Upper Tract Urothelial Carcinoma: Clinical Guidelines

List of Abbreviations

PFS – progression-free survival

IV – intravenous

WHO – World Health Organization

IHC – immunohistochemical

CT – computed tomography

RT – radiotherapy

LN(s) ‒ lymph node(s)

ICD-11 – International Statistical Classification of Diseases and Related Health Problems, 11th Revision

MRI – magnetic resonance imaging

MSCT – multislice computed tomography

MSCTU – multislice computed tomography urography

AEs – adverse events

OS – overall survival

BC – bladder cancer

RNU – radical nephroureterectomy

LS – Lynch syndrome

UC – urothelial cancer

UTUC – upper tract urothelial carcinoma

ChT – chemotherapy

ORR – objective response rate

CIS (English carcinoma in situ) – carcinoma in situ

ECOG – PS (Eastern Cooperative Oncology Group performance status) – assessment of the general status of an oncological patient according to the Eastern Cooperative Oncology Group scale

FISH – fluorescence in situ hybridization

RECIST (Response Evaluation Criteria in Solid Tumors) – Response Evaluation Criteria in Solid Tumors

iRECIST (Immune-modified Response Evaluation Criteria in Solid Tumors) – immune-modified response evaluation criteria in solid tumors

** – Vital and Essential Drugs

# – off-label drug, not approved by state regulatory authorities, or not mentioned in the instructions for use, or used for an indication or other parameters of use (dosage form, dosing regimen, for a population) in a manner not mentioned in the approved instructions.

Terms and Definitions

Adjuvant chemotherapy – drug therapy performed after radical surgery, aimed at destroying distant micrometastases in order to increase relapse-free and overall patient survival.

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

Neoadjuvant chemotherapy – drug chemotherapy performed immediately before surgical removal of the primary tumor to improve the results of surgery or radiation therapy, and to prevent metastasis.

Nephroureterectomy – surgery to remove the kidney and the entire ureter (including the intramural part of the ureter), in some cases requiring simultaneous resection of the urinary bladder.

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

Third stage of rehabilitation (period of residual effects of the disease course) – rehabilitation in the early and late rehabilitation periods in departments (offices) of rehabilitation, physiotherapy, exercise therapy, reflexology, manual therapy, psychotherapy, medical psychology, speech therapy (teacher-defectologist) offices providing medical care on an outpatient basis, as well as by mobile teams at home.

MMR (mismatch repair deficiency) – mismatch repair system for incorrectly incorporated undamaged unpaired nucleotides.

PD-1 – programmed cell death protein 1.

PD-L1 – programmed cell death 1 ligand 1.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

In terms of prevalence among malignant tumors, urothelial cancer (UC) ranks 4th after prostate, breast, lung, and colorectal cancer [1]. This type of tumor can occur both in the lower urinary tract (bladder or urethra) and the upper tract (renal collecting system or ureter).

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

Upper tract urothelial carcinoma (UTUC) is a more aggressive type of tumor by nature: thus, 60% of UTUC cases present with invasive forms at the time of diagnosis, and 7% of patients have metastases, whereas in bladder cancer (BC), invasive forms occur in 15–25% of cases [2, 3]. The peak incidence occurs at 70–90 years, with UTUC being 3 times more common in men than in women [4].

Hereditary cases of UTUC are associated with hereditary non-polyposis colorectal cancer [5]. Patients with a confirmed high risk of developing non-polyposis colorectal cancer should undergo DNA sequencing, as should their family members [6]. In 98% of patients with UTUC associated with Lynch syndrome (LS), immunohistochemical (IHC) analysis reveals a gene mutation that leads to the loss of expression of the protein responsible for predisposition to defects in the mismatch repair (MMR) system (microsatellite instability was noted in 46% of patients, and microsatellite stability in 54%) [7]. Most tumors developed in carriers of the MSH2 gene mutation [8].

Currently, a number of environmental factors influence the development of UTUC [9], however, published data confirming the role of these factors are insufficiently reliable, except for the influence of smoking and aristolochic acid.

Smoking increases the risk of developing UTUC by 2.5 to 7 times [10]. Occupational activities associated with certain aromatic amines (paint and varnish, textile, chemical, petroleum, and coal industries) also serve as a risk factor [9]. In people employed in such industries, the carcinogenic effect of certain chemicals (benzidine and β-naphthylamine) is realized. Exposure is about 7 years (latency period up to 20 years). The risk of developing UTUC after contact with aromatic amines increases 8-fold [9].

Aristolochic acid, a nitrophenanthrenecarboxylic acid produced by plants of the genus Aristolochia, exerts multiple effects on the urinary tract. Aristolochic acid irreversibly damages the proximal renal tubules, leading to chronic tubulointerstitial nephritis, while the mutagenic properties of this chemical carcinogen lead to the development of UTUC [11, 12]. Aristolochic acid is also associated with the development of bladder cancer, kidney cancer, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma [13]. There are 2 known routes of entry of aristolochic acid into the human body: contamination of agricultural products by plants of the genus Aristolochia (birthwort) (e.g., cases of Balkan endemic nephropathy [14]) and the use of remedies based on these plants [15, 16]. Aristolochia herbs are used worldwide, especially in traditional Chinese medicine and in Taiwan [12]. Less than 10% of people exposed to aristolochic acid develop UTUC [11].

1.3 Epidemiology of the Disease or Condition

Urothelial cancer is most commonly represented by bladder cancer (90–95%), while UTUC is much less frequent (5–10%) [17, 18, 19]; in Western countries, the annual incidence of UTUC is nearly 2 cases per 100,000 population. Over the past few decades, this figure has increased due to better detection and increased survival of bladder cancer patients [2]. Renal pelvis tumors occur twice as frequently as ureteral tumors. Concomitant carcinoma in situ (carcinoma in situ, CIS) of the upper urinary tract is diagnosed with a frequency of 11 to 36% [2]. Bladder cancer is also detected in 17% of patients with UTUC [20]. Bladder recurrence occurs in 31–50% of patients suffering from UTUC [21], whereas contralateral pelvic recurrence occurs in only 2–6% of cases [22].

1.4 Features of Coding the Disease or Condition

According to ICD-11, such neoplasms are classified according to the organ of primary origin of the neoplasm:

• C65 – malignant neoplasm of renal pelvis;

• C66 – malignant neoplasm of ureter.

1.5 Classification of the disease or condition

Histological types

More than 95% of urothelial tumors develop from the urothelium and belong to upper tract urothelial carcinoma (UTUC) or bladder cancer. As for UTUC, morphological variants are described as more commonly encountered in renal urothelial tumors. These variants are high-grade tumors and correspond to one of the following variants: micropapillary, clear cell, neuroendocrine, or lymphoepithelial. Collecting duct carcinoma shares similar characteristics with UTUC due to a common embryological origin.

Upper urinary tract tumors with non-urothelial morphological structure are quite rare. Epidermoid carcinoma of the upper urinary tract is diagnosed in less than 10% of cases of pelvicalyceal system tumors and is even rarer in ureteral tumors. Other morphological types include adenocarcinoma (<1%), neuroendocrine carcinoma, and sarcoma.

Classification

The classification and morphology of UTUC are similar to those of bladder cancer [17]. Non-invasive papillary tumors are distinguished: papillary urothelial carcinoma with low-grade or high-grade malignant potential, flat lesions (CIS), and invasive carcinoma. All variants of urothelial tumors described for the urinary bladder can also occur in the upper urinary tract.

TNM Classification of Malignant Tumors, Union for International Cancer Control, 2017 (8th edition)

According to the TNM classification (tumor, node, and metastasis), regional lymph nodes (LNs) are considered to be the renal hilar, para-aortic, paracaval LNs, and for the ureter – pelvic LNs. The side of the lesion does not affect the N classification.

Disease Staging

Staging of renal pelvis and ureter tumors is carried out in accordance with the 8th edition of the AJCC/UICC TNM classification (American Joint Committee on Cancer, AJCC; Union Internationale Contre le Cancer, UICC).

• T category (primary tumor)

o Tx – primary tumor cannot be assessed;

o T0 – no evidence of primary tumor;

o Ta – non-invasive papillary carcinoma;

o Tis – CIS;

o T1 – tumor invades subepithelial connective tissue;

o T2 – tumor invades muscular layer;

o T3 – (renal pelvis) tumor extends beyond the muscular layer into the peripelvic adipose tissue or renal parenchyma; (ureter) tumor extends beyond the muscular layer into the periureteral adipose tissue;

o T4 – tumor invades adjacent organs or penetrates through the kidney into the paranephric adipose tissue.

• N category (regional lymph nodes)

o Nx – regional LNs cannot be assessed;

o N0 – no regional LN metastases;

o N0 – absence of regional metastases;

o N1 – metastasis in a single LN 2 cm or less in greatest dimension;

o N2 – metastasis in a single LN greater than 2 cm or multiple LN metastases.

• M category (distant metastases)

o M0 – no distant metastases;

o M1 – distant metastases present.

The correlation of tumor stages according to TNM categories is presented in Table 1.

Table 1. Correlation of tumor stage with TNM categories

1.6 Clinical presentation of the disease or condition

The diagnosis of UTUC can be established based on symptoms or detected incidentally. The most common symptom is macro- or microhematuria, detected in 70–80% of cases [23, 24].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition based on:

1. anamnesis;

2. physical examination;

3. laboratory tests;

4. instrumental examination;

5. morphological examination.

Clinical diagnosis is based on the results of:

1. detection of a contrast-enhancing neoplasm of the renal pelvis, ureter, or calyces (using instrumental examination methods);

2. verification of a malignant neoplasm according to the morphological examination report of the biopsy and/or surgical specimen of the tumor.

Surgical treatment is also possible in the absence of morphological verification: in patients with identified solid contrast-enhancing neoplasms of the renal pelvis, ureter, or calyces on optimal imaging studies – contrast-enhanced computed tomography (CT) and/or contrast-enhanced magnetic resonance imaging (MRI).

2.1 Complaints and Anamnesis

Comment: the diagnosis of UTUC can be established based on symptoms or detected incidentally. The most common symptom is macro- or microhematuria, detected in 70–80% of cases [23, 24].

2.2 Physical Examination

Comment: flank pain is observed in approximately 20% of cases, and a palpable lumbar mass in about 10% of patients [26, 27]. Systemic symptoms (including anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough) associated with UTUC should raise suspicion and prompt a more thorough evaluation for metastatic disease, and they are also associated with a poorer prognosis [26, 27].

2.3 Laboratory Diagnostics

Comment: a positive urine cytology result allows for the suspicion of UTUC, provided that cystoscopy revealed no abnormalities and bladder and prostatic urethral CIS have been excluded [17]. In the diagnosis of UTUC, cytology has lower sensitivity than in bladder cancer, even for high-grade tumors, and ideally should be performed in situ (i.e., from the renal pelvis). A positive cytology result may aid in staging, as it is associated with muscle invasion and extrarenal spread of the tumor process.

The detection of molecular alterations using FISH is becoming increasingly popular for urothelial carcinoma screening, but the results are still preliminary. The use of FISH may be limited by the predominance of well-differentiated recurrent tumors in the patient population after organ-sparing surgery. Consequently, FISH currently has limited value as a monitoring method for UTUC [29, 30].

2.4 Instrumental Diagnostics

Comment: MSCTU is considered the "gold standard" for upper urinary tract imaging, replacing excretory urography (this study should be performed under optimal conditions, particularly including the excretory phase, and spiral scanning (with a 1 mm pitch) must be performed before and after contrast administration).

The detection rate of UTUC is considered sufficient for studies of this type: sensitivity is 96%, and specificity is 99% for polypoid tumors measuring 5 to 10 mm [26]. Sensitivity drops to 89% for polypoid tumors measuring less than 5 mm and is 40% for tumors measuring less than 3 mm. MSCT urography (MSCTU) can also be used to assess the wall thickness of the renal pelvis or ureter when UTUC is suspected. The main difficulty remains the identification of flat lesions, which are undetectable until massive infiltration develops.

It has been shown that the detection of hydronephrosis during the preoperative evaluation is associated with an advanced pathological process and poorer oncological outcomes [35]. The presence of enlarged lymph nodes is a predictor of an unfavorable prognosis in UTUC [36].

Comment: chest MSCT may be substituted with chest radiography if the optimal diagnostic imaging modality cannot be performed within 4 weeks.

Comment: MRI is indicated for patients in whom MSCTU cannot be successfully performed. The detection rate of UTUC by MRI is 75% (with contrast administration for tumors smaller than 2 cm). However, contrast-enhanced MRI is contraindicated in certain patients with impaired renal function (creatinine clearance less than 30 mL/min) due to the risk of nephrogenic systemic fibrosis. Non-contrast MRI is considered less valuable for the diagnosis of UTUC compared to MSCTU [39].

Comment: ureteroscopy is the best method for diagnosing UTUC. Using a flexible ureteroscope, the ureter and major renal calyces can be macroscopically visualized in 95% of cases, the tumor appearance can be assessed, a biopsy can be performed, and the tumor grade can be determined in 90% of cases with a low false-negative rate. This method also allows for obtaining material for cytological examination directly from the ureter and performing a retrograde pyelogram [41]. Flexible ureteroscopy is particularly useful in diagnostics for patients scheduled for kidney-sparing treatment and in patients with a solitary kidney. Data on tumor grade from biopsy during ureteroscopy, ipsilateral hydronephrosis, and urine cytology results can help guide the decision regarding radical nephroureterectomy (RNU) or endoscopic treatment. Nevertheless, recent studies suggest a higher rate of intravesical recurrence following RNU in patients who underwent diagnostic ureteroscopy prior to surgery [42, 43].

Technical developments in flexible ureteroscopy and the use of new imaging techniques improve the detection of flat lesions [44]. Narrow-band imaging (NBI) serves as a promising technique, although these findings are still preliminary [45–47].

2.5 Other Procedures

Comments: hereditary upper tract urothelial cancer occurs in an unselected cohort of patients with a frequency of about 0.5–1% and is mostly related to manifestations of Lynch syndrome (LS) – a hereditary cancer syndrome caused by a mutation in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS1, PMS2, or EpCAM. In decreasing order of frequency, colorectal cancer, endometrioid cancer, ovarian cancer, gastric cancer, urothelial carcinomas of various parts of the urinary system, prostate cancer, and certain other tumor types are described in this syndrome. Upper tract urothelial cancer most frequently develops with mutations in MSH2. A hereditary nature of the disease may be indicated by the patient's young age, an unfavorable family history of cancer, multiple primary tumors, and neoplasms in other target organs of LS in the patient's history. Molecular genetic diagnostics consist of analyzing microsatellite instability, a high level of which (MSI-H status – high-level microsatellite instability) is considered as probable confirmation of the disease. The minimal panel of 5 mononucleotide STR markers (short tandem repeats), often used in colorectal cancer, has insufficient sensitivity in tumors of other types. Therefore, MSI-H status in urothelial carcinomas should be determined using immunohistochemical (IHC) analysis to detect the loss of expression of one of the key mismatch repair proteins: MLH1, MSH2, MSH6, or PMS2 [48]. In cases where MSI-H is detected, the most informative genetic test is the determination of germline mutations in candidate LS genes using high-throughput sequencing (next-generation sequencing, or NGS) of an MMR gene panel. In individual cases, upper tract urothelial cancer may develop in carriers of germline mutations in the BRCA1/2, MUTYH, RB1, and other genes. If a young patient does not meet the diagnostic criteria for LS, exome or multi-gene cancer panel NGS may be performed [49].

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

3.1. Surgical treatment

Comment: surgical intervention performed 45 days or more from the time of diagnosis increases the risk of disease progression [50].

3.1.1. Treatment of patients with urothelial carcinoma of the renal collecting system without distant metastases

3.1.1.1. Organ-sparing surgical treatment

o with solitary tumors <1.5 cm with papillary LG UTUC histology and cTa–T1 collecting system stage [25, 51, 52];

o with bilateral renal pelvis tumors, tumors of the collecting system of a solitary kidney or a single functioning kidney, severe chronic kidney disease, and hereditary syndromes associated with a high risk of upper urinary tract tumors (primarily Lynch syndrome) [25, 51, 52].

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

Comment: According to a systematic literature review, organ-sparing endoscopic surgical treatment for low-grade (LG) UTUC provides oncological outcomes comparable to nephroureterectomy and bladder resection while preserving renal function [53]. The choice of treatment method is determined based on technical limitations and the surgeon's expertise. Endoscopic electroresection/laser coagulation is the most convenient approach for organ-sparing treatment of tumors in the renal pelvis and the middle and upper calyx groups, requiring a flexible ureteroscope for adequate execution [52, 54]. Renal pelvis and lower calyx Ta–T1 LG tumors that cannot be accessed pyeloscopically due to insufficient deflection of the distal tip of the ureteropyeloscope may be considered an indication for percutaneous electroresection/ablation. Percutaneous access is associated with a higher risk of tumor dissemination compared to endoscopic access [52, 55].

3.1.1.2. Radical nephroureterectomy with resection of the ureteral orifice

o for upper and middle ureteral tumors with cT >T1 and/or high grade (HG);

o when organ-sparing surgery is not technically feasible [52].

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

Comment: The incidence of regional lymph node metastasis in UTUC depends on the T category and tumor grade, being 2.2% for Ta–T1 and 0% for LG tumors [63, 66]. In cases where adequate preoperative T staging and/or grading is not feasible, the decision regarding lymph node dissection is made on an individual basis.

The therapeutic role of lymph node dissection in patients with UTUC has not been definitively proven; however, adequate staging of the tumor via histological examination of lymph node specimens allows for the selection of candidates for adjuvant therapy with proven efficacy (see below).

Optimal LND boundaries have not been defined. According to a single study, for UTUC of the right renal collecting system, dissection of paracaval lymph nodes from the crura of the diaphragm to the inferior mesenteric artery is recommended; for UTUC of the left renal collecting system, para-aortic lymph nodes from the crura of the diaphragm to the inferior mesenteric artery are recommended [68].

3.1.2. Organ-sparing treatment

o with solitary ureteral tumors <1.5 cm with papillary LG UTUC histology and cTa–T1 stage [25, 51, 52];

o with bilateral upper tract tumors, ureteral tumors in a solitary kidney or single functioning kidney, severe chronic kidney disease, and hereditary syndromes associated with a high risk of upper urinary tract tumors (primarily Lynch syndrome) [25, 51, 52].

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

o with Ta–T1 LG UTUC of the upper and middle ureter in whom endoscopic surgery is not feasible;

o with UTUC of the lower third of the ureter regardless of T category and grade;

o with ureteral tumors in the setting of severe chronic kidney disease or hereditary syndromes associated with a high risk of upper urinary tract tumors (primarily Lynch syndrome) [25, 51, 52].

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

Comment: Ureteral resection must be performed within visually normal tissue margins. For tumors of the lower third of the ureter, resection of the adjacent bladder wall with the ureteral orifice is also mandatory. The method of ureteral reconstruction is chosen individually and may include end-to-end anastomosis, reimplantation of the resected ureteral stump into the bladder, transuretero-ureterostomy, Boari flap, or ileal interposition [70–73].

Radical nephroureterectomy with bladder cuff resection

o with upper and middle ureteral UTUC staged cT >T1 and/or HG;

o with ureteral UTUC not amenable to organ-sparing treatment [52].

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

Comment: RNU with bladder cuff resection for ureteral UTUC is performed according to the same principles described for renal collecting system cancer: using an open approach for invasive tumors, preventing entry into the urinary tract lumen during surgery, and resecting the bladder cuff with the ureteral orifice on the affected side [52].

Comment: The incidence of regional lymph node metastasis in UTUC depends on the T category and tumor grade, being 2.2% for Ta–T1 and 0% for LG tumors [63, 66]. In cases where adequate preoperative T staging and/or grading is not feasible, the decision regarding lymph node dissection is made on an individual basis.

The therapeutic role of lymph node dissection in patients with UTUC has not been definitively proven; however, adequate staging of the tumor via histological examination of lymph node specimens allows for the selection of candidates for adjuvant therapy with proven efficacy (see below).

Optimal LND boundaries have not been defined. According to a single study, dissection of the following lymph nodes is recommended:

• for upper and middle ureteral cancer: from the crura of the diaphragm to the aortic bifurcation (paracaval for right-sided, para-aortic for left-sided tumors);

• for lower ureteral cancer: from the level of the aortic bifurcation superiorly to the internal inguinal ring inferiorly, bounded laterally by the lateral femoral cutaneous nerve and medially by the bladder wall [68].

• Recommended pathological examination of surgical specimens (resected tissues) in patients with UTUC [69].

Leveled Evidence ALevel of Evidence – A (Confidence Level of Recommendations – 1).

3.2. Perioperative treatment

3.2.1. Intravesical and intracavitary therapy

- #Mitomycin**: 40 mg in 40 mL of sodium chloride** intravesically, prior to removal of the urethral catheter placed after RNU, dwell time – 1–2 hours.

- #Doxorubicin**: 40–50 mg in 25–50 ml of 0.9% sodium chloride solution** intravesically, before removing the urethral catheter placed after RNU, exposure time: 1–2 hours.

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

Comments: the recurrence rate of UTUC in the urinary bladder after surgical treatment reaches 22–47%. Two randomized trials and a meta-analysis have shown that a single intravesical instillation of chemotherapy within 2–10 days after RNU with resection of the ureteral orifice reduces the risk of recurrence during the 1st year of follow-up. Prior to instillation, cystography must be performed to rule out the risk of the chemotherapeutic agent entering the peritoneal cavity [79–81]. There is no evidence of the method's efficacy after organ-sparing treatment; however, with a high degree of probability, the results should be similar to those obtained in patients undergoing RNU with resection of the ureteral orifice.

Comment: adjuvant intracavitary antegrade (via nephrostomy) and retrograde (via ureteral catheter) BCG therapy and chemotherapy (CT) in patients undergoing organ-sparing treatment for UTUC have been studied in several small trials. A systematic literature review and meta-analysis showed no differences in recurrence rate, progression, disease-specific survival, and OS depending on the method of adjuvant intracavitary therapy (antegrade or retrograde therapy or their combination), as well as no differences in recurrence rates after surveillance compared with adjuvant intracavitary therapy.

3.2.2. Neoadjuvant and adjuvant systemic therapy

The evidence base justifying the use of perioperative CT in patients with UTUC is extremely sparse.

Comment: according to several small studies and their meta-analysis, neoadjuvant CT in patients with UTUC scheduled for RNU with resection of the ureteral orifice reduces the T category, decreases the recurrence rate, and reduces the risk of death by 59% [83–87]. However, the methodological features of completed studies result in low evidentiary value of the obtained results and do not allow recommending neoadjuvant CT as a standard therapeutic approach for all patients.

Comment: in studies on neoadjuvant CT in patients with UTUC completed to date, the most frequently used regimens were: gemcitabine**, cisplatin**; gemcitabine**, carboplatin**; methotrexate**, doxorubicin**, cisplatin**, vinblastine** [83–87].

Comment: a phase III randomized trial demonstrated that adjuvant CT based on a platinum-based drug (cisplatin** or carboplatin** in case of contraindications to cisplatin**) and gemcitabine** increases disease-specific and metastasis-free survival in T2–T4 and/or N+ UTUC compared with surveillance. OS data are pending [50].

Comment: according to the phase III randomized trial CheckMate 275, which included 709 radically operated high-risk upper tract urothelial cancer patients (T2-4 and/or N+), including 21% of UTUC patients who received or did not receive neoadjuvant CT, adjuvant immunotherapy with #nivolumab** significantly increases disease-free survival, extra-urinary tract recurrence-free survival, and metastasis-free survival regardless of tumor PD-L1 status and administration of neoadjuvant CT. Adjuvant immunotherapy is associated with a favorable safety profile and does not impair patients' quality of life [93–95].

3.2.3 Adjuvant radiation therapy

Comment: presumably, adjuvant RT may reduce the rate of local recurrences after surgical treatment; however, data from various studies are contradictory [96, 97], therefore the method is not a standard and is used in selected cases with/without CT.

3.3. Treatment of patients with unresectable locally advanced and disseminated UTUC

3.3.1. Surgical treatment of oligometastatic UTUC

Comment: there are no data confirming the role of metastasectomy in patients with advanced oncological disease. Nevertheless, a study including patients with both UTUC and bladder cancer demonstrated that the removal of metastatic foci can be safe and oncologically justified in strictly selected patients with an expected long life expectancy [98]. In the absence of randomized trial data, the feasibility of metastasectomy should be evaluated on an individual basis.

3.3.2. Systemic Antitumor Therapy for Unresectable Locally Advanced and Disseminated UTUC

Chemotherapy and immunotherapy regimens used for unresectable locally advanced and disseminated UTUC in this section:

Chemotherapy regimens

• GC [73]:

o gemcitabine** – 1000 mg/m2 IV on days 1, 8, and 15;

o #cisplatin** – 70 mg/m2 IV on day 1(2) and hydration (isotonic sodium chloride solution** (≈ 2.5 l) to maintain diuresis > 100 ml/h during #cisplatin** administration and for the subsequent 3 hours.

The cycle is repeated every 4 weeks;

• GemCarbo [100]:

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

o #carboplatin** – AUC 4–5 on day 1 (the dosage regimen may be adjusted depending on the clinical situation – forced dose reduction or escalation within AUC 3–6).

The cycle is repeated every 3 weeks;

• MVAC [101, 107]:

o #vinblastine** – 3 mg/m2 IV on days 2, 15, 22;

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

o #methotrexate** – 30 mg/m2 IV on days 1, 15, 22;

o #cisplatin** – 70 mg/m2 on day 2 and hydration.

The cycle is repeated every 4 weeks;

• DD-MVAC [102, 107]:

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

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

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

o #cisplatin** – 70 mg/m2 on day 2 and hydration;

o rhG-CSF

The cycle is repeated every 2 weeks;

• vinflunine – slow intravenous infusion over 20 min, 320 mg/m2 every 3 weeks (the dosage regimen may be adjusted depending on the clinical situation – dose reduction to 250–280 mg/m2) [103];

• #paclitaxel** 80 mg/m2 on days 1, 8, 15; 28-day cycle, or 175 mg/m2 on day 1; 21-day cycle [161-163];

• #docetaxel** 75–100 mg/m2 on day 1 (21-day cycle) [161-165];

• #gemcitabine** 1000–1250 mg/m2 IV on days 1, 8, 15 (28-day cycle) [166-168].

Immuno-oncology agents (monoclonal antibodies)

• atezolizumab** – 840 mg (IV infusion every 2 weeks), or 1200 mg (IV infusion every 3 weeks), or 1680 mg (IV infusion every 4 weeks). The first dose of atezolizumab** must be administered over 60 minutes. If the 1st infusion is well tolerated, all subsequent infusions can be administered over 30 minutes [104];

• pembrolizumab** – 200 mg (IV infusion over 30 min every 3 weeks) or 400 mg every 6 weeks [105];

• avelumab** – 800 mg (IV infusion over 60 min every 2 weeks) [106];

• nivolumab** – 3 mg/kg or 240 mg (IV infusion every 2 weeks), or 480 mg (IV infusion every 4 weeks). The first infusion should be administered over 60 minutes; if well tolerated, all subsequent infusions – over 30 minutes [95].

Evaluation of CT efficacy is performed based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Evaluation of immunotherapy efficacy is performed based on immune-related response criteria in solid tumors (iRECIST 1.1) (Appendix G3).

First-line drug therapy

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

Comment: a contraindication to cisplatin** is the presence of at least 1 of the following criteria: ECOG performance status greater than 1; glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or less; hearing loss of grade 2 or higher; peripheral neuropathy of grade 2 or higher; New York Heart Association class III heart failure [109].

In a randomized phase III trial (n = 405), previously untreated patients with stage IV upper tract urothelial carcinoma were randomized to GC or M-VAC chemotherapy. The regimens demonstrated comparable objective response rate (ORR), time to progression, and 18-month overall survival (OS). The most significant toxicities were myelotoxicity, sepsis associated with febrile neutropenia, and mucositis. Severe anemia and thrombocytopenia were more frequent in patients receiving GC. Severe febrile neutropenia and severe mucositis were more frequently registered in the M-VAC group [108].

A large randomized phase III trial compared DD-MVAC with granulocyte colony-stimulating factor support versus standard MVAC. It was shown that DD-MVAC increased the ORR, but did not lead to a significant increase in median OS. Patients receiving DD-MVAC with granulocyte colony-stimulating factors experienced lower overall toxicity [107].

Comment: the approval of PD-(L)1 inhibitors for first-line therapy of advanced urothelial carcinoma in patients with contraindications to cisplatin** was based on phase II trials that utilized PD-L1 testing of tumor tissue. The #pembrolizumab** study used the combined positive score (CPS) for PD-L1 expression, which accounts for positive tumor cells and tumor-infiltrating immune cells [110]; the atezolizumab** study considered staining of immune cells only [104]. The outcomes of using these drugs when evaluating expression by other scoring systems have not been studied. Therefore, to select candidates for immunotherapy with pembrolizumab** and atezolizumab**, testing using scores with proven predictive value is required.

o in case of PD-L1 overexpression of 10% or more – pembrolizumab** monotherapy (200 mg IV infusion over 30 min every 3 weeks or 400 mg once every 6 weeks) [110];

o in case of PD-L1 overexpression of 5% or more – atezolizumab** monotherapy (840 mg IV infusion every 2 weeks, or 1200 mg IV infusion every 3 weeks, or 1680 mg IV infusion every 4 weeks) [104].

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

Comment: the efficacy and safety of pembrolizumab** in the first-line therapy of advanced urothelial carcinoma were evaluated in the multicenter phase II KEYNOTE-052 trial, which included 374 patients with contraindications to cisplatin** therapy. The primary endpoint was ORR in all patients and in those with PD-L1 overexpression. PD-L1 status was assessed using the CPS. The PD-L1 expression cutoff was established in the first 100 patients and was 10%. In all patients, the ORR was 24%; in patients with PD-L1 expression, it ranged from 10% to 38% and higher. The median time to response was 2 months, and at a median follow-up of 5 months, 83% of responses were ongoing, with the median duration of response not reached. The most common treatment-related grade 3–4 adverse events were fatigue (2%), increased serum alkaline phosphatase (1%), and decreased muscle strength (1%) [110].

The PD-L1 inhibitor atezolizumab** in the first-line therapy of advanced urothelial carcinoma in patients with contraindications to cisplatin** therapy was investigated in cohort 1 of the IMvigor210 study. PD-L1 expression status on tumor-infiltrating immune cells in the tumor microenvironment was defined as the percentage of positive immune cells: IC0 <1%, IC1 ≥1% (but <5%), and IC2/3 ≥5%. The primary endpoint was ORR, which was 23% in all patients and reached 28% in patients with PD-L1 overexpression IC2/3. At a median follow-up of 17.2 months, the median duration of response was not reached. Treatment-related adverse events were observed in 66% of patients (grade 3–4 in 16%) [104].

Comment: the randomized phase II/III EORTC 30986 trial compared 2 carboplatin**-containing regimens (methotrexate**, carboplatin**, vinblastine** [M-CAVI] and GemCarbo) in patients with cisplatin** contraindications such as a GFR of less than 60 mL/min/1.73 m2 and/or an ECOG performance status of 2. Both regimens demonstrated antitumor activity: the ORR was 42% for GemCarbo and 30% for M-CAVI. The incidence of severe adverse events reached 13.6% and 23% in the trial groups, respectively [112]. Based on these data, the GemCarbo combination became the standard of care for this patient population.

Comment: the randomized phase III JAVELIN Bladder 100 clinical trial investigated the effect of maintenance therapy with the PD-L1 inhibitor avelumab** following first-line treatment with a platinum compound and gemcitabine** combination in patients with advanced urothelial carcinoma who had an objective response or stable disease after 4–6 cycles of chemotherapy. Patients were randomized to avelumab** or best supportive care. Avelumab** significantly increased OS from 14.3 to 21.4 months (HR: 0.69; 95% CI: 0.56–0.86; p < 0.001). Grade 3 or higher adverse events were observed in 47% of patients in the avelumab** group (compared to 25% in the control group). Immune-mediated adverse events occurred in 29% of cases, reached grade 3 or higher in 7% of patients, and included colitis, pneumonitis, rash, elevated liver enzymes, hyperglycemia, myositis, and hypothyroidism [113].

• patients without contraindications to cisplatin**:

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

o #cisplatin** – 70 mg/m2 IV on day 1(2) and hydration (isotonic sodium chloride solution** [approx. 2.5 L] to maintain urine output above 100 mL/h during cisplatin** administration and for the subsequent 3 h).

The cycle is repeated every 3 weeks;

o #atezolizumab** – 1200 mg IV infusion every 3 weeks.

• patients with contraindications to cisplatin**:

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

o #carboplatin** – AUC 4.5 on day 1;

The cycle is repeated every 3 weeks;

o #atezolizumab** – 1200 mg IV infusion every 3 weeks.

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

Comment: the randomized IMvigor130 trial compared the combination of the PD-L1 inhibitor atezolizumab** plus GC/GemCarbo chemotherapy versus GC/GemCarbo chemotherapy combined with placebo or atezolizumab** monotherapy. The trial met its primary endpoint: immunochemotherapy provided a progression-free survival (PFS) benefit compared to chemotherapy plus placebo across the entire patient population (8.2 and 6.3 months, respectively; HR: 0.82 [95% CI: 0.70–0.96]; p = 0.007). Immature OS data at a median follow-up of 11.8 months showed no difference between the groups. Due to the hierarchical testing design, the comparison between chemotherapy and atezolizumab** monotherapy has not yet been performed [114].

o pembrolizumab** monotherapy (200 mg IV infusion over 30 min every 3 weeks or 400 mg once every 6 weeks) [110];

o atezolizumab** monotherapy (840 mg IV infusion every 2 weeks, or 1200 mg IV infusion every 3 weeks, or 1680 mg IV infusion every 4 weeks) [104, 172].

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

Comment: the efficacy and safety of pembrolizumab** in the first-line therapy of advanced UC were studied in the multicenter phase II KEYNOTE-052 trial involving 374 patients with contraindications to cisplatin** therapy. The ORR in all patients was 24%, and was similar in patients with PD-L1 expression of 10–38% and higher. The median time to response was 2 months, and at a median follow-up of 5 months, 83% of responses were ongoing, while 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%) [110].

The PD-L1 inhibitor atezolizumab** as first-line therapy for advanced UC in patients with contraindications to cisplatin** therapy was evaluated in cohort 1 of the IMvigor210 trial. The primary endpoint was ORR, which was 23% in all patients. At a median follow-up of 17.2 months, the median duration of response was not reached. Treatment-related AEs were observed in 66% of patients (grade 3–4 in 16%) [104].

Comment: a formal contraindication to carboplatin** is a marked decrease in bone marrow function. However, in clinical practice for patients with advanced UC, factors precluding the administration of carboplatin** are defined using criteria adapted from the EORTC 30986 randomized trial (poor performance status ECOG >2, GFR <30 mL/min/1.73 m2, or a combination of ECOG performance status 2 and GFR <60 mL/min/1.73 m2), as the prognosis for this patient population is poor regardless of whether platinum-based chemotherapy is administered [112]. Data on systemic antitumor treatment options in this patient group are limited to single-arm studies showing acceptable efficacy and safety of taxane and gemcitabine** monotherapy [115, 116]. The available evidence base is insufficient to formulate clinical guidelines.

Second-line systemic therapy

Comment: the randomized phase III trial KEYNOTE-045 compared the efficacy of pembrolizumab** versus standard chemotherapy in patients with unresectable locally advanced or metastatic urothelial carcinoma that progressed during or within 12 months after completion of cisplatin-based chemotherapy**. The trial enrolled 542 patients randomized to pembrolizumab therapy** or monochemotherapy (paclitaxel**, docetaxel**, or vinflunine). The primary endpoints were OS and PFS in the overall study population and in patients with PD-L1 expression of 10% or more by CPS. At a median follow-up of 18.5 months, pembrolizumab** significantly increased median overall survival from 7.4 to 10.3 months (HR 0.70; 95% CI: 0.57–0.86; p = 0.0004). Differences in progression-free survival between the groups were not statistically significant (median – 2.1 months in the pembrolizumab group** vs 3.3 months in the chemotherapy group, 18-month rate – 16.8% vs 3.5%, respectively; p = 0.32). In the pembrolizumab group** ORR and complete response rate were 21.1% and 7.8%, respectively, versus 11.0% and 2.9% in the chemotherapy group. Median duration of response was not reached with pembrolizumab** therapy and was 4.4 months with chemotherapy. PD-L1 expression status (CPS ≥10%) had no effect on ORR or survival outcomes. Immunotherapy was better tolerated by patients: any treatment-related AEs were reported in 61.3% of patients in the pembrolizumab** group and in 90.2% of patients receiving chemotherapy; grade ≥3 toxicity was reported in 16.5% and 49.8% of patients, respectively [105].

Comment: nivolumab** was evaluated as monotherapy for disseminated UC in the phase I/II CheckMate 032 study in patients who had received at least 1 prior line of therapy containing platinum agents, regardless of PD-L1 status. The primary endpoint was ORR, which was 24.4% and did not depend on the level of PD-L1 expression. Treatment-related grade 3–4 AEs developed in 22% of patients; the most frequent were increased serum lipase (5%) and amylase (4%) [117].

In the phase II CheckMate 275 trial (n = 270), nivolumab** in second-line therapy for platinum-resistant UC achieved an objective response in 19.6% of cases, with a median time to response of 1.9 months. As PD-L1 expression levels increased, the ORR rose, reaching 28.4% in patients with positive staining in 5% or more cells, and 16.1% in patients with PD-L1 expression of less than 5%. The median PFS was 2 months (1.87 months for PD-L1 expression <1% and 3.6 months for ≥1%). The 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 cases [95].

Comment: atezolizumab** therapy for resistant tumors was evaluated in cohort 2 of the IMvigor210 study, which included 315 patients with advanced UC who had previously received platinum-based therapy. The primary endpoint was the evaluation of ORR, which was 16% in all patients and reached 28% in patients with PD-L1 IC2/3 [118].

IMvigor211 is a randomized phase III trial comparing the efficacy and safety of atezolizumab** and chemotherapy (vinflunine, paclitaxel**, or docetaxel**) in patients with disseminated UC who progressed during or after at least one cytotoxic platinum-based regimen (n = 931). The study was negative: no significant differences in OS were found in the entire patient population receiving atezolizumab** or chemotherapy (median 8.6 vs 8.0 months, respectively, HR 0.85; 95% CI: 0.73–0.99) [119].

In the phase IIIb SAUL study, the efficacy and safety of atezolizumab** were evaluated in 1,004 patients with resistant locally advanced or metastatic urothelial or non-urothelial bladder cancer, including patients who did not meet standard clinical trial inclusion criteria, such as those who received non-platinum-based chemotherapy. The median OS was 8.7 months, the median progression-free survival was 2.2 months, and the ORR was 13%. Grade 3 or higher AEs were reported in 45% of patients, leading to treatment discontinuation due to toxicity in 8% of cases [117].

Comment: a randomized phase III trial (n = 370) comparing vinflunine with best supportive care in advanced UC in patients with progression following cisplatin**-based chemotherapy. Vinflunine demonstrated a non-significant OS benefit in the overall patient population compared with supportive care (6.9 vs 4.6 months, respectively, HR 0.88; 95% CI, 0.69–1.12; P = 0.287). However, an analysis of the actual treatment arms showed a statistically significant difference in favor of vinflunine regarding OS (6.9 vs 4.3 months, respectively, P = 0.04), as well as ORR (16% vs 0%, P = 0.0063), disease control rate (41.1% vs 24.8%, P = 0.0024), and median PFS (3.0 vs 1.5 months, P = 0.0012). The duration of objective response to vinflunine therapy was 7.4 months (95% CI, 4.5–17 months) [103].

3.4. Radiation therapy

Comment: the sequence of 1st- and 2nd-line standalone systemic therapy is presented in Tables 6 and 7 (Appendix B).

3.5. Analgesic therapy

The principles of analgesia and the optimal choice of pain management therapy for UTUC patients with chronic pain syndrome correspond to the principles of analgesia outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Medical Care".

3.6. Supportive care for patients with UTUC

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

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

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

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

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

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

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

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

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

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

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

3.7. Diet therapy

To date, no reliable evidence has been obtained regarding the impact of dietary habits on the risk of developing UTUC or on the risk of recurrence or progression of this disease in individuals with an established diagnosis.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

No specific rehabilitation methods have been developed. Recommendations for the prevention of chronic kidney disease should be followed.

Rehabilitation after chemotherapy

Comment: The scope and intensity of exercise therapy are selected individually based on the degree of fatigue (mild, moderate, severe). As the general condition improves, the intensity of exercise therapy is increased.

5. Prevention and Dispensary Observation

5.1. Prevention

Comment: if radical nephroureterectomy was performed, the development of local recurrence is unlikely; the risk of distant metastases directly depends on the risk factors mentioned earlier.

Comment: the incidence of disease recurrence in the urinary bladder after treatment of primary UTUC varies significantly from 15% to 50%. Therefore, bladder examination must be performed in all cases. A history of bladder cancer and multifocal UTUC involvement are risk factors for the development of bladder cancer following UTUC.

The follow-up protocol should include cystoscopy and urine cytology for at least 5 years. The development of a recurrence in the urinary bladder should not be considered as the appearance of distant metastases.

Comment: in case of kidney-sparing treatment, careful monitoring of the condition of the ipsilateral urinary tract is required due to the high risk of recurrence. Despite continuous improvements in endourological techniques, follow-up of conservatively treated patients remains challenging and often requires minimally invasive manipulations.

Following nephroureterectomy

Following organ-sparing treatment

5.2. Dispensary follow-up.

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

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

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

6. Organization of Medical Care

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

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

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

3) based on these clinical guidelines;

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

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

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

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

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

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

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

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

The oncologist of the ambulatory cancer care center (primary oncology office) refers the patient to an oncological dispensary (cancer hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive authority (hereinafter referred to as a federal medical organization), to clarify the diagnosis (in case of the impossibility of establishing a diagnosis, including the extent of the oncological process and the stage of the disease), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

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

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

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

digital images obtained from radiation imaging results to the remote diagnostic consultation center for radiation diagnostics through information interaction, including via telemedicine technologies for remote interaction between medical workers;

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

Treatment tactics are determined by a medical board (consilium) of physicians, including oncologists, a radiation oncologist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for the treatment of malignant neoplasms, systemic antineoplastic therapy, and radiation therapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians if necessary.

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

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

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization of specialized, including high-tech, medical care.

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

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

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

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

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

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

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

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

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

Indications for planned hospitalization in a medical organization are:

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

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

Indications for discharging a patient from a medical organization are:

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

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

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

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

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

7. Additional Information

Prognostic factors

Upper urinary tract urothelial carcinoma involving the muscle layer of the wall is characterized by a poor prognosis. The 5-year specific survival rate is less than 50% for pT2–3 and less than 10% for pT4. This section briefly describes modern prognostic factors [17].

According to most classifications, the primary prognostic factors are the tumor stage and the grade of tumor cells.

Race

A multicenter study revealed no differences in outcomes between patients of different races [145], but population-based studies showed that African Americans have worse outcomes than other ethnic groups. Differences between Chinese and American patients were also identified [146].

Lymph node metastases

Lymph node metastases and extranodal extension are significant predictors of survival in UTUC [63]. Lymphadenectomy performed during RNU allows for staging of the tumor process, but its therapeutic role remains debatable [64, 65].

Age and gender

The impact of gender on UTUC mortality has been recently challenged and is no longer considered an independent prognostic factor. In contrast, patient age is still considered an independent prognostic factor, as older age at the time of RNU is associated with reduced cancer-specific survival. However, older age per se should not be a limitation to aggressive treatment of UTUC. Most elderly patients can undergo RNU. This is confirmed by the fact that age alone serves as an inadequate criterion when assessing long-term outcomes in elderly UTUC patients.

Smoking

Smoking at the time of diagnosis increases the risk of disease recurrence and mortality after RNU [147, 148], as well as bladder recurrence. There is a close association between smoking and prognosis. Smoking cessation improves disease control.

Surgical delay

A delay between the diagnosis of an invasive tumor and its removal may increase the risk of disease progression. Once the decision to perform RNU is made, the surgery should be performed within 12 weeks as soon as possible [149–152].

Tumor location

According to recent data, the primary tumor location within the upper urinary tract (i.e., ureter or renal pelvis) is no longer considered a prognostic factor. This means that tumor location (ureter or renal collecting system) no longer affects tumor staging.

Lymphovascular invasion

Lymphovascular invasion occurs in approximately 20% of UTUC cases and serves as an independent predictor of survival. Information on the presence or absence of lymphovascular invasion must be included in the histological report after RNU. However, lymphovascular invasion has prognostic value only in patients without lymph node metastases.

Tumor necrosis

Widespread tumor necrosis serves as an independent predictor of clinical outcomes for patients undergoing RNU. Necrosis is considered widespread when it comprises 10% or more of the tumor.

Histological variant

The tumor architecture (papillary or sessile) in UTUC is associated with the prognosis after RNU. Sessile tumors are associated with a poorer prognosis. The presence of concomitant CIS in UTUC patients not extending beyond the organ is associated with a high risk of disease recurrence and cancer-specific mortality. As with lower urinary tract UC, the presence of CIS serves as an independent predictor of a worse prognosis.

Molecular markers

Several studies have investigated the prognostic impact of molecular markers related to cell adhesion (E-cadherin [153] and CD24), cell differentiation (human epidermal growth factor receptor HER-2 [2]), angiogenesis (hypoxia-inducible factor 1α and metalloproteinases), cell proliferation (Ki-67), epithelial-mesenchymal transition, mitosis (Aurora A), apoptosis (Bcl-2 and survivin), vascular invasion, and C-met protein (MET) [147, 154]. Microsatellite instability serves as an independent molecular prognostic marker [155]. Microsatellite instability typing can help detect hereditary mutations and hereditary cancer [5]. In patients with poorly differentiated UTUC, the prognostic value of PD-1 and PDL-1 expression is high [156]. Due to the low incidence of UTUC, the main limitations of molecular studies are their retrospective design and, for most studies, the small sample size. None of the markers has yet met the criteria required to support their introduction into routine clinical practice.

Bladder cancer recurrence

A meta-analysis identified significant prognostic factors for bladder recurrence of UTUC after RNU [53]. There are 3 categories of high-risk predictors for bladder recurrence:

1) patient-specific factors, such as male gender, history of bladder cancer, smoking, and preoperative chronic kidney disease;

2) tumor-specific factors, such as positive preoperative urine cytology, ureteral tumor location, multifocality, invasive pT stage, and necrosis;

3) treatment-specific factors, such as laparoscopic approach, extravesical removal of the bladder cuff, and positive surgical margin [53].

In addition, the use of diagnostic ureteroscopy was associated with a higher risk of subsequent bladder recurrence after radical nephroureterectomy [42, 43].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Andrey D. Kaprin – Academician of the RAS, D.Sc. (Med.), Professor, Honored Doctor of the Russian Federation, General Director of the National Medical Research Radiological Center of the Russian Ministry of Health, Director of the P.A. Herzen Moscow Oncology Research Institute, Chief freelance oncologist of the Russian Ministry of Health

2. Boris Ya. Alekseev – D.Sc. (Med.), Professor, Deputy Director for Research at the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Mariya I. Volkova – D.Sc. (Med.), Professor at the Department of Oncology and Palliative Medicine named after A.I. Savitsky, Russian Medical Academy of Continuous Professional Education, oncologist at the Moscow City Oncology Hospital No. 1 of the Moscow Healthcare Department

4. Bakhodur Sh. Kamolov – Ph.D. (Med.), Executive Director of the Russian Society of Onkourology, President of the Cancer Research Support Foundation «Together Against Cancer», journalist, member of the Union of Journalists of Russia, International Federation of Journalists.

5. Maxim P. Golovashchenko – Ph.D. (Med.), Researcher, Oncologist at the Urological Department of the Reproductive and Urinary Tract Tumors Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

6. Alexey S. Kalpinsky – Cand. of Sci. (Med.), Senior Research Fellow, Department of Reproductive and Urinary Tract Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

7. Albina A. Mukhomedyarova – Oncologist, Department of Reproductive and Urinary Tract Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

8. Elena V. Filonenko – Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

Medical Care Organization Section

1. Sergey A. Ivanov – Professor of the RAS, Dr. of Sci. (Med.), Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

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

3. Nevolskikh A.A., D. Sc. (Med.), Professor, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health;

4. Tigran G. Gevorkyan – Deputy Director for the Implementation of Federal Projects, N.N. Blokhin National Medical Research Center of Oncology.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of the clinical guidelines for upper tract urothelial carcinoma:

1. oncologists;

2. urologists;

3. radiologists;

4. radiotherapists;

5. surgeons;

6. anesthesiologists-intensivists;

7. general practitioners (internal medicine);

8. general practitioners (family doctors);

9. neurologists;

10. medical geneticists;

11. pathologists;

12. medical students, residents, and graduate students.

Table 3. Grading system for the levels of evidence for diagnostic methods (diagnostic interventions)

Table 4. Grading system for the levels of evidence for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 5. Grading system for the grades of recommendation for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

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

Appendix A3. Reference Materials

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

1. European Association of Urology Guidelines.

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

3. Order of the Russian Ministry of Health No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases".

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. 633n dated June 11, 2021, "On Approval of Standards of Medical Care for Adults with Upper Tract Urothelial Carcinoma".

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

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 Russian Ministry of Justice 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 package leaflets for the drugs mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru

Appendix B. Physician Action Algorithms

Monotherapy systemic therapy

Table No. 6: First-line systemic antitumor therapy

1 ECOG PS > 1; GFR ≤ 60 mL/min/1.73 m2; hearing loss ≥ grade 2; peripheral neuropathy ≥ grade 2; NYHA class II–IV heart failure.

2 EORTC 30986 RCT criteria (PS ECOG > 2; GFR < 30 mL/min/1.73 m2; ECOG PS 2 and GFR < 60 mL/min/1.73 m2).

*For atezolizumab, expression is considered positive if ≥5% (Ventana PD-L1 (SP142) Assay® (Ventana Medical Systems, Inc.))

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

1 ECOG PS > 1; GFR ≤ 60 mL/min/1.73 m2; hearing loss ≥ grade 2; peripheral neuropathy ≥ grade 2; NYHA class II–IV heart failure.

2 EORTC 30986 RCT criteria (PS ECOG > 2; GFR < 30 mL/min/1.73 m2; ECOG PS 2 and GFR < 60 mL/min/1.73 m2).

3 For atezolizumab, expression is considered positive if ≥5% (Ventana PD-L1 (SP142) Assay® (Ventana Medical Systems, Inc.))

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

Table No. 7: Second-line systemic antitumor therapy

Appendix C. Patient Information

Recommendations for CT complications: contact an oncologist (chemotherapy specialist).

If body temperature rises to 38 °C or higher, start taking antibiotics as recommended by the oncologist (CT specialist).

For stomatitis, the following are indicated:

• adherence to a diet – mechanical and thermal sparing;

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

• oral cavity care as recommended by the oncologist (CT specialist).

For diarrhea, the following are indicated:

• dietary adherence:

o exclude fatty, spicy, smoked, sweet, dairy foods, and fiber;

o lean meat, flour products, fermented dairy products, and rice broth are permitted;

o abundant fluid intake;

• taking medications as recommended by the oncologist (CT specialist).

For nausea, take medications as recommended by the oncologist (CT specialist).

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO/ECOG performance status scale.

Original title: World Health Organization/The Eastern Cooperative Oncology Group performance status (WHO/ECOG – PS).

Sources (official developer website, validation publication):

• https://ecog-acrin.org/resources/ecog-performance-status;

• Oken M.M., Creech R.H., Tormey D.C. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–55.

Type: rating scale.

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

Table 8. Content (template)

1 See Appendix G2. Karnofsky Performance Scale.

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

Appendix G2. Karnofsky Performance Scale

Russian title: Karnofsky scale.

Original title: Karnofsky Performance Status Scale.

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

Type: rating scale.

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

Table 9. Content (template)

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

Appendix G3. Criteria for tumor response evaluation to treatment

Criteria for evaluating tumor response to treatment RECIST 1.1

Russian title: criteria for evaluating tumor response to chemotherapy treatment (RECIST 1.1).

Original title: Response Evaluation Criteria In Solid Tumors 1.1.

Source (official developer website, validation publication): Eisenhauer E.A., Therasse P., Bogaerts J. et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–47. DOI: 10.1016/j.ejca.2008.10.026.

Type: rating scale.

Purpose: evaluation of response to chemotherapy treatment.

Content, key, and template in Russian are presented in the methodological recommendations No. 46 of the State Budgetary Healthcare Institution "Scientific and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Healthcare Department" and are available on the website: https://tele-med.ai/biblioteka-dokumentov/metodicheskie-rekomendacii-po-primeneniyu-kriteriev-otveta-solidnyh-opuholej-na-himioterapevticheskoe-lechenie-recist-11. This document is the property of the Moscow Healthcare Department and cannot be reproduced or distributed without appropriate permission.

Criteria for evaluating immune-related response in solid tumors iRECIST

Russian title: criteria for evaluating immune-related response in solid tumors.

Original title: Immune-Related Response Evaluation Criteria In Solid Tumors (iRECIST).

Source (official developer website, validation publication): Seymour L., Bogaerts J., Perrone A. et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18(3):e143–52. DOI: 10.1016/S1470-2045(17)30074-8.

Type: rating scale.

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

Table 10. Content (template)

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