Vaginal malignant neoplasms: clinical guidelines

List of Abbreviations

CTV — clinical target volume

ECOG — Eastern Cooperative Oncology Group

FIGO — International Federation of Gynecology and Obstetrics

GTV — gross tumor volume

IMRT — intensity-modulated radiotherapy

PTV — planning target volume

SCC — squamous cell carcinoma antigen, tumor marker.

TNM — TNM classification of malignant tumours

VMAT or RapidArc — volumetric modulated arc therapy

IV — intravenous

IM — intramuscular

HPV — human papillomavirus

Gy — gray

Malignant neoplasm

CT — computed tomography

RT - Radiation therapy

LN — lymph nodes

MRI — magnetic resonance imaging

PET-CT - Positron emission tomography-computed tomography

VC — vaginal cancer

SFD — single focal dose

RP — Radiopharmaceutical

CC — cervical cancer

CRT — combined radiotherapy

TFD — total focal dose

Ultrasound — ultrasound examination

CT - Chemotherapy

Terms and Definitions

Prehabilitation — rehabilitation from the moment of diagnosis until the start of treatment (surgical treatment/chemotherapy/radiotherapy).

Stage I rehabilitation — rehabilitation during the period of specialized treatment of the underlying disease (including surgical treatment/chemotherapy/radiotherapy) 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, 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, reflexotherapy, manual therapy, psychotherapy, medical psychology providing outpatient medical care, day hospitals, as well as by mobile teams at home (including in sanatorium-resort organizations), and speech therapy (defectology) offices.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Malignant neoplasm of the vagina (MN) — MN of the vaginal wall. Squamous cell carcinoma of the vagina (VC) — MN originating from the stratified squamous epithelium of the female vagina.

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

The etiology and pathogenesis of vaginal cancer (VC) largely remain unclear, primarily due to low incidence rates. Given the common embryogenesis of the vulva, vagina, and cervix from the urogenital sinus, it is hypothesized that they share a common etiology and pathogenesis [1].

The following factors may play a negative role in the pathogenesis of VC:

• lifetime infection of a woman with human papillomavirus (HPV) (in squamous cell VC, HPV is detected in more than 60% of cases), herpes simplex virus type 2, and human immunodeficiency virus with HPV manifesting as condylomata acuminata [1];

• postmenopausal hypoestrogenemia;

• severe chronic senile colpitis;

• involutive, postcastration dystrophic, and age-related processes;

• chronic nonspecific vaginitis;

• the carcinogenic effect of radiotherapy (RT) in the development of VC is confirmed by numerous reports of malignant neoplasms in this area occurring 10–30 years after combined radiotherapy (CRT) for cervical cancer (CC). The relative risk of developing VC after CRT for CC is 300 times greater than in the general population [2].

From a clinical perspective, 3 most likely causes of VC development should be considered today:

1. Development of a malignant tumor caused by HPV.

2. Radio-induced vaginal tumors following RT for CC.

3. Metastatic tumors (uterus, ovaries, etc.).

1.3 Epidemiology of the Disease or Condition

Primary VC is quite rare. In the structure of female genital malignancies, primary VC accounts for about 1%. In Russia, 549 newly diagnosed cases of VC were registered in 2021. The standardized incidence rate of VC in 2021 was 0.36 per 100,000 female population [3]. Almost 90% of all histological types of vaginal neoplasms are squamous cell carcinomas [4].

1.4 Features of Coding the Disease or Condition

D07.2 – Carcinoma in situ of vagina

C52 – Malignant neoplasm of vagina

*-Many in situ neoplasms are viewed as sequential morphological changes between dysplasia (intraepithelial neoplasia) and invasive cancer. For example, vaginal intraepithelial neoplasia (VAIN) is recognized in three grades, of which the third (VAIN III) includes both severe dysplasia and carcinoma in situ. This grading system also applies to other organs, such as the cervix and vulva. Descriptions of grade III intraepithelial neoplasia with or without specification of severe dysplasia are presented in this section under "carcinoma in situ"; grades I and II intraepithelial neoplasia are classified as dysplasias of the involved organ systems and should be coded according to the ICD classes corresponding to these organ systems.

1.5 Classification of the disease or condition

1.5.1. International Histological Classification

International morphological classification of VC (IARC classification, 5th edition, Lyon, 2020) [5]:

1.5.1. International histological classification

International morphological classification of vaginal cancer (IARC classification, 5th edition, Lyon, 2020) [5]:

I. Epithelial tumors

1. Squamous cell and precursor tumors:

• Vaginal intraepithelial neoplasia (VAIN)

• Human papillomavirus (HPV)-associated squamous cell carcinoma

• HPV-independent squamous cell carcinoma

• Squamous cell carcinoma, unspecified HPV status

2. Glandular tumors:

• HPV-associated adenocarcinoma

• Endometrioid carcinoma

• Clear cell carcinoma

• Gastric-type mucinous carcinoma

• Intestinal-type mucinous carcinoma

• Mesonephric adenocarcinoma

• Vaginal carcinosarcoma

3. Other epithelial tumors:

• Mixed epithelial tumor of the vagina

• Skene gland adenocarcinoma

• Adenosquamous carcinoma of the vagina

• Adenoid basal carcinoma of the vagina

II. Mixed epithelial-mesenchymal tumors

• Vaginal adenosarcoma

III. Other tumors

• Germ cell tumors of the vagina

Despite the fact that melanocytic tumors have been excluded from the 5th edition of the WHO histological classification of vaginal cancer (Lyon, 2020), given their incidence (<5%) and clinical significance, treatment decisions should be made by a multidisciplinary team including a gynecologic oncologist. [75]

1.5.2. Staging

Table 1 presents vaginal cancer staging according to two classifications: TNM 8th edition (2017) and FIGO (2009). This classification applies only to primary vaginal cancer. Metastatic vaginal tumors are excluded. A vaginal tumor extending to the vulva is classified as vulvar cancer.

Table 1. Vaginal cancer staging according to TNM (8th edition, 2017) and FIGO (2009).

*The presence of bullous edema is not sufficient to classify a tumor as T4.

N – regional lymph nodes (LNs)

N_X – regional LNs cannot be assessed

N₀ – no regional LN metastasis

N₁ – regional LN metastasis present

M – Distant metastasis

M₀ – no distant metastasis

M₁ – distant metastasis present

Note. Regional lymph nodes for the upper two-thirds of the vagina are pelvic LNs, including obturator, internal iliac (hypogastric), external iliac, and unspecified pelvic LNs; for the lower third of the vagina, they are inguinal and femoral LNs.

Table 2. TNM stage grouping for vaginal cancer.

Note. Stage III also includes tumors involving the pubic symphysis.

1.6 Clinical presentation of the disease or condition

The course of the disease, especially in the early stages, may be asymptomatic. As the tumor process progresses, pain, urinary and/or defecation disorders and/or difficulties, and lower limb lymphostasis develop. The disease occurs predominantly in women over 50–60 years of age [2, 3].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of the disease or condition:

1. anamnestic data;

2. physical examination findings;

3. pathological examination findings;

5. diagnostic imaging findings.

2.1 Complaints and Anamnesis

2.2 Physical Examination

The following criteria must be considered in the diagnosis of primary vaginal cancer:

• the primary tumor must be located exclusively in the vagina, with the upper third of the vagina being affected in the vast majority of cases;

• the epithelium of the cervix, cervical canal, and endometrium must be intact (negative aspiration biopsy);

• primary vaginal cancer may have an asymptomatic course [2, 6].

GCR CLEL 5Grade of Recommendations — C (Level of Evidence — 5)

Comment: Inspection and palpation of the vulva; examination of the vagina and cervix is performed using Sims vaginal specula, since some areas of the vagina (anterior and posterior walls) are poorly visualized when using Cusco vaginal specula [2, 6, 7].

2.3 Laboratory Diagnostics

1. complete blood count (CBC) with differential;

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

3. general (clinical) urinalysis;

4. coagulation profile (fibrinogen, prothrombin, international normalized ratio (INR), prothrombin time, prothrombin index, activated partial thromboplastin time (APTT), thrombin time) [2].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

Comments: A complete blood count is performed (repeated) at least 5 days before the start of each chemotherapy course. [2,7]

In a complete blood count (CBC) with differential, it is advisable to evaluate the following parameters: hemoglobin, hematocrit, erythrocytes, mean corpuscular volume, red cell distribution width, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, leukocytes, leukocyte differential, erythrocyte sedimentation rate; in a general routine biochemical blood test, liver and kidney function parameters are assessed; in a urinalysis, determination of urine color, transparency, specific gravity, protein, pH, glucose, ketone bodies, urobilinogen, leukocyte esterase, and by automated microscopy — epithelial cells, erythrocytes, casts, salts, mucus, bacteria, and fungi [2,6,7].

As part of the coagulation system assessment, a coagulogram is evaluated, and additionally, based on clinical indications, antithrombin III, D-dimer, plasminogen, % activity.

2.4 Instrumental Diagnostics

Performing a biopsy of the vaginal tumor followed by its morphological verification is the main diagnostic criterion for vaginal cancer.

Comment: If necessary for diagnostic verification, the pathomorphological examination of the biopsy (surgical) specimen may be supplemented with immunohistochemical typing, and the cytological examination with immunocytochemical typing.

Comments: performing fractional diagnostic curettage of the uterine cavity and endocervical canal (or an endometrial aspiration biopsy) is advisable in confirmed cases of vaginal adenocarcinoma to rule out primary endometrial cancer

Comment: Ultrasound is the most accessible imaging modality for assessing the extent of the tumor process in the abdominal cavity, pelvic cavity, and in regional and distant lymph nodes [2,6].

Comment: if this cannot be performed, targeted chest radiography is recommended. Chest CT has higher diagnostic efficacy compared to radiography in detecting metastatic lesions in the lungs, pleura, and intrathoracic lymph nodes [8].

Comment: if pelvic MRI with intravenous contrast enhancement cannot be performed, pelvic CT with intravenous contrast enhancement must be performed. MRI provides higher diagnostic informativeness compared to CT in assessing pelvic organs, pelvic floor tissues, and the perineum [77,78,79,80].

Comment: PET-CT is preferable if concurrent chemoradiotherapy is planned [82].

Comment: if MRI cannot be performed and/or if there are contraindications, brain CT with intravenous contrast enhancement may be performed. Contrast-enhanced MRI has higher diagnostic efficacy than CT in diagnosing brain metastases [83,84].

• When planning and evaluating the efficacy of chemoradiotherapy/radiotherapy, it is recommended to perform MRI of the pelvic organs and soft tissues of the perineum with intravenous contrast enhancement to assess local extent and regional lymph node status, and PET-CT with tumor-tropic radiopharmaceuticals (preferred) or chest and abdominal CT with intravenous bolus contrast enhancement to diagnose distant metastases, provided that the procedure timelines are met [76].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

2.5 Other Procedures

1. size and extent of the primary tumor;

2. depth of primary tumor invasion;

3. histological structure of the tumor;

4. tumor differentiation grade;

5. presence of perivascular, perilymphatic, and perineineural invasion (a negative result must also be explicitly stated);

6. regional lymph node status (pN) indicating the total number of examined and affected lymph nodes, and signs of extracapsular extension (ENE+/–);

7. microscopic assessment of resection margins (status) R0–1, indicating the distance to the closest resection margin in mm [6,8,14].

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

Comments: in case of doubtful or negative results from the initial neoplasm biopsy based on morphological examination in patients with suspected vaginal cancer, either a repeat biopsy or, if feasible, surgical intervention with intraoperative pathomorphological examination of the biopsy (surgical) specimen is indicated.

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

Comment: in certain cases discussed further below, various options for surgical interventions and chemotherapy (CT) may be used for vaginal cancer [2, 6, 14–17].

3.1. General principles of treatment depending on the stage

3.1.1. Treatment of vaginal cancer TisN0M0

3.1.2. Treatment of stage I vaginal cancer (T1N0M0)

Comment:

1. The option of intracavitary RT (brachytherapy), the endovaginal device (applicator) for its delivery, and consequently its delivery regimen and prescribed fractional dose are chosen taking into account the tumor localization within a specific part of the vagina and the extent of spread along the vaginal canal.

2. Intracavitary RT is preferred in cases of superficial vaginal tumor growth (with an depth of invasion <0.5 cm).

3. In cases of localized tumors with a maximum dimension of up to 1.5 cm, interstitial irradiation may be performed. [6, 10, 11, 14].

Comment: Surgical options such as wide local excision, vaginal resection, or vaginectomy with vaginal reconstruction may be considered [10].

3.1.3. Treatment of stage II vaginal cancer (T2N0M0)

Comment:

1. The most preferred treatment option is radical combined RT, which involves the sequential delivery of external beam and contact RT [9, 10, 12, 19–21].

2. If contraindications to contact RT are identified, including a lack of preference for or patient refusal of endovaginal treatment techniques, external beam irradiation to the primary lesion area at a radical equivalent dose (using high-precision techniques such as IMRT, VMAT, STRT) may be performed.

3. The most common contraindications to contact RT in locally advanced vaginal cancer are subcompensation of somatic pathology preventing adequate placement of endostatic devices, inability to achieve the conditions for adequate contact irradiation according to basic dosimetric parameters once an equivalent cumulative dose (EQD₂) of 40 Gy to the primary lesion is reached — specifically, covering the entire GTV and HR-CTV volume with an isodose of ≤80%, exceeding tolerance doses in organs at risk, and comorbid conditions affecting organs at risk (bladder, urethra, rectum, rectosigmoid) associated with a high risk of stage III–IV acute and late radiation injuries [6, 8, 12, 21–24].

4. Extrapolating the experience and positive treatment outcomes of vaginal spread patterns in etiopathogenetically similar cervical cancers, it is advisable to administer treatment concurrently with radiomodification, including platinum-based chemotherapy, as well as supplementing radiation therapy with adjuvant chemotherapy (see section 3.2 of the Clinical Guidelines) [22, 25, 26].

5. In cases of persistence of the primary tumor process (unstable stabilization or local progression during radiation therapy, documented by clinical and instrumental data [physical and visual examination, instrumental diagnostic methods] at an EQD₂ of 40 Gy), the question of further treatment tactics is reviewed by a multidisciplinary tumor board. In individual cases, extended and combined surgical interventions, including various types of pelvic exenteration [6, 8] and/or systemic medical therapy, may be performed.

3.1.4. Treatment of stage III vaginal cancer (T3N0M0; T1N1M0; T2N1M0; T3N1M0)

Comment:

1. The most preferred treatment option is radical combined RT, which involves the sequential delivery of external beam and contact RT [9, 12, 19, 20, 22, 24, 25].

2. Surgical treatment is not indicated for stage III vaginal cancer.

3. Follow treatment tactics for cases with contraindications to RT (see section 3.3 of the Clinical Guidelines).

3.1.5. Treatment of stage IVa vaginal cancer (TAnyNAnyM0)

Comment: Special attention during palliative therapy requires the assessment of the patient's performance status according to the WHO/ECOG scale and/or the Karnofsky scale (see Appendix G1-2).

3.1.6. Treatment of stage IVb vaginal cancer (TAnyNAnyM1)

Comment: Special attention during palliative therapy requires the assessment of the patient's performance status according to the WHO/ECOG scale and/or the Karnofsky scale (see Appendix G1-2).

3.1.7. Treatment of vaginal cancer recurrences.

3.2. Principles of radiotherapy

During RT, conformal external beam and contact RT techniques are used, based on individual volumetric planning of irradiation parameters using modern medical imaging methods—primarily multiparametric MRI, contrast-enhanced CT, and PET-CT—to ensure adequate oncological treatment outcomes, efficacy, and safety. Specific RT techniques depend on the localization of the primary tumor, the extent of its vertical spread along the vaginal canal, and the depth of tumor infiltration.

The issue of chemoradiotherapy using #cisplatin** 40 mg/m2 weekly concurrently with external beam radiotherapy, by analogy with the treatment of locally advanced cervical cancer (see clinical guidelines for cervical cancer), is being considered. Due to the small number of detected cases, large randomized trials are lacking. It is possible to rely on the study by Miyamoto D.T. et al., 2013, which demonstrated the superiority of chemoradiotherapy compared to the radiotherapy group (3-year overall and progression-free survival rates were 79% vs 56% and 73% vs 43%, respectively) [73] []

Topometric preparation

- topometric preparation is performed in the supine position with immobilization of the upper and lower body (headrest and knee support).

- is performed using external and endovaginal radiopaque markers to verify the lower tumor border (GTV) and the vaginal introitus. For more precise contouring of the primary tumor (GTV), pelvic and inguinal lymph nodes included in the irradiated volume (CTV, PTV), CT/MRI with intravenous contrast or PET-CT can be used, obtained either during the topometry procedure or by integrating primary examination data using fusion technologies [2, 18, 22, 30, 31].

GCR CLEL 5Grade of Recommendations — C (Level of Evidence — 5)

3.2.1. External beam radiotherapy

Comments:

Basic principles of external beam radiotherapy in vaginal cancer:

• When the tumor is localized in the upper two-thirds of the vagina, only the pelvic structures are included in the irradiated volume. The irradiated volume of the primary tumor site (CTV-T) includes the entire vaginal tube, cervix, paracervical region, and paravaginal tissues. The irradiated volume of regional lymphatic drainage pathways (CTV-N) includes various pelvic lymph nodes below the level of the common iliac lymph nodes, depending on the localization of the primary tumor: for localization in the upper two-thirds of the vagina – obturator, external and internal iliac, presacral, and pararectal lymph nodes [2, 18, 22, 30, 31].

• When the tumor is localized in the lower third of the vagina, pelvic irradiation is supplemented by irradiation of the inguinal regions. The irradiated volume of the primary tumor site (CTV-T) includes the entire vaginal tube, including the introitus, cervix, paracervical region, and paravaginal tissues. The irradiated volume of regional lymphatic drainage pathways (CTV-N) includes the inguinal-femoral and distal external/internal iliac lymph nodes [2, 18, 22, 30, 31].

• For tumors localized on the posterior wall of the vagina, the presacral and pararectal pelvic lymph nodes must be included in the irradiated volume of regional lymphatic drainage pathways (CTV-N).

Planned target volumes are defined as follows:

PTV1 = CTV-T + 7–12 mm

PTV2 = CTV-N + 5–7 mm

PTVsum = PTV1 + PTV2

• The margin size depends primarily on the set of medical imaging methods used for contouring: the lower the imaging accuracy, the larger the margin of confidence boundaries [2, 18, 22, 30, 31].

• ORGANS AT RISK. It is mandatory to contour the urinary bladder, rectum, loops of the small intestine, anus, bone marrow (sacrum, coccyx, L5 body, acetabulum, proximal femur), and femoral head for the calculation of delivered tolerance doses using dose-volume histograms (DVH).

  DOSE FRACTIONATION. It is recommended to perform the external beam radiation therapy phase using a conventional fractionation regimen — fractional dose to PTV_sum 1.8–2 Gy in 23–25 fractions up to a cumulative equivalent dose_eq of 45–50 Gy, followed by interstitial or intracavitary brachytherapy, depending on the clinical situation.

• In cases of locally advanced tumor processes or ulcerated vaginal tumors, to accelerate tumor regression by analogy with vaginal spread patterns of cervical cancer, dynamic fractionation regimens can be used — DPF of PTV_sum 4 Gy in 5 fractions. This is subsequently followed by continuation of treatment with a DPF of PTV_sum 1.25 Gy multifractionated twice daily with a 4-hour interval up to an EQD_eq of 45–50 Gy or conventional fractionation up to the specified total doses.

• If contraindications to contact radiotherapy are identified, including lack of preference for changing the irradiation method or the patient's refusal of endovaginal treatment techniques, it is possible to continue external beam irradiation to the primary tumor area as a local boost in a radical equivalent dose (using high-precision techniques [IMRT, VMAT, STRT] up to an EQD_eq of 60–64 Gy for T1–2 and 66–70 Gy for T3–4a stages) [2, 18, 22, 30, 31].

3.2.2. Brachytherapy (contact radiotherapy)

Comment:

Concept of brachytherapy for primary vaginal cancer.

Planning of the brachytherapy stage is based on the degree of primary tumor regression and its localization. Target volumes for contouring depend on the volume of the primary tumor and are designated as follows:

GTV-Tres - Macroscopic volume of gross residual tumor during brachytherapy, as described by clinical examination and/or imaging

CTV-THR - Clinical Target Volume High Risk includes GTV-Tres and areas of pathological tissue.

CTV-TIR - Clinical Target Volume Intermediate Risk should include all significant microscopic abnormalities adjacent to CTV-THR.

Clinically, this is a persistent visible and palpable residual macroscopic tumor upon gynecological examination. On T2-weighted MRI, this is visualized as a residual tumor volume with high to isointense signal intensity within the initial tumor extent at diagnosis, GTV-Tinit. Significant resorption of GTV-Tinit is usually observed, resulting in a small GTV-Tres.

For intracavitary irradiation, cylindrical applicators are most commonly used; their size must match the anatomical parameters of the patient's vagina and fit snugly against the irradiated vaginal walls. Interstitial brachytherapy is also used. [74]

The principles of topometry, contouring, and planning follow general principles. 3D-4D image-guided brachytherapy techniques have advantages in efficacy and safety over 2D contact irradiation planning techniques [2, 18, 22, 30, 31].

The preferred imaging method for defining the boundaries of the irradiated volumes (GTV, HR-CTV, IR-CTV) is multiparametric MRI with a magnetic field strength of at least 1.5 T.

Planning is based on the tumor in the zones of its visualization and 0.5 cm from the mucosal surface outside the tumor involvement zones.

DOSE FRACTIONATION in monotherapy mode: SD per fraction 3–7 Gy, 3–5 fractions per week up to EQD₂ 40–50 Gy; as a boost in combined RT: SD per fraction 3–5 Gy, 3–5 fractions per week up to EQD₂ 20–30 Gy (up to total equivalent doses EQD₂ 60–64 Gy to the primary lesion area for T1–2, EQD₂ 66–70 Gy for T3–4a stage).

When the tumor is localized in the upper two-thirds of the vagina, intracavitary RT is performed using appropriate applicators (Fletcher type, Manchester, central endostat with a ring vaginal applicator). The principles of topometry, contouring, and dosimetric planning correspond to those in the treatment of cervical cancer.

3.3. Principles of systemic chemotherapy

Comment:

- minimum volume chemotherapy is indicated for debilitated patients: #Cisplatin** 50 mg/m² once every 21 days for up to 6 cycles [32, 55, 56];

- regimens of optimal volume chemotherapy for vaginal cancer are similar to those for cervical cancer treatment [53, 53, 62-70]: #Paclitaxel** + #Cisplatin**, #Paclitaxel** ² + #Carboplatin**;

#Cisplatin** + #Gemcitabine**; #Paclitaxel** as monotherapy and are presented in the relevant clinical guidelines for cervical cancer.

• Patients with progressive vaginal cancer are recommended to receive:

- Pembrolizumab** 200 mg IV once every 3 weeks in the presence of microsatellite instability-high (MSI-H), including DNA mismatch repair deficiency (dMMR) upon disease relapse [69].

- #Capecitabine** 2500 mg/m²/day orally on days 1–14 of a 21-day cycle (as 2nd-line and subsequent chemotherapy) [66, 68].

GCP CLeL 4Grade of Recommendation — C (Level of Evidence — 4)

Comment: Re-administering platinum-based chemotherapy, as in the 1st line, is possible if the platinum-free interval is >6 months.

Currently, for advanced squamous cell vaginal cancer, radiation therapy with platinum-based radiosensitizing chemotherapy is performed, as in squamous cell carcinoma of the cervix, for example, #cisplatin** 40 mg/m² IV once a week for up to 7 cycles [70].

3.4. Management of pain syndrome

The procedure and recommendations for pain management in vaginal cancer correspond to the recommendations presented in the rubricator "Chronic Pain Syndrome (CPS) in Adult Patients in Need of Palliative Medical Care".

3.5. Nutritional therapy

• Currently, there is evidence of an increased risk of cancer in overweight or obese female patients [8]. In this regard, it is recommended to implement measures aimed at reducing the patients' excess weight to normal values. Modifying the habitual diet in such patients will help prevent complications from the administered treatment (surgical, medical, or radiation therapy). [8]

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Increasing physical activity 2 weeks before surgery improves quality of life in the postoperative period, allowing patients to return to full daily activities as early as 3 weeks postoperatively. Performing exercise therapy at the preoperative stage reduces the incidence of postoperative complications [37].

Comment: testing and consultation with a clinical psychologist include methods aimed at stress management (relaxation techniques, fostering a positive mindset), lasting 40–60 minutes 6 days a week, starting 5 days before surgery and continuing for 30 days after, which significantly improves patients' quality of life [35,57,58]

Comments: Early initiation of an exercise therapy program including aerobic, strength, and stretching exercises does not increase the incidence of postoperative complications while improving quality of life [38,39, 40,41,57,58].

The use of incentive spirometry, elevation of the head of the bed, early initiation of breathing exercises, and early patient mobilization help prevent pulmonary congestion in the postoperative period [38,39, 40,41,57,58].

• Treatment of postoperative pain is interdisciplinary in nature, and in addition to pharmacological management, patients with vulvar cancer are recommended physical rehabilitation (exercise therapy), positioning, psychological pain management methods (relaxation), transcutaneous electrical nerve stimulation, and acupuncture [43,57,58].

LE 5Level of recommendation evidence ‒ C (Level of data reliability - 5).

- intermittent pneumatic compression of the limbs combined with complete decongestive therapy [51, 52]

- low-level laser therapy combined with complete decongestive therapy [52]

- electrotherapy combined with complete decongestive therapy [71]

- low-frequency magnetotherapy combined with complete decongestive therapy [72].

LE 5Level of recommendation evidence ‒ C (Level of data reliability - 5).

5. Prevention and Dispensary Observation

- every 3 months during the first 2 years;

- every 6 months from the 3rd to the 5th year after completion of treatment;

- every 12 months starting from the 6th year after completion of treatment;

- or upon the appearance of symptoms [8, 14, 55].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: in patients with a high risk of disease progression, the interval between examinations may be shortened.

- medical history taking and physical examination;

- comprehensive ultrasound of the abdominal organs, comprehensive pelvic ultrasound (transvaginal and transabdominal), and regional lymph node ultrasound;

- pelvic MRI with intravenous contrast / pelvic CT with contrast (if MRI is not feasible); abdominal CT with intravenous contrast / abdominal MRI with intravenous contrast (if CT is not feasible) is indicated when pelvic ultrasound is insufficiently informative or when vaginal malignancy recurrence is suspected;

- Targeted chest X-ray or chest CT.

- Whole-body PET-CT with a tumor-tropic radiopharmaceutical if distant metastases are suspected and CT or MRI is insufficiently informative [12].

Level of Evidence CGrade of Evidence 5Level of recommendation confidence — C (level of evidence validity — 5)

Comments: the objective of follow-up is the early detection of disease progression for the purpose of prompt initiation of surgical and/or chemoradiotherapy. In patients with a high risk of disease progression, the interval between examinations may be shortened.

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, which is approved by the authorized federal executive body;

2. in accordance with the procedures for the provision of medical care approved by the authorized federal executive body and mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by an oncologist and other medical specialists at an ambulatory cancer care center, or, in its absence, at a primary oncology office or the outpatient department of an oncological dispensary (cancer hospital).

In case of suspicion or detection of an oncological disease in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient oncological care center, or, in its absence, to a primary oncological office or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

Consultation at an outpatient oncological care center, primary oncological office, or outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 3 working days from the date of issuing the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of such a center, the oncologist of the primary oncological office or outpatient department of the oncological dispensary/hospital) arranges for the acquisition of biopsy (surgical) material, as well as the performance of other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that includes the ambulatory cancer care center (primary oncology office), the patient is referred by the oncologist to an oncological dispensary (cancer hospital) or to a medical organization providing medical care to patients with oncological diseases.

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

The timeframe for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation, which is 7 working days from the date of prescribing the examinations.

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

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

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

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

digital images obtained from pathomorphological studies to the pathoanatomical bureau (department) of the fourth group (reference center) [1] via information interaction, including the use of telemedicine technologies 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 re-examination of pathomorphological, immunohistochemical, and molecular genetic studies: to the department of pathological anatomy of the fourth group (reference center), as well as to molecular genetic laboratories for molecular genetic testing.

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

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

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

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

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

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

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

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

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

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

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

1. presence of oncological disease complications requiring emergency and urgent specialized medical care;

2. presence of complications from cancer treatment (surgical intervention, radiotherapy, drug therapy, etc.) requiring the provision of emergency and urgent specialized medical care

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

1. need to perform complex interventional diagnostic medical procedures, as well as endoscopic examinations when they cannot be performed on an outpatient basis, requiring subsequent monitoring in a 24-hour or day hospital setting;

2. presence of indications for specialized antitumor treatment (surgical intervention, radiation therapy including brachytherapy, external beam radiation therapy, and other types of radiation therapy, drug therapy, etc.) requiring inpatient or day-hospital monitoring.

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 a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2. refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-care setting, as determined by a medical concilium of the oncology-providing organization

3. in cases of non-compliance by the patient with prescriptions or internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

4. need to transfer the patient to another medical organization in the relevant medical specialty.

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.

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. 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

10. 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.

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

12. Demidova L.V., D.Sc. (Medicine), Leading Researcher at the Radiation Therapy Department, P. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center 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., D.Sc. (Medicine), Leading Researcher at the Pelvic Floor Oncosurgery Department, 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. Meshcheryakova L.A., D.Sc. (Medicine), Physician, Federal Research Center of Physico-Chemical Medicine named after Yu.M. Lopukhin of the FMBA of Russia.

19. 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.

20. Reynina Yu.M., D.Sc. (Medicine), Leading Researcher at the Laboratory of Innovative Technologies in Radiotherapy and Chemoradiation Treatment of Malignant Neoplasms, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.

21. 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

22. 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.

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

24. 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.

25. 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.

26. 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

27. Ovodenko D.L., D.Sc. (Medicine), Head of the Department of Innovative Oncology and Gynecology, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

28. 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.

29. Snegovoy A.V., D.Sc. (Medicine), Head of the Outpatient Chemotherapy and Day Hospital Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

30. Yureneva S.V., Deputy Director for Science at the Institute of Oncogynecology and Breast Diseases, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, D.Sc. (Medicine), Professor at the Department of Obstetrics and Gynecology.

31. Slonov A.V., Ph.D. (Medicine), Chief Medical Officer of Clinical Hospital No. 123, Federal Research Center of Physico-Chemical Medicine named after Yu.M. Lopukhin of the FMBA of Russia

Medical Rehabilitation Section:

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

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

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

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

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

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

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

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

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

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

11. Semiglazova T.Yu., MD, PhD, Leading Researcher at the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor at the Department of Oncology, I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health.

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

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

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

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

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

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

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

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

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

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

Healthcare Organization Section:

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

2. Khailova Zh.V., PhD, Chief Medical Officer of the Clinic, A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

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

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

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• medical geneticists;

• dermatovenerologists;

• pathologists

Methods used for evidence collection/selection: electronic database searches; analysis of current scientific developments on the problem of RB in Russia and abroad; synthesis of the practical experience of Russian and international specialists.

Methods used for formulating recommendations – expert consensus.

Economic analysis

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

Method of recommendation validation:

• external expert review;

• internal expert review.

Description of the recommendation validation method

The draft of these recommendations was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

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

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

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

Table 1. Levels of Evidence (LoE) rating scale for diagnostic methods (diagnostic interventions).

Table 2. Levels of Evidence (LoE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions).

Table 3. Scale for grading levels of recommendation evidence (LRE) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

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

Appendix B. Physician Action Algorithms

Flowchart of diagnosis and treatment of a female patient diagnosed with vaginal cancer.

Appendix C. Patient Information

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

• consult an oncologist

2. In case of stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• frequent mouth rinsing (every hour) with chamomile, oak bark, sage; apply sea buckthorn (peach) oil to the oral mucosa as recommended by the oncologist;

• treat the oral cavity as recommended by the oncologist.

3. In case of diarrhea:

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

• take medications as recommended by the oncologist.

4. In case of nausea:

• take medications as recommended by the oncologist.

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

Appendix G1. WHO/ECOG Performance Status Scale

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

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

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

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

Type: rating scale

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

Contents:

Key (interpretation): provided within the scale itself

Appendix G2. Karnofsky Performance Scale

Name in Russian: Karnofsky Performance Scale [83].

Original title (if applicable): KARNOFSKY PERFORMANCE STATUS

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

Type: rating scale

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

Content (template):

Key (interpretation): provided within the scale itself