al. Hormone-mediated adverse events [57].

 https://rosoncoweb.ru/standarts/?chapter=hormone-mediated_side_events

• For patients with pancreatic cancer, enzyme replacement therapy is recommended in case of secretory insufficiency [58].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The algorithms for the diagnosis and treatment of exocrine insufficiency in pancreatic cancer are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A.V. et al. Enzyme replacement therapy in pancreatic cancer [59].

https://rosoncoweb.ru/standarts/?chapter=pancreatic_enzyme_replacement_therapy 

3.6. Pain management

The procedure and recommendations for pain management in ovarian cancer correspond to the recommendations presented in the rubricator "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care" [121].

3.7. Diet therapy

• To date, there is evidence of an increased risk of cancer in overweight (obese) patients; therefore, interventions aimed at reducing patients' excess body weight to normal values are recommended. Correction of usual dietary intake in such patients will help prevent complications of the administered treatment (surgical, drug, or radiation therapy). [2]

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1. Prehabilitation

Prerehabilitation significantly accelerates functional recovery, shortens hospital stay after surgery, and reduces the incidence of complications and mortality during cancer treatment. Prerehabilitation includes physical training (exercise therapy), psychological and nutritional support, and patient education [122].

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 after surgery [123].

Increased physical activity significantly improves the quality of life and survival of patients with ovarian cancer [124].

4.2. Stage I rehabilitation in surgical treatment

• In order to reduce the duration of patients' hospital stay and the incidence of postoperative complications, it is recommended to rehabilitate patients undergoing surgical treatment according to the fast-track rehabilitation and ERAS (early rehabilitation after surgery) programs, including multimodal 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, which does not increase the risks of early postoperative complications or the rate of readmissions [128, 129].

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

4.3. Stage II of rehabilitation in surgical treatment

• Physical activity—a combination of strength training, aerobic exercise, and stretching exercises—is recommended for all patients, as it significantly improves their quality of life and helps control body weight [137].

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

- intermittent pneumatic compression of the limbs in combination with complete decongestive therapy [139];

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

- low-level laser therapy in combination with complete decongestive therapy [140];

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

- electrotherapy in combination with complete decongestive therapy [141];

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

- low-frequency magnetotherapy in combination with complete decongestive therapy [142];

Level of Evidence CGrade of Recommendation 5 Level of Evidence – C (Quality of Evidence – 5).

- deep oscillation (massage with a variable electrostatic field) in combination with complete decongestive therapy [143].

CGR BLEL 1Level of recommendation grade – B (level of evidence – 1).

• Acupuncture sessions are recommended for all patients, as it significantly reduces fatigue and improves quality of life [144].

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

4.4. Stage III of rehabilitation in surgical treatment

Functional disorders of the pelvic organs significantly hinder the social adaptation of patients with female reproductive system tumors, leading to their physical and psychological disability [145].

A healthy lifestyle and daily physical activity help control clinical manifestations of menopause such as depression and fatigue, as well as prevent cardiovascular complications and osteoporosis-related complications in patients after combined-modality treatment of malignant neoplasms [63, 64]. Increased physical activity has a positive effect on sexual function in patients with ovarian cancer [148].

4.5. Rehabilitation during chemotherapy

Comment: Gradual, progressively increasing physical exertion improves chemotherapy tolerance in patients with gynecological malignancies [151].

• To reduce fatigue, weakness, and depression during chemotherapy, it is recommended to perform exercise therapy. Combining exercise therapy with psychological support in treating chemotherapy-induced fatigue and depression is more effective than pharmacological correction alone [153].

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

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

• Patients receiving chemotherapy are recommended a 6-week course of terrain cure (walking therapy) to control the clinical manifestations of polyneuropathy [156].

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

• All patients are recommended to perform a set of exercise therapy to reduce the incidence of cardiac complications during chemotherapy [163].

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

5. Prevention and Dispensary Observation

Comment: The principles of patient follow-up after primary treatment are not fully defined. The results of the large international MRC OV-05 trial [64] demonstrated no need for rigorous instrumental examination aimed at the earliest possible detection of recurrence. Second-line chemotherapy should ideally be initiated when clinical symptoms appear. Early initiation of second-line chemotherapy, for example upon marker relapse, does not increase overall survival, but impairs quality of life due to treatment toxicities.

At the same time, repeat optimal cytoreductive surgery may improve long-term treatment outcomes in patients who previously underwent optimal cytoreductive surgery and had a platinum-free interval of >6 months after the end of chemotherapy. For this reason, the working group proposes the following patient follow-up algorithm:

- blood test for cancer antigen CA125, gynecological examination, and comprehensive abdominal and pelvic ultrasound (transvaginal or transabdominal) every 3 months for the first 2 years, every 4 months during the 3rd year, and every 6 months thereafter;

- comprehensive evaluation (abdominal and pelvic CT or MRI, targeted chest X-ray / chest CT, PET-CT) upon elevation of CA125, appearance of symptoms, or detection of abnormalities during gynecological examination or comprehensive pelvic ultrasound (transvaginal and transabdominal).

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:

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 during 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

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 Russian Academy of Sciences, D.Sc. (Medicine), Professor, Deputy Director of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Director of the Institute of Oncogynecology and Breast Diseases.

2. Novikova E.G., D.Sc. (Medicine), Professor, Head of the Oncogynecology Department, P. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Khokhlova S.V., D.Sc. (Medicine), Head of the Oncological 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., D.Sc. (Medicine), Professor, Leading Researcher at the Oncogynecology Department, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

5. Berlev I.V., D.Sc. (Medicine), 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., D.Sc. (Medicine), 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., D.Sc. (Medicine), Leading Researcher at the Institute of Oncogynecology and Breast Diseases, 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., Ph.D. (Medicine), Senior Researcher at the Institute of Oncogynecology and Breast Diseases, 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., D.Sc. (Medicine), Head of the Oncogynecology Department, P. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

10. Verenikina E.V., Ph.D. (Medicine), Head of the Oncogynecology Department, Rostov Research Institute of Oncology of the Russian Ministry of Health.

11. Demidova, L.V., MD, PhD, Leading Researcher, Department of Radiation Therapy, Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

12. Zhordania, K.I., MD, PhD, Professor, Leading Researcher, Department of Oncogynecology, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health

13. Shevchuk A.S., Ph.D. (Medicine), 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.

14. Ulrikh E.A., D.Sc. (Medicine), Professor, Chief Researcher at the Research Laboratory of Reproductive Technologies, Head of the "Oncofertility" Competence Center, Almazov National Medical Research Centre.

15. Krasilnikov S.E., D.Sc. (Medicine), Professor, Director of the Institute of Oncology and Neurosurgery, Oncologist, E.N. Meshalkin National Medical Research Center of the Russian Ministry of Health

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

17. Krikunova L.I., D.Sc. (Medicine), 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.

18. Kolomietz L.A., D.Sc. (Medicine), Professor, Head of the Gynecological Department, Research Institute of Oncology, Tomsk National Research Medical Center of the Russian Academy of Sciences.

19. Kravets, O.A., MD, PhD, Head of Brachytherapy Unit (Office), JSC Medicine (Academician Roytberg Clinic).

20. Kreynina Yu.M., MD, DSc, Leading Researcher at the Laboratory of Innovative Technologies of Radiotherapy and Chemoradiotherapy for Malignant Neoplasms, Russian Scientific Center of Roentgenoradiology of the Russian Ministry of Health.

21. Meshcheryakova, L.A., MD, PhD, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health.

22. Dubinina A.V., Ph.D. (Medicine), Senior Researcher at the Radiotherapy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

23. Karseladze A.I., Professor, D.Sc. (Medicine), V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

24. Rumyantsev A.A., Ph.D. (Medicine), Head of the Antineoplastic Drug Therapy Department No. 4 of the Drug Treatment Division, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow

25. Imyanitov, E.N., MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Scientific Department of Tumor Growth Biology, National Medical Research Center for Oncology named after N.N. Petrov of the Russian Ministry of Health, Saint Petersburg

26. Tryakin, A.A., MD, PhD, Professor, Deputy Director for Research (Research Institute of Clinical Oncology), Head of the Department of Antineoplastic Drug Therapy No. 2, Department of Drug Treatment, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health.

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

28. Bychenko V.G., Ph.D. (Medicine), Head of the Diagnostic Radiology Department at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

29. Solopova A.E., D.Sc. (Medicine), Associate Professor, Radiologist at the Diagnostic Radiology Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

30. Ryzhkova D.V., D.Sc. (Medicine), 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, Almazov National Medical Research Centre of the Russian Ministry of Health

31. Ovodenko, D.L., MD, PhD, Department of Innovative Oncology and Gynecology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

32. Grinevich V.N., Ph.D. (Medicine), Head of the Oncopathology Department, P. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

33. Snegovoy, A.V., MD, PhD, Head of the Department of Tumor Drug Treatment, Lopatkin Scientific Research Institute of Urology and Interventional Radiology – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

34. Gerfanova, E.V., PhD, Oncogynecologist, Institute of Oncogynecology and Mammology, Department of Innovative Oncology and Gynecology National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health

35. Masliyev, K.S., PhD, Head of the Department of Preventive Medicine with a Course in Biohacking, Medical Institute of RUDN University

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 Medical Physical Training 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. Butenko, A.V., MD, PhD, Professor, Deputy Director for Clinical Work, Petrovsky National Research Centre of Surgery.

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

No conflict of interest declared.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1) radiation oncologists;

2) oncologists;

3) radiologists (diagnostic);

4) radiologists (therapeutic/nuclear medicine);

5) surgeons;

6) anesthesiologists-intensivists;

7) general internists;

8) general practitioners (family medicine);

9) medical geneticists;

10) pathologists;

11) healthcare and public health specialists;

12) rehabilitation specialists (medical rehabilitation specialists);

13) clinical pharmacologists;

14) medical students, residents, and postgraduate students.

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

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

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

Table А2. Level of Evidence (LoE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table P3. Levels of Evidence (LoE) grading scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Good Practice Points (GPPs): good practice points of the recommendations are based on the qualifications and clinical experience of the authoring team.

Methods used for formulating recommendations – expert consensus.

Economic analysis:

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

Method of recommendation validation:

• External peer review

• Internal expert review.

Description of the guideline validation method:

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

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

Consultations and peer review:

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

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

Procedure for updating clinical guidelines

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

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

Appendix A3. Reference Materials

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

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

2. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on April 16, 2019) "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808).

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

Up-to-date instructions for medicinal products mentioned in these clinical guidelines can be found in the State Register of Medicinal Products posted on the website of the Russian Ministry of Health: http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Figure 1. Flowchart for the diagnosis and treatment of a patient diagnosed with ovarian cancer

Appendix C. Patient Information

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

It is necessary to reassure the patient to prevent psychological distress related to the disease and to encourage reading popular science literature on ovarian cancer.

The patient should be informed about the nature of follow-up care after ovarian cancer treatment and the importance of regular examinations.

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

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

Benefits of quitting smoking and alcohol consumption:

• Higher survival rates

• Greater treatment efficacy

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

• Accelerated recovery of general condition after treatment

• Lower risk of recurrence

• Lower risk of second primary tumors

• Lower risk of infections

• Higher quality of life

Recommendations for complications of chemotherapy/radiation therapy – contact your oncologist/medical oncologist/radiation oncologist!

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

2) For stomatitis:

• Diet – mechanical and thermal sparing;

• Frequent mouth rinsing (every hour) using German chamomile flowers, oak bark, or common sage medicinal product; lubricate the oral mucosa with sea buckthorn (peach) oil;

• Treat the oral cavity as recommended by the oncologist/medical oncologist.

3) For diarrhea:

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

• Take medications as recommended by the oncologist/medical oncologist.

4) For nausea:

• Take medications as recommended by the oncologist/medical oncologist.

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

Appendix G1. WHO/ECOG Performance Status Scale

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

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

Original publication: Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649−55 [165].

Type: rating scale.

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

Content (template):

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

Appendix G2. Karnofsky Performance Scale

Russian title: Karnofsky Performance Scale.

Original title (if applicable): Karnofsky Performance Status.

Source (official developer website, validation publication): Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [166].

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):

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

Appendix G3. Tumor regression grading (TRG)

Russian title: Tumor regression grading scale. Original title (if applicable): Tumor regression grading

Source (official developer website, validation publication): AJCC. PART III. In: Edge S.B., Byrd D.R., Compton C.C., Fritz A.G., Greene .FL., Trotti A. III, eds. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. P. 103–26 [35].

Type: rating scale.

Purpose: to describe the degree of tumor regression.

Content (template):

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

Appendix G4. Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1)

Russian title: Response Evaluation Criteria In Solid Tumors 1.1.

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

Source (official developer website, validation publication): Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026 [167]. Type: rating scale.

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

Content (template):

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

Appendix G5. Visual Analog Scale for pain intensity assessment

Russian title: Visual Analog Scale for pain assessment.

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

Source (official developer website, validation publication): Hawker G.A., Mian S., Kendzerska T., French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S240–52 [168].

Type: rating scale.

Purpose: designed for quantitative assessment of pain syndrome taking into account the patient's subjective sensations and selection of analgesic therapy.

Content (template):

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

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

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

Appendix G6. Assessment of tumor spread and severity of peritoneal carcinomatosis

Russian title: Severity of peritoneal carcinomatosis and tumor spread.

Original title: Peritoneal cancer index (PCI) Source (official developer website, validation publication): ESGO Guidelines, Recommendations and Assurance Quality Committee, ESGO, 2022. Electronic access https://www.esgo.org/media/2016/10/ESGO-Operative-Report.pdf

Type: rating scale.

Purpose: designed to assess the spread of the tumor process and the severity of peritoneal carcinomatosis using both diagnostic imaging methods and video-endoscopic visualization; it plays a leading role in planning treatment for patients with advanced ovarian cancer, helping to reduce the rate of suboptimal surgical interventions.

Content (Template G6):

Instructions: To calculate the PCI, the classification proposed in 1998 by P.H. Sugarbaker [202] and included in the assessment of dissemination in ovarian cancer by the European Society of Gynaecological Oncology (ESGO) in 2017 is used, according to which the abdominal cavity is divided into 13 regions:

• 0 – central region: mid-abdomen, greater omentum, transverse colon;

• 1 – right upper quadrant: capsule of the right lobe of the liver, surface of the right hemidiaphragm, right subhepatic space;

• 2 – epigastric region: left lobe of the liver, falciform ligament of the liver, lesser omentum;

• 3 – left upper quadrant: surface of the left hemidiaphragm, tail of the pancreas, stomach;

• 4 – left flank: descending colon, left paracolic gutter;

• 5 – left lower quadrant: left pelvic sidewall, sigmoid colon;

• 6 – pelvis: uterus, ovaries, fallopian tubes, urinary bladder, pouch of Douglas, rectum;

• 7 – right iliac fossa: right pelvic wall, cecum, appendix;

• 8 – right flank: ascending colon, right paracolic gutter;

• 9 – upper jejunum;

• 10 – lower jejunum;

• 11 – upper ileum;

• 12 – lower ileum.

Each region is assigned a specific score depending on the size of the tumor nodules (0 – no tumor, 1 – nodules up to 5 mm, 2 – nodules from 5 mm to 5 cm, 3 – nodules >5 cm or confluent invasive infiltrates), and the total PCI can range from 0 to 39 points. If infiltrative changes are present regardless of the nodule size, a score of 3 is assigned.

- There is no universally accepted reference imaging method for assessing peritoneal carcinomatosis, and magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) demonstrate similar efficacy with certain limitations.

- When performing pelvic MRI and abdominopelvic CT, there is an overlap in the intersection of regions 7 and 8, 0 and 6, and 4 and 5. When calculating the final index, overlapping regions are not summed; instead, the highest score in each overlapping region is taken into account.

Key: A high total score in PCI assessment is a prognostic factor for the inability to perform optimal cytoreductive surgery.

According to several authors, during intraoperative exploration with a score of 0 to 15, the rate of optimal surgeries ranges from 62 to 99%, whereas with an index >16 points it does not exceed 35%. With a score >20, performing optimal cytoreduction is virtually excluded [203].

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Appendix G6. Assessment of tumor spread and severity of peritoneal carcinomatosis