Bladder cancer: clinical guidelines

List of Abbreviations

PFS – progression-free survival

RFS – relapse-free survival

EFS – event-free survival

BCG – Bacillus Calmette–Guérin

IV – intravenous

MFS – metastasis-free survival

PFS – progression-free survival

UTUR – upper urinary tract

WHO – World Health Organization

UTI – urinary tract infection

Gy – Gray

CI – confidence interval

EBRT – external beam radiation therapy

Malignancy – malignant neoplasm

IT – immunotherapy

IOCT – immuno-chemotherapy

CT – clinical trial

CT – computed tomography

RT – radiotherapy

LN – lymph node

PT – physical therapy

MIBC – muscle-invasive bladder cancer

mAB – monoclonal antibodies (ATC classification code: L01XC)

ICD-10 – International Classification of Diseases 10th Revision

UB – urinary bladder

mpMRI – multiparametric magnetic resonance imaging

MRI – magnetic resonance imaging

NMIBC – non-muscle-invasive bladder cancer

HCS – hereditary cancer syndrome

AE – adverse event

OS – overall survival

HR – hazard ratio

CR – complete response

PSA – prostate-specific antigen

PCT – polychemotherapy

PET/CT – positron emission tomography combined with computed tomography

CY – cytological examination

RCT – randomized controlled trial

G-CSF – granulocyte colony-stimulating factor (colony-stimulating factors group according to the Anatomical Therapeutic Chemical classification)

BC – bladder cancer

FSD – fraction single dose

RC – radical cystectomy

SS – specific survival

GFR – glomerular filtration rate

TSD – total absorbed dose

USA – United States of America

TUR – transurethral resection of the bladder

LE – level of evidence

Ultrasound – ultrasound examination

FD – fluorescence diagnostics

ChT – chemotherapy

LND – lymph node dissection

TMT – trimodality therapy

CKD – chronic kidney disease

CRT – chemoradiotherapy

CY – cytological examination

CE – cystectomy

ORR – objective response rate

RMS – rehabilitation routing scale

ED – erectile dysfunction

AUC – area under the curve; carboplatin dose calculation based on the area under the curve is performed using the Calvert formula (1989): carboplatin dose = AUC × (creatinine clearance + 25)

BTA – bladder tumor antigen

CKD-EPI – Chronic Kidney Disease Epidemiology Collaboration

CIS – carcinoma in situ

CPS – combined positive score for PD-L1 expression

ECOG – Eastern Cooperative Oncology Group

FGFR – fibroblast growth factor receptor

HG – high grade

IC – PD-L1 expression scoring scale on immune-competent cells

IGRT – Image-Guided Radiation Therapy

IMRT – Intensity-Modulated Radiation Therapy

iRECIST – Immune-Related Response Evaluation Criteria In Solid Tumors

LG – low grade

MMR – mismatch repair deficiency

NYHA – New York Heart Association

PD-1 – programmed cell death protein 1

PD-L1 – programmed cell death 1 ligand 1

PUNLMP – papillary urothelial neoplasm of low malignant potential

RECIST – Response Evaluation Criteria In Solid Tumors

RTOG – Radiation Therapy Oncology Group

UBC – urinary bladder cancer

VMAT – Volumetric Modulated Arc Therapy

** – Vital and Essential Drugs

# – off-label drug use (used outside the scope of indications, contraindications, routes of administration, or dosages specified in the drug's package leaflet)

Terms and Definitions

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

BCG therapy – immunotherapy using attenuated tuberculosis bacteria, administered postoperatively to reduce the likelihood of bladder cancer recurrence using a vaccine for bladder cancer immunotherapy**.

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.

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

Bricker procedure – a urinary diversion procedure involving an isolated segment of the ileum to create a urinary stoma or ileal conduit.

Orthotopic bladder substitution – a urinary diversion procedure via the urethra involving the use of various gastrointestinal reservoirs connected to the urethra; orthotopic urinary diversion (neobladder, orthotopic bladder replacement).

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 (surgery/chemotherapy/radiation therapy).

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

Three-glass urinary test – an analysis of three sequential urine specimens obtained during a single voiding, which helps localize the pathological process causing elevated leukocyte and/or erythrocyte counts in the urine.

Transurethral resection of the bladder – an endoscopic procedure performed to remove a bladder neoplasm/foreign body, followed by microscopic examination of the retrieved tissue.

Ureterocutaneostomy – a surgical procedure to create an external ureteral stoma by bringing the distal ureter out through the surgical wound and suturing its mucosa to the skin.

Urethrocystoscopy – an endoscopic procedure used to visually assess the lumen of the urethra and bladder, identify any pathological lesions, and simultaneously perform endoscopic interventions.

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 three main criteria: qualitative and quantitative characteristics, and consistency of evidence.

Grades of recommendation – unlike levels of evidence, reflect not only the degree of certainty regarding the intervention effect but also the degree of confidence that following the recommendations will bring more benefit than harm in a specific clinical situation.

Fluorescence cystoscopy – cystoscopy (insertion of a thin metal tube with a camera and light source into the bladder) performed using violet light after intravesical administration of a special agent that accumulates in tumor cells and fluoresces brightly.

The composition of the working group, methodology, and reference materials used in developing and revising the clinical guidelines are presented in Appendix A3.1.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Bladder cancer (BC) – a severe and often disabling disease for which active screening systems have not been developed, requiring careful differential diagnosis and characterized by a tendency toward recurrence and progression.

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

Bladder cancer is a multi-etiological disease. A significant number of cases are associated with the effect of urinary-excreted carcinogens on the urothelium.

Smoking

Tobacco smoking is the most significant risk factor for bladder cancer. Tobacco smoke contains aromatic amines and polycyclic aromatic hydrocarbons, which are excreted by the kidneys. The likelihood of developing bladder cancer is 50–60% higher in smoking men and 20–30% higher in smoking women compared to non-smokers [1, 2]. There is a direct correlation between the risk of developing the disease, the number of cigarettes smoked, smoking duration, and the type of tobacco product [3]. The results of a meta-analysis of 216 clinical studies demonstrated a significant association for both former and current smokers [4]. The duration of abstinence following smoking cessation proportionally reduces the risk of developing the disease. Upon immediate cessation, the risk of developing bladder cancer decreases by 40% within the first 4 years and by 60% within 25 years [3].

Occupational and environmental hazards

The association between occupational hazards and bladder cancer has been known for over 100 years. It has been demonstrated that mortality from bladder cancer among dye and rubber industry workers is 30 times higher than in the general population. Most carcinogens are aromatic amines and their derivatives. Currently, about 40 potentially hazardous industries have been identified: dyeing, rubber, synthetic rubber, petroleum, aluminum, textile industries, and those using resins, plastics, etc. [6, 7, 8]. There is evidence of an increased risk of bladder cancer among motor vehicle drivers. For instance, one study found that the relative risk of the disease is 1.17 times higher in truck drivers and 1.33 times higher in bus drivers [8]. An increased risk of the disease has been noted with the consumption of water with a high arsenic content (Chile, Argentina, Taiwan) and chlorination byproducts formed by the interaction of chlorine with organic matter in water, which may be carcinogenic [5]. A study by Steinmaus C. et al. showed that the risk of developing the disease from consuming chlorinated water increases 1.8-fold in men and 1.6-fold in women [9]. There is no conclusive evidence of a significant impact from various dietary products [10, 11, 12, 13].

Medicinal products

The following medicinal products can influence the development of bladder cancer:

● phenacetin-containing analgesics – several studies have proven a 2.0- to 6.5-fold increase in the risk of bladder cancer with their regular use. Currently, this analgesic and products containing it have been withdrawn from circulation in the Russian Federation and many other countries [5];

● cyclophosphamide** – an alkylating agent used to treat malignant tumors. Results of international studies have demonstrated more than a 4.5-fold increase in the risk of bladder cancer with its use [5, 6, 7, 8, 9].

Radiation

Radiation increases the risk of bladder cancer 1.5- to 4-fold in patients who underwent pelvic irradiation for cervical, ovarian, or prostate cancer, proportionally to the radiation dose. The highest risk of developing the disease was identified in patients irradiated 5–10 years ago. They are characterized by the development of high-grade invasive cancer [15, 16]. It has been noted that modern intensity-modulated radiation therapy approaches may improve these outcomes, although long-term results are still needed [17].

Schistosomiasis

Endemic regions: Middle East, Southeast Asia, North Africa. Bladder cancer develops more frequently in individuals with schistosomiasis than in the general population. The risk of developing the disease is 3.9 times higher in men and 5.7 times higher in women. It is typically characterized by the development of squamous cell carcinoma [5].

Chronic cystitis

The risk of bladder cancer is increased in patients with chronic cystitis, bladder stones, and urostasis. Patients with long-term indwelling bladder catheters are characterized by an increased risk of developing bladder adenocarcinoma [18].

1.3 Epidemiology of the Disease or Condition

Bladder cancer is the most common malignant tumor of the urinary tract, ranking 6th in cancer prevalence among men and 9th for both sexes combined [18]. In 2025, 656 thousand new cases of bladder cancer were registered worldwide, with a mortality of 234 thousand people [19].

Depending on geographic location, risk factors, screening and diagnostic methods, as well as treatment availability, the incidence rate of bladder cancer varies dozens of times across different countries. For instance, the incidence is higher in Western Europe and the USA than in Eastern Europe and Asian countries. In the European Union, the age-standardized incidence rate is 20 for men and 4.6 for women. Worldwide, the age-standardized incidence rate (per 100,000 population) is 9.5 for men and 2.4 for women [20].

In the structure of cancer incidence among the population of Russia, bladder cancer ranks 8th among men and 16th among women. The age-standardized incidence rate per 100,000 population in 2024 was 12.15 for men and 2.15 for women. The increase in incidence for both sexes over the last 10 years was 9.5% [21]. The age-standardized mortality rate in 2023 for men and women was 4.02 and 0.6, respectively. Regarding age distribution, patients in the 65-69 age group predominate, accounting for 78% in Russia. The average age of patients diagnosed with bladder cancer in Russia is 67.5 years for men and 70.3 for women [22].

Bladder cancer is more common in men than in women (a 3:1 ratio), which is associated with a higher prevalence of smoking among men and occupations involving carcinogenic substances that increase the risk of developing the disease [23]. There are racial differences in bladder cancer incidence. For example, in the USA, among Black men and American Indians, the incidence is 2 and 8 times lower, respectively, and in Asian populations, it is 60% lower than among white Americans [19].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems (hereinafter referred to as ICD-10) [24], bladder cancer has the code:

D09.0 Carcinoma in situ of bladder. Applies to carcinoma in situ ("flat") and non-invasive papillary urothelial carcinoma (pTa)

C67 Malignant neoplasm of bladder:

C67.0 Trigone of bladder

C67.1 Dome of bladder

C67.2 Lateral wall of bladder

C67.3 Anterior wall of bladder

C67.4 Posterior wall of bladder

C67.5 Neck of bladder

C67.6 Ureteric orifice

C67.7 Urachus

C67.8 Overlapping lesion of bladder

C67.9 Bladder, unspecified

D41.4 Neoplasm of uncertain or unknown behavior of bladder

1.5 Classification of the disease or condition

ICD-O Classification of Urinary Tract Tumors (WHO, 2022)

Non-invasive urothelial tumors

8120/0 Urothelial papilloma

8121/0 Inverted urothelial papilloma

8130/1 Papillary urothelial neoplasm of low malignant potential

8130/1 Inverted papillary urothelial neoplasm of low malignant potential

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

8130/2 Non-invasive papillary urothelial carcinoma with inverted growth pattern, low grade

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

8130/2 Non-invasive papillary urothelial carcinoma with inverted growth pattern, high grade

8120/2 Urothelial carcinoma in situ

Invasive urothelial tumors

8120/3 Invasive urothelial carcinoma

8120/3 Typical urothelial carcinoma

8120/3 Urothelial carcinoma with squamous differentiation

8120/3 Urothelial carcinoma with glandular differentiation

8120/3 Urothelial carcinoma with trophoblastic differentiation

8120/3 Nested urothelial carcinoma

8120/3 Large nested urothelial carcinoma

8120/3 Tubular and microcystic urothelial carcinoma

8131/3 Micropapillary urothelial carcinoma

8082/3 Lymphoepithelioma-like urothelial carcinoma

8122/3 Plasmacytoid urothelial carcinoma

8031/3 Giant cell urothelial carcinoma

8120/3 Lipid-rich urothelial carcinoma

8120/3 Glycogen-rich urothelial carcinoma

8120/3 Sarcomatoid urothelial carcinoma

8020/3 Poorly differentiated urothelial carcinoma

Squamous cell tumors of the urinary tract

8052/0 Squamous papilloma

Squamous cell carcinoma of the urinary tract

8051/3 Verrucous carcinoma

8070/3 Pure squamous cell carcinoma of the urinary tract

Glandular tumors

Adenomas

8261/0 Villous adenoma

8211/0 Tubular adenoma

8263/0 Tubulovillous adenoma

Adenocarcinomas

8140/3 Adenocarcinoma, NOS

8144/3 Enteric-type adenocarcinoma

8480/3 Mucinous adenocarcinoma

8323/3 Mixed adenocarcinoma

8490/3 Squamous cell adenocarcinoma

8140/2 Adenocarcinoma in situ

Urachal and diverticular tumors

8010/3 Urachal carcinoma

8120/3 Invasive urothelial carcinoma

Urethral tumors

Tumors of urethral glands

8140/3 Carcinoma of Littré glands

8140/3 Carcinoma of Skene glands

8140/3 Carcinoma of Cowper glands

Müllerian-type tumors

8310/3 Clear cell carcinoma

8380/3 Endometrioid carcinoma

TNM Classification (9th Edition)

The 2009 TNM classification approved by the Union for International Cancer Control (UICC) was updated in 2025 (9th edition) [26].

T – primary tumor

The suffix (m) should be added to the appropriate T category to indicate multiple lesions. Multifocality of urothelial carcinomas is a frequent phenomenon explained by the field cancerization theory. The suffix (is) can be added to the T category to indicate the concurrent presence of carcinoma in situ. Clinical staging is performed based on clinical examination results, while pathologic staging is based on the pathologist's post-operative report. Clinical ("c") and pathologic ("p") staging categories coincide. For recurrent tumors, the prefix "r" is added.

• cTx – primary tumor cannot be assessed

• cT0 – no evidence of primary tumor

• cTa – non-invasive papillary carcinoma

• cTis – carcinoma in situ: "flat tumor"

• cT1 – tumor invades subepithelial connective tissue

• cT2 – invasion into the muscularis propria of the wall (detrusor)

− cT2a – tumor invasion of the superficial muscle layer (inner half)

− cT2b – tumor invasion of the deep muscle layer (outer half)

• cT3 – tumor invades perivesical soft tissue

− cT3a – microscopically

− cT3b – macroscopically

• cT4 – tumor invades any of the following: prostate stroma, uterus, vagina, pelvic wall, abdominal wall

− cT4a – invasion of the prostate stroma / seminal vesicles / uterus / vagina

− cT4b – tumor invasion of the pelvic wall or abdominal wall

N – regional lymph nodes (LNs)

• cNx – regional LNs cannot be assessed

• cN0 – no regional LN metastases

• cN1 – metastasis in a single regional pelvic LN (hypogastric, obturator, external iliac, or presacral)

• cN2 – metastases in multiple pelvic LNs (hypogastric, obturator, external iliac, or presacral)

• cN3 – metastases in common iliac LNs (one or more)

M – distant metastases

• M0 – no distant metastasis

• M1 – distant metastasis

− M1a – metastases in non-regional lymph nodes

− M1b – other distant metastases

pTNM – pathologic classification. The categories pT, pN, and pM correspond to cT, cN, and cM categories.

Staging of advanced bladder cancer involving the prostate should be approached with caution: transmucosal invasion from the prostatic urethra into the prostatic stroma without transmural invasion is classified as a T2 urethral carcinoma, while concomitant bladder cancer is classified as a separate stage in accordance with bladder cancer staging. Category T4 corresponds strictly to direct invasion of bladder cancer into the prostatic stroma. Therefore, prostatic involvement by urothelial carcinoma detected on TURBT should not be automatically classified as stage T4 disease [27].

Tumors of a bladder pseudodiverticulum do not have a pT2 category due to the absence of the muscularis propria layer in this type of diverticulum.

The stage grouping of bladder cancer is presented in Table 1.

Table 1. Bladder cancer stage grouping

The most important prognostic factor is the TNM stage. Additional factors include grade (G), histological tumor type, presence of lymphovascular invasion, concomitant carcinoma in situ, multifocality, tumor size, surgical margin status, presence of hydronephrosis, HER2 and PD-L1 expression, and FGFR3 gene alterations [26].

Histological grading

The grade of malignancy is determined for papillary, inverted non-invasive, and invasive carcinomas. Flat lesions of the urinary tract (dysplasia and carcinoma in situ) are not graded. For the grading of other carcinomas, the 1973 and 2022 systems are used. Approaches for determining the grade differ between non-invasive papillary (pTa) tumors and invasive urothelial carcinoma [28]. It is advisable to indicate both (two-tier and three-tier) grades in the pathology report.

Three-tier grading (WHO 1973):

• G1: well-differentiated carcinoma;

• G2: moderately differentiated carcinoma;

• G3: poorly differentiated carcinoma.

Two-tier grading (2022):

• Low-grade: low grade of malignancy (corresponds to G1 tumors and some G2 tumors);

• High-grade: high grade of malignancy (corresponds to most G2 tumors and G3 tumors).

Non-invasive papillary urothelial carcinomas (pTa) can be either low-grade or high-grade. To assign a high-grade category, 5% of the low-differentiated (high-grade) component of the affected area is sufficient. If the high-grade component in a low-grade carcinoma accounts for less than 5%, this should be reported as "low-grade tumor with a high-grade component comprising less than 5% of the tumor area." In cases of tumor heterogeneity, it is recommended to specify the percentage of the poorly differentiated component [29].

Invasive urothelial carcinomas (pT1-4) are generally poorly differentiated, high-grade (G2 or G3), according to the 2022 WHO classification. Low-grade (G1) pT1 urothelial carcinomas are rare. Muscle-invasive tumors (≥ T2) are always classified as high-grade [25].

Tumors with divergent differentiation (squamous or glandular) are classified as poorly differentiated, high-grade, according to the 2022 WHO classification rules [25].

Specific subtypes of urothelial carcinoma are classified as poorly differentiated tumors.

Squamous cell carcinoma is graded on a 3-tier system, similarly to squamous cell carcinomas of other sites.

Bladder adenocarcinoma is graded on a 3-tier system based on the ability to form glandular structures and the presence of destructive invasion. Clear cell adenocarcinoma (Müllerian type) is not graded. Both 3-tier and 2-tier grading systems are used for endometrioid adenocarcinoma (similar to uterine tumors).

Assessment of pathomorphological response after neoadjuvant/perioperative therapy.

Standardized assessment of tumor pathomorphological response following treatment is essential for harmonizing multi-center data and adequately evaluating the efficacy of therapeutic regimens. Due to the continuous evolution of evaluation criteria, when examining surgical specimens post-treatment, it is advisable to use the ypTMN system (ypT0N0 corresponds to complete response, pCR; stage ≤ ypT1N0 to partial response, pPR; stage ≥ ypT2 or ypN+ to no response) and, whenever possible (depending on the specimen volume), the viable tumor percentage assessment system, as it is easily reproducible, flexible, and adaptable [500].

1.6 Clinical presentation of the disease or condition

Clinical manifestations of the disease depend on the stage of bladder cancer. Early stages are most often asymptomatic or mimic symptoms of other urinary tract disorders, such as UTIs, prostatitis, urolithiasis, etc.

Painless hematuria is the most common manifestation of bladder cancer. Gross hematuria has been noted to be associated with a more advanced disease stage compared to microscopic hematuria at its initial presentation [56].

Frequent and painful urination with urgency, and pelvic pain can all indicate invasive, advanced forms of bladder cancer. Persistent dysuria is characteristic of CIS.

The onset of lumbar pain is associated with tumor blockage of the ureteral orifices and the development of hydronephrosis. Bone pain frequently occurs with skeletal metastasis. Symptoms indicating systemic spread include weakness, rapid fatigue, sharp weight loss, and anorexia.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1. Complaints and medical history.

2. Results of physical examination.

3. Results of laboratory tests.

4. Results of instrumental examinations.

5. Results of endoscopic examination.

6. Results of morphological diagnostic methods (pathological examination of altered bladder tissue and/or cytological examination of urine for tumor (atypical) cells).

Patient complaints, disease history, physical examination findings, and laboratory tests allow for a suspicion of bladder cancer.

Detection of a bladder tumor by ultrasound (US), magnetic resonance imaging (MRI), or computed tomography (CT) is an indication for further workup and does not constitute a definitive diagnosis.

Visualization of the tumor via cystoscopy provides a reasonable presumption of a bladder cancer diagnosis. During cystoscopy, a biopsy of the bladder wall is performed according to indications. The absence of a visually discernible tumor does not rule out a flat lesion of urothelial carcinoma (carcinoma in situ) in patients with tumor cells found in urine or washings during cytological examination.

If technically feasible to perform a biopsy of a tumor suspected of being bladder cancer, the diagnosis must be verified histologically. If tumor biopsy is technically unfeasible or carries a risk of life-threatening uncontrollable complications, verification of the diagnosis by cytological methods is acceptable.

Pathological examination of biopsy material is not used for tumor staging. Pathological examination of transurethral resection (TUR) specimens of the bladder can evaluate tumor invasion into the lamina propria and detrusor muscle. Pathological examination of radical cystectomy (RC) specimens is the method for evaluating pT and pN categories.

Radiological examination allows for the assessment of cT, cN, and M categories.

2.1 Complaints and Anamnesis

Comment: early stages of bladder cancer may be asymptomatic. Clinical manifestations of bladder cancer include symptoms of the primary tumor (hematuria, dysuria, lower abdominal pain, urinary retention or incontinence, palpable mass), regional metastases (lower extremity edema), and distant metastases (according to their location). Urinary outflow obstruction from the upper urinary tracts due to a locally advanced tumor involving the ureteral orifices can lead to chronic urinary infection accompanied by fever and lower back pain. General symptoms of advanced forms of bladder cancer manifest as weakness and cachexia [56, 106, 107, 108, 109].

Patient information is provided in Appendix B.

2.2 Physical Examination

Comments: during physical examination, patients with suspected bladder cancer must be evaluated for performance status (Appendix G) and local status (via deep abdominal palpation, examination of the renal region with determination of the costovertebral angle tenderness (Pasternatsky sign), inspection and palpation of peripheral lymph nodes). In patients with early forms of bladder cancer, physical examination reveals no clinically significant abnormalities. In locally advanced forms of bladder cancer, palpation may reveal an enlarged bladder due to the tumor and/or a large volume of residual urine. In massive regional metastases, palpable conglomerates of iliac lymph nodes and lower extremity edema may be detected. When a ureteral orifice is blocked by a tumor with the development of hydronephrosis, the costovertebral angle tenderness may be positive. In disseminated bladder cancer, tumor-affected peripheral lymph nodes may be palpable [57, 58, 59].

2.3 Laboratory Diagnostics

Comment: abnormalities in complete blood count, biochemical blood test, and coagulogram parameters allow for a complex of additional diagnostic measures aimed at the timely detection and correction of pathological conditions that hinder the initiation of specific anti-tumor treatment, as well as reducing the risk of potential complications [110, 111, 112, 113, 114].

Comment: microscopic hematuria is a symptom of bladder cancer. In cases of leukocyturia or bacteriuria, it is recommended to perform urine culture with antibiotic susceptibility testing for targeted antimicrobial therapy [115].

2.4 Instrumental Diagnostics

Comments: ultrasound allows for assessing the localization, size, and growth pattern of the tumor, as well as detecting concomitant hydronephrosis [389]. The method has a sensitivity of 63% and a specificity of 99% in detecting tumors, but its diagnostic value drops sharply for lesions smaller than 5 mm and flat lesions (CIS) [396].

Comments: mpMRI is the most accurate method for differential diagnosis between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [398, 404]. The study is preferably performed before TURBT or at least 2 weeks after it to avoid image interpretation difficulties caused by inflammation [398]. The VI-RADS system allows for standardized assessment of detrusor invasion with an accuracy of about 90% [387, 397, 398].

The VI-RADS system is based on a comprehensive assessment of three MRI sequences to determine the likelihood of tumor invasion into the muscular layer (detrusor) [398]:

1. T2-weighted imaging (T2W): used to assess the structural integrity of the muscle layer, which appears as a hypointense line. Loss of integrity, disruption of the contour with or without extension of tumor tissue into the perivesical fat indicates invasion.

2. Diffusion-weighted imaging (DWI/ADC): used to assess cellularity. Muscle-invasive bladder cancer is characterized by a hyperintense tumor lesion on DWI and hypointense on apparent diffusion coefficient (ADC) maps with extension into the muscle layer with or without involvement of the perivesical fat.

3. Dynamic contrast-enhanced (DCE) MRI: used to detect early enhancement of the muscular layer. Muscle invasion is characterized by early enhancement of the muscular layer extending beyond the submucosal layer and into the muscle layer with or without involvement of the perivesical fat.

VI-RADS score:

VI-RADS 1: Muscle invasion is highly unlikely.

VI-RADS 2: Muscle invasion is unlikely (continuous muscular layer).

VI-RADS 3: Equivocal findings (ambiguous assessment).

VI-RADS 4: Muscle invasion is likely.

VI-RADS 5: Definite muscle invasion with extension beyond the bladder wall.

Regional lymph nodes measuring ≥ 8 mm are considered pathologically enlarged [400].

Comments: the excretory phase of CT is recognized as the "gold standard" for detecting synchronous UUT tumors [400, 401]. Synchronous upper tract urothelial carcinoma occurs in 2–4% of patients with bladder cancer [389].

CT is the primary method for detecting distant visceral metastases and assessing regional lymph nodes [397, 400]. Regional lymph nodes with a short axis of ≥ 8 mm and non-regional ones of ≥ 10 mm are considered pathologically enlarged [400]. Chest CT has an advantage over radiography in detecting lung metastases [396].

In the presence of contraindications to iodine-containing contrast agents (GFR < 30 mL/min), magnetic resonance imaging with macrocyclic contrast agents is performed.

• In selected patients with bladder cancer who present with symptoms (pain, mass, pathological fracture) and/or laboratory signs (elevated serum alkaline phosphatase) of bone metastases in anatomical areas not covered by the CT scan, skeletal scintigraphy (bone scan) is recommended to determine the extent of bone metastasis [103, 396, 399, 401].

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

Comments: given the low specificity of skeletal scintigraphy for the predominantly lytic type of bone metastases in bladder cancer, single findings must be further evaluated using targeted CT (bone computed tomography, or SPECT/CT (single-photon emission computed tomography combined with computed tomography), or MRI (bone magnetic resonance imaging) [396]. The probability of bone metastases is significantly higher in cases of deep muscular invasion (stage ≥ cT3) [103, 399, 401].

• In selected patients with bladder cancer and neurological symptoms, brain MRI with intravenous contrast enhancement is recommended [396, 402].

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

Comments: brain metastases in bladder cancer are rare (less than 5% of cases) [402]. Special attention should be paid to patients with aggressive histological subtypes, such as small cell carcinoma [397].

Comments: PET/CT has a higher sensitivity in detecting lymph node metastases (up to 79%) compared to standard CT. The method can alter treatment tactics by detecting occult metastases prior to radical surgery [396, 400]. The method has limited capabilities in detecting the primary tumor due to the high amount of radioactive urine [400].

2.5 Other Procedures

2.5.1 Endoscopic diagnostic procedures

Comments: cystoscopy may be performed as a standalone procedure or combined with transurethral resection (TUR) of the bladder. It is advisable to perform cystoscopy using local anesthesia [85]. The use of a flexible cystoscope is preferred [84]. The cystoscopy report should reflect the condition of the mucosa and the diameter of the urethra, bladder capacity, location of the ureteral orifices and urine excretion from them indicating color, number, size, location and appearance of tumors, and the presence of areas of altered mucosa. The results of diagnostic cystoscopy should be documented using a bladder diagram [88].

The use of blue-light fluorescence cystoscopy after administration of a photosensitizing agent [88, 89, 90, 91, 92, 93], which allows for better visualization of both small papillary tumors and flat lesions, and narrow-band imaging (NBI), which increases the contrast between unchanged mucosa and hypervascular tumor tissue, can improve the diagnostic efficacy of cystoscopy [94, 95, 96, 97, 98], but do not affect the recurrence rate or mortality from bladder cancer [98].

If areas suspicious for tumor involvement are detected, a biopsy may be performed. If diagnostic cystoscopy and transurethral resection (TUR) of the bladder are planned as separate procedures (see section 3.1.1), the biopsy may be deferred until the surgical intervention.

2.5.2 Morphological diagnostic methods

• To verify the diagnosis, stage the tumor process, and identify prognostic factors influencing the choice of treatment and follow-up strategy, it is recommended to perform pathomorphological examination of the biopsy (surgical) material in all patients with suspected bladder cancer, as well as patients with primary and recurrent bladder cancer [81, 82, 83, 405].

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

Comments: all tissue samples obtained during biopsy or surgery in patients with bladder cancer are submitted for pathomorphological examination. Specimens obtained during different biopsies and resection stages are sent to the pathomorphology department (laboratory) in separately labeled containers indicating the diagnosis, medical history (including prior treatment), radiological findings, and tissue acquisition methods (biopsy and/or surgical report).

The pathomorphological examination report must contain the mandatory information listed below.

• Biopsy material: cancer type and grade (if evaluable in the submitted volume of tumor material); ICD-O histological code.

• Surgical specimens obtained via transurethral resection of the bladder: histological type of the tumor; percentage of divergent differentiation (squamous/glandular/trophoblastic, etc.) and/or specific urothelial carcinoma subtype, if present; histological grade of the tumor (differentiation grade) according to the 1973 WHO and 2022 ISUP/WHO criteria; presence or absence of subepithelial stromal invasion; presence or absence of the muscular layer and tumor invasion into it; presence or absence of lymphovascular invasion; presence or absence of carcinoma in situ; T category; ICD-O histological code.

• Surgical specimens obtained after radical cystectomy: histological tumor type; presence of divergent differentiation (squamous/glandular/trophoblastic, etc.) and/or specific subtype of urothelial carcinoma and their percentage of the tumor area; histological grade according to the 1973 WHO and ISUP/WHO 2022 criteria; presence or absence of carcinoma in situ; depth of invasion: inner or outer muscular layer; perivesical adipose tissue (based on microscopic examination); presence or absence of lymphovascular invasion; resection margin status with detailed description in case of a positive margin (focality, extent); number of retrieved and metastatic lymph nodes; pTNM stage; ICD-O histological code.

The 2022 WHO classification must be used for pathomorphological examination of the material. It should be borne in mind that non-invasive urothelial carcinoma has two major manifestations: papillary and flat, while the terms "non-invasive" and "in situ" are not synonymous. The term "superficial bladder cancer" is not recommended.

Flat lesions (dysplasia, carcinoma in situ) are not graded.

The grade of non-invasive papillary urothelial carcinoma must be determined according to the 1973 WHO and ISUP/WHO 2022 criteria (indicate both values, see section 1.5).

It is necessary to indicate the stage and grade of the tumor process when examining recurrences (staging with the "r" prefix) [81, 82, 83, 405].

Comments: nivolumab** in the adjuvant setting in patients with urothelial carcinoma who have undergone radical surgery and are at high risk of progression has proven its efficacy in the phase III RCT CheckMate-274. The greatest clinical benefit was observed in patients with PD-L1 membranous staining on tumor cells ≥ 1% [302, 303].

The approval of PD-L1 inhibitors for the first-line therapy of advanced urothelial carcinoma in patients with contraindications to cisplatin** was based on phase II studies utilizing PD-L1 testing of tumor tissue. The pembrolizumab** trial used the combined positive score (CPS) for PD-L1 expression, which accounts for both positive tumor cells and tumor-infiltrating immune cells [299]; the atezolizumab** trial evaluated staining exclusively in immune cells [243]. The efficacy of these drugs has not been studied using other expression scoring systems. Therefore, to select candidates for immunotherapy with pembrolizumab** and atezolizumab**, testing using scales with proven predictive value is required.

Comments: in the population of patients with advanced urothelial carcinoma progressing after PD-(L)1 inhibitor immunotherapy who harbor the FGFR3 gene mutations listed in the recommendation, the phase III RCT THOR (cohort 1) demonstrated a significant benefit of targeted therapy with erdafitinib compared to monochemotherapy [373]. A diagnostic test for the aforementioned FGFR gene aberrations in urothelial carcinoma based on reverse transcription and PCR demonstrated high diagnostic efficacy comparable to NGS data in the BLC2001 clinical trial (concordance rate of 93.5%) [30].

Comments: the most appropriate material is washout fluid obtained during cystoscopy [60]. Urine cytology has high sensitivity in T1 and G3 (84%), and low sensitivity in Ta and G1 (16%) [61]. Sensitivity in CIS ranges from 28% to 100% [62]. Positive cytology results may indicate the presence of a tumor in any part of the urinary tract [63]. However, negative results do not rule out the presence of a tumor [64].

2.5.3 Genetic counseling

Comments: Hereditary bladder cancer occurs in an undifferentiated cohort of patients with a frequency of about 0.5-1% and is mainly related to Lynch syndrome (HNPCC), which is caused by a mutation in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS1, PMS2, or EPCAM [255]. In this syndrome, in descending order of frequency, colorectal cancer, endometrioid cancer, ovarian cancer, gastric cancer, urothelial carcinomas of various parts of the urinary tract, prostate cancer, and several other types of tumors are described. Bladder cancer most frequently develops with a mutation in MSH2. The hereditary nature of the disease may be indicated by the patient's young age, an unfavorable family history of cancer, multiple primary tumors, and a history of neoplasms in other target organs of Lynch syndrome. Molecular genetic diagnostics consists of analyzing microsatellite instability, the presence of which (MSI status) is considered as a likely confirmation of the disease [312, 387, 391]. The minimal panel of 5 mononucleotide STR markers, often used in colorectal cancer, has insufficient sensitivity in other types of tumors. Therefore, the MSI status in urothelial carcinomas should be determined either during NGS testing or by IHC analysis to detect the loss of expression of one of the key mismatch repair proteins MLH1, MSH2, MSH6, or PMS2 at the protein level (dMMR – mismatch repair deficiency) [393, 394]. If MSI/dMMR is detected, the most informative genetic test is the determination of a germline mutation in Lynch syndrome candidate genes using an MMR gene NGS panel. In some cases, bladder cancer may develop in carriers of germline mutations in the BRCA1/2, MUTYH, RB1, and some other genes. If a young patient does not meet the diagnostic criteria for Lynch syndrome, whole genome sequencing, exome sequencing, or a multigene cancer panel can be performed [313, 387, 395].

Differential diagnosis of bladder cancer is carried out with the following diseases (conditions): inflammatory diseases of the urinary tract; nephrogenic metaplasia; developmental anomalies of the urinary tract; squamous cell metaplasia of the urothelium; benign epithelial neoplasms of the urinary bladder; tuberculosis; syphilis; endometriosis; chronic cystitis; metastases of other malignant tumors.

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

The choice of treatment method for urothelial cancer is primarily determined by the presence of metastases, the depth of invasion of the primary tumor, the degree of its differentiation, and concomitant CIS. Important factors influencing treatment tactics are the localization and number of tumor foci. When individually selecting a treatment method for patients with urothelial cancer, the functional preservation of the affected area of the urinary tract, comorbid background, and expected life expectancy are also taken into account.

Clinically, urothelial cancer can be divided into 3 categories, which fundamentally differ in prognosis, types, and goals of treatment. The first category includes non-muscle-invasive tumors, the treatment of which is aimed at radical removal of the neoplasm, reducing the risk of recurrence, and preventing tumor progression into muscle-invasive urothelial cancer.

The second group includes muscle-invasive urothelial carcinomas. The goal of their treatment is radical tumor removal, reduction of the risk of metastasis, and maintenance of quality of life by preserving the affected organ. Organ-preserving treatment is possible only in cases where it will not lead to a decrease in survival. Depending on the individual risk of dissemination of muscle-invasive urothelial cancer, a decision is made regarding the need to prescribe systemic antineoplastic therapy.

The third group of urothelial cancers includes unresectable locally advanced and disseminated forms of the disease. The goal of treatment for this category of patients is to increase life expectancy and preserve quality of life through the sequential use of antineoplastic agents of various mechanisms of action and their combinations.

3.1 Treatment of non-muscle-invasive bladder cancer Tis-T1N0M0

The standard approach to the treatment of non-muscle-invasive bladder cancer (NMIBC) is transurethral resection (TUR) of the bladder followed by intravesical therapy, the regimen of which is determined individually. An alternative is early radical cystectomy (RC). The treatment algorithm for patients with non-muscle-invasive bladder cancer (Tis-T1N0M0) is presented in Fig. 1 of Appendix B1.

3.1.1 Transurethral resection

Comments: TUR of the bladder includes bimanual palpation of the bladder under anesthesia, examination of the urethra and bladder, resection of the tumor en block or fractionally (exophytic part of the tumor, underlying bladder wall, and resection margins). Biopsy of all areas of altered urothelium is indicated. Biopsy of normal mucosa (random biopsy) according to the scheme – trigone of the bladder, bladder dome, right, left, anterior, and posterior bladder walls – is required:

• in case of positive results of urine cytology and the absence of a tumor visualized on cystoscopy;

• in patients with a history of HG/G3 tumors;

• in non-papillary bladder tumors [99, 100, 101, 102, 103, 104].

Biopsy of the prostatic urethra in men is performed from abnormal areas and from the precollicular area between the 5 and 7 o'clock positions:

• in tumors of the bladder neck;

• in CIS;

• in case of positive results of urine cytology and the absence of a tumor visualized on cystoscopy in the bladder;

• in case of changes in the prostatic urethra [101, 102].

Quality control of bladder TUR in narrow-band imaging mode or fluorescence control with the photosensitizer 5-aminolevulinic acid reduces the number of unremoved tumors [89, 90, 92]. During bladder TUR, one should strive to avoid tissue coagulation to improve the conditions for pathohistological examination.

The surgery protocol should reflect the localization, type, size, number of tumors, stages of the procedure, degree, and completeness of resection.

The obtained specimens are sent to the pathologist in separately labeled containers.

Transurethral coagulation (TUC) / laser vaporization of small papillary tumors can only be used in patients with a history of TaG1/LG tumors [122, 123, 124, 125].

The most common complications of bladder TUR are:

• bleeding (intraoperative and postoperative), sometimes requiring open surgical intervention;

• bladder wall perforation (intraperitoneal perforation requires laparotomy or laparoscopy, abdominal drainage, suturing of the bladder wall defect) [122, 123, 124, 125].

• after incomplete removal of all tumors during the initial bladder TUR;

• if there is doubt about the complete removal of all tumors during the initial bladder TUR;

• in the absence of detrusor muscle in the specimen obtained during the initial bladder TUR, except for TaLG papillary urothelial carcinoma without CIS;

• in case of T1 urothelial carcinoma in the specimen obtained during the initial bladder TUR;

• in case of HG (G3) urothelial carcinoma in the specimen obtained during the initial bladder TUR;

• in case of CIS [117, 118, 119, 120, 121].

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

Comments: repeat bladder TUR allows the detection of residual tumors and muscle-invasive tumors regarded as NMIBC during the initial bladder TUR. Repeat TUR helps to increase the recurrence-free survival of patients [117, 118, 119, 120, 121].

3.1.2 Management tactics for patients with non-muscle-invasive bladder cancer after transurethral resection

To reduce the risk of recurrence and tumor progression of non-muscle-invasive bladder cancer, adjuvant intravesical therapy is used. Indications and regimens for intravesical therapy are determined depending on the stage of the disease, tumor grade, and risk group.

3.1.2.1 Single immediate intravesical instillation of chemotherapy

Comments: immediate intravesical chemotherapy reduces the recurrence rate in specific patient subgroups. A systematic review and meta-analysis of 13 randomized trials demonstrated a 35% reduction in recurrence risk (RR 0.65; 95% CI, 0.58–0.74; P < 0.001) and a decrease in the 5-year recurrence rate from 58.8% to 44.8% when TUR was combined with immediate intravesical chemotherapy compared to TUR alone. Instillation did not reduce the recurrence rate in patients with a prior recurrence rate of more than one tumor per year, or with an EORTC recurrence score ≥ 5. Immediate instillation of the chemotherapy agent also did not increase the time to progression and bladder cancer-specific death [210].

3.1.2.2 Adjuvant intravesical therapy

Table 2. Risk stratification of patients with non-muscle-invasive bladder cancer.

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

Comments: in low-risk patients under 5-year surveillance, the local recurrence rate is 37%, the rate of tumor progression to muscle-invasive bladder cancer (MIBC) is 1.7%, and the 10-year progression-related mortality is 4.3%. Post-treatment surveillance aims at the early diagnosis of recurrence [279, 280, 281].

Comments: in intermediate-risk patients, the 5-year recurrence and tumor progression rates are 65% and 8%, respectively; the 10-year bladder cancer-specific mortality is 12.8%. In high-risk patients, these figures reach 84%, 55%, and 36.1%, respectively. Several meta-analyses have demonstrated that BCG therapy following TUR of the bladder is superior to TUR alone or TUR combined with adjuvant intravesical chemotherapy in reducing the recurrence rate of high-grade Ta and T1 tumors [217, 218], as well as in decreasing the risk of tumor progression [202, 205].

Comments: the incidence of BCG infections following BCG therapy is 1%. The use of a live attenuated vaccine in patients with tuberculosis infection and/or immunodeficiency of any etiology is associated with an increased risk of developing BCG infection or progression of tuberculosis infection. The safety of BCG** live vaccine for bladder cancer has not been established in pregnant and lactating women [199, 200, 201, 202, 203, 204, 205, 206, 207, 209, 217, 218].

Comments: the presence of leukocyturia or asymptomatic bacteriuria is not a contraindication for BCG therapy; in these cases, antibiotic prophylaxis is not necessary [204, 205].

Comments: the management algorithm for local complications is presented in Table 3 [209].

Table 3. Management algorithm for local complications of BCG** live vaccine therapy for bladder cancer.

The management algorithm for systemic complications is presented in Table 4 [209].

Table 4. Management algorithm for systemic complications of BCG bladder cancer vaccine therapy**.

Dwell time for all drugs is 1 hour; administered in 6 weekly cycles (Appendix A3.2.1) [212, 213, 214, 215, 216, 217, 240].

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

Comments: several RCTs and meta-analyses have demonstrated that induction intravesical chemotherapy reduces the risk of local NMIBC recurrence compared to observation after bladder TUR. Maintenance intravesical chemotherapy has no proven efficacy and is not recommended for use. Administering more than 2 courses of induction chemotherapy is impractical [211, 212, 213, 214, 215, 216].

In the absence of contraindications or refusal of BCG therapy, preference should be given to BCG therapy, which provides clinical benefits compared to chemotherapy [202, 204, 217, 218].

3.1.3 Radical cystectomy

The clinical benefit of radical cystectomy (RC) in NMIBC is high 5-year recurrence-free survival rates, reaching up to 80%. Disadvantages of the method include surgical complications, loss of the organ, and the associated deterioration in quality of life [137, 138, 139, 140, 143, 144, 145, 146].

In NMIBC, a distinction is made between early radical cystectomy (RC), performed immediately after diagnosis, and delayed RC, performed when there are signs of failure of bladder TUR with adjuvant therapy. A systematic literature review based on 9 retrospective and 1 prospective non-randomized clinical trial showed the benefits of early RC in reducing the rate of pN+ category and increasing survival [341].

Comments: if the patient refuses early RC, high-risk patients are indicated for bladder TUR and adjuvant BCG therapy for 36 months [127, 128].

3.1.4 Management of patients with non-muscle-invasive bladder cancer and any signs of BCG failure other than tumor progression

This section provides recommendations for the treatment of patients with any signs of BCG failure other than tumor progression (refractoriness, recurrence, non-response, and BCG intolerance). Treatment of patients with tumor progression to muscle-invasive bladder cancer (MIBC) and/or tumor dissemination is carried out according to the recommendations in sections 3.2 and 3.3.

The method of choice for treating NMIBC in patients with signs of BCG failure is RC [127, 128, 341]. Alternatives to RC include continuing BCG therapy for BCG-refractory CIS [127, 128], systemic immunotherapy with pembrolizumab [320, 344, 345], and intravesical mono- and polychemotherapy. Some studies have demonstrated promising efficacy of photodynamic therapy with a photosensitizer (aminolevulinic acid) [271], external beam radiation therapy, and trimodal therapy (bladder TUR followed by chemoradiotherapy) [346].

Comments: delaying RC may lead to a decrease in survival rates [143, 144, 145, 146, 341, 342].

Comments: maintenance BCG therapy achieves a complete response in 50% of patients with CIS persisting by the 3rd month of adjuvant treatment [343].

Comments: at a median follow-up of 36.4 months, pembrolizumab** in BCG-resistant CIS with or without papillary tumor provides a complete response rate of 39% with a median duration of 16.2 months [320]. In BCG-refractory Ta-T1HG urothelial papillary carcinoma, pembrolizumab** provides a median HG urothelial cancer-free survival of 7.7 months, any urothelial cancer-free survival of 6.0 months, grade, stage or death-free survival of 44.5 months, invasion-free survival of 46.2 months, and 1-year overall survival (OS) of 96.2% [344]. The safety profile of immunotherapy is satisfactory, with a severe adverse event rate of 13–14% [320, 344].

Instillations should be performed weekly for 6 weeks, then monthly for 2 years [347, 348].

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

Comments: when using intravesical polychemotherapy with #gemcitabine** and #docetaxel** in patients with NMIBC and signs of BCG failure at a median follow-up of 9 months, recurrence was reported in 27% of cases, and RRC was required in 6.7% of observations. The 1-year urothelial carcinoma-free survival was 73%, 1-year high-grade (HG) urothelial carcinoma-free survival was 79%, and 1-year tumor progression-free survival was 95%. The incidence of adverse events (AEs) was 45%, including grade 3–4 AEs in 8.7% of cases [348].

3.2 Treatment of resectable muscle-invasive bladder cancer T2-T4aN0-1M0

The standard approach to the treatment of MIBC T2-T4aN0-1M0 is RRC with perioperative systemic antineoplastic therapy [358]. Approaches such as neoadjuvant immunochemotherapy (ICT) with adjuvant immunotherapy [350], neoadjuvant cisplatin-based CT [354, 355] with or without adjuvant immunotherapy (IT) [302], and adjuvant cisplatin-based CT [357] have proven efficacy as perioperative therapy.

Perioperative ICT (neoadjuvant therapy with durvalumab** + GC [gemcitabine** with cisplatin**] followed by RRC and adjuvant monotherapy with durvalumab**) increases OS compared to neoadjuvant GC CT in patients with MIBC [350].

Neoadjuvant ddMVAC CT (dose-dense methotrexate**, vinblastine**, doxorubicin**, and #cisplatin** with granulocyte colony-stimulating factor) provides an OS advantage over neoadjuvant GC CT, but is associated with a higher incidence of severe AEs [354]. Carboplatin**-based regimens do not increase OS, but are associated with the development of AEs [355].

Adjuvant IT with nivolumab** provided a survival advantage compared to observation after RRC in patients at high risk of recurrence, with the greatest clinical benefit observed in patients with PD-L1 overexpression [302].

Adjuvant cisplatin-based polychemotherapy provides a modest increase in OS compared to observation in patients undergoing RRC without neoadjuvant CT [357]. No RCT comparisons between adjuvant IT and CT have been conducted.

The choice of perioperative therapy method is determined by the tumor stage, the presence of contraindications to cisplatin** and IT, as well as physician and patient preferences.

Trimodality therapy, providing comparable oncological outcomes, is an alternative to RRC with perioperative therapy in carefully selected patients with solitary small tumors of a mobile urinary bladder wall (T2N0M0) [318].

An alternative treatment method for MIBC in patients with multiple, bulky T2N0M0 tumors, as well as T3a-T4aN0-N1M0 urothelial carcinoma, is RT with or without radiosensitizing CT. RT in this category of patients is inferior to RRC regarding OS [33].

In patients with contraindications or refusal of radical local treatment, standalone systemic antineoplastic therapy is used in accordance with the recommendations in section 3.3.

Treatment algorithms for patients with resectable muscle-invasive bladder cancer T2-4aN0-N1M0 are presented in Fig. 2 and Fig. 3 of Appendix B1.

3.2.1 Radical cystectomy with perioperative therapy

3.2.1.1 Perioperative therapy

• To determine the treatment strategy for patients with MIBC T2-T4aN0-N1M0 who are candidates for RRC, it is recommended to perform an assessment of physical status to identify contraindications to cisplatin**-based CT according to the following criteria:

o ECOG performance status > 1;

o creatinine clearance or glomerular filtration rate (GFR) ≤ 60 mL/min/1.73 m² by the CKD-EPI formula;

o hearing loss ≥ grade 2;

o peripheral neuropathy ≥ grade 2;

o New York Heart Association (NYHA) class III heart failure [351].

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

Comments: according to the expert consensus on bladder cancer treatment, a contraindication to prescribing cisplatin** is the presence of at least one of the following criteria: ECOG performance status > 1; glomerular filtration rate (GFR) ≤ 60 mL/min/1.73 m²; hearing loss ≥ grade 2; peripheral neuropathy ≥ grade 2, or New York Heart Association (NYHA) class III heart failure [351]. About 50% of patients with urothelial carcinoma have contraindications to cisplatin**-based CT [352]. The most common reason for restrictions on cisplatin** use in this category of patients is impaired renal function. The main causes of this are impaired urine outflow from the upper urinary tract and urinary tract infection, leading to the development and progression of chronic kidney disease (CKD). To assess whether a patient meets the criteria for cisplatin** administration, GFR must be calculated using the GFR estimation equation for patients with chronic kidney disease [353].

Comments: in patients with MIBC T2-T4aN0-N1M0 and a glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m², RRC with perioperative therapy with durvalumab** and 4 cycles of GC in the neoadjuvant phase, compared to RRC and neoadjuvant GC therapy, provides a significant increase in event-free survival, EFS (hazard ratio [HR] 0.68; 95% confidence interval [CI]: 0.56–0.82; p < 0.001) and OS (HR 0.75; 95% CI: 0.59–0.93; p = 0.01). The safety profile of perioperative immunochemotherapy is acceptable: the incidence of treatment-related grade 3–4 AEs is 40.6%; treatment-related fatal AEs is 0.6%. The rate of RRC performance after neoadjuvant immunochemotherapy is 88.0% [350].

3.2.1.2 Neoadjuvant therapy

• To increase OS, it is recommended to administer neoadjuvant cisplatin-based polychemotherapy to patients with MIBC T2-T4aN0-N1M0 who are candidates for RRC and have no contraindications to cisplatin**, using one of the following regimens [228, 355]:

  • Preferred regimen – ddMVAC

  methotrexate** – 30 mg/m² IV on day 1;

  vinblastine** – 3 mg/m² IV on day 2;

  doxorubicin** – 30 mg/m² IV on day 2;

  #cisplatin** – 70 mg/m² on day 2;

  granulocyte colony-stimulating factor (G-CSF, colony-stimulating factors).

  Cycle every 14 days, 6 cycles [226, 238, 293, 354].

  • Alternative regimens

  GC

  gemcitabine** – 1000 mg/m² IV on days 1 and 8;

  cisplatin** – 70 mg/m² IV on day 1.

  Cycle every 21 days, 3–4 cycles [223, 354, 366].

  Split-dose cisplatin** GC (Split GC)

  gemcitabine** – 1000 mg/m² IV on days 1 and 8;

  cisplatin** – 35 mg/m² IV on days 1 and 8.

  Cycle every 21 days [366, 369].

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

Comments: neoadjuvant cisplatin-based CT significantly reduces the risk of death by 13% (HR 0.87; 95% CI: 0.78–0.96; p = 0.006) and provides an absolute increase in OS of 6.5%. Mortality from combination CT is 1.1%. Monochemotherapy and carboplatin**-based CT do not improve treatment outcomes [355]. In patients with MIBC cT2N0M0, neoadjuvant CT does not lead to a significant increase in OS (HR 0.83; 95% CI: 0.69–1.01; p = 0.06) [356]. The high frequency of discordance between cT and pT categories does not allow neoadjuvant CT to be abandoned in this category of patients, but if there are doubts about the choice of treatment strategy, this information can serve as an argument in favor of omitting CT prior to RRC in individual patients. ddMVAC demonstrated superiority over the GC regimen in terms of OS (66% vs. 57%, HR 0.71 [95% CI: 0.52–0.97]) and time to death from MIBC (24% vs. 38%, HR 0.55 [95% CI: 0.39–0.78]) with an acceptable worsening of the CT safety profile [354]. Previously used neoadjuvant CT regimens MCV and MVAC are currently not used [233, 238, 339].

• Patients with MIBC T2–4aN0-1M0 who are candidates for RRC are not recommended to undergo neoadjuvant RT [265, 266, 267, 268, 269, 270].

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

Comments: a limited number of studies and their meta-analysis have demonstrated that preoperative RT can reduce bladder tumor size and lower the risk of local recurrence, but does not affect OS [265, 266, 267, 268, 269, 270].

3.2.1.3 Adjuvant therapy

Patients with MIBC pT > T1 and/or pN > N0 have a high risk of recurrence and death from bladder cancer after radical cystectomy (RC). Adjuvant therapy is administered to reduce the risk of disease progression. Based on RCT results, adjuvant immunotherapy (IT) is preferred in patients with tumor PD-L1 expression ≥ 1 %, as well as in the presence of contraindications to adjuvant chemotherapy (CT), including prior neoadjuvant CT and contraindications to cisplatin**. Adjuvant CT is preferred in patients who have not received prior neoadjuvant CT and have tumor PD-L1 expression < 1 % [228, 229, 230, 231, 302, 303, 357].

Comments: according to the phase III randomized clinical trial CheckMate 274 (which included 709 radically operated patients with high-risk urothelial carcinoma (T2-4 and/or N+)), adjuvant immunotherapy with nivolumab** significantly increases disease-free survival, non-urothelial tract recurrence-free survival, and progression-free survival regardless of prior neoadjuvant chemotherapy. The greatest benefit was observed in patients with tumor cell PD-L1 expression ≥ 1 %. Adjuvant immunotherapy is associated with a favorable safety profile and does not impair patients' quality of life [302].

Comments: in patients who have not received neoadjuvant CT, adjuvant platinum-based CT reduces the risk of death by 18 % (HR 0.82; 95 % CI: 0.70–0.96, p = 0.02) with an absolute 5-year OS increase of 6 %, and also increases DFS (HR 0.71; 95 % CI: 0.60–0.83; p < 0.001), reduces the risk of locoregional recurrence (HR 0.68; 95 % CI: 0.55–0.85; p < 0.001) and metastases (HR 0.79; 95 % CI: 0.65–0.95; p = 0.01) compared to observation [357].

• In patients with MIBC pT2–4bN0-3M0R0 who underwent RC, adjuvant RT is not recommended [270].

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

Comments: there are no clinical trials that unambiguously prove the benefit of adjuvant RT after RC.

• In carefully selected non-metastatic MIBC patients with pT2–4bN0-3M0R1 with residual tumor after an attempted RC, postoperative RT with radiosensitizing CT is recommended [269, 270].

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

Comments: in some studies, postoperative RT increased the rate of locoregional control without improving metastasis-free survival, CSS, and OS in MIBC patients with pT3-4, pN+, R1 [54, 268, 269, 270].

RT is administered using conventional fractionation to the tumor bed area with a DPD of 2 Gy up to a TSD of 50 Gy, followed by a boost to the residual tumor with a DPD of 2 Gy up to a TSD of 10-16 Gy (total cumulative dose for both stages is 60-66 Gy). In case of metastatic involvement of regional lymph nodes, the initial radiation volume includes the regional pelvic lymph nodes with a DPD of 2 Gy up to a TSD of 50 Gy, followed by CT-defined metastatic lymph nodes with a DPD of 2 Gy up to a TSD of 10-16 Gy (total cumulative dose for both stages is 60-66 Gy).

Due to changes in topographic and anatomical relationships after bladder removal, an increase in post-radiation complications is noted, especially from the gastrointestinal tract [54, 268, 269, 270].

3.2.1.4 Radical cystectomy

• For the purpose of curing MIBC, RC is recommended:

  • in patients with MIBC T2–4aN0-1M0 who have completed neoadjuvant therapy and have no progression in the form of continued growth of the primary tumor preventing radical surgery and/or the appearance of metastases;

  • in patients with MIBC T2–4aN0-1M0 with contraindications to or refusal of neoadjuvant therapy [141, 146, 147, 148, 149, 150, 151, 359].

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

Comments: 5-year OS of MIBC patients who underwent RC reaches 50 %, depends on the disease stage, and is as follows: pT2 – 63-70 %; pT3a – 47-53 %; pT3b – 31-33 %; pT4 – 19-28 %; N1-3 – 11-30 % [152]. The superiority of RC over organ-sparing treatment regarding 5-year OS has been demonstrated (HR 1.30; 95 % CI: 1.06–1.59; P = 0.01) [358].

• To increase OS, RC is recommended in patients with MIBC T2–4aN0-1M0 and contraindications to or refusal of neoadjuvant therapy within 90 days after diagnosis [150, 151, 152].

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

Comments: waiting for RC for 3 months or longer leads to a significant decrease in OS in operated patients [359, 360]. There is no evidence of a negative impact of waiting for RC during or after neoadjuvant treatment on OS [145].

• To achieve optimal treatment outcomes, RC is recommended to be performed in the standard volume, including en bloc removal of the urinary bladder with the prostate and seminal vesicles in men, or the uterus with appendages and the anterior vaginal wall in women. Pelvic lymph node dissection is a mandatory step of radical cystectomy. Variants of the technical performance of RC are permissible in selected patients [143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 358].

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

Comments: this comment reflects permissible variants of the technical performance of RC.

1) Surgical approach

Laparoscopic and robot-assisted laparoscopic RCs are technically feasible. Perioperative advantages provided by the endoscopic approach compared to open laparotomy include reduced blood loss, lower transfusion rates, fewer complications, and shorter hospital stays [173, 174, 175, 176]. A retrospective clinical trial comparing open RC, laparoscopic RC, and robot-assisted RC (n = 607) revealed no differences in OS (p = 0.216 and p = 0.961) and disease-free survival (DFS) (p = 0.826 and p = 0.462) between the groups [361]. However, evidence demonstrating the oncological safety of endoscopic RC, especially in patients with extravesical tumor extension and lymph node metastases, is lacking.

2) Pelvic lymphadenectomy

The standard volume of pelvic lymphadenectomy (PLND) includes obturator, internal, and external iliac lymph nodes bilaterally. In the randomized clinical trial LEA AUO AB 25/02 (n = 401), standard PLND was compared with extended PLND up to the inferior mesenteric artery bifurcation. The primary endpoint of the study was DFS, and secondary endpoints included OS and cancer-specific survival (CSS). At a median follow-up of 58 months, extended PLND did not demonstrate superiority over standard PLND in terms of DFS (5-year DFS: 68 % vs. 60 %; HR 0.80; 95 % CI: 0.56-1.14; p = 0.2) and OS (5-year OS: 57 % vs. 51 %; HR 0.84; 95 % CI: 0.64-1.12; p = 0.2), but significantly increased CSS (5-year CSS: 76 % vs. 65 %; HR 0.65; 95 % CI: 0.43-0.96; p = 0.031), which is of clinical importance [362]. Thus, a formally negative RCT does not provide unambiguous confirmation of the necessity to limit the extent of PLND in all cases. The extent of PLND remains at the surgeon's discretion and cannot be less than standard.

3) Preservation of functionally significant zones

There are technical possibilities to improve the quality of life of selected patients by preserving functionally significant zones during the resection stage. Techniques for function-preserving RC have been developed in men: a) organ-sparing RC (preservation of the prostate, seminal vesicles, vas deferens, neurovascular bundles); b) capsule-sparing RC (preservation of the prostatic capsule, seminal vesicles, vas deferens, neurovascular bundles); c) RC with preservation of seminal vesicles, vas deferens, neurovascular bundles; d) nerve-sparing RC (preservation of neurovascular bundles). Techniques for function-preserving RC have been developed in women: a) total genitalia-sparing RC; b) vagina-sparing RC; c) nerve-sparing RC.

According to a meta-analysis of 19 clinical trials (1,886 men and 305 women), preservation of functionally significant zones at the resection stage improves functional outcomes, including daytime and nighttime urinary continence and erectile function in men [363].

Preservation of functionally significant zones during the resection stage does not increase the risk of local recurrence and metastasis [363]. Achieving optimal oncological outcomes requires adequate selection of patients who do not have tumor involvement in the immediate vicinity of the preserved anatomical structures. Clear patient selection criteria have not been established, which requires great caution when choosing nerve- and organ-sparing techniques for radical cystectomy.

4) Urethrectomy

Indications for urethrectomy have not been definitively established. Currently, removal of the urethra is considered necessary in cases of bladder neck involvement in women and prostatic urethral involvement in men.

• To ensure an optimal balance of safety, functional outcomes, and quality of life, an individualized choice of urinary diversion method after radical cystectomy is recommended [143, 147, 148, 149, 150, 151, 152, 177, 178, 179, 180, 181, 182, 292, 358].

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

Comments: a number of urinary diversion methods have been developed following radical cystectomy, including ureterocutaneous diversion, ileal conduit, ureterosigmoidostomy, as well as the creation of continent reservoirs opening onto the skin via a dry stoma and orthotopic neobladders. Detubularized segments of the gastrointestinal tract (stomach, ileal segment, ileocecal region, colon) are used to construct the reservoirs. The terminal ileum and colon serve as optimal plastic materials suitable for urinary diversion.

1) Ureterocutaneous diversion

Advantages: low invasiveness, short operative time, feasibility independent of the extent of tissue resection.

Disadvantages: high rate of late postoperative complications associated with the risk of stoma stenosis, persistent urinary tract infection, development of severe chronic kidney disease; necessity of using urological collection bags.

Patient category: patients at high risk of perioperative death (those undergoing extensive surgery, emergency surgery due to bleeding, with severe comorbidities, etc.) [179, 180].

2) Heterotopic conduit with wet stoma formation

Advantages: short length of the resected intestinal segment, short operative time, feasibility independent of the extent of tissue resection.

Disadvantages: high rate of late postoperative complications associated with the risk of stoma stenosis, uretero-enteric anastomotic strictures, persistent urinary tract infection; necessity of using urological collection bags.

Patient category: all patients, including elderly patients, those with fine motor impairments, lack of motivation, and renal or hepatic dysfunction [181, 182, 183, 184].

3) Heterotopic ileal conduit with dry stoma formation requiring self-catheterization

Advantages: short length of the resected intestinal segment, feasibility independent of the extent of tissue resection.

Disadvantages: increased duration of the reconstructive phase of the surgery, need for self-catheterization, risk of stoma stenosis, uretero-enteric anastomotic strictures, persistent urinary tract infection; risk of stoma dilation and urinary incontinence requiring the use of urological pads/bags.

Patient category: impossibility of orthotopic reconstruction (tumor, urethral stricture), satisfactory renal (eGFR > 35–40 ml/min/1.73 m²) and hepatic function, preserved fine motor skills of the upper extremities, mental capacity, and motivation to perform reservoir self-catheterization [188, 189].

4) Urinary diversion into the intact bowel (ureterosigmoidostomy)

Advantages: controlled urine excretion, feasibility independent of the extent of tissue resection.

Disadvantages: risk of uretero-enteric anastomotic strictures, extremely high risk of persistent urinary tract infection, development of severe chronic kidney disease, risk of reservoir content incontinence requiring the use of pads.

Patient category: impossibility of orthotopic reconstruction (tumor, urethral stricture), satisfactory renal (eGFR > 35–40 ml/min/1.73 m²) and hepatic function, motivation [188, 189, 190].

5) Orthotopic continent reservoir

Advantages: preservation of voluntary urination, absence of a stoma.

Disadvantages: increased duration of the reconstructive phase of the surgery, risk of uretero-enteric anastomotic strictures, persistent urinary tract infection; risk of urinary incontinence requiring the use of pads.

Patient category: absence of tumor in the urethra and bladder neck in women, satisfactory renal (eGFR > 35–40 ml/min/1.73 m²) and hepatic function, motivation [147, 190, 191, 192, 193, 194].

The method of urinary diversion does not affect the oncological outcomes of radical cystectomy. A systematic review of 27 studies (n = 3754) using FACT and SF-36 questionnaires revealed no difference in quality of life (p = 0.31), mental health (p = 0.35), or social health (p = 0.81) between continent and incontinent diversions, demonstrated better physical well-being with wet stomas (p = 0.002), and a better emotional state and body image satisfaction with continent reservoirs [364].

• To reduce the risk of mortality and shorten the convalescence period, it is recommended to perform RCE in specialized clinical centers, carefully monitor the condition of patients undergoing RCE, and provide timely and adequate management of developed complications [143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 177, 178, 292, 358].

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

Comments: perioperative mortality is 1.2–3.2% at 30 days and 2.3–8.0% at 90 days after radical cystectomy [145, 146, 157, 191]. Early complications (within three months after surgery) are recorded in 58% of patients. The most common early complications are lymphorrhea (0–3%), ileus (1–5%), gastrointestinal bleeding (1.5–2%); late complications include erectile dysfunction in men (30–85%), lymphocele (0.1–2.6%), and anterior abdominal wall hernias (1.5–5.0%). The incidence of delayed complications depends on the urinary diversion method [146]. Short-term surgical outcomes for muscle-invasive bladder cancer are better in hospitals performing at least 10 radical cystectomies per year [365].

Comments: in one phase III RCT, a phase II clinical trial, and several retrospective studies, radiotherapy following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer demonstrated satisfactory efficacy and an acceptable safety profile [381, 382, 383]. Analysis of the SEER database revealed overall survival benefits in patients with locally advanced muscle-invasive bladder cancer and pelvic lymph node metastases who received chemotherapy followed by consolidative radiotherapy compared to chemotherapy alone [380].

Comment: principles of systemic drug therapy are provided in section 3.3.

3.2.1.5 Management of patients with muscle-invasive bladder cancer and disease progression after radical cystectomy with or without perioperative therapy

Comment: principles of systemic drug therapy are provided in section 3.3.

3.2.2 Radiotherapy

Trimodal therapy

• For the purpose of cure and bladder preservation, trimodal therapy (TMT)—including maximal transurethral resection of the bladder tumor (TURBT) followed by definitive radiotherapy and radiosensitizing chemotherapy—is recommended for carefully selected patients with muscle-invasive bladder cancer meeting the following criteria:

  • T2a–bN0M0 without CIS;

  • solitary tumor on a mobile bladder wall < 3 cm;

  • absence of tumor-induced hydronephrosis;

  • preserved bladder capacity and function prior to treatment;

  • absence of long urethral strictures [31, 32, 33, 34, 195].

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

Comments: with a follow-up of < 10 years, TMT provides OS comparable to radical cystectomy; with a follow-up of ≥ 10 years, radical cystectomy is significantly inferior (p < 0.0001) [34]. Adequate selection of candidates for TMT in accordance with the criteria listed above is a favorable prognostic factor for OS, CSS, RFS, and the absence of indications for salvage radical cystectomy [34, 195]. The combination of TURBT and RT aims to achieve complete local control, while radiosensitizing chemotherapy enhances the effect of RT and eliminates micrometastases [31, 32, 33, 34, 195]. There are 2 methods of TMT: 1) continuous (maximal transurethral resection of the bladder followed by full-course RT combined with radiomodifying chemotherapy; control cystoscopy with bladder biopsy is performed after completion of the entire treatment course); 2) split-course (maximal transurethral resection of the bladder followed by RT up to a total dose of 40 Gy combined with radiomodifying chemotherapy; control cystoscopy with bladder biopsy; consolidative chemoradiotherapy up to the full planned dose in patients with a complete response (T0) or near-complete response (Tis-Ta) to treatment). Both TMT techniques are acceptable, and no direct comparison between them has been performed [197].

• To achieve optimal outcomes at the first stage of TMT, patients with T2N0M0 MIBC who meet the selection criteria for TMT are recommended to undergo complete removal of the entire bladder tumor via TURBT [31, 32, 33, 34, 195].

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

Comments: complete TURBT is a favorable prognostic factor for a complete response to TMT [31, 34, 194], as well as for OS and CSS [195].

• To improve the safety profile of TMT, patients with T2N0M0 MIBC who meet the selection criteria for TMT are not recommended to undergo neoadjuvant chemotherapy [382].

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

Comments: administering 2 cycles of neoadjuvant chemotherapy in the MVAC regimen (methotrexate, cisplatin, vinblastine) did not improve RT outcomes in MIBC [382].

• To achieve optimal TMT outcomes, patients with T2N0M0 MIBC who meet the selection criteria for TMT are recommended to undergo external beam radiotherapy using standard fractionation to the bladder area at a fractional dose (FD) of 2 Gy up to a total dose (TD) of 60 Gy, and to the bladder tumor at an FD of 2 Gy up to a TD of 64–66 Gy [36].

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

Comments: administering RT at the full planned dose compared to an incomplete course of RT is associated with a significant increase in OS and CSS [36].

The use of modern image-guided radiation therapy (IGRT) technologies and intensity-modulated radiation therapy (IMRT / VMAT — Volumetric Modulated Arc Therapy) in static and rotational delivery modes reduces the incidence and severity of radiation-induced complications [37].

Moderate hypofractionation of RT to the bladder and/or bladder tumor area at an FD of 2.75 Gy up to a TD of 55 Gy may be used [259, 264, 321].

Prophylactic irradiation of regional pelvic lymph nodes increases OS and CSS in patients with T2–4aN0–1M0 MIBC; however, the role of RT targeting regional metastasis zones in TMT candidates with T2N0M0 bladder cancer has not been studied [38].

• To achieve optimal TMT outcomes, patients with T2N0M0 MIBC who meet the selection criteria for TMT are recommended to undergo radiomodifying chemotherapy during the course of external beam radiotherapy using the following regimens [39, 40, 41, 42, 43, 44, 314, 315, 316, 323]:

  · #cisplatin** 100 mg/m² IV on days 1, 15, and 29 [314];

  · #cisplatin** 40 mg/m² IV weekly for 6 administrations [315];

  · #gemcitabine** 27 mg/m² IV on days 1 and 4 of each week (interval of at least 72 hours) [316];

  · #cisplatin** 15 mg/m² IV on days 1–3, 8–10, and 15–17 + fluorouracil** 400 mg/m² IV on days 1–3, 8–10, and 15–17 [323].

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

Comments: in patients with MIBC, chemoradiotherapy compared to RT provided an advantage in locoregional control, invasive urothelial carcinoma-free survival, and OS. During treatment, the incidence of grade 3–4 adverse events was slightly higher in patients receiving chemoradiotherapy compared to RT (36.0% vs. 27.5%, P = 0.07). During follow-up after treatment completion, the incidence of severe adverse events between chemoradiotherapy and RT was comparable (8.3% vs. 15.7%, P = 0.07) [39]. The advantage of radiomodification incorporating cisplatin** over other regimens regarding CSS and OS has been demonstrated [36]. Gemcitabine** is not inferior to cisplatin** with fluorouracil** regarding the 3-year metastasis rate while having a better safety profile [44].

Comments: TMT efficacy is assessed after the completion of continuous TMT or after induction RT up to a TD of 40 Gy with radiomodifying chemotherapy when using the split-course treatment approach.

The criteria for a complete response to TMT include negative urine cytology results, negative cystoscopy, and the absence of residual tumor upon examination of bladder biopsy specimens. The complete response rate of completed TMT is ≈70% [30–37, 42–44].

Patients with a complete response to TMT are candidates for active surveillance, whereas those with an incomplete response are candidates for salvage radical cystectomy. Patients with a near-complete response to the induction TMT course (Tis-Ta) undergo a consolidation treatment course, after which final response assessment is performed [323].

The 5-year OS of patients after TMT ranges from 49% to 63%.

The bladder preservation rate after TMT reaches 47–67%. Microcystis requiring radical cystectomy develops in 0–2% of patients [41, 42, 43, 44]. Normal bladder function according to urodynamic studies after TMT is 75% [46], and satisfaction with bladder function after TMT is 79% [346].

Late grade 3 genitourinary toxicity occurs in 5.7%, grade 3 gastrointestinal toxicity in 5.7%, and sexual dysfunction in 8–38% of patients [45, 346].

3.2.2.2 Chemoradiotherapy

Comments: no direct comparison between RT and radical cystectomy in MIBC has been performed. Indirect comparison shows that RT is inferior to radical cystectomy in terms of OS. The 5-year survival rate of MIBC patients treated with RT is 21–30%, compared to 36–47% for radical cystectomy [47, 48], and the relative risk of death from all causes using standard multivariable adjustments ranges from 1.4 to 1.5 [49, 50].

• To achieve optimal outcomes of external beam radiotherapy with radiomodifying chemotherapy in patients with T2–T4aN0–N1M0 MIBC, it is recommended to administer external beam radiotherapy using standard fractionation:

  • to the bladder area at an FD of 2 Gy up to a TD of 60 Gy;

  • to the bladder tumor at an FD of 2 Gy up to a TD of 64–66 Gy;

  • in the absence of radiologically detected metastases in regional lymph nodes — to regional metastasis zones at an FD of 2 Gy up to a TD of 44–50 Gy;

  • in the presence of radiologically detected metastases in regional lymph nodes — to regional metastasis zones at an FD of 2 Gy up to a TD of 44–50 Gy with an additional dose escalation to the metastatic lymph nodes up to a TD of 60–66 Gy [36, 260, 264, 315, 331].

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

Comments: administering RT at the full planned dose compared to an incomplete course of RT is associated with a significant increase in OS and CSS [36].

The use of modern image-guided radiation therapy (IGRT) technologies and intensity-modulated radiation therapy (IMRT / VMAT — Volumetric Modulated Arc Therapy) in static and rotational delivery modes reduces the incidence and severity of radiation-induced complications [37].

Moderate hypofractionation of RT to the bladder and/or bladder tumor area at an FD of 2.75 Gy up to a TD of 55 Gy may be used [259, 264, 321].

Prophylactic irradiation of regional pelvic lymph nodes increases OS and CSS in patients with T2–4aN0–1M0 MIBC; however, the role of RT targeting regional metastasis zones in TMT candidates with T2N0M0 bladder cancer has not been studied [38].

• To achieve optimal outcomes of chemoradiotherapy in patients with T2–T4aN0–N1M0 MIBC, it is recommended to administer radiomodifying chemotherapy during the course of external beam radiotherapy using the following regimens [39, 40, 41, 42, 43, 44, 315, 316, 323].

  • #cisplatin** 100 mg/m² IV on days 1, 15, and 29 [314];

  • #cisplatin** 40 mg/m² IV weekly for 6 administrations [315];

  • #gemcitabine** 27 mg/m² IV on days 1 and 4 of each week (interval of at least 72 hours) [316];

  • #cisplatin** 15 mg/m² IV on days 1–3, 8–10, and 15–17 + fluorouracil** 400 mg/m² IV on days 1–3, 8–10, and 15–17 [323].

Regimens of radiomodifying chemotherapy are provided in Appendix A3.2.3.

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

Comments: in patients with MIBC, trimodality therapy compared with radiotherapy provided a survival advantage in terms of locoregional control, invasive urothelial carcinoma-free survival, and OS. CRT increases the rate of grade 3-4 AEs during treatment (36.0% vs. 27.5%, P = 0.07), but not during the follow-up of treated patients (8.3% vs. 15.7%, P = 0.07) [39].

The treatment algorithm for patients with unresectable muscle-invasive bladder cancer (T4b and/or N2-3 and M0) is presented in Fig. 4 of Appendix B1.

3.2.2.3 Management of patients with disease progression after radiotherapy

Comments: at a median follow-up of 61.1 months in patients with MIBC treated with radiotherapy, the rate of incomplete response is 15.5%, and the rate of muscle-invasive local recurrence is 28.7%. Meanwhile, the rate of salvage cystectomy is much lower (19.2%). Salvage cystectomy is a technically complex procedure associated with a high surgical risk. The complication rate of salvage cystectomy reaches 67–72%, and 30-day mortality is 0–8.8%. The pooled 5- and 10-year RFS rates after salvage cystectomy are 54.3% and 45.6%, respectively [358].

Comments: the principles of systemic drug therapy are provided in section 3.3.

3.3 Treatment of inoperable locally advanced bladder cancer (T4bN0-3M0 and/or Ta-4bN2-N3M0) and disseminated bladder cancer

The standard approach to the treatment of inoperable locally advanced bladder cancer (T4bN0-3M0 and/or Ta-4bN2-N3M0) and disseminated bladder cancer is the administration of systemic antitumor drug therapy.

For standalone drug therapy of urothelial carcinoma, chemotherapy, immunotherapy, chemoimmunotherapy, antibody-drug conjugate therapy, and targeted therapy are used. The drug therapy regimens used for bladder cancer are given in Appendix B2.

Local treatment of advanced BC is not standard, but may be used in carefully selected patients.

The treatment algorithm for advanced bladder cancer is presented in Fig. 5 of Appendix B1.

3.3.1 Local treatment

Comments: no direct comparison has been made between systemic drug therapy and induction therapy with local effect consolidation in inoperable MIBC T4b and/or N2-N3. In MIBC patients with regional lymph node metastases, CRT (n = 395) provides an OS advantage compared to chemotherapy (n = 1388) [380]. In MIBC T2-4aN0-2M0, chemotherapy prior to radiotherapy increases PFS and OS [53]. In MIBC patients with N1-3, chemotherapy combined with radical cystectomy increases OS compared to chemotherapy alone [51]. The best results of local effect consolidation are achieved in inoperable MIBC patients who attain a complete response to induction chemotherapy [52].

Comments: possible fractionation regimens for hemostatic radiation therapy: dose per fraction (DPF) 7 Gy up to a total dose (TD) of 21 Gy; DPF 3.5 Gy up to a TD of 35 Gy; DPF 6 Gy up to a TD of 30 Gy; single-fraction irradiation at a weekly DPF of 8 Gy or DPF 6 Gy up to a TD of 36 Gy [386].

Comments: there are no data confirming the role of metastasectomy in patients with advanced oncological disease. Nevertheless, a study including patients with BC and upper urinary tract urothelial carcinoma demonstrated that the removal of metastatic foci can be safe and oncologically justified in strictly selected patients with an expected long life expectancy [378]. Similar data have been demonstrated in several clinical trials using radiotherapy [55, 384, 385]. In the absence of randomized trial data, the advisability of metastasectomy should be evaluated on an individual basis.

• To improve quality of life, it is recommended to administer palliative radiation therapy to BC patients to relieve or reduce the intensity of metastatic symptoms [322].

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

Comments: the fractionation regimen is determined by the specific clinical situation. Extreme hypofractionation regimens used in IG-IMRT (SBRT) involving a DPF ≥ 7 Gy delivered in several fractions are permissible to achieve a better analgesic effect [322]. This radiotherapy regimen is possible only in specialized centers with the appropriate level of technical equipment, trained personnel, and clinical experience in performing this technology.

3.3.2 Systemic antitumor drug therapy regimens used in inoperable MIBC and metastatic BC

• To increase the survival of patients with inoperable MIBC and metastatic BC, it is recommended to administer systemic antitumor drug therapy using the following regimens:

Chemotherapy

· ddMVAC

methotrexate** – 30 mg/m² IV on day 1;

vinblastine** – 3 mg/m² IV on day 2;

doxorubicin** – 30 mg/m² IV on day 2;

#cisplatin** – 70 mg/m² on day 2;

G-CSF

Cycle every 14 days [293].

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

· GC

gemcitabine** – 1000 mg/m² IV on days 1 and 8;

cisplatin** – 70 mg/m² IV on day 1.

Cycle every 21 days [366].

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

· GC with split-dose cisplatin**

(Split GC)

gemcitabine** – 1000 mg/m² IV on days 1 and 8;

cisplatin** – 35 mg/m² IV on days 1 and 8.

Cycle every 21 days [366, 369].

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

· GemCarbo

#gemcitabine** – 1000 mg/m² IV on days 1 and 8;

carboplatin** – AUC 4-5 on day 1.

Cycle every 21 days [224].

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

· Vinflunine

– 320 mg/m² intravenously over 20 minutes, every 3 weeks [241, 256, 257].

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

· #Gemcitabine**

1000–1250 mg/m² IV on days 1, 8, 15; 28-day cycle [257, 295, 325, 326, 327, 328, 335].

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

· #Docetaxel**

75–100 mg/m² on day 1; 21-day cycle [257, 307, 333, 334].

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

· #Paclitaxel**

80 mg/m² on days 1, 8, 15; 28-day cycle, or 175 mg/m² on day 1; 21-day cycle [257, 306, 332].

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

Immuno-oncology agents (monoclonal antibodies) and combinations based on them

· Avelumab**

– 800 mg as an IV infusion over 60 minutes every 2 weeks [301].

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

· Atezolizumab**

– 840 mg as an IV infusion every 2 weeks, or 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks, or 1875 mg as a SC injection every 3 weeks. The first dose of atezolizumab** must be administered over 60 minutes. If the first infusion is well tolerated, all subsequent administrations can be performed over 30 minutes [222, 288].

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

· Nivolumab**

– 3 mg/kg or 240 mg as an IV infusion every 2 weeks, or 480 mg as an IV infusion every 4 weeks. The first administration should be performed over 60 minutes; if well tolerated, all subsequent ones over 30 minutes [308].

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

· Nivolumab with gemcitabine and cisplatin**

nivolumab** 360 mg, IV, every 3 weeks for 6 cycles, then, after completion of chemotherapy, 480 mg, IV, every 4 weeks, for up to 2 years.

#gemcitabine** – 1000 mg/m² IV on days 1 and 8;

#cisplatin** – 70 mg/m² IV on day 1;

Chemotherapy cycles every 21 days, up to 6 cycles [370, 376].

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

· Pembrolizumab**

– 200 mg as an IV infusion over 30 minutes every 3 weeks, or 400 mg as an IV infusion over 30 minutes every 6 weeks [289, 294, 336].

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

Conjugates

· Enfortumab vedotin

– 1.25 mg/kg as an intravenous infusion over 30 min, once weekly for 3 weeks; cycles every 28 days. Dose reduction is permitted in the event of individually intolerable grade 2 toxicity or certain grade 3 adverse events recorded during previous conjugate therapy cycles (level 1 – 1 mg/kg, level 2 – 0.75 mg/kg, level 3 – 0.5 mg/kg) [372].

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

Targeted therapy

· Erdafitinib

- 8 mg once daily, orally, with examination and monitoring of serum phosphate levels after 14 days; if phosphate concentration is < 9 mg/dL, absence of ocular adverse events and any adverse events of grade 2 and above – dose escalation to 9 mg once daily orally; if phosphate concentration is ≥ 9 mg/dL and/or ocular adverse events and/or any adverse events of grade 2 and above – therapy interruption and possible dose de-escalation (level 1 to 6 mg/day, level 2 to 5 mg/day, level 3 to 4 mg/day) with the administration of a phosphate binder [373].

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

Regimes recommended for the first line of therapy are shown in Table 9 (Appendix A3.2.2), and for the second and subsequent lines of therapy in Table 10 (Appendix A.3.2.4).

3.3.3 Sequence of systemic antineoplastic drug therapy in unresectable MIBC and metastatic BC

The sequence of systemic therapy is presented in Figure 5 and Table 9 (Appendix A3.2.2) and Table 10 (Appendix A3.2.4).

3.3.3.1 First-line drug therapy

The choice of drug therapy method is determined based on the presence of contraindications to cisplatin**, contraindications to carboplatin**, and PD-L1 expression in the tumor tissue.

Patients without contraindications to cisplatin** are candidates for cisplatin**-based polychemotherapy (ddMVAC, GC) [233, 238, 339] or chemoimmunotherapy (nivolumab** + 6 cycles of GC) [376].

Patients with contraindications to cisplatin** and no contraindications to carboplatin** are prescribed chemotherapy in the GemCarbo regimen [240]. Replacing cisplatin** with carboplatin** is not recommended if there are no contraindications to cisplatin** [375]. Four cycles of platinum-based induction chemotherapy are administered. Administering 5–6 cycles of consolidation chemotherapy is permissible in patients with a progressive objective response to treatment who do not have severe therapy-related AEs [374].

Patients who achieve tumor control after 4 or more cycles of platinum-based chemotherapy (complete response, partial response, or stable disease) should receive maintenance immunotherapy with avelumab [301].

Patients with contraindications to cisplatin** but without contraindications to carboplatin**, and with high PD-L1 expression in the tumor, may be prescribed immunotherapy (pembrolizumab**, atezolizumab**) as an alternative to chemotherapy [243, 299].

Patients with contraindications to platinum derivatives in the first line of therapy may be prescribed immunotherapy regardless of the tumor PD-L1 expression status (pembrolizumab**, atezolizumab**) [243, 299] or monochemotherapy (#gemcitabine**, #paclitaxel**, #docetaxel**) [306, 307, 325, 326, 327, 328].

• To determine the treatment strategy for patients with advanced BC who are candidates for systemic antineoplastic therapy, it is recommended to perform an assessment of the patient's condition to identify contraindications to cisplatin**-based chemotherapy according to the following criteria:

  o ECOG status > 1;

  o creatinine clearance or glomerular filtration rate (GFR) ≤ 60 mL/min/1.73 m² by the CKD-EPI formula;

  o hearing loss ≥ grade 2;

  o peripheral neuropathy ≥ grade 2;

  o New York Heart Association (NYHA) class III heart failure [351].

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

Comments: these criteria were developed by a consensus of bladder cancer treatment experts [351].

• To determine the treatment strategy for patients with advanced BC who are candidates for systemic antineoplastic therapy, it is recommended to perform an assessment of the patient's condition to identify contraindications to carboplatin**-based chemotherapy according to the following criteria:

  o ECOG status > 2;

  o GFR < 30 mL/min/1.73 m² by the CDK-EPI formula;

  o ECOG status 2 and GFR < 60 mL/min/1.73 m² by the CDK-EPI formula [351].

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

Comments: these criteria were developed by a consensus of bladder cancer treatment experts [351].

Comments: in stage IV urothelial carcinoma patients who have not received prior therapy, the GC and M-VAC chemotherapy regimens showed comparable objective response rates, time to progression, and 18-month overall survival. The most significant toxicities were myelotoxicity, sepsis associated with febrile neutropenia, and mucositis. Severe anemia and thrombocytopenia were more frequent with the GC regimen, whereas severe or febrile neutropenia and severe mucositis were more frequent with the M-VAC regimen [233].

The ddMVAC regimen with G-CSF maintenance therapy increased the objective response rate compared to standard MVAC, but did not lead to a significant increase in median overall survival. Patients receiving dd-MVAC with G-CSF experienced lower overall toxicity [238].

The use of previously employed MCV and MVAC regimens [233, 238, 339] is impractical.

Comments: at a median follow-up of 33.6 months in patients with unresectable locally advanced and disseminated urothelial carcinoma, the combination of nivolumab** with GC compared to GC chemotherapy alone demonstrated a benefit in OS (median 21.7 vs. 18.9 months; HR 0.78; 95% CI: 0.63–0.96), progression-free survival, PFS (median 7.9 vs. 7.6 months; HR 0.72; 95% CI: 0.59–0.88), objective response rate, ORR (57.6% vs. 43.1%), and complete response rate, CR (21.7% vs. 11.8%), as well as duration of the achieved CR (37.1 vs. 13.2 months). The rate of grade ≥ 3 AEs with chemoimmunotherapy is 61.8% (vs. 51.7% with GC) [370, 376].

Intensification of cisplatin**-based chemotherapy by incorporating nivolumab** into the treatment regimen is advisable in patients with significant tumor burden and a complicated clinical course who can tolerate chemoimmunotherapy and require the maximum possible response to first-line therapy.

Comments: in patients with advanced BC and cisplatin** contraindications such as GFR < 60 mL/min/1.73 m² and/or ECOG performance status 2, two carboplatin**-containing regimens were compared: methotrexate**, carboplatin**, vinblastine** (M-CAVI) and GemCarbo. Both regimens demonstrated antitumor activity: the ORR was 42% for GemCarbo and 30% for M-CAVI. The incidence of severe AEs reached 13.6% and 23% in the study arms, respectively [224]. Based on these data, the GemCarbo combination became the standard of care for this patient group.

Comments: in patients with advanced urothelial carcinoma who achieved an objective response or disease stabilization after 4–6 cycles of chemotherapy, avelumab** maintenance immunotherapy significantly increased median OS compared to best supportive care from 14.3 to 21.4 months (HR: 0.69; 95% CI: 0.56–0.86; p < 0.001). During and after maintenance immunotherapy, grade ≥ 3 AEs were observed in 47% of patients; immune-mediated AEs were noted in 29% of cases, reached grade ≥ 3 in 7% of patients, and included colitis, pneumonitis, rash, elevated liver enzymes, hyperglycemia, myositis, and hypothyroidism [301].

Comments: pembrolizumab** in the first-line therapy of advanced urothelial carcinoma in patients with contraindications to cisplatin therapy provided an ORR of 24% (in patients with PD-L1 expression by CPS ≥ 10%, 38%). The median time to response was 2 months; at a median follow-up of 5 months, 83% of responses were ongoing, and the median duration of response was not reached. The most common treatment-related grade 3–4 AEs were fatigue (2%), increased serum alkaline phosphatase (1%), and decreased muscle strength (1%) [299].

Atezolizumab** in the first-line therapy of advanced urothelial cancer in patients with contraindications to cisplatin** therapy provided an ORR of 23% (28% in patients with PD-L1 expression on IC ≥ 5%). With a median follow-up of 17.2 months, the median response duration was not reached. Treatment-related AEs were observed in 66% of patients (grades 3–4 in 16%) [243].

Comments: pembrolizumab** in the first-line therapy of advanced urothelial carcinoma in patients with contraindications to cisplatin therapy provided an ORR of 24% (in patients with PD-L1 expression by CPS ≥ 10%, 38%). The median time to response was 2 months; at a median follow-up of 5 months, 83% of responses were ongoing, and the median duration of response was not reached. The most common treatment-related grade 3–4 AEs were fatigue (2%), increased serum alkaline phosphatase (1%), and decreased muscle strength (1%) [299].

Atezolizumab** in the first-line therapy of advanced urothelial cancer in patients with contraindications to cisplatin** therapy provided an ORR of 23% (28% in patients with PD-L1 expression on IC ≥ 5%). With a median follow-up of 17.2 months, the median response duration was not reached. Treatment-related AEs were observed in 66% of patients (grades 3–4 in 16%) [243].

Comments: data on the possibilities of drug antitumor treatment in this group of patients are limited to individual single-arm studies showing acceptable efficacy and safety of taxane-based [306, 307] and gemcitabine** [325, 326, 327, 328] monotherapy. The available evidence base is insufficient to form clinical guidelines.

3.3.3.2 Second- and subsequent-line drug therapy

The standard second-line therapy for patients with advanced bladder cancer progressing during or after platinum-based chemotherapy is pembrolizumab** monotherapy [257].

A less desirable alternative is immunotherapy with nivolumab** or atezolizumab** [245, 300, 309, 310].

If immunotherapy is contraindicated, single-agent chemotherapy (vinflunine, taxanes) and re-induction of platinum-based chemotherapy are acceptable in selected patients [379].

Patients with progression after immunotherapy may be administered #enfortumab vedotin [372] and, if the FGFR3 gene mutation status is positive, erdafitinib [373].

For tumors resistant to platinum-based chemotherapy and immunotherapy, enfortumab vedotin is indicated [372]. An alternative is re-induction of previously effective platinum-based chemotherapy [379].

Comments: in patients with unresectable locally advanced and disseminated urothelial cancer progressing during or within 12 months after completion of cisplatin-based chemotherapy**, at a median follow-up of 18.5 months, pembrolizumab** compared with conventional chemotherapy (paclitaxel**, docetaxel** or vinflunine) significantly increased median OS from 7.4 to 10.3 months (HR 0.70; 95% CI: 0.57–0.86; p = 0.0004), ORR (21.1% vs 11.0%), and CR (7.8% vs 2.9%, respectively). The median duration of response with pembrolizumab** therapy was not reached, while with chemotherapy it was 4.4 months. The presence of PD-L1 expression (CPS ≥ 10) had no effect on ORR and survival rates. Any AEs associated with immunotherapy were reported in 61.3% of patients (grade ≥ 3 in 16.5%) [257].

Comments: nivolumab** as monotherapy for disseminated urothelial cancer in patients who received at least 1 prior line of therapy including platinum derivatives provided an ORR of 24.4%, which was independent of the level of PD-L1 expression. Treatment-related grade 3–4 AEs developed in 22% of patients; the most frequent of these were increased serum lipase (5%) and amylase (4%) [308].

Nivolumab** in the second-line therapy of platinum-resistant urothelial cancer achieved an objective response in 19.6% of cases with a median time to response of 1.9 months. ORR increased with increasing PD-L1 expression levels, reaching 28.4% with positive staining of ≥ 5% of cells, and 16.1% in patients with PD-L1 expression < 5%. Median PFS was 2 months (1.87 months for PD-L1 expression < 1% and 3.6 months for ≥ 1%). Median OS was 8.74 months in all patients (5.95 months for PD-L1 expression < 1% and 11.3 months for PD-L1 expression ≥ 1%). Treatment-related grade 3–4 AEs occurred in 18% of observations [245].

Comments: atezolizumab** therapy in patients with advanced urothelial cancer previously treated with platinum derivatives provided an ORR of 16%, which reached 28% in patients with PD-L1 IC2/3 [310].

In patients with disseminated urothelial cancer progressing during or after platinum-containing chemotherapy, atezolizumab** and chemotherapy (vinflunine, paclitaxel** or docetaxel**) provided comparable OS (median 8.6 vs 8.0 months, respectively; HR 0.85; 95% CI: 0.73–0.99) [309].

In patients with resistant advanced urothelial or non-urothelial urinary tract cancer, including patients who received non-platinum-based chemotherapy, immunocompromised patients, patients receiving glucocorticosteroids, and patients on hemodialysis, the median OS was 8.7 months, median PFS was 2.2 months, and ORR was 13%. Grade ≥ 3 AEs were reported in 45% of patients, leading to treatment discontinuation due to toxicity in 8% of cases [311].

Comments: a multicenter retrospective study compared subsequent platinum-based (n = 135) and non-platinum-based (n = 161) therapy in patients with urothelial carcinoma progressing during second- and later-line therapy who had previously received platinum-based chemotherapy (median time from completion of platinum administration in the groups was 4.4 and 2.2 months, respectively). Re-induction of platinum-based chemotherapy significantly increased OS (median 7.9 months vs 5.5 months, respectively; p = 0.035) and ORR (44.8% vs 27.0%, p = 0.041) compared with alternative drug treatment regimens, which mainly included chemotherapy (96.7%) [379].

Comments: vinflunine, compared with best supportive care in advanced urothelial cancer in patients with progression after cisplatin-based chemotherapy**, demonstrated an OS benefit (6.9 vs 4.3 months, respectively; P = 0.04), as well as improved ORR (16% vs 0%, P = 0.0063), disease control (41.1% vs 24.8%, P = 0.0024), and median PFS (3.0 vs 1.5 months, P = 0.0012). The duration of the objective response to vinflunine therapy was 7.4 months (95% CI 4.5–17.0 months) [256].

Comments: in patients with disseminated urothelial cancer progressing during or after platinum-based chemotherapy, chemotherapy (vinflunine, paclitaxel**, or docetaxel**) was not inferior to immunotherapy regarding OS (median 8.6 vs. 8.0 months, respectively, HR 0.85; 95% CI: 0.73–0.99) [309].

Comments: in resistant advanced urothelial carcinoma, #gemcitabine** demonstrated a response rate ranging from 23% to 28% [326, 327, 328].

Comments: the efficacy and safety of enfortumab vedotin as second-line therapy for advanced urothelial cancer were evaluated in the multicenter phase II EV-201 study, which included 89 patients with contraindications to cisplatin** therapy who experienced disease progression after PD-(L)1 inhibitor treatment. The objective response rate was 52%, including complete responses in 20% and partial responses in 31%. The median time to response was 1.8 months, and the median duration of response was 10.9 months. The most common grade 3–4 treatment-related adverse events were neutropenia (9%), rash (8%), and fatigue (7%) [377].

Comments: in the phase III RCT EV-301, enfortumab vedotin compared with taxane chemotherapy or vinflunine in patients with progressive locally advanced or metastatic urothelial bladder cancer who had previously received platinum-based chemotherapy and PD-(L)1 inhibitors demonstrated a significant improvement in overall survival (12.9 vs. 8.9 months; HR 0.70; 95% CI: 0.56–0.89, p = 0.001) and progression-free survival (5.6 vs. 3.7 months; HR 0.62; 95% CI: 0.51–0.75; p < 0.001). The median duration of enfortumab vedotin therapy was 5 months. The most frequent treatment-related adverse events with enfortumab vedotin included alopecia (45%), peripheral neuropathy (34%), fatigue (31%), decreased appetite (31%), diarrhea (24%), nausea (23%), and rash (16%) [372].

Comments: in patients with progressive advanced urothelial cancer who received PD-(L)1 inhibitors and harbored predictive FGFR3 gene mutations in tumor tissue, erdafitinib compared with chemotherapy (docetaxel or vinflunine) demonstrated a significant increase in median OS (12.1 vs. 7.8 months; HR 0.64 (95% CI: 0.47–0.88), p = 0.005), PFS (5.6 vs. 2.7 months (HR 0.58 (95% CI: 0.44–0.78), p = 0.0002), and ORR (45.6% vs. 11.5%, p < 0.001). Grade 3–4 adverse events during targeted therapy were observed in 45.9% of cases. Adverse events of special interest during erdafitinib therapy included hyperphosphatemia (78.5%), central serous retinopathy (17.0%), and onycholysis (23.0%) [373].

3.3.4 Evaluation of the efficacy of systemic antineoplastic drug therapy in unresectable MIBC and metastatic bladder cancer

Treatment monitoring is performed to assess efficacy and toxicity, and includes periodic physical examination and assessment of various symptoms, laboratory data, and instrumental imaging results. Response assessment should be carried out after every 2–3 cycles of chemotherapy using physical examination, symptom review, cystoscopy, and urine cytologic examination (in patients with the bladder in place), as well as instrumental imaging modalities used at the initial staging. CT of the chest, CT or MRI of the abdomen, retroperitoneal space, and pelvis are performed at least once every 3 months or more frequently based on clinical indications.

Comments: this monitoring schedule is adopted from RCTs of drug therapy regimens with proven efficacy in bladder cancer.

3.4 Pain Management

The principles of analgesia and optimal selection of pain management therapy in bladder cancer patients with chronic pain syndrome comply with the pain management guidelines set forth by the Russian Society of Clinical Oncology [406].

3.5 Supportive care in patients with bladder cancer

• To prevent adverse events and reduce their severity if they occur, it is recommended that patients receiving antineoplastic drug therapy with emetogenic side effects undergo prevention and treatment of nausea and vomiting [503, 504].

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

Comments: the principles of diagnosis, prevention, and treatment of nausea and vomiting during antineoplastic drug therapy are outlined in the Guidelines of the Russian Society of Clinical Oncology [407].

Comments. The principles of diagnosis, prevention, and treatment of bone complications are outlined in the Guidelines of the Russian Society of Clinical Oncology [408].

Comments. The principles of diagnosis, prevention, and treatment of venous thromboembolic complications are outlined in the Guidelines of the Russian Society of Clinical Oncology [409].

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, as well as principles of antibacterial therapy, are outlined in the Guidelines of the Russian Society of Clinical Oncology [410].

Comments. The principles of diagnosis, prevention, and treatment of hepatotoxicity are outlined in the Guidelines of the Russian Society of Clinical Oncology [411].

Comments. The principles of diagnosis, prevention, and treatment of cardiovascular complications during antitumor therapy are outlined in the Guidelines of the Russian Society of Clinical Oncology [412].

Comments. The principles of diagnosis, prevention, and treatment of skin complications are outlined in the Guidelines of the Russian Society of Clinical Oncology [413].

Comments. The principles of nutritional support are presented in the Guidelines of the Russian Society of Clinical Oncology [414]. The nutritional risk screening scale can be found in Appendix G4.

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of nephrotoxicity is presented in the Guidelines of the Russian Society of Clinical Oncology [415].

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of immune-mediated adverse events is outlined in the Guidelines of the Russian Society of Clinical Oncology [416].

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of mucositis is outlined in the Guidelines of the Russian Society of Clinical Oncology [417].

• To prevent the development of AEs and reduce their severity should they occur, it is recommended to treat anemia arising as a symptom of a malignant neoplasm and as an adverse event in patients receiving antitumor drug therapy [529, 530].

Level of Recommendation − B (Level of Evidence − 1).

Comments. The procedure and principles for the prevention and treatment of anemia comply with the principles set forth in the clinical guidelines "Anemia in Malignant Neoplasms" (ID: KR624.2, approval year 2024) [418] and in the Guidelines of the Russian Society of Clinical Oncology [419].

Comments. A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the Guidelines of the Russian Society of Clinical Oncology [420].

• To prevent the development of AEs and reduce their severity should they occur during cycle-based antitumor drug therapy involving continuous prolonged (over 6 hours) infusions of antitumor drugs (fluorouracil, doxorubicin, etc.) or in case of poor peripheral venous access, it is recommended to use central venous access and infusion pumps [532].

Level of Recommendation − B (Level of Evidence − 2).

Comments. The choice of central access option is determined by the planned duration of the entire course of treatment, patient preferences, and anatomical features. For prolonged courses of therapy (exceeding 3 months), implantation of a subcutaneous venous port system is the most convenient. For shorter durations, a peripherally inserted central venous catheter can serve as an alternative. The principles of using central venous access are outlined in the Guidelines of the Russian Society of Clinical Oncology [421].

• To prevent the development of adverse events (AEs) and reduce their severity should they occur during antineoplastic drug therapy, patients are recommended to receive prophylaxis and treatment for antineoplastic drug extravasation. When planning antineoplastic drug therapy, proper selection of vascular access is crucial for preventing antineoplastic drug extravasation [533].

Grade of Recommendation − C (Level of Evidence − 5).

Comments. Algorithms for vascular access selection, as well as the prevention, diagnosis, and treatment of extravasation, are outlined in the Guidelines of the Russian Society of Clinical Oncology [422].

• In order to reduce pain intensity and improve quality of life, it is recommended to provide treatment for chronic pain syndrome in patients receiving antitumor therapy [534].

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

Comments. Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the Guidelines of the Russian Society of Clinical Oncology [423].

Comments. Algorithms for the prevention, diagnosis, and treatment of infusion reactions are outlined in the Guidelines of the Russian Society of Clinical Oncology [424].

• To prevent the development of adverse events (AEs) and reduce their severity should they occur, it is recommended to monitor and treat reactivation/exacerbation of chronic viral hepatitis in patients receiving antitumor therapy [536].

Grade of Recommendation − C (Level of Evidence − 4).

Comments. The principles of monitoring and management tactics in cancer patients with chronic viral hepatitis are outlined in the Guidelines of the Russian Society of Clinical Oncology [425].

Comments. The principles of diagnosis, prophylaxis, and treatment of neurological complications of antitumor therapy are outlined in the Guidelines of the Russian Society of Clinical Oncology [426].

¹Induction systemic antitumor therapy is carried out in the regimens reflected in the recommendations of section 3.3.3.1.

²Surgical treatment is carried out in accordance with the recommendations of section 3.2.1.2.

³Radiation therapy is carried out in accordance with the recommendations of section 3.2.2.2.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1 General issues

• With the aim of improving the quality of life of patients with bladder cancer, it is recommended that medical rehabilitation measures be carried out by a multidisciplinary rehabilitation team (MDRT) of specialists [427].

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

Comments: medical rehabilitation is a set of medical and psychological measures aimed at the complete or partial restoration of impaired and/or compensation for lost functions of the affected organ or body system, the maintenance of body functions during the resolution of an acutely developing pathological process or the exacerbation of a chronic pathological process in the body, as well as the prevention, early diagnosis, and correction of potential dysfunctions of damaged organs or body systems, the prevention and reduction of potential disability, the improvement of quality of life, the preservation of the patient's working capacity, and their social integration into society. According to the RRS, patients with malignant neoplasms belong to the "somatic diseases" category.

• To achieve an optimal quality of life, it is recommended to formulate an individual rehabilitation program for a bladder cancer patient, taking into account the assessment of their condition and the possibilities of correcting body structure and function, activity and participation limitations, as well as personal and environmental factors within the categories of the International Classification of Functioning (ICF) [427].

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

Comment: in 2018, the Global Leadership Initiative on Malnutrition (GLIM) developed universal diagnostic criteria for malnutrition in adult patients [430]. A diagnosis of malnutrition can be established if at least one phenotypic and one etiologic criterion are met. According to the GLIM classification, phenotypic criteria for diagnosing malnutrition include: unintentional weight loss (> 5% within ≤ 6 months or > 10% within > 6 months); body mass index (< 20 kg/m² in patients aged < 70 years or < 22 kg/m² in patients aged ≥ 70 years); reduced muscle mass (determined by dual-energy X-ray absorptiometry, computed tomography, magnetic resonance imaging, bioelectrical impedance analysis, or physical examination with anthropometric measurements). Etiologic criteria for diagnosing malnutrition include: reduced food intake or assimilation (≤ 50% of requirement for > 1 week or any reduction for > 2 weeks, or chronic gastrointestinal diseases impairing nutrient intake and absorption [dysphagia, nausea, vomiting, diarrhea, constipation, etc.]; presence of acute disease/injury or chronic disease-related inflammation.

• To reduce distress levels and improve quality of life, psychological support is recommended for patients with bladder cancer from the time of diagnosis, throughout the entire treatment period, and after its completion [435].

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

4.2 Prehabilitation phase

Prehabilitation is defined as rehabilitation starting from the moment of diagnosis until the initiation of treatment, whether systemic or local. The primary goal of prehabilitation is to prevent or reduce the severity of anticipated treatment-related physical impairments and psychological disorders that could potentially lead to significant disability.

Comments: the approach to selecting the intensity of physical therapy is always individualized. When designing the exercise regimen, consideration is given to sex, age, constitutional features, the patient's level of physical development, the duration of forced hypokinesia, general condition, the course of the underlying disease, and the nature of the main clinical manifestations. The recommended volume of physical exertion must correspond to the body's functional reserves and prior physical conditioning. Functional tests, such as the squat test, cycle ergometry, etc., are also taken into account. Individually tailored complex training in the preoperative period promotes the development of adaptation mechanisms and nonspecific resistance of the entire body.

4.3 Stage I rehabilitation (rehabilitation after surgical treatment)

• To reduce the risk of postoperative intestinal paresis after radical cystectomy in patients with bladder cancer, early enteral nutrition (no later than 24 hours after surgery) is recommended [442].

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

Comments: monitoring the effectiveness of nutritional support in the postoperative period in a stable surgical patient includes assessing total serum protein every 3–5 days, albumin every 3–5 days, peripheral blood absolute lymphocyte count every 3–5 days, and body weight and body mass index every 7–10 days [444]. The frequency of testing these parameters may vary depending on the specific clinical situation.

Comments: physical therapy exercises begin on the first day after surgery, including in intensive care units if the patient is in a stable condition and under hemodynamic monitoring. Exercises for small and medium muscle groups with partial unloading and a low number of repetitions are used, combined with breathing exercises focusing on diaphragmatic breathing and relaxation exercises. At the same time, the patient must be taught abdominal breathing with a small amplitude of abdominal wall movement, as this causes mild changes in intra-abdominal pressure, which helps improve blood circulation, reduce spastic phenomena, and stimulate, and subsequently improve, intestinal motility. In addition, the early initiation of breathing exercises helps improve pulmonary ventilation, activates blood circulation and gas exchange, and reduces pulmonary congestion. An incentive spirometer can be used, which, in combination with early mobilization, reduces the incidence of cardiopulmonary complications, the length of hospital stay, and the number of pulmonary complications.

Comment: emptying begins with the relaxation of the sphincter and pelvic floor while softly increasing intra-abdominal pressure. A gradual increase in bladder capacity is achieved by lengthening the intervals between voiding. Voiding intervals can be progressively extended as the neobladder capacity increases until a voiding frequency of every 5-6 hours during the day and once at night is reached, thereby achieving its final functional capacity of approximately 150-200 ml to 400-500 ml. To assess effectiveness, residual urine volume should be periodically measured. If ineffective and a large amount of residual urine persists, the patient should be instructed on the possibility of performing intermittent self-catheterization [467].

Comment: massage is safe for cancer patients. To date, it is included in clinical guidelines for the supplementary management of pain in cancer patients [452].

4.4 Stage II and III rehabilitation

4.4.1 Rehabilitation during systemic antineoplastic therapy

Comment: implementing physical rehabilitation during systemic therapy for bladder cancer helps prevent fatigue and exhaustion: moderate-intensity physical exercises combining aerobic training, resistance exercises, and graded walking are indicated [456].

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

• Patients with bladder cancer receiving neurotoxic systemic antineoplastic therapy are recommended to perform exercise therapy incorporating coordination and fine motor skill maintenance exercises to prevent toxic peripheral polyneuropathy [457].

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

• Patients with bladder cancer receiving neurotoxic systemic antineoplastic therapy are recommended to undergo massage to reduce the risk of peripheral polyneuropathy [458].

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

4.4.2 Rehabilitation during radiotherapy

• Patients with bladder cancer receiving radiotherapy are recommended to perform resistance training to increase muscle strength and maintain muscle mass during treatment [459, 460].

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

• Patients with bladder cancer and radiation dermatitis developed during or after radiotherapy are recommended to receive low-level laser therapy for the management of this adverse event [461].

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

4.4.3 Rehabilitation after completion of therapy

• Patients with bladder cancer who have completed antineoplastic treatment are recommended lifestyle modifications (maintaining body weight, increasing physical activity, dietary adjustments, smoking cessation) to improve quality of life [462].

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

Comment: resection of the terminal ileum can lead to vitamin B₁₂ deficiency [433].

Comment: tibial neuromodulation is comparable in efficacy to sacral nerve stimulation for managing pelvic organ dysfunction [485].

Comments: currently, sanatorium-resort treatment can be prescribed to patients in clinical group III of dispensary follow-up who have received radical antineoplastic treatment, fully completed it, and have no signs of tumor recurrence or metastases. To refer a patient for medical rehabilitation, an oncologist from a specialized outpatient oncological facility must issue a medical certificate valid for 1 month, signed by the head of the department. This certificate shall indicate the primary diagnosis and the clinical group of dispensary follow-up confirmed by the results of a comprehensive follow-up examination. 1–2 months after completing the course of medical rehabilitation at a sanatorium-resort facility, the patient must appear for a follow-up examination by the oncologist at the outpatient facility where they are registered. 3–6 months after completing radical treatment, patients may be referred to local sanatoriums or resorts in their permanent climate zone at any time of the year. For residents of northern regions, southern resorts are recommended during the winter period and no earlier than 6–12 months after completing radical treatment. Patients are not recommended to be referred to resorts with an unfavorable clinical weather class characterized by pronounced seasonal and daily abrupt weather fluctuations, resorts with thermal springs, or climates with high temperatures, elevated humidity, and high ultraviolet radiation intensity.

5. Prevention and Dispensary Observation

5.1 Disease prevention

Preventive measures for bladder cancer have not been established.

5.2 Dispensary monitoring

Comments: in accordance with Order of the Ministry of Health of the Russian Federation No. 548n dated June 4, 2020, "On approval of the procedure for dispensary follow-up of adults with oncological diseases," patients with upper tract urothelial carcinoma are assigned to dispensary follow-up group (2-DN-onko). The category of monitored patients consists of individuals with a confirmed diagnosis of malignant neoplasms.

5.2.1 Follow-up after radical treatment of patients with bladder cancer

5.2.1.1 Follow-up after treatment of patients with non-muscle-invasive bladder cancer

• For the early detection of recurrence, recommended follow-up is carried out for patients cured of non-muscle-invasive bladder cancer. The intensity of follow-up varies depending on the risk and expected time of recurrence [349].

  o Low-risk group: in the first year after transurethral resection of the bladder — cystoscopy at 3 and 12 months, then annually for 5 years, followed by clinical indications.

  o Intermediate-risk group: in the first year after transurethral resection of the bladder — cystoscopy and urine cytology at 3, 6, and 12 months, in the second year — every 6 months, then annually for 5 years, followed by clinical indications.

  o High-risk group, including the highest-risk subgroup: in the first 2 years after transurethral resection — cystoscopy and urine cytology every 3 months, years 3–5 — every 6 months, then annually, after 10 years of follow-up — based on clinical indications. Contrast-enhanced CT of the abdomen and pelvis — at 12 months, then every 1 year up to 10 years, followed by clinical indications [127, 281].

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

5.2.1.2 Follow-up of patients cured of muscle-invasive bladder cancer T2-T4aN0-N1M0

• For the timely detection of recurrence, it is recommended to conduct dynamic monitoring of patients with muscle-invasive bladder cancer who underwent radical cystectomy or achieved a complete response after radiotherapy [142, 146, 147, 148, 149, 150, 151, 152, 358].

  After radical cystectomy with or without perioperative therapy:

  o Contrast-enhanced CT or MRI of the abdomen and pelvis, and chest CT — every 3 months for 2 years, then every 6 months up to 5 years; for the next 5 years, annual ultrasound of the abdominal cavity, retroperitoneum, and pelvis is indicated;

  o Urine cytology every 6 months for 2 years, then based on clinical indications;

  o Physical examination, complete blood count, and blood chemistry, including assessment of renal function if chemotherapy was administered, every 3 months for 1 year, then based on clinical indications.

  After radiotherapy with or without radiosensitizing chemotherapy:

  o Contrast-enhanced CT or MRI of the abdomen and pelvis, and chest CT — every 3–6 months for 2 years, then annually up to 5 years;

  o Cystoscopy — every 3 months for 2 years, every 6 months for years 3 and 4, then annually up to 10 years;

  o Urine cytology every 6 months for 2 years, then based on clinical indications;

  o Physical examination, complete blood count, and blood chemistry — every 3 months for 2 years, then based on clinical indications [142, 146, 147, 148, 149, 150, 151, 152, 358].

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

Comment: the follow-up schedule is based on the frequency and localization of disease recurrence in patients with muscle-invasive bladder cancer who received radical treatment [143, 147, 148, 149, 150, 151, 152, 358].

5.3 Monitoring during treatment of patients with advanced bladder cancer

Treatment monitoring is performed to assess efficacy and toxicity, and includes periodic physical examination and assessment of various symptoms, laboratory data, and instrumental imaging results. Response assessment should be carried out after every 2–3 cycles of chemotherapy using physical examination, symptom review, cystoscopy, and urine cytologic examination (in patients with the bladder in place), as well as instrumental imaging modalities used at the initial staging. CT of the chest, CT or MRI of the abdomen, retroperitoneal space, and pelvis are performed at least once every 3 months or more frequently based on clinical indications.

Comments: this monitoring schedule is adopted from RCTs of drug therapy regimens with proven efficacy in bladder cancer.

6. Organization of Medical Care

Medical care, with the exception of medical care within clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting Public Health 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 body and mandatory within the territory of the Russian Federation for 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 ambulatory cancer care center or at a primary oncology office or outpatient department of an oncological dispensary (cancer hospital) shall not exceed the timeframe established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation. The oncologist of the ambulatory cancer care center (in the absence of an ambulatory cancer care center, the oncologist of the primary oncology office or outpatient department of the oncological dispensary (cancer hospital)) arranges for the acquisition of biopsy (surgical) material, as well as the performance of other diagnostic tests necessary to establish a 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 turnaround time for pathomorphological examinations required for the histological verification of malignant neoplasms shall not exceed the timeframe established in the state guarantee program for free medical care to citizens, approved by the Government of the Russian Federation.

The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

The diagnosis of an oncological disease is established by 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.

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 a pathologo-anatomical bureau (department) of the fourth group (reference center) via information interaction, including the use of telemedical 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, excluding high-tech, medical care in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated by the procedure for referring patients to medical organizations and other entities subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as provided in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care. If several federal medical organizations participate in the implementation of the Program, 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.

Waiting times 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 for citizens, approved by the Government of the Russian Federation.

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

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

Palliative medical care for a patient with oncological diseases is provided in accordance with the 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 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 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.

The first stage of medical rehabilitation for cancer patients must be carried out in structural subdivisions of a medical organization providing specialized, including high-tech, inpatient medical care in the following profiles: "anesthesiology and intensive care", "oncology". The second stage of medical rehabilitation should be carried out during the provision of specialized, including high-tech, inpatient medical care in a medical rehabilitation department for patients with somatic diseases, established in medical organizations, including medical rehabilitation centers and sanatorium-resort organizations. The third stage of medical rehabilitation must be carried out during the provision of primary health care in outpatient settings and/or in day care settings (outpatient medical rehabilitation department, day care medical rehabilitation department), including in medical rehabilitation centers and sanatorium-resort organizations [427].

7. Additional Information

7.1 Prognostic factors in patients with bladder cancer

The most significant factors for NMIBC determining the likelihood of recurrence and progression are: number of tumors, their size, history of recurrence rates, T category, presence of concomitant CIS, and tumor grade.

Independent factors negatively affecting overall survival during chemotherapy are: Karnofsky performance status < 80 %, ECOG score ≤ 2, (Appendix G1 and G2), and the presence of visceral metastases.

Adverse prognostic factors during 2nd-line chemotherapy include: ECOG performance status > 1 (Appendix G1), hemoglobin level < 10 g/dL. Another additional factor of prognostic significance during 2nd-line chemotherapy is the efficacy of 1st-line therapy and a progression-free survival of more than 12 months after its administration. Accordingly, re-administering chemotherapy 12 months after a previously achieved response from the prior line may be a justified treatment strategy for patients with favorable prognostic characteristics.

7.2 Molecular non-invasive diagnostics with the determination of protein and cytogenetic tumor markers in urine

Comments: considering the ambiguous sensitivity and specificity of urine cytology, a number of urine markers have been proposed for use [65]. However, none of them is currently used in routine practice or specified in clinical guidelines. Table 5 presents some diagnostic urine tests whose results have been evaluated in various clinical studies with a sufficient number of patients [66, 67, 68].

Table 5. Brief information on main markers detected in urine

OSens – overall sensitivity, OSpec – overall specificity

Available data based on the results of evaluating various test systems allow the following conclusions:

• Sensitivity is usually higher due to lower specificity compared to urine cytology [69, 70, 71, 72, 73].

• Benign processes and prior intravesical instillations of BCG** vaccine for bladder cancer treatment can affect the results of many urine marker tests [69, 70].

• Requirements for the sensitivity and specificity of a urine marker test largely depend on the clinical picture (screening, primary process, follow-up [risk group: high risk, low or intermediate]) [70, 71, 72, 73, 74].

• Positive results of cytological analysis, FISH test, nuclear matrix protein 22, and microsatellite analysis in patients with negative cystoscopy and upper urinary tract CT data make it possible to identify the occurrence of recurrence and, possibly, progression with greater probability [75, 76, 77, 78, 79, 80].

Molecular genetic research methods are used in the laboratory diagnostics of bladder cancer mainly to solve three practical tasks: refined non-invasive diagnosis of NMIBC recurrence to reduce the number of unnecessary cystoscopies with biopsies, identification of molecular targets in metastatic bladder cancer for targeted therapy, and diagnosis of rare hereditary forms of bladder cancer [133].

Test systems for the non-invasive diagnosis of bladder cancer and its recurrence in urine are in most cases a combined test for several frequent bladder cancer mutations (FGFR3, TERT), aberrantly hypermethylated genes, RNA expression, and/or protein tumor markers. These tests are primarily intended for refined diagnostics during the monitoring of NMIBC recurrence in narrow cohorts of patients characterized by low sensitivity of cytological analysis (small high-grade tumors, hematuria) [134, 135, 136, 236, 243, 245].

However, multicenter studies with these test systems have not yet been conducted; they are mainly used in an LDT format, and currently, molecular genetic test systems for the non-invasive diagnosis of bladder cancer are not included in current versions of leading foreign and domestic clinical guidelines (consensus documents).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kaprin Andrey Dmitrievich, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Honored Physician of the Russian Federation, General Director of the National Medical Research Radiological Center, 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 (Moscow, Russia).

2. Alekseev Boris Yakovlevich, Doctor of Medical Sciences, Professor, Deputy Director for Science at the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Matveev Vsevolod Borisovich, Corresponding Member of the RAS, Professor, Doctor of Medical Sciences, Deputy Director for Science and Innovation and Head of the Urology Department at the National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health, President of the Russian Society of Onkourology.

4. Volkova Maria Igorevna, Doctor of Medical Sciences, Oncology Center No. 1 of the City Clinical Hospital named after S.S. Yudin of the Moscow Healthcare Department, Professor at the Department of Oncology and Palliative Medicine of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

5. Andreeva Yulia Yuryevna, Doctor of Medical Sciences, Pathologist, Professor at the Department of Pathological Anatomy of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

6. Belokhvostova Anna Sergeevna, Candidate of Medical Sciences, Head of the Antineoplastic Drug Therapy Department at the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Associate Professor at the Department of Radionuclide Medicine of IATE MEPhI.

7. Bolotina Larisa Vladimirovna, Doctor of Medical Sciences, Professor of the RAS, Head of the Chemotherapy Department at the Tumor Drug Treatment Division of the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

8. Bulychkin Petr Vladislavovich, Candidate of Medical Sciences, Radiation Oncologist, Senior Researcher at the Radiotherapy Department of the Research Institute of Clinical and Experimental Radiology of the National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health.

9. Gameeva Elena Vladimirovna, Doctor of Medical Sciences, Director of the M.F. Vladimirsky Moscow Regional Research Clinical Institute (MONIKI).

10. Govorov Alexander Viktorovich, Doctor of Medical Sciences, Professor at the Department of Urology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health (Moscow, Russia), Russian Society of Urology.

11. Golovashchenko Maxim Petrovich, Candidate of Medical Sciences, Researcher, Oncologist at the Urology Department of the Reproductive and Urinary Tract Tumors Division of the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

12. Gorban Nina Andreevna, Candidate of Medical Sciences, Head of the Center for Pathomorphology and Molecular Genetic Diagnostics at the Central Clinical Hospital with Policlinic of the Executive Directorate of the President of the Russian Federation, Russian Society of Oncopathologists.

13. Gordon Konstantin Borisovich, Candidate of Medical Sciences, Radiation Oncologist, Radiologist, Leading Researcher at the Proton and Photon Therapy Department of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

14. Kamolov Bakhodur Sharifovich, Candidate of Medical Sciences, Executive Director of the Russian Society of Onkourology, President of the "Together Against Cancer" Anti-Cancer Organizations Support Foundation, Journalist, Member of the Union of Journalists of Russia, International Federation of Journalists.

15. Karyakin Oleg Borisovich, Doctor of Medical Sciences, Head of the Department of Radiation and Surgical Treatment of Urological Diseases with a Prostate Cancer Brachytherapy Group at the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Russian Society of Clinical Oncology.

16. Mikhaylenko Dmitry Sergeevich, Candidate of Medical Sciences, Associate Professor, Head of the Department of Oncogenetics at the Institute of Higher and Additional Professional Education of the Academician N.P. Bochkov Research Centre for Medical Genetics; Head of the Oncogenetics Working Group of the Russian Society of Medical Geneticists.

17. Moskvina Larisa Vyacheslavovna, Candidate of Medical Sciences, Pathologist, Head of the Department of Pathological Anatomy at Clinical Hospital No. 1 (Volynskaya) of the Administrative Directorate of the President of the Russian Federation.

18. Nosov Dmitry Alexandrovich, Doctor of Medical Sciences, Professor, Head of the Oncology Department at the Central Clinical Hospital with Polyclinic of the Administrative Directorate of the President of the Russian Federation (Moscow, Russia), Russian Society of Clinical Oncology.

19. Nyushko Kirill Mikhailovich, Doctor of Medical Sciences, Oncologist, Leading Researcher at the Onkourology Department of the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

20. Paichadze Anna Alexandrovna, Candidate of Medical Sciences, Head of the Combined Treatment Department No. 1 at the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

21. Pushkar Dmitry Yuryevich, Academician of the RAS, Doctor of Medical Sciences, 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 (Moscow, Russia), Chief Urologist of the Russian Ministry of Health, Russian Society of Urology.

22. Rubtsova Natalia Aleftinovna, Doctor of Medical Sciences, Head of the Diagnostic Radiology Department, Radiologist at the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

23. Safiullin Kadir Nazipovich, Doctor of Medical Sciences, Leading Researcher at the Department of Radiation and Surgical Treatment of Urological Diseases with a Prostate Cancer Brachytherapy Group at the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

24. Smolyarchuk Maxim Yaroslavovich, Radiologist, Expert at the Advisory Department of the Moscow Center for Diagnostics and Telemedicine of the Moscow Healthcare Department. President of the Regional Public Organization "Nuclear Medicine Society".

25. Stepanova Alexandra Mikhailovna, Candidate of Medical Sciences, Chief Medical Officer of the M.F. Vladimirsky Moscow Regional Research Clinical Institute (MONIKI).

26. Falaleeva Natalia Alexandrovna, Doctor of Medical Sciences, Head of the Department of Drug Treatment for Malignant Neoplasms at the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

27. Kharchilava Revaz Revazovich, Candidate of Medical Sciences, Director of the "Praxi Medica" Medical Practice Training Center, I.M. Sechenov First Moscow State Medical University.

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

29. Shevchuk Irina Musaevna, Candidate of Medical Sciences, Oncologist, Leading Researcher at the Onkourology Department of the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

Supportive Care Section:

1. Gladkov Oleg Alexandrovich, Professor, Doctor of Medical Sciences, Director of EVIMED Medical Center LLC.

Healthcare Organization Section:

1. Ivanov Sergey Anatolyevich, Doctor of Medical Sciences, Professor, Corresponding Member of the RAS, Honored Doctor of the Russian Federation, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Chief Freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

2. Khailova Zhanna Vladimirovna, Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work at the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Gevorkyan Tigran Gagikovich, Deputy Director for Federal Project Implementation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

4. Komarov Yury Igorevich, Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work at the N.P. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

5. Fomenko Yury Alexandrovich, PhD, Deputy General Director for Clinical and Expert Work, National Medical Research Center of Oncology of the Russian Ministry of Health.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines: specialists with higher medical education in the following specialties:

1. Urologists.

2. Oncologists.

3. General practitioners.

4. General practitioners (family physicians).

5. Surgeons.

6. Anesthesiologists-resuscitators.

7. Radiologists.

8. Radiation oncologists.

9. Pathologists.

10. Medical students, residents, and postgraduate students.

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

Table 6. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 7. Levels of Evidence grading scale for prevention, treatment, and rehabilitation methods, including those based on natural healing factors (preventive, therapeutic, and rehabilitative interventions)

Table 8. Grades of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

Appendix A3.1 Regulatory and legal documents used to develop the clinical guidelines

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

1. European Association of Urology Guidelines.

2. Order of the Russian Ministry of Health No. 203n dated April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care."

3. 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", with amendments and additions dated January 24, 2022.

4. 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".

5. Order of the Russian Ministry of Health No. 188n dated March 11, 2021, "On Approval of Standards of Medical Care for Adults with Bladder Cancer".

6. Resolution 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".

7. 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 Ministry of Justice of Russia on May 8, 2019, No. 54588).

8. 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.

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

Appendix A3.2 Drug therapy regimens used in bladder cancer

Appendix A3.2.1 Drug therapy regimens used in NMIBC

Intravesical therapy regimens

• BCG vaccine for bladder cancer treatment**: 50–100 mg of the vaccine diluted in 50 ml of 0.9% sodium chloride solution**, administered intravesically for 2 hours with the recommendation to change body position every 15 minutes. The 50 mg dose is intended for patients with poor individual tolerance to therapy. The induction treatment course is administered according to the schedule: weekly for 6 weeks. The maintenance treatment course is administered according to one of the following schedules:

  • monthly for 12 months;

  • 3 weekly instillations of the drug at months 3, 6, 12, 18, 24, 30, and 36;

  • monthly for 36 months.

• #Gemcitabine** 2000 mg in 50 ml of 0.9% sodium chloride solution**; intravesically for 1 hour, once a week, for 6 weeks.

• Doxorubicin** 30–40 mg in 50 ml of 0.9% sodium chloride solution**; intravesically for 1 hour, once a week, for 6 weeks.

• Mitomycin 40 mg in 50 ml of 0.9% sodium chloride solution**; intravesically for 1 hour, once a week, for 6 weeks.

• #Gemcitabine** with #docetaxel**

  • #gemcitabine** 1000 mg in 50 ml of 0.9% sodium chloride solution**; administer intravesically, exposure time – 90 min., empty the bladder;

  • docetaxel** 40 mg in 50 ml of 0.9% sodium chloride solution**; administer intravesically immediately after evacuating the gemcitabine solution, exposure time – 90 min.

Perform #gemcitabine** and #docetaxel** instillations weekly for 6 weeks, then monthly for 2 years.

Systemic therapy regimens

• Pembrolizumab** 200 mg once every 3 weeks or 400 mg once every 6 weeks IV drip for 24 months or until disease progression or unacceptable toxicity.

Appendix A3.2.2 Drug therapy regimens used for MIBC and in first-line therapy of advanced BC

Table 9. First-line systemic antineoplastic therapy

¹ECOG PS > 1; GFR ≤ 60 ml/min/1.73 m^2; hearing loss ≥ grade 2; peripheral neuropathy ≥ grade 2; NYHA class II–IV heart failure.

² EORTC 30986 clinical trial criteria (PS ECOG > 2; GFR < 30 ml/min/1.73 m^2; ECOG PS 2 and GFR < 60 ml/min/1.73 m²).

³Tumor control – absence of progression (complete or partial response or stabilization of the tumor process).

⁴For atezolizumab, positive expression is defined as ≥ 5% (Ventana PD-L1 (SP142) Assay® (Ventana Medical Systems, Inc.))

⁵For pembrolizumab, positive expression is defined as ≥ 10% (Dako PD-L1 IHC 22C3 PharmDx Assay test system (Dako North America, Inc.))

Appendix A3.2.3 Radiomodifying drug therapy regimens used in MIBC and advanced BC

• #cisplatin** 100 mg/m² IV on days 1, 15, and 29;

• #cisplatin** 40 mg/m² IV weekly for 6 administrations;

• #gemcitabine** 27 mg/m² IV on days 1 and 4 of each week (interval of at least 72 hours);

• #cisplatin** 15 mg/m² IV on days 1–3, 8–10, and 15–17 + fluorouracil** 400 mg/m¹ IV on days 1–3, 8–10, and 15–17.

Appendix A3.2.4 Drug therapy regimens used in second- and subsequent-line therapy of advanced BC

Table 10. Second- and subsequent-line systemic antineoplastic therapy.

Appendix B. Physician Action Algorithms

Appendix B1. Treatment algorithms for patients with bladder cancer

Figure 1. Treatment algorithm for patients with non-muscle-invasive bladder cancer (Tis-T1N0M0).

^are-induction of platinum-based chemotherapy is permissible if tumor control was previously achieved with platinum-based chemotherapy completed ≥ 6 months ago.

Appendix C. Patient Information

The patient is informed about the clinical presentation of BC, introduced to various treatment methods, their potential outcomes, and complications.

The patient should be informed about the symptoms and various complications of BC. It is especially important to warn patients with metastatic spinal lesions about potential spinal cord compression to ensure immediate medical consultation if this complication occurs.

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

Patients with metastatic BC should be informed about clinical trials currently conducted in the Russian Federation for patients with this disease stage.

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

Recommendations for chemotherapy complications – contact your doctor!

1) If body temperature rises to 38°C or higher, antimicrobial therapy is recommended as prescribed by a physician.

2) For stomatitis:

• Diet – mechanical and thermal sparing;

• Frequent mouth rinsing (every hour) with chamomile, oak bark, or sage decoction; apply sea buckthorn (or peach) oil to the oral mucosa;

• Treat the oral cavity as prescribed by a physician.

3) For diarrhea:

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

• Take medications as prescribed by a physician.

4) For nausea:

• Take medications as prescribed by a physician.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian name: WHO/ECOG performance status scale.

Original name: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS) [249].

Type: rating scale.

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

Content (template):

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

Appendix G2. Karnofsky Performance Scale

Russian name: Karnofsky scale.

Original name: KARNOFSKY PERFORMANCE STATUS [249].

Type: rating scale.

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

Content (template):

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

Appendix G3. Criteria for evaluating solid tumor response to treatment

Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Russian title: Response Evaluation Criteria in Solid Tumors 1.1.

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

Source (official developer website, validation publication): [252].

Type: rating scale.

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

Content (template):

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

iRECIST criteria for evaluating solid tumor response to immunotherapy

Russian title: Immune-Related Response Evaluation Criteria in Solid Tumors.

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

Source (official developer website, validation publication): [237].

Type: rating scale.

Purpose: standardization of the evaluation of solid tumor response to immunotherapy.

Content (template):

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

Appendix G4. Scales for determining indications for rehabilitation methods in patients with bladder cancer

Rehabilitation Routing Scale (RRS) for somatic patients, including those with malignancies.

Source: Order of the Russian Ministry of Health No. 788n dated July 31, 2020, "On Approval of the Procedure for Organizing Medical Care for Medical Rehabilitation of Adults" [https://roszdravnadzor.gov.ru/medactivities/documents/74892].

Type: rating scale.

Purpose: assessment of the Rehabilitation Routing Scale score depending on the state of functioning and activity limitation.

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

Table 11. Rehabilitation Routing Scale (RRS) for somatic patients, including those with malignancies.

¹ Six-minute walk test

² Exercise Stress Tests

Table 12. Nutritional Risk Screening Scale (NRS 2002)

The European Society for Clinical Nutrition and Metabolism (ESPEN) recommends using the NRS-2002 (Nutritional Risk Screening, NRS) scale for screening assessment of nutritional risk, consisting of two stages. It is recommended for assessing the nutritional status of hospitalized patients [499].

Initial screening

Final screening

Notes:

1. Patient age 70 years or older — add 1 point to the total score.

2. More than 3 points — high risk of malnutrition, requiring the development of a nutritional support program.

3. Less than 3 points — repeat screening every week. If surgical treatment is planned, a preoperative preparation program is necessary.

MUST (Malnutrition Universal Screening Tool)

1. Body mass index, kg/m²

• > 20.0 — 0 points

• 18.5–20.0 – 1 point

• < 18.5 — 2 points

2. Unintentional weight loss in the preceding 3–6 months

• < 5% — 0 points

• 5–10% — 1 point

• > 10% — 2 points

3. Presence of an acute disease AND no food intake > 5 days / likelihood of no food intake > 5 days — 2 points

Key (interpretation):

0 points — low risk of malnutrition. Routine care. Repeat screening: in an inpatient setting — weekly; for independent community-dwelling individuals — annually for risk groups.

1 point — medium risk of malnutrition. Monitoring: inpatient setting — monitor food and fluid intake for 3 days, followed by repeat screening (dietary modification if necessary). Repeat screening: inpatient setting — weekly, at home — every 2–3 months.

≥ 2 points — high risk of malnutrition. Treatment of malnutrition: consultation with a clinical dietitian/rehabilitation specialist, additional protein and nutrient supplementation (sipping) as needed, dietary modification.