Vulvar Cancer: 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 (macroscopically visible)

HSIL – high-grade squamous intraepithelial lesion

IMRT – intensity-modulated radiation therapy

LSIL – low-grade squamous intraepithelial lesion

PTV – planning target volume

SCC – squamous cell carcinoma antigen

TNM – TNM Classification of Malignant Tumours

VIN – vulvar intraepithelial neoplasia

IV – intravenous

i.m. – intramuscularly

WHO – World Health Organization

HPV – human papillomavirus

Gy – gray

units

CT – computed tomography

RT – radiotherapy

PT – physical therapy

MRI – magnetic resonance imaging

PET – positron emission tomography

VC – vulvar cancer

SFD – single focal dose

TFD – total focal dose

US – ultrasound examination

CT – chemotherapy

ECG – electrocardiography

Terms and Definitions

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

Stage I rehabilitation – rehabilitation during specialized treatment of the underlying disease (including surgery/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, the late rehabilitation period, and the period of residual disease manifestations.

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

Wide local excision of the tumor is performed within healthy tissues, with the incision line running at least 1 cm away from the visually defined edge of the tumor along its entire circumference.

Vulvectomy is performed through a hockey-stick or butterfly incision outlining the vulva externally such that the upper point of the incision is 1.5–2.0 cm above the clitoris, and the lower point is at the same distance from the posterior commissure of the vulva. The skin and mucous membrane of the vulva, as well as 1.0–1.5 cm of the underlying adipose tissue, are excised.

Radical vulvectomy is performed through 3 separate non-communicating incisions (one of the options). The postoperative specimen consists of 3 separately resected blocks of tissue: the vulva and 2 skin-adipose flaps sequentially excised from the inguinofemoral regions.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Vulvar cancer (VC) is a malignant neoplasm originating from the surface squamous epithelium of the female external genitalia [1].

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

Two factors play a leading role in the etiology and pathogenesis of VC: age-related involutive and atrophic processes of the external genitalia and human papillomavirus (HPV) infection. HPV genotypes 6 and 11 are detected with the highest frequency, and as a rule, these 2 serotypes are detected simultaneously. An association of genotype 18 with 55, 59, and 83 is frequently identified, as well as various combinations of genotypes 31, 33, and 45. Genotype 16 is isolated in the majority of cases. Overall, the presence of HPV in VC is established in 75–85% of observations [2]. Metabolic syndrome, frequently diagnosed in patients with VC, is of considerable importance.

The following pathogenetic chain of events leads to VC: age-related involution of the skin and mucous membranes (against the background of absolute estradiol deficiency, as well as a sharp decrease in the level of steroid receptors) -> development of involutive and atrophic processes -> alteration of the vulvar microbiocenosis (development of opportunistic and pathogenic microflora) -> formation of chronic inflammatory and dystrophic changes, appearance of trauma and fissures -> chronic regenerative-proliferative processes -> presence of HPV -> development of dysplasia -> progression of dysplasia into preinvasive and invasive cancer [2]. This largely explains the fact that VC occurs in relatively elderly women [3].

In 90% of cases, squamous cell carcinoma—a malignant neoplasm arising from the surface squamous epithelium of the female external genitalia—is morphologically verified [4].

1.3 Epidemiology of the Disease or Condition

Primary VC is a rare tumor. VC accounts for 1% of all cancers in women. In the incidence structure of female reproductive system malignancies, the proportion of primary VC is about 2–5% [5]. In 2021, the incidence of VC in Russia was 2.57 cases per 100,000 women, which in absolute numbers amounted to 2,011 cases [7].

1.4 Features of Coding the Disease or Condition

D07.1 – Carcinoma in situ of vulva

C51.0 – Malignant neoplasm of labium majus

C51.1 – Malignant neoplasm of labium minus

C51.2 – Malignant neoplasm of clitoris

C51.8 – Malignant neoplasm of vulva overlapping lesion

C51.9 – Malignant neoplasm of vulva, unspecified

* – Many in situ neoplasms are considered sequential morphological changes between dysplasia and invasive cancer. For example, vulvar intraepithelial neoplasia (VIN) is recognized in three grades, of which the third (VIN III) includes both severe dysplasia and carcinoma in situ. This grading system extends to other organs, such as the cervix and vagina. Descriptions of grade III intraepithelial neoplasia with or without 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 those organ systems.

1.5 Classification of the disease or condition

1.5.1. International Morphological Classification of VC (IARC Classification, 5th Edition, Lyon, 2020) [6]

EPITHELIAL TUMORS

Squamous cell tumors and precursors

Vulvar intraepithelial neoplasia, HPV-associated

Vulvar intraepithelial neoplasia, HPV-independent

Squamous cell carcinoma of the vulva, HPV-associated

Squamous cell carcinoma of the vulva, HPV-independent

Squamous cell carcinoma of the vulva, HPV-unspecified

Basal cell carcinoma

Glandular tumors

Mammary-type gland lesions

Phyllodes tumor (malignant)

Mammary-type adenocarcinoma

Bartholin gland disorders

Bartholin gland adenocarcinoma

Other types of adenocarcinoma

Paget's disease

Sweat gland carcinoma

Intestinal-type adenocarcinoma

GERMINAL TUMORS

Germ cell tumors of the vulva

Although melanocytic tumors were excluded from the WHO Classification of Tumours of the Female Reproductive Organs (5th edition, Lyon, 2020), given their frequency (5–10%) and clinical significance, decisions regarding management should be made by a multidisciplinary team involving a gynecologic oncologist [62].

Staging of squamous cell vulvar cancer is performed according to two classifications: TNM (8th edition, 2017) and FIGO (2009) (see table). It is applied only to primary vulvar cancer. Histological (pathological) confirmation of the diagnosis is required. Tumors extending to the vagina must be classified as vulvar cancer.

1.5.2. International clinical classification of vulvar cancer according to TNM 8 (2017) and FIGO (2009) criteria

* In this classification, stage 0 (carcinoma in situ) was removed because this is a preinvasive lesion.

N – Regional lymph nodes

N_x – regional lymph nodes cannot be assessed

N₀ – no regional lymph node metastasis

N_1–3 – regional lymph node metastasis present

M – Distant metastasis

M₀ – no distant metastasis

M₁ – distant metastasis present

G – histological grade of the tumor

Gx – grade of differentiation cannot be assessed

G1 – well-differentiated

G2 – moderately differentiated

G3 – poorly differentiated or undifferentiated

Note. N – regional lymph nodes. Inguinal and femoral lymph nodes are considered regional. Involvement of pelvic lymph nodes (external and internal iliac, obturator, and common iliac) is classified as distant metastasis.

1.6 Clinical presentation of the disease or condition

The most frequent symptoms of vulvar cancer include irritation or persistent and worsening vulvar pruritus; a wart-like tumor and/or bright pink, red, or white erosion; a painful ulcer lasting more than 1 month; chronic, recurrent, and refractory vulvar pain; and dysuria. The affected vulvar area may appear pale and uneven to the touch. Less commonly, the initial manifestations are bloody or purulent discharge, or enlargement of the inguinal lymph nodes.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of a disease or condition are based on:

1) anamnesis data;

2) physical examination, including a thorough gynecological examination;

3) cytological examination of biopsy specimens from enlarged or suspicious lymph nodes;

4) pathological examination of biopsy (surgical) material from the vulva and lymph nodes;

5) instrumental and radiological examination, including complex ultrasound examination of the pelvic organs (transvaginal and transabdominal), ultrasound examination of regional lymph nodes (inguinal and femoral) and distant lymph nodes – external and internal iliac, obturator, and common iliac lymph nodes. According to indications – magnetic resonance imaging of the pelvic organs, soft tissues of the perineum with or without intravenous contrast (if contraindicated), etc., and/or computed tomography (CT) of the chest, abdominal organs, kidneys, retroperitoneal space with or without intravenous contrast, and in case of contraindications to MRI – CT of the pelvic organs, soft tissues of the perineum with or without i.v. contrast; if distant metastasis is suspected – positron emission tomography combined with computed tomography of the whole body using tumorotropic radiopharmaceuticals (A07.30.043 Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals) (see Section 2.4 below).

2.1 Complaints and Anamnesis

The primary complaint of patients is vulvar pruritus. In 30% of cases, the disease is asymptomatic. Patients with vulvar cancer also typically complain of burning, perineal pain, leukorrhea, and bloody or purulent discharge. The most frequently affected anatomical sites are the labia majora (52%), clitoris (12–20%), and less commonly the labia minora (7.1%) and periurethral area (1.7%) [4].

2.2 Physical Examination

• All patients with vulvar cancer or suspected vulvar cancer are recommended to undergo a thorough physical examination during the initial examination (appointment, consultation) by an oncogynaecologist and/or obstetrician-gynecologist, including visual inspection of the external genitalia, speculum examination of the cervix and vaginal walls, bimanual vaginal examination, transrectal digital (rectovaginal) examination, and palpation of regional (inguinal and femoral) lymph nodes for diagnosis verification, treatment planning and algorithm determination, and assessment of disease prognosis [4].

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

Comments: During visual inspection of the external genitalia, it is necessary to specify the tumor localization within the anatomical region, indicate the extent and size of the tumor, and the presence of surrounding tissue infiltration. During speculum examination of the cervix and vaginal walls, it is preferable to use Sims vaginal specula (02.20.001 Speculum examination of the cervix), since Cusco bivalve vaginal specula poorly visualize certain areas of the vagina (anterior and posterior walls). During lymph node palpation, special attention should be paid to the inguinal and femoral lymph nodes, which are considered regional lymph nodes in vulvar malignancies.

Medical documentation should specify:

- tumor localization (anatomical region – labia majora/minora/Bartholin gland/clitoris/perineum);

- extent of the tumor process (unilateral/bilateral involvement, closest distance to the midline/urethra/vagina/anus); - size of the tumor lesion, and if multiple lesions are present – the size of each; - tumor mobility / presence of surrounding tissue infiltration

- photographs or a clinical drawing may be attached

2.3 Laboratory Diagnostics

• All patients with vulvar cancer or suspected vulvar cancer are recommended non-specific laboratory diagnostics, including a complete blood count, general biochemical blood test, coagulogram (exploratory hemostasis assay), and urinalysis to assess their general condition, determine treatment tactics and algorithms, and evaluate disease prognosis. Squamous cell carcinoma (SCC) antigen blood levels may be measured for subsequent monitoring of squamous cell vulvar cancer [4].

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

Comment: patients with vulvar cancer or suspected vulvar cancer may undergo molecular biological testing of vaginal discharge for human papillomavirus (HPV) (testing of vaginal discharge for oncogenic HPV types by PCR) to identify etiological factors of the disease [2, 3]

2.4 Instrumental Diagnostics

Cytological, immunocytochemical, histological, and immunohistochemical methods are used to verify the diagnosis. Tumor biopsy, biopsy of soft tissue tumors of the perineum, and pathological examination of biopsy (surgical) material are the main diagnostic methods for vulvar cancer.

• All patients with vulvar cancer (VC) and suspected VC are recommended to obtain a vulvar scraping; a touch imprint smear from the skin surface; pathoanatomical examination of vulvar biopsy (surgical) material; performance of lymph node puncture; cytological examination of lymph node biopsy specimens; pathoanatomical examination of lymph node biopsy (surgical) material for the purpose of morphological verification [2, 6, 7].

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

Comment: to rule out primary multiple malignancies, secondary involvement, and tumor dissemination, it is recommended to take smears from the cervix and cervical canal (obtaining a cervical smear) and perform aspiration biopsy of uterine (endometrial) tissues with cytological followed by pathoanatomical examinations [8].

Comment: vulvoscopy is the simplest method for visualizing a tumor formation.

Comment: Ultrasound is the most accessible imaging method for assessing the extent of the tumor process in the abdominal cavity, pelvic cavity, as well as in regional and distant lymph nodes.

Comment: If chest CT cannot be performed, targeted chest radiography is performed.

Chest CT has higher diagnostic efficacy compared to radiography in detecting metastatic lesions of the lungs, pleura, and intrathoracic lymph nodes [9, 63].

Comment: If MRI cannot be performed and/or if there are contraindications to it, contrast-enhanced pelvic CT is indicated in women.

MRI in evaluating the pelvic organs, pelvic floor tissues, and perineum has higher diagnostic information yield compared to CT [63, 66, 67, 68]

Comment: PET-CT is preferred in cases of planned surgical treatment or radiation therapy, including after neoadjuvant therapy, with a tumor size greater than 2 cm [70, 71, 72].

Comment: if MRI cannot be performed and/or if there are contraindications, contrast-enhanced brain CT may be performed. Contrast-enhanced MRI has higher diagnostic efficacy compared to CT in diagnosing metastatic brain involvement [74, 75].

• For patients with VC preparing for surgical treatment or radiation therapy, it is recommended to assess general condition and functional status, with additional examinations performed as indicated: echocardiography, taking into account ECG data, Holter heart rhythm monitoring, study of unforced respiratory volumes and flows, duplex scanning of extracranial segments of brachiocephalic arteries, ultrasonic Dopplerography of lower extremity vessels (arteries and veins), primary and follow-up appointments (examination, consultation) with a cardiologist, endocrinologist, neurologist, etc., taking into account concomitant diseases [9].

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

• For radiation therapy planning as the method of choice, contrast-enhanced pelvic MRI is recommended as it provides the most informative assessment of local tumor extent and regional lymph node status [76].

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

Comment: if MRI cannot be performed, contrast-enhanced pelvic CT in women may be used for radiation therapy planning. Unenhanced CT is not informative for visualizing VC [63]. Consideration should be given to performing PET-CT for more precise radiation therapy planning [77].

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, perineural invasion (a negative result must also be stated);

6) lymph node examination must include regional lymph node status (pN) indicating the total number of examined and affected lymph nodes, the size of the largest metastasis, and signs of extranodal tumor extension (ENE+/–);

7) microscopic evaluation of resection margins (status) R0-1 indicating the distance to the nearest resection margin in mm;

8) degree of therapeutic pathomorphosis in case of preoperative therapy. [8, 10, 12].

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

Comment:

- in case of doubtful or negative results of the initial vulvar neoplasm biopsy based on pathoanatomical examination, patients with suspected VC are indicated to undergo either a repeat biopsy or, if possible, surgical intervention with pathoanatomical examination of the biopsy (surgical) material;

- if morphological verification of the VC diagnosis is necessary, the pathoanatomical examination of the biopsy (surgical) material may be supplemented by immunohistochemical typing — pathoanatomical examination of the biopsy (surgical) material using immunohistochemical methods is advisable.

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

The prescription and use of medications specified in the clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medications, implementing the precautions presented in the instructions, and dose adjustments are also possible taking into account the patient's condition. Treatment should be carried out in a specialized clinic with modern diagnostic capabilities and experience in the successful treatment of this category of patients. Treatment tactics should be determined at a multidisciplinary board meeting.

Comment: adjuvant radiation or chemoradiation therapy is additionally performed according to indications. Radiation therapy (both as an independent treatment method and in combination with chemotherapy) is prescribed when surgical intervention is contraindicated. An individualized approach (combination of radiation, drug, and surgical methods) is used for stage IV and disease recurrence [8, 10–13, 14].

3.1. General principles of treatment depending on the stage

3.1.1. Treatment of vulvar cancer TisN0M0

3.1.2. Treatment of stage Ia vulvar cancer (T1aN0M0)

• All patients with stage Ia vulvar cancer (T1aN0M0) are recommended surgical treatment. Primary radiation therapy is performed in cases of general somatic contraindications to surgery or patient refusal of surgery. In patients with microinvasive vulvar cancer with a tumor diameter of ≤2 cm and stromal invasion of ≤1 mm, wide local excision without inguinofemoral lymphadenectomy is possible in the absence of severe diffuse vulvar dystrophy. All other patients must undergo vulvectomy without inguinofemoral lymphadenectomy [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: clinically, the incision line should run at a distance of at least 1 cm from the visually determined tumor edge along its entire circumference. Vulvectomy without inguinofemoral lymphadenectomy is performed for multifocal lesions and when the tumor develops against the background of dystrophic changes across the entire vulvar surface.

3.1.3. Treatment of stage Ib vulvar cancer (TIbN0M0)

Surgical treatment

• All patients with stage Ib vulvar cancer (TIbN0M0) with lateral vulvar involvement (≥2 cm from the midline) are recommended to undergo vulvectomy with bilateral ilio-inguinofemoral lymphadenectomy (radical vulvectomy). When the tumor is located laterally 2–4 cm from the midline, vulvectomy with sentinel lymph node mapping and subsequent lymphadenectomy according to indications is recommended [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: clinically, the incision line should run at a distance of ≥1 cm (but <2 cm) from the visually determined tumor edge along its entire circumference.

• All patients with stage Ib vulvar cancer (TIbN0M0) with central vulvar involvement (anterior or posterior, within 2 cm of the midline) are recommended to undergo vulvectomy with bilateral ilio-inguinofemoral lymphadenectomy (if metastases are detected, adjuvant chemoradiotherapy or bilateral inguinofemoral lymphadenectomy followed by chemoradiotherapy is recommended) [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: clinically, the incision line should run at a distance of ≥1 cm (but <2 cm) from the visually determined tumor edge along its entire circumference.

• Patients with stage Ib vulvar cancer (TIbN0M0) with a vulvar tumor size ≤4 cm are recommended to undergo vulvectomy with bilateral ilio-inguinofemoral lymphadenectomy or sentinel lymph node biopsy (if metastases are detected, bilateral inguinofemoral lymphadenectomy followed by chemoradiotherapy is recommended) [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comments:

- clinically, the incision line should run at a distance of ≥1 cm (but <2 cm) from the visually and palpatorily determined tumor edge along its entire circumference;

- postoperative radiation therapy (vulvar irradiation) or chemoradiotherapy is considered if histological signs of tumor are found at the resection margins with an incision line <1 cm from the tumor, lymphovascular invasion, or tumor stromal invasion >5 мм;

- for patients in whom surgery is unfeasible due to concomitant diseases or the extent of the disease, an alternative treatment method is radical-dose radiation therapy [13, 15, 16];

• All patients with stage Ib vulvar cancer (TIbN0M0) with a tumor size ≥4 cm are recommended the primary treatment method: surgery (vulvectomy with bilateral ilio-inguinofemoral lymphadenectomy and possible reconstruction using a transposed myocutaneous flap [free flap autotransplantation with vascular anastomosis formation]) [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

• Patients with stage Ib vulvar cancer (TIbN0M0) with questionable tumor resectability are recommended neoadjuvant chemotherapy followed by vulvectomy with inguinofemoral lymphadenectomy (radical vulvectomy). In case of ineffective neoadjuvant chemotherapy and questionable resectability – chemoradiotherapy [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: for patients in whom surgery is unfeasible due to concomitant diseases or the extent of the disease, an alternative treatment method is radical-dose radiation therapy [15, 16].

3.1.4. Treatment of stage II vulvar cancer (TIIN0M0)

• Patients with stage II vulvar cancer (T2N0M0) are recommended radical chemoradiotherapy. With minimal tumor extension to the lower third of the urethra and/or vagina, combined surgical intervention with distal urethrectomy (urethral resection) and/or distal vaginectomy (local excision of the vagina) followed by adjuvant radiation therapy is recommended [8, 12].

GPR CLOE 5Grade of Recommendations – C (Level of Evidence – 5)

Comments:

- primary radiation therapy is performed in the presence of contraindications to surgery or if the patient refuses surgery;

- if the tumor extends to the anal canal, treatment as for stage IV is recommended;

3.1.5 Treatment of Stage III Vulvar Cancer (T1–2N1a–bM0, T1–2N2a–bM0)

• Patients with stage III vulvar cancer (T1–2N1a–bM0, T1–2N2a–bM0) with resectable tumors are recommended the following treatment options: surgery + adjuvant chemoradiotherapy or surgery + adjuvant radiation therapy (in the presence of contraindications to chemotherapy or if the patient refuses chemotherapy) [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

• Patients with stage III vulvar cancer (T1–2N1a–bM0, T1–2N2a–bM0) with unresectable tumors are recommended radical-dose chemoradiotherapy or radical-dose radiation therapy (in the presence of contraindications to chemotherapy or if the patient refuses chemotherapy) [15, 16, 21].

LOE 4Grade of Recommendation – C (Level of Evidence – 4)

• Patients with stage III vulvar cancer (T1–2N1a–bM0, T1–2N2a–bM0) may be recommended neoadjuvant chemotherapy if subsequent radical surgery is feasible [21].

LOE 4Grade of Recommendation – C (Level of Evidence – 4)

• Patients with stage III vulvar cancer (T1–2N1a–bM0, T1–2N2a–bM0) are recommended primary radiation therapy in the presence of general somatic contraindications to surgery and chemotherapy or if the patient refuses surgery and chemotherapy [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comments:

- if the tumor extends to the lower third of the urethra and/or vagina, combined surgical intervention including radical vulvectomy, bilateral inguinofemoral lymphadenectomy with distal urethrectomy (urethral resection) and/or distal vaginectomy (local excision of the vagina), and postoperative chemoradiotherapy is recommended;

- if the tumor extends to the anal canal, the same treatment as for stage IV is recommended;

- postoperative radiation therapy or chemoradiotherapy (to the regional and external iliac lymph nodes) is considered in the following cases: macroscopic metastases in regional lymph nodes; presence of >2 microscopic metastases in regional lymph nodes; or extracapsular extension [8].

3.1.6 Treatment of stage IV vulvar cancer

Each clinical case must be discussed at a multidisciplinary tumor board to determine the optimal treatment method and feasibility.

• All patients with stage IVA vulvar cancer (T1–2N3M0, T3N0–3M0) are recommended chemoradiotherapy [8, 9, 12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: In cases of persistence of the primary tumor process (unstable stabilization or local progression during radiation therapy up to a cumulative equivalent dose of 40 Gy) documented by physical and visual examination, and comprehensive pelvic ultrasound (transvaginal and transabdominal), the issue of further management is reviewed by a multidisciplinary tumor board. In selected cases, extended and combined surgical interventions, including various types of pelvic exenteration and courses of consolidative chemotherapy, may be performed [8, 9, 12].

• All patients with stage IVB vulvar cancer (T1–3N0–3M1) (distant metastases) are recommended to undergo individualized chemotherapy or radiation therapy [8, 12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: the course of chemoradiotherapy should be initiated no later than the 28th day after the detection of metastatic disease or cytoreductive surgery in the presence of metastases (in the absence of postoperative complications) [8, 12].

• All patients with recurrent vulvar cancer are recommended individualized treatment (surgery of any scope with or without radiation therapy and platinum-based radiosensitizing chemotherapy for local recurrences, or chemoradiotherapy with or without surgery, or palliative care with chemotherapy) [12].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comments:

- in patients with resectable iliac lymph node involvement, bilateral iliac lymphadenectomy followed by chemoradiotherapy is possible [12].

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

3.2. Radiation therapy

General principles:

Radiation therapy is recommended as part of combined treatment as adjuvant therapy after surgery; as a monotherapy for locally advanced tumor process; as palliative care in recurrence/metastases. The use of conformal external beam radiation therapy based on individual volumetric planning of irradiation parameters using modern medical imaging methods (see section 2 Diagnosis of the disease) to ensure adequate oncological treatment outcomes, its efficacy and safety. Specific radiation therapy techniques depend on the primary tumor localization, extent, and depth of tumor invasion [12].

LOU 5Level of Evidence – C (Level of Confidence – 5)

Comments:

- Adjuvant radiation therapy should be initiated no later than 6–8 weeks after surgery;

- external beam RT is delivered to the vulva and/or regional metastasis sites: inguinal-femoral, external, and internal iliac lymph nodes;

- interstitial RT (brachytherapy) as a localized irradiation method is in some cases delivered to the primary lesion site—the vulva;

- external beam RT is delivered in a daily fractionation regimen (FDose 1.8–2.0 Gy) 5 times a week. Breaks during the course of treatment are not permitted. It is important to deliver maximum doses using

3D-conformal radiation therapy or IMRT technology (conformal external beam radiation therapy, including IMRT, IGRT, VMAT, stereotactic) (intensity-modulated radiation therapy) up to a TDD of 46–50 Gy (FDose 2 Gy) or up to a TDD of 45–50.4 Gy (FDose 1.8 Gy) in adjuvant postoperative treatment, and up to 60–64 Gy (FDose 2 Gy) or 59.4–64.8 Gy (at FDose 1.8 Gy) in radical definitive radiation therapy. For the area of clinically and/or radiologically uninvolved inguinal-femoral lymph nodes, the TDD is 45–50 Gy. Inguinal-femoral lymph nodes (positive, without extracapsular extension or prominent residual tumor tissue): TDD 50–55 Gy. Inguinal-femoral lymph nodes: TDD 54–64 Gy

- in some cases, in the presence of large regional lymph nodes (residual or unresectable), a local boost up to a total dose of 60–70 Gy may be delivered [22, 23];

- in case of superficial localization of the vulvar or lymph node tumor lesion, the use of a bolus is permitted to ensure adequate superficial dose distribution during external beam radiation therapy

- management of radiation reactions during external beam irradiation and chemoradiotherapy (diarrhea, cystitis, local inflammatory reaction of the skin and mucosa) is carried out using anti-inflammatory symptomatic therapy (including care for the skin and labial mucosa). This makes it possible to avoid treatment interruptions.

3.2.1. Topographic and topometric planning of radiation therapy

Topographic and tomometric planning of radiation therapy for external beam radiation therapy is performed in the supine position or with immobilization of the upper and lower body using a headrest and an individual vacuum mattress. External and endovaginal radiopaque markers can be used to verify the lower border of the tumor (GTV) and the vaginal introitus (introittus). For more precise contouring of the primary tumor (GTV), pelvic and inguinal lymph nodes included in the target volume (CTV, PTV), medical imaging data (CT/MRI with intravenous contrast, PET-CT, etc.) obtained both during the tomometry procedure and by integrating primary examination data using fusion technologies can be used.

3.2.2. External beam radiation therapy

• In patients with vulvar cancer without pelvic lymph node involvement, it is recommended that the upper boundary of the field be placed no lower than the middle of the sacroiliac joint or no higher than the L4/L5 border [12].

LOU 5Level of Evidence – C (Level of Confidence – 5)

Comment: In case of pelvic lymph node involvement, the upper border of the field should be 5 cm above the metastatically involved lymph node. The upper border of the field should run horizontally at the level of the anterior inferior iliac spine so that the inguinal-femoral lymph nodes are included in the irradiation volume. The lateral border of the field is a vertical line from the anterior inferior iliac spine. For good coverage of the inguinal lymph nodes, the anterolateral border should run parallel to the inguinal fold and inferiorly should adequately cover the inguinal-femoral lymph nodes along the intertrochanteric line of the femur. The lower border of the irradiation field should be at least 2 cm below the most distal part of the vulva. Radiation exposure to the femoral head and neck should be avoided [12].

Following topographic and tomometric planning of radiation therapy, target volume contouring is performed—contouring of the primary tumor and critical organs (one anatomical zone). Any tumor volume of the vulva is outlined as GTV and includes the visualized or palpable volume of infiltration of the tumor process into the vaginal tube [12].

Vulva:

- CTV-T includes the GTV or the tumor bed, adjacent skin, subcutaneous tissue, mucosa; bones are excluded;

- CTV-N includes pelvic and bilateral inguinal-femoral lymph nodes. Pelvic lymph nodes (common iliac, external and internal iliac) are outlined with a 7 mm margin around the vessels. The presacral region is included in the volume if infiltration extends to the vagina 1 cm anterior to S1-S2. In patients with infiltration extending to the ampullary part/rectum, regional perirectal lymph nodes are included in the volume.

- Inguinal-femoral lymph nodes are included in the total volume with surrounding vessels up to 1.0–1.5 cm (bones, muscles, and skin are excluded), as well as any visualized nodes in the adipose tissue;

PTV1 = CTV-T + 5–10 mm

PTV2 = CTV-N + 5–7 mm

PTVtot = PTV1 + PTV2

PTVtot may be reduced from the skin surface in the inguinal-femoral fold area [12].

Organs at risk. Mandatory structures to be contoured for calculating delivered tolerance doses using dose-volume histograms are the urinary bladder, rectum, small bowel loops, anus, bone marrow (sacrum, coccyx, L5 body, acetabulum, proximal femur), and femoral head [12].

3.3. Principles of systemic chemotherapy

• Patients with advanced vulvar cancer who are not candidates for primary surgery or chemoradiotherapy at the first stage may be recommended neoadjuvant platinum-based combination chemotherapy [12, 56, 45].

LOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comment:

Currently, advanced vulvar cancer is treated with radiation therapy combined with platinum-based radiosensitizing chemotherapy, similarly to cervical cancer, e.g., #cisplatin** [12, 56, 45]. Platinum-based combination chemotherapy should be considered as first-line treatment in metastatic or recurrent disease [12].

Although the optimal platinum-based combination regimen in advanced vulvar cancer remains unclear, #cisplatin** or #carboplatin** plus #paclitaxel** can be considered the preferred regimen [12].

- Chemotherapy is also possible in unresectable vulvar cancer to avoid exenterative surgeries, in the presence of positive surgical margins if radiation therapy is declined or deemed inappropriate in a specific clinical situation [78].

— minimal chemotherapy volume that can be recommended for patients with vulvar cancer, similar to chemotherapy for cervical cancer: #cisplatin** 50 mg/m² IV on day 1 every 21 days for up to 4–6 cycles [12, 59].

LoE 5Grade of recommendation – C (Level of evidence – 5)

— optimal chemotherapy volume—the following chemotherapy options:

— #paclitaxel** 175 mg/m² IV on day 1 + #cisplatin** 70 mg/m² IV on day 1 every 21 days for up to 6 cycles [12, 57];

— #paclitaxel** 175 mg/m² IV on day 1 + #carboplatin** AUC 5–6 IV on day 1 every 21 days for up to 6 cycles [46];

— #paclitaxel** 175 mg/m² IV on day 1 every 21 days for up to 6 cycles [47];

— #pembrolizumab** 200 mg IV every 21 days in the presence of high microsatellite instability, including DNA mismatch repair deficiencies [48].

LoE 4Level of Recommendations Consensus – C (Level of Evidence – 4)

• If the disease recurs in patients with vulvar cancer, chemotherapy is recommended according to regimens similar to those for recurrent squamous cell vulvar cancer specified in the relevant clinical guidelines for vulvar cancer [49, 55–61].

Level of evidence 3Grade of recommendation – B (level of evidence – 3)

3.4. Pain Management

Procedures and recommendations for pain management in malignant neoplasms of the uterine corpus comply with the recommendations presented in the rubricator "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care" [http://cr.rosminzdrav.ru/#!/recomend/708]

3.5 Diet therapy

• To date, there is evidence of an increased risk of cancer development in overweight and obese female patients [15]. In this regard, measures aimed at reducing patients' excess weight to normal values are recommended. Correcting the habitual diet in such patients will help prevent complications of ongoing treatment (surgical, drug, or radiation therapy) [15–16].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Prehabilitation significantly accelerates functional recovery, shortens hospital stay after surgery, and reduces the incidence of complications and mortality during cancer treatment. Prehabilitation includes physical therapy (PT) for female reproductive system diseases, psychological and nutritional support, and patient education [29].

• Psychological support is recommended for all patients with vulvar cancer as part of prehabilitation – it improves mood and reduces anxiety and depression. Patients who have undergone psychological prehabilitation adapt better to daily life after surgical treatment [29].

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

Comment: Psychological prehabilitation using stress-coping techniques (relaxation techniques, positive mindset formation), starting 5 days before surgery and continuing for 30 days after, is conducted for 40–60 min 6 days a week [29].

• Fast-track rehabilitation and ERAS (early rehabilitation after surgery) tactics are recommended for all patients with vulvar cancer, including multimodal analgesia, early enteral nutrition, avoidance of routine use of tubes and drains, and early mobilization (getting patients out of bed and into a vertical position) as early as 1–2 days after surgery to reduce the risk of early postoperative complications and hospital readmission rates [33, 52].

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

• Early initiation of physical therapy including aerobic, strength training, and stretching exercises is recommended for all patients with vulvar cancer to improve their quality of life [29].

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

• Early initiation of breathing exercises, elevation of the head of the bed, and early mobilization are recommended for patients with vulvar cancer to prevent postoperative pulmonary congestion [34].

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

• Early mobilization, prophylactic administration of anticoagulants (antithrombotic agents), and wearing compression stockings are recommended for all patients with vulvar cancer to prevent postoperative thrombotic complications [37, 54].

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

• For the treatment of postoperative pain – which is interdisciplinary in nature – in addition to drug therapy, recommended interventions include physical therapy for female reproductive system diseases (PT), positioning, psychological pain management techniques (relaxation), transcutaneous electrical nerve stimulation (TENS), and acupuncture (stimulation of acupuncture points by other physical factors) [38].

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

— intermittent pneumatic compression of the lower extremities in combination with complete decongestive therapy [44, 53].

— low-level laser therapy (intravenous laser blood irradiation) in combination with complete decongestive therapy;

— deep oscillation therapy (massage via a variable electrostatic field) in combination with complete decongestive therapy [34, 39].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 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 [12].

GCP CLEL 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 and abdominal CT with intravenous bolus contrast (if CT is not feasible, pelvic MRI with intravenous contrast is indicated, and if MRI is not feasible, pelvic CT with contrast is indicated for women);

- Targeted chest X-ray or chest CT.

- PET-CT with tumor-tropic radiopharmaceuticals if distant metastases are suspected and CT/MRI is inconclusive [12].

Grade of recommendation CLevel of evidence 5Grade of recommendation – C (level of evidence – 5)

Comments: the goal of follow-up is the early detection of disease progression to allow for the early initiation of surgical and/or chemoradiotherapy.

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation," is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized Federal Executive Authority;

2) in accordance with the procedures for the provision of medical care approved by the authorized federal executive authority and mandatory for implementation across the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized Federal Executive Authority.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Indications for discharging a patient from a medical organization are:

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

2) refusal by the patient or their legal representative of specialized, including high-tech, medical care in an inpatient or day hospital setting established by the concilium of the medical organization providing cancer care

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

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

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

7. Additional Information

No additional information available

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ashrafyan L.A., Academician of the 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., MD, DSc, Head of the Department of Antitumor Drug Therapy, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov 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., MD, PhD, Senior Researcher at the Institute of Oncogynecology and Mammology, Oncologist at the Oncological Department of Surgical Treatment, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

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

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. Ulrich E.A., MD, DSc, 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., MD, DSc, Professor, Director of the Institute of Oncology and Neurosurgery, Oncologist, 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., MD, DSc, Expert in the Diagnosis and Treatment of Trophoblastic Tumors, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

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. 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. Dubinina A.V., MD, PhD, Senior Researcher at the Radiotherapy Department, National Medical Research Center of Oncology named after N.N. Blokhin 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., MD, DSc, Head of the Department of Diagnostic Radiology, Radiologist, Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health

24. Bychenko V.G., MD, PhD, Head of the Department of Diagnostic Radiology at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov 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., MD, PhD, Head of the Department of Biomedical Technologies and Cellular Technologies Laboratory, Transfusiologist, Dermatovenerologist, Specialist in Cellular Technologies, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health.

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

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

6. Nazarenko A.V., MD, PhD, Physician of the Highest Qualification Category, Head of the Radiology Department, National Medical Research Center of Oncology named after N.N. Blokhin 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 Research 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, DSc, 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, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health.

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

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

14. Kasparov B.S., MD, PhD, Deputy Chief Medical Officer 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 of the Russian Ministry of Health.

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

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

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

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

Healthcare Organization Section:

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

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

3. Ivanov S.A., Professor of the RAS, MD, DSc, Director of the Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

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

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• surgeons;

• radiologists;

• medical oncologists (chemotherapy specialists);

• medical geneticists;

• dermatovenerologists;

• pathologists;

• medical students, residents, and graduate students.

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.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for evaluating the levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural healing factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Methods used for formulating recommendations – expert consensus.

Economic analysis

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

Method of recommendation validation:

• external expert review;

• internal expert review.

Description of the recommendation validation method

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

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

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

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

Procedure for updating clinical guidelines

The clinical guideline update mechanism provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention of specific diseases, and patient rehabilitation, 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

Appendix C. Patient Information

Recommendation for chemotherapy complications: contact your medical oncologist.

Recommendations for radiation therapy complications: contact your radiation oncologist.

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

• start systemic antibacterial drugs as prescribed by the medical oncologist.

2. For stomatitis:

• diet — mechanically and thermally sparing;

• frequently (every hour) rinse the mouth with decoctions of chamomile, oak bark, sage, lubricate the mouth with sea buckthorn (peach) oil;

• treat the oral cavity as recommended by the oncologist.

3. For diarrhea:

• diet: exclude fatty, spicy, smoked, sweet, dairy products, fiber;

• lean meat, flour products, fermented dairy products, rice water are allowed;

• abundant fluid intake;

• take medications as prescribed by the medical oncologist.

For nausea:

• take medications as prescribed by the medical oncologist.

Most side effects (fatigue, which may increase about 2 weeks after the start of treatment; nausea and vomiting, diarrhea, skin changes, low blood counts) are temporary and resolve after treatment completion.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO/ECOG Performance Status Scale [55]

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

Russian title: Karnofsky Performance Scale [56]

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