Urethral cancer: clinical guidelines

List of Abbreviations

IV – intravenous

WHO – World Health Organization

CI – confidence interval

CT ‒ computed tomography

PT – physical therapy

LN ‒ lymph node(s)

ICD-10 ‒ International Statistical Classification of Diseases and Related Health Problems 10th Revision

MRI ‒ magnetic resonance imaging

AEs – adverse events

OS – overall survival

HR – hazard ratio

PET/CT – positron emission tomography combined with computed tomography

TAD – total absorbed dose

US ‒ ultrasound

ECOG PS (Eastern Cooperative Oncology Group performance status) – assessment of the general condition of a cancer patient using the scale developed by the Eastern Cooperative Oncology Group

RECIST (Response Evaluation Criteria In Solid Tumors) – criteria for evaluating the response of solid tumors to therapy

** – vital and essential drugs

# – drug used off-label (not in accordance with the instructions for use, contraindications, routes of administration, or doses contained in the product information)

Terms and Definitions

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

Second stage of rehabilitation – inpatient rehabilitation in medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual disease symptoms.

Malignant priapism – painful pathological erection caused by the spread of the tumor process to the corpora cavernosa of the penis.

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

Duquesne operation – ilioinguinal lymphadenectomy.

First stage of rehabilitation – rehabilitation during the period of specialized treatment for the primary disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the primary disease.

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

Third phase of rehabilitation – rehabilitation in the early and late rehabilitation periods, and the period of residual effects of the disease in departments (rooms) of rehabilitation, physiotherapy, physical therapy, reflexology, manual therapy, psychotherapy, medical psychology, speech therapy (teacher-defectologist) offices providing medical care in outpatient settings, day hospitals, as well as by mobile teams at home (including in sanatorium-resort organizations).

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

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Urethral cancer is a rare oncological disease associated with the development of a malignant neoplasm in the tissues of the urethral wall [1].

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

Risk factors for the development of urethral cancer in men include urethral strictures, chronic mucosal irritation, external beam and interstitial radiotherapy, as well as chronic urethritis [2–9]. Risk factors for the development of urethral cancer in women include urethral diverticula, chronic urinary tract infections, and urethral sling placement [10–12].

1.3 Epidemiology of the Disease or Condition

Primary cancer of the urethra in men is extremely rare. The tumor occurs at any age, although men over 50 are more commonly affected. In women, urethral cancer is somewhat more common. Its primary forms account for 0.02–0.5% of malignant neoplasms of the female urogenital system. The tumor usually develops during the postmenopausal period; 75% of patients suffering from urethral cancer are over 50 years old [13, 14].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (hereinafter referred to as ICD-10), urethral cancer has the code C68.0 – malignant neoplasm of urethra.

1.5 Classification of the disease or condition

Histological classification of urethral cancer:

Urothelial tumors

Infiltrative urothelial carcinoma 8120/3

Nodular, including large-noduled

Microcystic

Micropapillary 8131/3

Lymphoepithelioma-like 8082/3

Plasmacytoid/signet-ring cell/diffuse

Sarcomatoid 8122/3

Giant cell 8031/3

Undifferentiated 8020/3

Lipid-rich

Clear cell

Non-invasive urothelial lesions

Urothelial carcinoma in situ 8120/2

Non-invasive papillary urothelial carcinoma, low grade 8130/3

Non-invasive papillary urothelial carcinoma, high grade 8130/2

Papillary urothelial neoplasm

of low malignant potential 8130/1

Urothelial papilloma 8120/0

Inverted urothelial papilloma 8121/0

Urothelial proliferation of uncertain malignant potential Urothelial dysplasia

Squamous cell tumors

Pure squamous cell carcinoma 8070/3

Verrucous carcinoma 8051/3

Squamous papilloma 8052/0

Glandular tumors

Adenocarcinoma, not otherwise specified 8140/3

Enteric 8144/3

Mucinous 8480/3

Mixed 8140/3

Villous adenoma 8261/0

Urachal carcinoma 8010/3

Müllerian-type tumors

Clear cell carcinoma 8310/3

Endometrioid carcinoma 8380/3

Histopathological grading of urethral cancer [15]:

1) PUNLMP – papillary urothelial neoplasm of low malignant potential;

2) low grade – well-differentiated;

3) high grade – poorly differentiated.

Histopathological grading of non-urothelial urethral carcinoma:

1) Gx – cannot be assessed;

2) G1 – well-differentiated;

3) G2 – moderately differentiated;

4) G3 – poorly differentiated.

Staging

Staging of urethral cancer is performed in accordance with the AJCC/UICC TNM classification, 8th edition [16].

T criterion – primary tumor (men and women):

● Tx – primary tumor cannot be assessed;

● T0 – no evidence of primary tumor;

● Ta – non-invasive papillary, polypoid, or verrucous carcinoma;

● Tis – carcinoma in situ (preinvasive);

● T1 – tumor invades subepithelial connective tissue;

● T2 – tumor invades prostate stroma, corpus cavernosum, or periurethral muscle;

● T3 – tumor invades corpus cavernosum, beyond the prostatic capsule, anterior vaginal wall, or bladder neck;

● T4 – tumor invades other adjacent organs.

N criterion – regional lymph nodes:

● Nx – regional lymph nodes cannot be assessed;

● N0 – no regional lymph node metastasis;

● N1 – metastasis in a single lymph node;

● N2 – metastases in more than one lymph node.

M criterion – distant metastases:

● Mx – distant metastases cannot be assessed;

● M0 – no distant metastasis;

● M1 – distant metastasis.

pTNM pathologic classification: the pT, pN, and pM categories correspond to the T, N, and M categories.

G – histopathological grade [9]:

● Gx – grade cannot be assessed;

● G1 – well-differentiated tumor;

● G2 – moderately differentiated tumor;

● G3–4 – poorly differentiated / undifferentiated tumor.

Stage grouping

1.6 Clinical presentation of the disease or condition

Early clinical symptoms of urethral cancer in women include:

● purulent and bloody discharge from the urethra;

● presence of a mass in the area of the external urethral meatus, often discovered by the patients themselves;

● mild difficulty urinating.

In late stages, the following appear:

● intense pain in the urethra and perineum,

● abundant bloody-purulent discharge.

Urinary retention in women with urethral cancer develops rarely due to the anatomical features of the female urethra.

Infiltration of the urethral wall can lead to urinary incontinence.

When the tumor process spreads to the vagina with the formation of a urethrovaginal fistula, patients experience leakage of urine from the genital tract.

Development of severe vaginal bleeding is possible.

The clinical presentation of male urethral cancer in the early stages is masked and largely depends on the underlying disease against which the malignant process develops. The non-specificity of symptoms leads to late diagnosis of cancer, as its initial manifestations are often attributed to urethral diseases leading to stricture development. Under the guise of urethral obstruction, the tumor is sometimes not detected for 12–18 months from the onset of the first manifestations.

The first symptoms of male urethral cancer are:

● scanty serous discharge;

● aching pain in the urethra during urination and erection;

● difficulty urinating.

At later stages, the following may appear:

● purulent-bloody discharge from the urethra;

● palpable induration in the area of the urethra;

● intense pain radiating to the perineum and thighs.

Further growth of the tumor infiltrating the urethral wall can lead to urinary retention. Periurethral abscesses and fistulas may appear. When the tumor process spreads to the corpora cavernosa of the penis, malignant priapism develops in some cases. Tumor thrombosis of the lymphatic vessels of the pelvis and inguinal region can lead to edema of the scrotum, penis, and lower extremities.

In ⅓ of patients, palpation of the inguinal regions reveals enlarged lymph nodes. As they grow, the nodes merge into conglomerates, become fixed, and can ulcerate.

The appearance of metastases in parenchymal organs causes the development of corresponding symptoms.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1. history data;

2. physical examination data;

3. laboratory test data;

4. instrumental examination data;

5. morphological examination data.

The clinical diagnosis is based on the results of:

1. physical examination, which allows the detection of a suspicious urethral mass;

2. morphological examination report of the tumor tissue;

3. diagnostic imaging data, which allow correct staging of the disease.

2.1 Complaints and Anamnesis

2.2 Physical Examination

• All patients with suspected urethral cancer are recommended a physical examination, including inspection and palpation of the penis in men, the external urethral meatus and vaginal walls in women, as well as inspection and palpation of the perineum and regional metastasis zones (inguinal regions) to assess the localization, number, and extent of the primary tumor and determine the status of regional lymph nodes [17, 18].

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

Comment: tumors of the external urethral meatus are usually clearly visible to the naked eye and present as solid, bluish-purple masses without clear boundaries, prone to ulceration and bleeding.

Neoplasms located more proximally can be diagnosed by palpation. A thorough examination of the corpus spongiosum and corpora cavernosa of the penis is necessary to identify their involvement in the tumor process. Vaginal and rectal examinations provide an opportunity to assess the condition of the periurethral tissues and detect infiltration of the vaginal walls and prostate gland. When examining a patient with urethral cancer, special attention should be paid to the condition of the inguinal lymph nodes, enlargement of which usually indicates their metastatic involvement.

2.3 Laboratory Diagnostics

• All patients with urethral cancer are recommended to undergo a complete clinical blood count to select additional diagnostic methods and determine treatment tactics [17, 18].

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

• All patients with urethral cancer are recommended to undergo a general biochemical blood test (including determination of glucose, creatinine, urea, bilirubin, transaminases, alkaline phosphatase, and serum potassium) to select additional diagnostic methods and determine treatment tactics [17, 18].

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

• All patients with urethral cancer are recommended to undergo a coagulogram (exploratory study of the hemostatic system), including the determination of prothrombin, prothrombin time, international normalized ratio, activated partial thromboplastin time, and fibrinogen, to select additional diagnostic methods and determine treatment tactics [17].

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

• All patients with urethral cancer are recommended a general clinical urinalysis to select additional diagnostic methods and determine treatment tactics [17, 18].

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

• All patients with urethral cancer are recommended to perform a microbiological (culture) urine test for aerobic and facultatively anaerobic opportunistic microorganisms in order to determine treatment tactics and secondary prevention [17, 18].

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

• All patients with suspected urethral cancer are recommended to undergo urine cytology (urine examination to detect tumor cells) [73, 74].

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

Comment: the diagnostic sensitivity of the method in men ranges from 50% to 80% (for transitional cell and squamous cell carcinoma, respectively), and in women from 50% to 77% (for transitional cell and squamous cell carcinoma), respectively.

• All patients with suspected urethral cancer are recommended a cytologic and/or pathomorphologic examination of the tumor biopsy (surgical) material, including, if necessary, pathomorphologic examination of the tumor biopsy (surgical) material using immunohistochemical methods, to verify the diagnosis and determine treatment tactics [17, 18].

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

Comment: morphological confirmation of the diagnosis is obtained by histological examination of the tumor biopsy. Cytological examination of touch smears and scrapings from the urethral neoplasm is also possible. In cases where the tumor is located in the proximal urethra, urethral discharge is examined. It should be borne in mind that negative results of cytological examination do not mean the absence of a tumor.

According to literature data, diagnostic errors in urethral tumors occur in 10% of cases. In men, the differential diagnosis of urethral cancer should be made with benign tumors, urethral stricture, hypertrophy of the urethral crest, chronic urethritis, tuberculosis, prostate cancer, calculi, and urethral syphilis. A case of squamous cell carcinoma of the urethra clinically mimicking a scrotal abscess has been described [2]. In women, urethral cancer should be differentiated from vulvar and vaginal tumors, benign neoplasms and inflammatory diseases of the urethra, paravestibular cysts, as well as prolapse of the urethral mucosa combined with laxity of the vaginal walls. The only reliable criterion allowing the exclusion of urethral cancer is morphological verification of the diagnosis.

2.4 Instrumental Diagnostics

• All patients with suspected urethral cancer are recommended to undergo urethrocystoscopy to detect the tumor [17, 18].

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

Comment: urethrocystoscopy makes it possible to assess the localization, size of the tumor, color and nature of its surface, and the state of the surrounding mucosa. Urethral cancer is characterized by the presence of a solid tumor on a broad base, with an easily bleeding and often ulcerated surface.

• All patients with urethral cancer are recommended to perform an ultrasound examination of the inguinal regions in order to assess the condition of the inguinal lymph nodes [17, 18].

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

• All patients with urethral cancer are recommended to undergo magnetic resonance imaging (hereinafter referred to as MRI) of the pelvic organs with intravenous bolus contrast enhancement in order to assess the extent of the tumor process and staging (assessment of the state of regional lymph nodes) [9, 19].

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

• All patients with urethral cancer are recommended to perform a three-phase CT scan of the abdominal cavity and retroperitoneum with intravenous bolus contrast enhancement to assess the extent and staging of the tumor process. Patients with contraindications to contrast-enhanced CT are indicated for MRI of the abdominal cavity and retroperitoneum [17, 18].

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

• All patients with urethral cancer are recommended to undergo chest X-ray or computed tomography (hereinafter referred to as CT) to assess the extent and staging of the tumor process [17, 18].

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

• Patients with urethral cancer presenting with bone symptoms (pain, pathological fracture), elevated serum alkaline phosphatase levels, as well as those with metastatic urethral cancer, are recommended to undergo whole-body bone scintigraphy (osteoscintigraphy) to detect metastatic skeletal bone lesions [17, 18].

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

• Patients with urethral cancer presenting with neurological symptoms are recommended to undergo brain MRI with intravenous contrast enhancement to detect brain metastases, except in cases where MRI is contraindicated—in such cases, MRI may be replaced by contrast-enhanced brain CT [17].

Level of Evidence: 5Grade of Recommendation: C (Level of Evidence: 5)

2.5 Other Procedures

No other diagnostic procedures are indicated.

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

The prescription and use of medicinal products specified in the clinical guideline are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions described in the instructions, and dose adjustments may also be made taking into account the patient's condition.

3.1. Treatment of urethral cancer in women

Comment: the scope of surgical treatment is determined by tumor size and may include excision, electroresection, laser vaporization or coagulation of the tumor, or circular resection of the urethra.

Radiation therapy for superficial distal urethral cancer is administered as intracavitary or interstitial brachytherapy, delivering a total focal dose (TFD) of 50–65 Gy to the tumor. These techniques achieve a good local effect while preserving spontaneous urination.

Comment: intracavitary/interstitial radiation therapy is used utilizing 1 or 2 192Ir implants in combination with external beam radiation to the tumor area and regional lymph nodes. A TFD of 70 to 85 Gy is delivered to the tumor focus depending on the size of the neoplasm. The TFD to the inguinal and iliac regions in the absence of enlarged lymph nodes is 50 Gy. The presence of metastases in the inguinal and pelvic lymph nodes requires an increase in TFD to 60–65 Gy. Severe radiation complications (intestinal obstruction, fistulas, urethral strictures, urinary incontinence) occur in 15–40% of patients. Patients with an incomplete response to radiation therapy are recommended to undergo removal of the residual tumor 4–6 weeks after the completion of irradiation. The scope of surgery may include urethral resection or urethrectomy with cystostomy.

In the absence of contraindications to cisplatin**:

• M-VAC (#methotrexate** 30 mg/m² intravenous (IV) infusion on days 1, 15, and 22, #vinblastine** 3 mg/m² IV infusion on days 2, 15, and 22, #doxorubicin** 30 mg/m² IV infusion on day 2, and #cisplatin** 70 mg/m² IV infusion on day 2, every 28 days, for up to 4–6 cycles) [21, 22].

Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)

• MCV (#methotrexate** 30 mg/m², IV infusion, on days 1 and 8, #vinblastine** 4 mg/m² IV infusion, on days 1 and 8, and #cisplatin** 100 mg/m², IV infusion, on day 2, every 21 days, for up to 4–6 cycles) [70].

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

• GC (gemcitabine** 1000 mg/m2 IV infusion on days 1, 8, and 15, #cisplatin** IV infusion, 70 mg/m2 on day 2, every 28 days, for up to 4–6 cycles) [21, 24].

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

• GTC (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #paclitaxel** 80 mg/m2 IV infusion on days 1 and 8, #cisplatin** 70 mg/m2, IV infusion on day 2, every 21 days, for up to 4–6 cycles) [24, 82, 83].

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

• In patients with contraindications to #cisplatin**, regimens based on #carboplatin** are recommended:

CarboGem (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #carboplatin** AUC 4-5 IV infusion on day 1 or 2 (administration on day 2 is safer for the patient), every 21 days, for up to 4–6 cycles) [25-28].

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

In the absence of contraindications to cisplatin**:

• GTC (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #paclitaxel** 80 mg/m2, IV infusion on days 1 and 8, #cisplatin** 70 mg/m2, IV infusion on day 2, every 21 days, for up to 4–6 cycles) [24, 82, 83].

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

• In case of contraindications to #cisplatin**, its replacement with #carboplatin** (intravenous infusion, AUC 4–5, every 21 days) is recommended [25-28].

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

Comment: the feasibility of using chemoradiotherapy as an alternative to surgical intervention in squamous cell carcinoma of the urethra has been proven in several case series [30–32]. The complete response rate using external beam radiation therapy combined with radiosensitizing agents (#mitomycin** IV bolus, 10 mg/m2, on days 1 and 29; #fluorouracil** 1000 mg/m2 IV infusion over 24 hours, on days 1–4 and 29–32) is 80%, with 5-year overall and cause-specific survival rates of 52% and 68%, respectively. In case of an incomplete response to chemoradiotherapy, surgical removal of the residual tumor increases survival [32, 80].

Comment: surgical intervention is performed 4–6 weeks after the completion of neoadjuvant treatment. For a neoplasm located within the urethra (T1), urethrectomy may be performed. Extension of the tumor to periurethral tissues or the vagina (T2–3) requires urethrectomy, vulvectomy, and excision of the anterior vaginal wall. When the bladder neck is involved (T3), urethrectomy with resection of the bladder neck is recommended. For more extensive tumor involvement (T3–4), cystourethrectomy with resection of the anterior vaginal wall is performed.

To achieve radical tumor removal, an expanded surgical scope may be required in some cases:

• in case of involvement of adjacent tissues and organs, hysterectomy with adnexectomy may be performed;

• removal of the inferior pubic rami;

• partial or total symphysiotomy;

• resection of the urogenital diaphragm.

Following urethrectomy with bladder preservation, cystostomy placement is recommended. Following cystourethrectomy, Bricker urinary diversion is the most common method. In debilitated patients, ureterocutaneostomy may be performed to reduce the duration and invasiveness of the surgical procedure.

Comment: the necessity of performing lymphadenectomy currently remains an open question. Most researchers believe that the incidence of micrometastases in non-enlarged pelvic and inguinal lymph nodes is extremely low. Therefore, prophylactic lymph node dissection is generally not used.

3.2. Treatment of urethral cancer in men

3.2.1. Treatment of distal urethral cancer

3.2.2. Treatment of bulbo-membranous and prostatic urethral cancer

In the absence of contraindications to cisplatin**:

• M-VAC (#methotrexate** 30 mg/m² intravenous (IV) infusion on days 1, 15, and 22, #vinblastine** 3 mg/m² IV infusion on days 2, 15, and 22, #doxorubicin** 30 mg/m² IV infusion on day 2, and #cisplatin** 70 mg/m² IV infusion on day 2, every 28 days, for up to 4–6 cycles) [21, 22].

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

• MCV (#methotrexate** 30 mg/m², IV infusion, on days 1 and 8, #vinblastine** 4 mg/m² IV infusion, on days 1 and 8, and #cisplatin** 100 mg/m², IV infusion, on day 2, every 21 days, for up to 4–6 cycles) [70].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4)

• GC (gemcitabine** 1000 mg/m2 IV infusion on days 1, 8, and 15, #cisplatin** IV infusion, 70 mg/m2 on day 2, every 28 days, for up to 4–6 cycles) [21, 24].

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

• GTC (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #paclitaxel** 80 mg/m2 IV infusion on days 1 and 8, #cisplatin** 70 mg/m2, IV infusion on day 2, every 21 days, for up to 4–6 cycles) [24, 82, 83].

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

• For patients with contraindications to #cisplatin**, recommended regimens are based on #carboplatin**:

• CarboGem (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #carboplatin** AUC 4–5 IV infusion on day 1 or 2 (administering on day 2 is safer for the patient), every 21 days, up to 4–6 cycles) [25–28].

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

In the absence of contraindications to cisplatin**:

• GTC (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #paclitaxel** 80 mg/m2 IV infusion on days 1 and 8, #cisplatin** 70 mg/m2 IV infusion on day 2, every 21 days, up to 4–6 cycles) [24, 82, 83].

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

• In case of contraindications to #cisplatin**, it is recommended to replace it with #carboplatin** (IV infusion, AUC 4–5, every 21 days) [25–28].

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

Comment: surgery is performed 4–6 weeks after the completion of neoadjuvant chemotherapy. The scope of surgery is determined individually and may include penectomy, cystostomy; emasculation, cystostomy; penectomy, prostatectomy, cystostomy; or cystoprostatectomy with urethrectomy and Bricker urinary diversion.

Comment: currently, the necessity of lymphadenectomy remains a matter of debate. Most researchers believe that the incidence of micrometastases in non-enlarged pelvic and inguinal lymph nodes is extremely low. Therefore, prophylactic lymph node dissection is generally not performed.

3.3. Treatment of unresectable locally advanced and metastatic urethral cancer

In the absence of contraindications to cisplatin**:

• M-VAC (#methotrexate** 30 mg/m² intravenous (IV) infusion on days 1, 15, and 22, #vinblastine** 3 mg/m² IV infusion on days 2, 15, and 22, #doxorubicin** 30 mg/m² IV infusion on day 2, and #cisplatin** 70 mg/m² IV infusion on day 2, every 28 days, for up to 4–6 cycles) [21, 22].

LoR BGoE 3Level of Recommendation – B (Level of Evidence – 3)

• MCV (#methotrexate** 30 mg/m², IV infusion, on days 1 and 8, #vinblastine** 4 mg/m² IV infusion, on days 1 and 8, and #cisplatin** 100 mg/m², IV infusion, on day 2, every 21 days, for up to 4–6 cycles) [70].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

• GC (gemcitabine** 1000 mg/m2 IV infusion on days 1, 8, and 15, #cisplatin** IV infusion, 70 mg/m2 on day 2, every 28 days, for up to 4–6 cycles) [21, 24].

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

• GTC (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #paclitaxel** 80 mg/m2 IV infusion on days 1 and 8, #cisplatin** 70 mg/m2, IV infusion on day 2, every 21 days, for up to 4–6 cycles) [24, 82, 83].

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

• In patients with contraindications to cisplatin**, #carboplatin**-based regimens are recommended:

• CarboGem (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #carboplatin** AUC 4–5 IV infusion on day 2, every 21 days, up to 4–6 cycles) [25-28].

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

• For patients with transitional cell (urothelial) cancer who have achieved disease control (complete, partial response, or stabilization) after 4–6 cycles of platinum-based chemotherapy, maintenance immunotherapy with #avelumab** 10 mg/kg or 800 mg IV infusion every 2 weeks is recommended. Treatment is administered until disease progression or unmanageable toxicity [71, 81].

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

In the absence of contraindications to cisplatin**:

• GTC (#gemcitabine** 1000 mg/m2 IV infusion on days 1 and 8, #paclitaxel** 80 mg/m2 IV infusion on days 1 and 8, #cisplatin** 70 mg/m2 IV infusion on day 2, every 21 days, up to 4–6 cycles) [24, 82].

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

• If there are contraindications to #cisplatin**, replacing it with #carboplatin** (IV infusion, AUC 4–5, every 21 days) is recommended [25-28].

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

Comment: there are no standard second-line drug therapy regimens. If the administration of second- and subsequent-line systemic antitumor therapy is necessary, the decision is made on an individual basis [17, 20, 29].

3.4. Pain Management

The principles of pain management and the optimal selection of analgesic therapy in patients with urethral cancer suffering from chronic pain syndrome comply with the pain management principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Medical Care".

3.5. Supportive care in patients with urethral cancer

The principles of prevention and treatment of anemia in patients with bladder cancer correspond to the principles set forth in the clinical guidelines "Anemia in Malignant Neoplasms", available in the Russian Ministry of Health's clinical guidelines clearinghouse https://cr.minzdrav.gov.ru.

The principles of treatment and prevention of nausea and vomiting in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Prevention and Treatment of Nausea and Vomiting" (authors: Vladimirova L.Yu., Gladkov O.A., Kogonia L.M., Koroleva I.A., Semiglazova T.Yu. DOI: 10.18027/2224-5057-2018-8-3s2-502-511, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-35.pdf).

The principles of treatment and prevention of bone complications in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Use of Osteomodifying Agents for the Prevention and Treatment of Bone Pathology in Malignant Neoplasms" (authors: Manzyuk L.V., Bagrova S.G., Kopp M.V., Kutukova S.I., Semiglazova T.Yu. DOI: 10.18027/2224-5057-2018-8-3s2-512-520, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-36.pdf).

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Treatment of Infectious Complications of Febrile Neutropenia and Administration of Colony-Stimulating Factors" (authors: Sakaeva D.D., Orlova R.V., Shabaeva M.M. DOI: 10.18 027/2224-5057-2018-8-3s2-521-530, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-37.pdf).

The principles of prevention and treatment of hepatotoxicity in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Management of Hepatotoxicity" (authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V. DOI: 10.18027/2224-5057-2018-8-3s2-531-544, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-38.pdf).

The principles of prevention and treatment of cardiovascular complications in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Practical Guidelines for the Management of Cardiovascular Toxicity Associated with Antineoplastic Drug Therapy" (authors: Vitsenya M.V., Ageev F.T., Gilyarov M.Yu., Ovchinnikov A.G., Orlova R.V., Poltavskaya M.G., Sycheva E.A. DOI: 10.18027/2224-5057-2018-8-3s2-545-563, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-39.pdf).

The principles of prevention and treatment of dermatological complications in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Practical Guidelines for the Medical Management of Dermatological Reactions in Patients Receiving Antineoplastic Drug Therapy" (authors: Koroleva I.A., Bolotina L.V., Gladkov O.A., Gorbunova V.A., Kruglova L.S., Manzyuk L.V., Orlova R.V. DOI: 10.18027/2224-5057-2018-8-3s2-564-574, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-40.pdf).

The principles of nutritional support in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Practical Guidelines for Nutritional Support in Cancer Patients" (authors: Sytov A.V., Leyderman I.N., Lomidze S.V., Nekhaev I.V., Khoteev A.Zh. DOI: 10.18027/2224-5057-2018-8-3s2-575-583, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-41.pdf).

The principles of prevention and treatment of nephrotoxicity in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Practical Guidelines for the Management of Antineoplastic Drug-Induced Nephrotoxicity" (authors: Gromova E.G., Biryukova L.S., Dzhumabaeva B.T., Kurmukov I.A. DOI: 10.18027/2224-5057-2018-8-3s2-591-603, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-44.pdf).

The principles of prevention and treatment of thromboembolic complications in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" (authors: Somonova O.V., Antukh E.A., Elizarova A.L., Matveeva I.I., Selchuk V.Yu., Cherkasov V.A., DOI: 10.18027/2224-5057-2018-8-3s2-604-609, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-45.pdf).

The principles of prevention and treatment of drug extravasation sequelae in patients with urethral cancer correspond to the principles outlined in the methodological recommendations "Guidelines for the Management of Antineoplastic Drug Extravasation Sequelae" (author: Buydenok Yu.V. DOI: 10.18027/2224-5057-2018-8-3s2-610-616, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-46.pdf).

3.6. Dietary therapy

To date, no reliable data have been obtained regarding the impact of dietary habits on the risk of developing urethral cancer or the risk of recurrence or disease progression in patients with an already established diagnosis.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, there are no clinical trials involving patients with urethral cancer for most types of medical rehabilitation. These recommendations are based on the fact that numerous studies, including meta-analyses (D. Steffens et al., 2018) and systematic reviews (L. Nicole, N.L. Stout et al., 2017, and R. Segal et al., 2017), have demonstrated that various forms of medical rehabilitation significantly accelerate functional recovery, shorten postoperative hospital stays, and reduce the rate of complications and mortality in patients with other malignancies.

4.1. Pre-rehabilitation

Commentary: pre-rehabilitation significantly accelerates functional recovery, shortens postoperative hospital stays, and reduces complication and mortality rates during the treatment of urological malignancies [56]. Preoperative pelvic floor muscle training reduces the incidence of postoperative urinary incontinence [58].

4.2. Rehabilitation after surgical treatment

4.2.1. First stage of rehabilitation

4.2.2. Second stage of rehabilitation

4.2.3. Third stage of rehabilitation

4.3. Radiotherapy

4.4. Rehabilitation during chemotherapy

5. Prevention and Dispensary Observation

5.1. Prevention

There is no effective prevention for urethral cancer.

5.2. Dispensary follow-up

Adults with oncological diseases included in ICD-10 categories C00-D09 are subject to dispensary observation (follow-up).

Dispensary observation is organized at the outpatient oncological care center, or in the primary oncological office of a medical organization, oncological dispensary (oncological hospital), or other medical organizations providing medical care to patients with oncological diseases.

Comments: in accordance with Order No. 548n of the Russian Ministry of Health dated June 4, 2020, "On Approval of the Procedure for Dispensary Observation of Adults with Oncological Diseases," patients with urethral cancer are assigned to a dispensary observation group (2-DN-onco). The category of observed patients consists of individuals with a confirmed diagnosis of malignant neoplasms. The recommended frequency of follow-up visits with a physician is: once every 3 months during the first year, once every 6 months during the second year, and once a year thereafter (unless the course of the disease requires a change in patient management tactics).

The primary goal of monitoring is the earliest possible detection of local recurrences and progression of urethral cancer, as this ensures the feasibility of effective treatment.

Comment: the diagnostic algorithm is determined by the attending physician depending on the clinical situation.

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.

The oncologist of the ambulatory cancer care center (primary oncology office) refers the patient to an oncological dispensary (cancer hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive authority (hereinafter referred to as a federal medical organization), to clarify the diagnosis (in case of the impossibility of establishing a diagnosis, including the extent of the oncological process and the stage of the disease), 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 corresponding International Classification of Diseases for Oncology (ICD-O) 3rd edition codes 8936, 906–909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, the oncologist of an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall, in order to determine treatment tactics, 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 for the purposes of this Procedure as national medical research centers).

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 examination results to the pathoanatomical bureau (department) of the fourth group (reference center) through information interaction, including via telemedicine technologies for remote interaction between medical workers;

digital images obtained from radiation imaging results to the remote diagnostic consultation center for radiation diagnostics through information interaction, including via 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 determined by a medical board (consilium) of physicians, including oncologists, a radiation oncologist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for the treatment of malignant neoplasms, systemic antineoplastic therapy, and radiation therapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians if necessary.

Dispanserization (follow-up) by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for follow-up 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 with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization 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 paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, provided for in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care. (Paragraph 5: to receive specialized medical care on a planned basis, the choice of a federal medical organization is carried out upon the referral of the attending physician.) If the Program involves several federal medical organizations providing specialized medical care for diseases, conditions (group of diseases, conditions) corresponding to the patient's diseases, conditions (group of diseases, 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 medical care to citizens.

The waiting time for the provision of specialized (excluding high-tech) medical care must not exceed the timeframes established in the program of state guarantees of free medical care to citizens approved by the Government of the Russian Federation, 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 provision on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, 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 planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures, as well as endoscopic examinations when it is impossible to perform them on an outpatient basis, requiring subsequent monitoring in a round-the-clock or day hospital setting;

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

Indications for discharging a patient from a medical organization are:

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

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in a round-the-clock or day hospital setting established by a concilium of a medical organization providing oncological 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

The 5-year survival rate for patients with urethral cancer is 35–40%. Men live slightly longer than women: the 5-year survival rates in these groups are 42% and 32%, respectively.

The most significant factor affecting life expectancy is the stage of the disease. The 42.1-month disease-free survival rate for stages T1–2N0M0 is 89%, and for stages T3–4N0–2M0 it is 42% (p = 0.03). The 5-year survival rate for women with stage T1–2N0 urethral cancer is significantly higher than in the group of patients with stage T3–4N0–2 tumors: 78% and 22%, respectively. For men, the corresponding figures are 83% and 36%, respectively.

Lymph node involvement is a reliable adverse prognostic factor in urethral cancer.

Tumors of the distal urethra are generally characterized by a higher degree of differentiation, less aggressive growth, and a lower stage. When the neoplasm is located in the proximal part of the urethra, a lower degree of differentiation is observed, along with more frequent invasive growth spreading to adjacent tissues and organs. Therefore, tumor localization has a significant impact on prognosis. Thus, in men, the disease-specific 5-year survival rate for distal urethral involvement is 40%, whereas for bulbomembranous urethral cancer it is only 5%. In women, the corresponding figures are 50% and 10–20%, respectively.

The survival rate of patients with urethral cancer is significantly influenced by the type of treatment. According to most researchers, surgery alone is associated with a poor prognosis in most cases. Thus, the 5-year survival rate of women after anterior pelvic exenteration used as a monotherapy is 10–17%, and the local recurrence rate reaches 67%. The 5-year survival rate for men with pendulous urethral tumors is 40%, and for localization of the process in the bulbomembranous part of the urethra, it is 0%.

According to the literature, the results of monotherapy radiation therapy for urethral cancer remain unsatisfactory. The 5- and 10-year survival rates for women treated with radiation therapy alone are 41% and 31%, respectively, while the 5-year local recurrence rate is 64%.

The treatment outcomes of 42 women were compared: 10 underwent surgery alone and 32 received monotherapy radiation therapy. Survival rates were similar between the groups, but the recurrence rate following irradiation was lower than that after surgery (40% and 64%, respectively).

Combined modality treatment improves survival and reduces recurrence rates in patients with urethral cancer compared to surgery or radiation monotherapy. The long-term disease-specific survival of patients with stage T3–4N0–2M0 urethral cancer after combined treatment, including neoadjuvant chemoradiotherapy followed by surgery, is 60%.

The survival rate of male patients treated with radiation therapy alone followed by surgery for local recurrence is significantly lower than that of the primary combined treatment group (radiation therapy and surgery).

Neoadjuvant irradiation does not affect the overall survival of women with urethral cancer, but only reduces the rate of local recurrence. The 5-year recurrence-free survival rate for patients who underwent irradiation followed by surgery is 55%, which is significantly higher than that of the radiation-only group (34%).

Recently, encouraging data have emerged regarding the use of chemoradiotherapy for urethral cancer. There are reports of complete response to combined chemoradiotherapy in squamous cell carcinoma of the urethra with regional lymph node metastases. A case of complete response to neoadjuvant chemoradiotherapy in invasive carcinoma of the pendulous urethra followed by distal urethrectomy has been described. The efficacy of chemoradiotherapy is supported by a publication presenting a 54-year-old patient with primary urethral adenocarcinoma metastasizing to the inguinal lymph nodes and the glans penis. The authors successfully administered 2 cycles of chemotherapy with #fluorouracil** and #cisplatin** combined with external beam radiation therapy, achieving complete clinical remission.

In a multivariate analysis of data from 72 women, the most significant prognostic factors affecting survival in urethral cancer were T stage, regional lymph node status, and tumor location. According to regression analysis, the most significant adverse factors in men were the presence of regional metastases, squamous cell histology, and tumor location in the proximal urethra.

Thus, urethral cancer is a rare tumor that occurs more frequently in postmenopausal women and extremely rarely in men. Squamous cell carcinoma is the most common histological type. The clinical manifestations of this neoplasm are nonspecific, and a significant proportion of patients present to specialized centers with advanced stages of the disease. The low incidence of urethral cancer accounts for the lack of a standardized treatment approach for this patient population. Organ-preserving radiation monotherapy is associated with a high recurrence rate and low survival in most cases. Surgery alone is also insufficiently effective. Recently, the best results have been achieved with combined treatment comprising neoadjuvant chemoradiotherapy followed by surgery. Prophylactic lymphadenectomy does not prolong survival. The 5-year survival rate for patients with urethral cancer is 35–40%. Significant prognostic factors include disease stage, tumor location, size, histology, and regional lymph node status. Future studies will focus on defining criteria for the individualized selection of patients for specific treatment modalities based on prognostic features.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Andrey D. Kaprin – Academician of the RAS, Dr. Sci. (Med.), Professor, Honored Doctor of the Russian Federation, General Director of the National Medical Research Radiological Centre of the Russian Ministry of Health, Head of the Department of Urology and Operative Nephrology with a Course in Oncourology at the Medical Institute of the Peoples' Friendship University of Russia.

2. Vsevolod B. Matveev – Corresponding Member of the RAS, Dr. Sci. (Med.), Professor, Deputy Director for Research and Innovation and Head of the Urological Department at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, President of the Russian Society of Oncourology.

3. Boris Ya. Alekseev– Dr. Sci. (Med.), Professor, Deputy Director for Science at the National Medical Research Radiological Centre of the Russian Ministry of Health.

4. Dmitry Yu. Pushkar – Corresponding Member of the RAS, Dr. Sci. (Med.), Professor, Head of the Department of Urology at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Chief Urologist of the Russian Ministry of Health, Member of the Russian Society of Urology.

5. Bahodur Sh. Kamolov – Cand. Sci. (Med.), Executive Director of the Russian Society of Oncourology, President of the "Together Against Cancer" Foundation for Support of Anti-Cancer Organizations, Journalist, Member of the Union of Journalists of Russia and the International Federation of Journalists.

6. Aleksandr V. Govorov– Dr. Sci. (Med.), Professor at the Department of Urology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Member of the Russian Society of Urology.

7. Andrey A. Kirichek – Assistant at the Department of Surgical Diseases with a Course in Oncology, F.P. Haase Moscow Medical and Social Institute, Oncologist at Moscow City Oncology Hospital No. 62, Member of the Russian Society of Urology.

8. Maria I. Volkova – Dr. Sci. (Med.), Leading Researcher at the Urological Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

9. Nina A. Gorban – Cand. Sci. (Med.), Head of the Center for Pathomorphology and Molecular Genetic Diagnostics, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation, Member of the Russian Society of Urology.

10. Chernyaev Vitaly Alexandrovich – Cand. of Sci. (Med.), Senior Researcher, Urology Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Russian Society of Urology.

11. Khmelevsky Evgeny Vitalievich, Head of the Department of Radiation Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

12. Fedenko Alexander Alexandrovich, Head of the Department of Tumor Drug Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

13. Bolotina Larisa Vladimirovna Head of the Chemotherapy Department of the Department of Tumor Drug Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

14. Falaleeva Natalya Alexandrovna, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

15. Filonenko Elena Vyacheslavovna, 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.

16. Kostin Andrey Alexandrovich, Deputy Director General for Science, National Medical Research Radiological Center of the Russian Ministry of Health.

Medical Rehabilitation Section:

1. Konchugova Tatyana Venediktovna – Physiotherapist, Head of the Department of Preformed Physical Factors, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health, Dr. of Sci. (Med.), Professor

2. Obukhova Olga Arkadievna – 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), Member of the Russian Society for Parenteral and Enteral Nutrition (RESPEN), Cand. of Sci. (Med.)

3. Semiglazova Tatyana Yuryevna – Dr. of Sci. (Med.), Associate Professor, Head of Department – Leading Researcher, 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,

4. Stepanova Alexandra Mikhailovna – Deputy Director for Science, Head of the Rehabilitation Department, Private Multidisciplinary Diagnostic and Rehabilitation Center "Vosstanovlenie"

5. Filonenko Elena Vyacheslavovna – 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, Dr. of Sci. (Med.), Professor

Healthcare Organization Section:

1. Nevolskikh Alexey Alekseevich – Dr. of Sci. (Med.), Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

2. Ivanov Sergey Anatolyevich – Professor of the Russian Academy of Sciences, Dr. of Sci. (Med.), Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Khaylova Zhanna Vladimirovna – Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

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

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. oncologists;

2. urologists;

3. radiologists;

4. radiotherapists;

5. surgeons;

6. general practitioners (internal medicine);

7. general practitioners (family doctors);

8. anesthesiologists-intensivists;

9. pathologists;

10. Medical students, residents, and postgraduate students.

Methods used for evidence collection/selection: search in electronic databases, analysis of current scientific developments on urethral cancer in Russia and abroad, synthesis of practical experience of Russian and foreign specialists.

Table 1. Scale for assessing levels of evidence certainty for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence certainty for preventive, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing recommendation grades for preventive, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines. The mechanism for updating clinical guidelines provides for their systematic revision at least once every 3 years, as well as upon the emergence of new data from the perspective of evidence-based medicine regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or 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

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. clinical guidelines of the European Association of Urology;

2. Order of the Russian Ministry of Health No. 907n dated November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Urology'";

3. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of the Criteria for Assessing the Quality of Medical Care".

4. Order of the Ministry of Health of the Russian Federation No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases" as amended on January 24, 2022.

5. Order of the Russian Ministry of Health No. 548n dated June 4, 2020, "On Approval of the Procedure for Dispensary Observation of Adults with Oncological Diseases".

6. Order of the Russian Ministry of Health No. 115n dated February 19, 2021, "On Approval of Standards of Medical Care for Adults with Urethral Cancer".

7. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Medicines, as well as Lists of Medicines for Medical Use and the Minimum Assortment of Medicines Required for the Provision of Medical Care".

8. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines" (registered with the Russian Ministry of Justice on May 8, 2019, No. 54588).

9. Methodological recommendations for assessing the scientific validity of information included in clinical guidelines, Center for Expertise and Quality Control of Medical Care of the Ministry of Health of the Russian Federation, 2019.

10. 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

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

It is necessary to persuade the patient not to experience psychological distress due to the disease and to read popular science literature on urethral cancer.

Patients with urethral cancer should be informed about clinical trials being conducted in the Russian Federation for patients with the specified stage of the disease.

The patient should be informed about the nature of follow-up care after urethral cancer treatment and the importance of regular examinations. Independent monitoring of the disease course by the patient is impossible; the frequency of doctor visits is determined individually in each specific case.

Benefits of quitting smoking and alcohol consumption

• Higher survival rates

• Greater treatment efficacy

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

• Accelerated recovery of general condition after treatment

• Lower risk of recurrence

• Lower risk of second primary tumors

• Lower risk of infections

• Higher quality of life

Recommendations for chemotherapy complications – contact an oncologist (chemotherapy specialist).

If body temperature rises to 38 °C or higher – start taking antibiotics as prescribed by the oncologist (chemotherapy specialist).

For stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• frequent (every hour) mouth rinsing with decoctions of chamomile, oak bark, sage; lubricating the oral mucosa with sea buckthorn (peach) oil;

• treat the oral cavity as recommended by the oncologist (chemotherapy specialist)

For diarrhea:

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

• take medications as prescribed by a clinical oncologist (chemotherapy specialist).

For nausea – take medications as prescribed by the oncologist (chemotherapy specialist).

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

Appendix G1. WHO/ECOG performance status scale [75]

Russian title: WHO/ECOG Performance Status Scale.

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

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

Original publication: Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649−55 [75].

Type: rating scale.

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

Content (template):

Key (interpretation): Provided within the scale itself.

Appendix G2. Karnofsky scale [76]

Name in Russian: Karnofsky Scale.

Original title (if any): KARNOFSKY PERFORMANCE STATUS.

Source (official developer website, validation publication): Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [76].

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.

Appendix G3. Visual analogue scale for pain assessment [77]

Name in Russian: Visual Analog Scale for Pain Assessment.

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

Source (official developer website, validation publication): Hawker G.A., Mian S., Kendzerska T., French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S240–52 [77].

Type: rating scale.

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

Content (template):

“Rate the severity of pain on a scale, where 0 is no pain and 10 is excruciating pain of maximum severity.”

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

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

Appendix G4. Criteria for evaluating the response of solid tumors to treatment: RECIST 1.1 (Response Evaluation Criteria In Solid Tumors 1.1) [78]

Name in Russian: Criteria for evaluating the response of solid tumors to treatment 1.1.

Original name (if any): Response Evaluation Criteria In Solid Tumors 1.1 (RECIST).

Source (official developer website, validation publication): Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026 [78].

Type: rating scale.

Purpose: unification of the assessment of solid tumor response to treatment.

Content (template):

Key (interpretation): Provided within the scale itself.

Appendix G5. Criteria for evaluating immune-related response of solid tumors: iRECIST (Immune-Related Response Evaluation Criteria In Solid Tumors) [79]

Name in Russian: Criteria for evaluating immune-related response of solid tumors.

Original name (if any): Immune-Related Response Evaluation Criteria In Solid Tumors (iRECIST).

Source (official developer website, validated publication): Seymour L., Bogaerts J., Perrone A. et al. RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18(3):e143–52. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2 [79].

Type: rating scale.

Purpose: standardization of solid tumor response assessment to immunotherapy.

Content (template):

Key (interpretation): Provided within the scale itself.