Malignant neoplasms of kidney, renal pelvis, ureter, and other and unspecified urinary organs: clinical guidelines

List of Abbreviations

EU-RHAB – European Rhabdoid Registry

SIOP – The International Society of Paediatric Oncology

NSS – Nephron-sparing surgery

PD – progressive disease

SD – stable disease

WAGR Syndrome – Wilms tumor – Aniridia – Genital anomalies – mental Retardation Syndrome

AG – angiography

ALT – alanine aminotransferase

AST – aspartate aminotransferase

aPTT – activated partial thromboplastin time

EFS – event-free survival

VMA – vanillylmandelic acid

CMN – congenital mesoblastic nephroma

IV drip – intravenous drip

IV bolus – intravenous bolus

HVA – homovanillic acid

Gy – gray

Malignancy – malignant neoplasm

MRT – malignant rhabdoid tumor of the kidney

CT – computed tomography

CE – contrast enhancement

LDH – lactate dehydrogenase

RT – radiotherapy

LN – lymph nodes

mg/kg – milligrams per kilogram

mg/m² – milligrams per square meter

Ministry of Health of the Russian Federation – Ministry of Health of the Russian Federation

mcg/kg – micrograms per kilogram

mcg/m² – micrograms per square meter

INR – international normalized ratio

MRI – magnetic resonance imaging

WT – Wilms tumor

IVC – inferior vena cava

Abdominal organs – abdominal cavity organs

WT – Wilms tumor

Chest organs – thoracic organs

PN – parenteral nutrition

PET-CT – positron emission tomography computed tomography

PCT – polychemotherapy

RAS – Russian Academy of Sciences

RD – radioisotope diagnostics

RCT – randomized controlled trial

SFD – single focal dose

RF – Russian Federation

CCS – clear cell sarcoma

TT – thrombin time

TBI – total body irradiation

TLI – total lung irradiation

TFD – total focal dose

US – ultrasound examination

CT – chemotherapy

Pelvicalyceal system – pelvicalyceal system

ALP – alkaline phosphatase

ECG – electrocardiogram

Echo-CG – echocardiography

99mTc – Sodium pertechnetate [99mTc]

Terms and Definitions

Event-free survival (EFS) – the observation time from the moment of disease diagnosis to the occurrence of an event

Bilateral Wilms tumor – bilateral kidney involvement by Wilms tumor

Overall survival – the observation time from the start of treatment to the patient's death

Polychemotherapy – a regimen for administering multiple chemotherapy drugs, taking into account the dose, frequency, days, and route of administration of the cytostatic agent

Disease progression – the appearance of a new lesion and/or any growth of primary lesions by more than 25%

Radiotherapy – a method of local radiation exposure to the tumor/tissues/organs

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Wilms tumor (WT) – a malignant embryonal kidney tumor in children, developing from pluripotent progenitor cells of nephrogenic tissue [1].

Malignant rhabdoid tumor of the kidney (MRTK) – a highly malignant neoplasm with an aggressive clinical course, developing predominantly in early childhood and associated with an extremely unfavorable prognosis for life [2].

Clear cell sarcoma of the kidney (CCSK) – a rare malignant kidney tumor in children, accounting for 2-5% of all pediatric renal tumors [3].

Congenital mesoblastic nephroma (CMN) – a rare malignancy accounting for 3% of all pediatric renal neoplasms. CMN is the most common renal tumor in infants during the first 6 months of life [4; 5].

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

WT. The kidney develops from three sources: nephrogenic tissue/blastema (forms the stroma and differentiates into renal tubules via mesenchymal-epithelial transition), the mesonephric duct (gives rise to the ureter, renal pelvis, renal calyces, papillary ducts, and collecting ducts), and mesenchyme (vascular system). The blastema usually disappears by 36 weeks of gestation, but approximately 1% of children may have persistent nephrogenic rests after birth [6; 1; 7]. Remnants of the nephrogenic stroma have a high malignant potential and are found in 40% of patients with Wilms tumor [8; 9].

Up to 40 genes whose alterations lead to the development of Wilms tumor have been described in world literature; the most studied of these are the WT1 and WT2 genes, which are associated with a number of genetic syndromes such as Beckwith-Wiedemann, Denys-Drash, Perlman syndromes, isolated hemihypertrophy, and WAGR syndrome [10; 11]. Genetic syndromes occur in 5-10% of Wilms tumor cases and generally represent a combination of the tumor with urogenital malformations, nephropathy, and macrosomia [10; 11; 12].

Clinical criteria for a hereditary predisposition to WT include: bilaterality (up to 10% of Wilms tumor cases) and multifocal involvement, early childhood clinical manifestation of the disease, the presence of a similar tumor in other family members (familial form occurs in 1% of cases), and the combination of the tumor with genetic syndromes [6; 7].

Renal medullary carcinoma. Biallelic inactivation of the tumor suppressor gene SMARCB1 is a "molecular marker" of the disease. The gene encodes one of the central subunits of the ATP-dependent chromatin remodeling complex SWI/SNF, BAF43 [13]. In a small percentage of cases, alterations in the SMARCA4 gene are the cause of renal medullary carcinoma development [14; 15].

Approximately 30% of patients are characterized by germline events in genes, which warrants the definition of predisposition syndromes (SMARCB1- and SMARCA4-related types) [16; 17; 18]. Clinical criteria for a hereditary nature of MRTK include: advanced stages of the disease, including specific metastatic patterns such as subcutaneous nodules, multifocality, or synchronous development of multiple tumors; earlier childhood clinical manifestation of the disease or its congenital nature; presence of a similar tumor in other family members (familial form described in isolated cases) or tumors associated with alterations in the SMARCB1 or SMARCA4 genes [17; 18].

CCSK. Molecular genetic markers have been described to date, including internal tandem duplications of the gene BCOR (hereinafter BCOR-internal tandem duplication, BCOR-ITD) [19] and the chromosomal translocation t(10;17) leading to the formation of chimeric genes YWHAE-NUTM2, which distinguishes clear cell sarcoma of the kidney (CCSK) from other pediatric renal tumors. Tandem duplications of the gene BCOR are considered the primary molecular genetic event in pediatric CCSK, first described in 2015 by three independent research groups. The detection rate of BCOR-ITD ranged from 85 to 100% [20; 21; 22]. Translocation t(10;17) (chimeric gene YWHAE-NUTM2) is detected in 6.4–12% of cases [23; 24], while clinically this molecular genetic event correlates with younger age, smaller median tumor volume, and the absence of stage I disease [24]. BCOR-ITD and YWHAE-NUTM2 are considered mutually exclusive genetic events, but they do not explain all cases of CCSK [23]. Thus, the chimeric gene BCOR-CCBN3 has been described as a third molecular event in patients with CCSK [25]. Interestingly, both BCOR-ITD and the chimeric gene YWHAE-NUTM2 have been described in young children with soft tissue tumors, including undifferentiated round cell sarcoma and primitive myxoid mesenchymal tumor of infancy, indicating a common pathogenesis of these diseases with CCSK [26].

CMN of the kidney. CMN is characterized by the presence of a reciprocal translocation t(12;15)(p13,q25) resulting in the formation of the ETV6/NTRK3 fusion gene in patients with cellular and mixed types of CMN. Cellular and classical types of CMN are considered the renal counterpart of soft tissue infantile fibrosarcoma, given the similar histological picture and molecular-genetic features of these neoplasms (ETV6/NTRK3 gene) [27; 28; 29].

1.3 Epidemiology of the Disease or Condition

WT. The incidence ranges from 0.7-0.8 up to 1 per 100,000 children under 14 years of age, which accounts for about 5% of all childhood malignancies. Wilms tumor accounts for approximately 90% of all pediatric renal tumors. About 80% of cases are diagnosed under the age of 5 years, of which 15% are under 1 year of age; the median age is 3.5 years. The incidence is approximately equal in girls and boys. Bilateral renal involvement occurs in 5-10% of cases. Cases involving a single horseshoe kidney, as well as extrarenal WT, have been described [30; 31].

MRTK. Disease manifestation typically occurs within the first 2 years of life, with a median age at diagnosis of 16-24 months [32]. MRTK accounts for about 1% of all renal tumors [33]. The survival rate is approximately 0.019 per 100,000 children per year in patients under 15 years of age [34]. There is no gender predominance; according to various data, the male-to-female ratio ranges from 0.86-1.2:1 [34; 32].

CCSK. CCSK accounted for 3% of all renal tumors in children aged 0-14 years during the period 2001-2010 (n = 431); the age-standardized incidence rate was 0.02 per 100,000 children [35]. CCSK is characteristic of children aged 2 to 3 years, with this age interval accounting for 50% of cases, while the tumor is extremely rare in infants under 6 months of life. The median age at diagnosis is 36 months [36]. Unlike Wilms tumor, CCSK shows a male predominance (male-to-female ratio ranges from 1.8:1 to 2.04:1) [35].

CMN of the kidney. A rare primary renal tumor in young children, characterized by intermediate biological behavior [4; 27]. CMN accounts for 3% of all pediatric renal tumors. CMN is diagnosed in infants during the first 6 months of life, representing 50% of all renal neoplasms diagnosed in this patient cohort. In 15% of cases, they are detected prenatally or in the first days of life, demonstrating the embryonal origin of the tumor. CMN is more common in boys than in girls [27].

1.4 Features of Coding the Disease or Condition

C64 – Malignant neoplasms of the urinary tract, except renal pelvis;

C65 – Malignant neoplasm of the renal pelvis;

C66 – Malignant neoplasm of the ureter;

C68 – Malignant neoplasms of other and unspecified urinary organs.

1.5 Classification of the disease or condition

The 2022 WHO International Classification of Pediatric Tumors defines various types of renal tumors based on histological and molecular characteristics (Table 1) [37]

Table 1. Classification of renal tumors (WHO, 2022)

Nephroblastoma (Wilms tumor) is classified by tumor histological type (see Section 1.5.1 International Histological Classification of Wilms Tumor), by stage based on the radicality of surgical intervention (see Section 1.5.2 Postoperative Staging Classification), and by risk groups according to the histological tumor variant (see Section 1.5.3 Risk Groups According to Histological Tumor Variant). Classifications are based on SIOP recommendations [33, 38].

Malignant rhabdoid tumor of the kidney is classified by stage based on the radicality of surgical intervention (see Section 1.5.2 Postoperative Staging Classification), and as a high-risk tumor according to the histological variant (see Section 1.5.3 Risk Groups According to Histological Tumor Variant). Classifications are based on SIOP recommendations [9, 33].

Clear cell sarcoma of the kidney is classified by stage based on the radicality of surgical intervention (see Section 1.5.2 Postoperative Staging Classification), and as a high-risk tumor according to the histological variant (see Section 1.5.3 Risk Groups According to Histological Tumor Variant). Classifications are based on SIOP recommendations [9, 33].

Mesoblastic nephroma of the kidney is classified by stage based on the radicality of surgical intervention (see Section 1.5.2 Postoperative Staging Classification), and as a low-risk tumor according to the histological variant (see Section 1.5.3 Risk Groups According to Histological Tumor Variant). Classifications are based on SIOP recommendations [9, 33].

1.5.1 International Histological Classification of Nephroblastoma

The histological classification is based on the results of the pathological examination of the tumor tissue (Table 2).

Table 2. Histological classification of nephroblastoma

1.5.2 Postoperative Staging Classification

The classification is based on the radicality of surgical intervention and the extent of the disease. In metastatic or bilateral cases, the local stage may not coincide with the clinical stage (e.g., Stage IV, local Stage III).

Stage I:

• The tumor is confined to the kidney or surrounded by a capsule/pseudocapsule if it extends beyond the renal contour. The capsule/pseudocapsule may be infiltrated by the tumor, but the neoplastic tissue does not reach its outer margin;

• The tumor may protrude into the renal pelvis (so-called "bulging") or "drape" into the ureter without infiltrating its walls;

• The vessels of the renal sinus are intact;

• Invasion and tumor emboli in the vessels of the renal parenchyma may be present.

In nephroblastoma, the presence of mature tubular structures in the soft tissues of the renal sinus does not indicate its infiltration and represents structures of intralobar nephrogenic rest remnants. Perilobular nephrogenic rest remnants may also occasionally be found in the soft tissues of the renal sinus. True infiltration of the soft tissues of the renal sinus/renal hilum is defined as the detection of blastemal foci in direct proximity to nerve trunks.

A history of aspiration or core-needle ("tru-cut", trephine) biopsy does not upstage the tumor.

The presence of necrosis or signs of therapeutic pathomorphosis (hemosiderosis, infiltration by foamy macrophages) in the soft tissues of the renal sinus, renal vein, and/or perirenal adipose tissue does not upstage the tumor.

Infiltration of the adrenal gland does not upstage the tumor unless the outer surface of its capsule is involved in the tumor process.

The tumor may abut the liver capsule, which is not considered adjacent organ infiltration. Only true infiltration of the hepatic parenchyma should be classified as Stage III.

Stage II:

• Viable tumor is visualized in the perirenal adipose tissue and is not covered by a capsule/pseudocapsule, but has been completely resected ("negative" surgical margins);

• Viable tumor infiltrates the soft tissues of the renal sinus;

• Viable tumor infiltrates the blood and lymphatic vessels of the renal sinus or renal vein, or is visualized in the perirenal soft tissues, but has been completely resected;

• Viable tumor infiltrates the wall of the ureter;

• Viable tumor infiltrates adjacent organs or the inferior vena cava, but has been completely resected.

Only the presence of nerves in the soft tissues, along with vessels, provides grounds for considering the visualized structures as the renal sinus.

Stage III:

• Viable tumor is visualized at the inked surgical margins ("tumor on ink"). If a tumor with pathomorphosis is present at the surgical margin, Stage III is assigned provided that viable tumor is detected less than 5 mm from the inked surgical margin. If viable tumor is more than 5 mm from the inked surgical margin, the stage is not upgraded to Stage III. A distance of at least 5 mm from the viable tumor to the margin with pathomorphosis must be confirmed by multiple tissue blocks sampled from this area;

• Any abdominal lymph nodes are involved by viable tumor or tumor with therapeutic pathomorphosis;

• Pre- or intraoperative tumor rupture identified during pathological examination, regardless of other staging criteria;

• Presence of a tumor thrombus at the resection margin of the ureter, renal vein, or inferior vena cava (resection margins in this case are always discussed with the surgeon);

• A tumor thrombus closely adhering to the wall of the inferior vena cava, removed piecemeal by the surgeon;

• Open/wedge biopsy of the tumor prior to preoperative chemotherapy or surgical treatment;

• Vital tumor or tumor with pathomorphosis extending beyond the retroperitoneal space;

• Tumor implants (vital or with pathomorphosis) found anywhere in the abdominal/retroperitoneal cavity.

Involvement of the renal vein: frequently, a tumor thrombus protrudes into the renal vein and extends beyond the macroscopic resection margins. This is more noticeable after surgical resection followed by fixation. Such cases must be discussed with the surgeon to determine whether the thrombus was easily dissected and removed by them or firmly attached to the wall of the inferior vena cava; and whether the surgeon exerted additional effort or even used instruments for its removal. If the surgeon simply pulled out the thrombus with ease, the thrombus protruding at the resection margins does not indicate stage III. Stage III is designated only if the thrombus fragmented during dissection or if the dissection caused significant difficulty for the surgeon.

The presence of a necrotic tumor or a tumor with pathomorphosis in lymph nodes is regarded as a pre-existing vital metastasis, and stage III is assigned (the vital tumor may possibly be present outside the evaluated lymph node). Regressive (therapeutically induced) changes in the lymph node must take the form of a pre-existing metastasis. Intrasinusoidal distribution of foamy macrophages is not considered a tumor with pathomorphosis.

Occasionally, mature tubular structures may be found within the lymph node tissue, which are associated with Tamm-Horsfall protein deposits, but may also occur without them. This phenomenon is not regarded as a metastasis.

The presence of tumor damage/rupture is considered significant for stage III only if visualized during nephrectomy. If not, staging is performed according to the remaining criteria, and the case must be discussed at a multidisciplinary team meeting/tumor board.

Stage IV:   

Hematogenous metastases (lungs, liver, bones, brain, etc.) or metastases to distant lymph nodes (outside the abdominal and pelvic cavities).

Stage V:

Bilateral renal involvement.

The tumor on each side is staged separately according to the described criteria.

1.5.3 Risk Groups (according to tumor histological variant)

Histological risk stratification for nephroblastoma depends on whether preoperative chemotherapy was administered; clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumor of the kidney (MRTK) are classified in the high histological risk group in any case.

Histological classification in cases of preoperative chemotherapy:

Low-risk group:

• Cystic partially differentiated nephroblastoma;

• Completely necrotic nephroblastoma;

• Congenital mesoblastic nephroma.

Intermediate-risk group:

• Epithelial type;

• Stromal type;

• Mixed type;

• Regressive type;

• Focal anaplasia.

High-risk group:

• Blastemal type;

• Diffuse anaplasia;

• Malignant rhabdoid tumor of the kidney;

• CCSK.

Histological classification in cases of upfront nephrectomy:

Low-risk group:

• Cystic partially differentiated nephroblastoma;

• Congenital mesoblastic nephroma.

Intermediate-risk group:

• Nephroblastoma without anaplasia and its variants;

• Focal anaplasia.

High-risk group:

• Diffuse anaplasia;

• Malignant rhabdoid tumor of the kidney;

• CCSK.

In addition to the anaplastic types of nephroblastoma, three main types should be distinguished for subsequent therapy: totally necrotic (low-risk group), blastemal type (high-risk group), and other types (intermediate risk). Nevertheless, from a prognostic standpoint, it is important to indicate the percentage ratio of each tumor component. Cystic partially differentiated nephroblastoma is diagnosed by imaging methods, and surgery is the sole treatment. 

1.5.4 Nephroblastoma staging in case of nephron-sparing surgery [33; 38]:

R0: Intact renal parenchyma at the tumor margin (excluding nephroblastomatosis);

R1: Intact pseudocapsule at the tumor margin;

R2: Tumor at the resection margin.

In such cases, it is necessary to examine the resection margins carefully and thoroughly, as lesions are frequently excised with a small rim of renal parenchyma at the edge (especially in cases of multinodular renal involvement).

Surgical terms used:

• resection/partial nephrectomy – removal of the lesion with a rim of renal parenchyma;

• enucleation – dissection of the tumor node without renal parenchyma;

Pathological examination of the entire renal resection margin must be performed. If the volume of the node is small, it is submitted entirely. The minimum distance to the resection margin must be indicated. The intact margin (renal parenchyma) must not be less than 1 mm. If remnants of nephrogenic stroma are detected at the resection margin, such a margin is not considered involved in the tumor process, and the stage is not upgraded [33; 38].

1.6 Clinical presentation of the disease or condition

The clinical presentation may consist of general and local symptoms. The severity of symptoms will depend on the tumor's location within the kidney, its size, and the presence of distant metastasis. In small tumors without pelvicalyceal system involvement, the tumor may be an incidental finding on ultrasound, whereas a large mass with pelvicalyceal system invasion and involvement of adjacent structures may be accompanied by macro-/microhematuria, arterial hypertension due to renal vessel involvement, and vomiting when a large mass of the left kidney compresses the stomach. General symptoms may include intoxication symptoms and abdominal pain. When distant metastases are localized in the lungs, respiratory symptoms may develop.

2. Diagnostics, medical indications and contraindications for diagnostic methods

A preliminary diagnosis of malignant renal neoplasm is established based on the clinical presentation (see section 1.6 Clinical presentation of the disease or condition (groups of diseases or conditions)) and instrumental diagnostic data. The definitive histological diagnosis is established based on pathological and immunohistochemical examinations according to the algorithms for pathological diagnosis of renal tumors [33].

The primary diagnostic algorithm is presented in Appendix B1 [33].

2.1 Complaints and Anamnesis

• In all patients with malignant renal neoplasms, it is necessary to collect complaints and determine the duration of symptoms. It is recommended to conduct a detailed inquiry into the mother's obstetric history, the course of pregnancy, and the patient's development [7; 33; 38; 39; 40].

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

Comments: it is advisable to obtain a detailed family oncological history—the presence of benign or malignant tumors in family members, as well as the presence of congenital malformations in the family or the patient. Identifying cases of tumor disease in the family requires genetic counseling to identify the genetic mechanisms underlying predisposition [7; 11].

The patient's general condition should be assessed using the ECOG scale (see Appendix G3) and/or the Lansky scale (see Appendix G4)

2.2 Physical Examination

• All patients with suspected malignant renal neoplasm during the initial examination are recommended to undergo a clinical assessment (initial examination (assessment, consultation) by an oncologist) including measurement of height, body weight; size, consistency, and mobility of palpable tumor nodes; and assessment of organ failure [33; 38; 39].

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

• Blood pressure measurement on peripheral arteries is strongly recommended for all patients with malignant renal neoplasms to detect renal hypertension [33; 38; 39; 40].

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

• Special attention during the examination is recommended to be paid to the presence of stigmata of dysembriogenesis and congenital malformations, especially of the urogenital tract [33; 38; 39; 40; 41].

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

Comments: Congenital malformations—aniridia, hemihypertrophy, cryptorchidism, hypospadias [41]—also require genetic counseling (initial examination (assessment, consultation) by a geneticist) to identify the genetic mechanisms underlying predisposition.

2.3 Laboratory Diagnostics

• In all patients with a tumor originating from the upper pole of the kidney, for differential diagnosis between nephroblastoma and neuroblastoma, when technically feasible, it is recommended to test the levels of urine catecholamine metabolites (testing the level of vanillylmandelic acid in urine, testing the level of homovanillic acid in urine) as well as the level of neuron-specific enolase (NSE) [33; 39; 42; 43].

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

• All patients with malignant renal neoplasms are recommended to undergo the following laboratory tests to assess the patient's general somatic status [33; 44; 45]:

— complete blood count (testing the level of total hemoglobin in the blood; testing the level of erythrocytes in the blood; testing the level of platelets in the blood; testing the level of leukocytes in the blood) – before starting treatment at the preoperative therapy stage, before starting specific therapy, during treatment on days 0, 15, and 28 of therapy (for localized stages) or on days 0, 15, 28, and 42 of therapy (for generalized stages), at the postoperative therapy stage – before each administration of chemotherapy drugs or, if the interval between drug administrations is greater than 1 week, at least once a week (more frequent sampling is possible according to clinical indications);

— routine general clinical blood biochemistry (blood urea testing, blood creatinine testing, blood sodium testing, blood sodium testing, blood chloride testing, blood glucose testing, blood lactate dehydrogenase activity determination, blood alanine aminotransferase activity determination, blood aspartate aminotransferase activity determination, blood total bilirubin testing, blood conjugated bilirubin testing, blood alkaline phosphatase activity determination, blood total protein testing, blood albumin testing) – before starting treatment at the preoperative therapy stage, before starting targeted therapy, during treatment on days 0, 15, 28 of therapy (for localized stages) or on days 0, 15, 28, 42 of therapy (for generalized stages), at the postoperative therapy stage – before each administration of chemotherapy drugs or, if the interval between drug administrations is greater than 1 week, then at least 1 time per week (more frequent blood sampling is possible according to clinical indications);

— coagulogram (prothrombin level, blood fibrinogen testing, blood antithrombin III activity determination, international normalized ratio (INR) determination, activated partial thromboplastin time (APTT), determination of prothrombin (thromboplastin) time in blood or plasma (PT)) – before starting treatment at the preoperative therapy stage, before starting specific therapy;

— determination of ABO blood groups, determination of Rh factor (D antigen), determination of erythrocyte antigen phenotype (determination of MNS erythrocyte antigen phenotype and/or determination of Lewis erythrocyte antigen phenotype) to enable blood transfusion if indicated – before starting treatment at the preoperative therapy stage;

— general urinalysis – before starting treatment at the preoperative therapy stage, before starting specific therapy, at the postoperative therapy stage – before each administration of chemotherapy drugs or, if the interval between drug administrations is greater than 1 week, then at least 1 time per week (more frequent sampling is possible according to clinical indications);

— hospital screening upon admission to a medical organization – qualitative determination of hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) in blood, determination of antibodies to hepatitis C virus (Hepatitis C virus) in blood, determination of class M and G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) in blood [36];

— patients with renal malignant bone tumors are indicated for genetic counseling (initial consultation (examination, consultation) with a geneticist) to determine the scope of examination for detecting hereditary renal tumor predisposition syndromes [16].

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

Comments: the most frequent clinical and laboratory manifestation of renal tumors is macro-/microhematuria due to hemorrhage into the renal pelvicalyceal system, accompanied by the development of anemia syndrome [39].

The ongoing therapy may lead to the development of treatment-induced hematopoietic aplasia, which may require therapy with colony-stimulating factors as well as blood component transfusions.

2.4 Instrumental Diagnostics

• Patients with renal malignancies are recommended to undergo ultrasound of the abdominal cavity and retroperitoneal space (comprehensive abdominal ultrasound, ultrasound of the kidneys and adrenal glands) to assess disease stage in the following situations [33; 39; 46]:

— all patients – before starting treatment at the preoperative therapy stage, as well as before starting specific therapy

— patients with generalized renal malignancy at the preoperative therapy stage – on days 0, 15, 28, 42 of therapy

— patients with generalized neuroblastoma at the postoperative therapy stage – at weeks 1, 6, 10, 24 and at the end of therapy

— patients with generalized renal malignant bone tumors at the postoperative intensive therapy stage – at weeks 1, 4, 8, 12 and at the end of therapy

— patients with generalized renal malignant bone tumors at the postoperative metronomic therapy stage – at week 12 and at the end of therapy

— patients with generalized renal clear cell sarcoma at the postoperative therapy stage at weeks 1, 9, 18, 27 and at the end of therapy

— patients with localized renal malignancy at the preoperative therapy stage – on days 0, 15; patients with generalized renal clear cell sarcoma at the postoperative therapy stage at weeks 1, 9, 18, 27 and at the end of therapy

— patients with localized neuroblastoma at the postoperative therapy stage – at weeks 1, 6, 10, 24 and at the end of therapy

— patients with localized renal malignant bone tumors at the postoperative therapy stage – at weeks 1, 4, 8, 12 and at the end of therapy

— patients with localized renal clear cell sarcoma at the postoperative therapy stage at weeks 1, 9, 18, 27 and at the end of therapy

— patients with localized renal urothelial carcinoma do not require postoperative chemotherapy; if there are indications for its administration, the management and therapy strategy should be discussed with a federal/national center

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

Comments: the entire abdominal cavity must be examined, with a mandatory detailed examination of the contralateral kidney (also in the supine and lateral decubitus positions) for bilateral tumors, nephrogenic rests, or other pathological changes that may affect renal function. Screening of the liver parenchyma for metastases (liver ultrasound) must be performed. Ultrasound is the method of choice for evaluating the renal vein and inferior vena cava for intravenous tumor thrombus, using both 2D ultrasound and color Doppler mapping (duplex scanning of the inferior vena cava and portal system veins), as well as for assessing the relationship of the tumor with adjacent organs in real time.

• Patients with renal malignancies are recommended MRI of the abdominal cavity with intravenous contrast and MRI of the kidneys with intravenous contrast (or alternatively – Computed tomography of the abdominal cavity and retroperitoneal space with intravenous bolus contrast enhancement, if MRI is not feasible) to assess disease stage in the following situations [16; 33; 46; 47; 48; 49; 50]:

— all patients – before starting treatment at the preoperative therapy stage, as well as before starting specific therapy

— patients with generalized renal malignancy at the preoperative therapy stage – on days 0, 42 of therapy

— patients with generalized neuroblastoma at the postoperative therapy stage – only if residual tumor component is suspected and/or upon progression according to ultrasound data (comprehensive abdominal ultrasound, ultrasound of the kidneys and adrenal glands)

— patients with generalized renal malignant bone tumors at the postoperative intensive therapy stage – at weeks 1, 4, 8, 12 and at the end of therapy

— patients with generalized renal malignant bone tumors at the postoperative metronomic therapy stage – at week 12 and at the end of therapy

— patients with generalized renal clear cell sarcoma at the postoperative therapy stage at weeks 1, 9, 18, 27 and at the end of therapy

— patients with localized renal malignancy at the preoperative therapy stage – on days 0, 28 of therapy

— patients with localized renal malignant bone tumors at the postoperative intensive therapy stage – at weeks 1, 4, 8, 12 and at the end of therapy

— patients with localized renal malignant bone tumors at the postoperative metronomic therapy stage – at week 12 and at the end of therapy

— patients with localized renal clear cell sarcoma at the postoperative therapy stage at weeks 1, 9, 18, 27 and at the end of therapy

— patients with localized renal urothelial carcinoma do not require postoperative chemotherapy; if there are indications for its administration, the management and therapy strategy should be discussed with a federal/national center

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

Comments: the study is performed to determine the topography and organ origin of the mass, identify the tumor in three dimensions and determine tumor volume, and search for distant metastasis sites. Due to the absence of ionizing radiation and high soft-tissue contrast, MRI is the preferred method compared to CT. The entire abdominal cavity must be examined (from the liver dome to the pelvic cavity inclusive). The imaging protocol must be performed by MRI radiologists experienced in pediatric abdominal MRI. Sedation or general anesthesia is recommended for young children in accordance with established local practice. Gadolinium administration is recommended but not mandatory. Abdominal CT is an additional "second-choice" imaging modality complementary to ultrasound. Administration of an intravenous iodinated contrast agent is a prerequisite for the procedure. Volumetric scanning of the first (portal-venous) phase must be performed. The entire abdominal cavity must be examined (including the entire liver and the pelvic cavity).

• Patients with renal malignancies are recommended CT of the chest cavity (or alternatively – chest radiography in 2 projections, if CT cannot be performed) to assess disease stage in the following situations [16; 33; 39; 46; 47; 48; 50]:

— all patients – before starting treatment at the preoperative therapy stage, as well as before starting specific therapy

— patients with generalized renal malignancy at the preoperative therapy stage – on days 0 (CT and radiography), 28 (radiography), 42 (CT) of therapy

— patients with generalized neuroblastoma at the postoperative therapy stage – at week 10 and at the end of therapy (if complete clearance of lesions was not achieved by week 10)

— for patients with generalized renal malignant tumor at the postoperative intensive therapy stage — at week 1, week 8, and at the end of therapy

— patients with generalized renal malignant bone tumors at the postoperative metronomic therapy stage – at week 12 and at the end of therapy

— patients with generalized renal clear cell sarcoma at the postoperative therapy stage at weeks 1, 9, 18, 27 and at the end of therapy

— patients with localized renal malignancy at the preoperative therapy stage – on days 0, 28 of therapy

— for patients with localized neuroblastoma at the postoperative therapy stage — radiography at week 10 and at the end of therapy; CT only if metastatic lesions are suspected based on chest X-ray

— for patients with localized renal malignant tumor at the postoperative intensive therapy stage — at week 1 and week 8 at the end of therapy

— patients with localized renal malignant bone tumors at the postoperative metronomic therapy stage – at week 12 and at the end of therapy

— patients with localized renal clear cell sarcoma at the postoperative therapy stage at weeks 1, 9, 18, 27 and at the end of therapy

— patients with localized renal urothelial carcinoma do not require postoperative chemotherapy; if there are indications for its administration, the management and therapy strategy should be discussed with a federal/national center

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

Comments: non-contrast chest CT is a mandatory diagnostic procedure required to assess the presence of pulmonary metastases. Intravenous contrast enhancement is optional (but may be used if chest CT is performed in combination with abdominal CT rather than abdominal MRI).

The lungs are the most common target organs for distant metastasis. According to SIOP guidelines, there are specific characteristics of focal lung lesions interpreted as metastatic or non-metastatic:

— round solid lesions 1–2 mm in size are not classified as metastases; these patients receive preoperative chemotherapy as for localized stages;

— round solid lesions 3–5 mm in size are classified as metastases; such patients receive preoperative chemotherapy as for the generalized form of the disease. Prior to nephrectomy, the dynamics of pulmonary metastases are evaluated (CT). If the lesions in the lungs persist, their surgical removal after nephrectomy is recommended. If histology of the removed lesions reveals the absence of tumor cells or total necrosis, postoperative treatment is carried out according to the local stage. If viable tumor cells are detected in the metastases, treatment is continued according to the recommendations for stage IV;

— lesions >5 mm in size are classified as metastases. Such patients receive preoperative chemotherapy as for the generalized form of the disease. Prior to nephrectomy, the dynamics of pulmonary metastases are evaluated (CT).

• In patients with renal malignant tumor or clear cell sarcoma of the kidney, to search for metastatic lesions in the brain as well as synchronous/metachronous tumors (renal malignant tumor), it is recommended to perform contrast-enhanced brain MRI (magnetic resonance imaging of the brain with contrast enhancement) (or alternatively, contrast-enhanced brain CT (computed tomography of the brain with intravenous contrast enhancement) if MRI is not feasible) in the following situations [16; 33; 39; 50; 51]:

— for patients with generalized renal malignant tumor at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

— for patients with generalized renal malignant tumor at the postoperative metronomic therapy stage — at the end of therapy;

— for patients with generalized clear cell sarcoma of the kidney at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

— for patients with localized renal malignant tumor at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

— for patients with localized clear cell sarcoma of the kidney at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

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

• If metastatic brain involvement is detected based on contrast-enhanced brain MRI/CT (magnetic resonance imaging of the brain with contrast enhancement; computed tomography of the brain with intravenous contrast enhancement) in patients with renal malignant tumor and clear cell sarcoma of the kidney, it is recommended to perform contrast-enhanced spinal cord MRI (all sections separately, according to medical service nomenclature) / contrast-enhanced spinal cord CT (spine CT with intravenous contrast enhancement), as well as a lumbar puncture to assess the spread of the tumor process within the central nervous system [16; 33; 39; 50; 51]

AC RLEL 5     Level of evidence strength — C (level of data reliability — 5).

• In patients with renal malignant tumor and clear cell sarcoma of the kidney, to search for metastatic bone lesions, it is recommended to perform PET/CT (positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement) with 18F-FDG (fluorodeoxyglucose) or whole-body bone scintigraphy with 99mTc (whole-body bone scan) in the following situations [16; 33; 50]:

— for patients with generalized renal malignant tumor at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

— for patients with generalized renal malignant tumor at the postoperative metronomic therapy stage — at the end of therapy;

— for patients with generalized clear cell sarcoma of the kidney at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

— for patients with localized renal malignant tumor at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

— for patients with localized clear cell sarcoma of the kidney at the postoperative intensive therapy stage — at week 1 and at the end of intensive therapy;

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

• In patients with suspected malignant renal tumor, if neuroblastoma cannot be ruled out, it is recommended to perform scintigraphy (whole-body scintigraphy with tumorotropic radiopharmaceuticals) with 123I-metaiodobenzylguanidine (Iobenguane [123I]) before initiating specific therapy [33; 47; 48; 52].

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

Comments: suspicion of neuroblastoma may arise if visualization methods (abdominal CT/MRI) show: no involvement of the renal calyces or renal pelvis in the process; involvement of major abdominal blood vessels; presence of calcifications within the tumor; the mass involves the entire kidney. Urinary catecholamine levels are elevated.

Comments: it is preferable that it is performed by an experienced radiologist immediately before surgery.

• In all patients with malignant renal tumors before initiating therapy, in order to timely detect concomitant cardiovascular pathology, assess treatment risks, and determine safe treatment tactics, it is recommended to perform electrocardiography (electrocardiogram recording) and echocardiography [33; 39; 53; 54; 55]

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

Comments: shortening fraction, ejection fraction, and end-systolic wall stress values must be documented prior to the administration of the first dose of #doxorubicin** in all patients scheduled to receive #doxorubicin**, i.e., patients with stage IV disease and high-risk histological group.

• In patients with malignant renal tumors, it is recommended to perform echocardiography in the following situations [16; 33; 39]:

— in patients with generalized malignant renal tumors at the preoperative therapy stage on days 0 and 42;

— in patients with generalized form of neuroblastoma at the postoperative therapy stage – at week 10 and at the end of therapy;

— in patients with malignant renal tumors at the postoperative therapy stage – at weeks 0, 6, 9, and at the end of therapy;

— in patients with generalized renal clear cell sarcoma at the preoperative therapy stage on week 0, before weeks 19 and 30, and at the end of therapy;

— in patients with localized renal clear cell sarcoma at the preoperative therapy stage on week 0, before weeks 19 and 30, and at the end of therapy.

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

Comments: shortening fraction, ejection fraction, and end-systolic wall stress values must be documented prior to the administration of the first dose of #doxorubicin** in all patients scheduled to receive #doxorubicin**, i.e., patients with stage IV disease and high-risk histological group of neuroblastoma, and echocardiography is recommended before starting therapy to timely detect concomitant cardiovascular pathology, assess treatment risks, and determine safe treatment tactics.

— Pure-tone audiometry in standard and extended high-frequency ranges up to 16–20 kHz (the method for determining pure-tone hearing thresholds depends on the child's age and developmental level: visual reinforcement audiometry from 6 to 24 months, play audiometry from 2 to 5 years, or standard audiometry from 5 years). Recording of otoacoustic emissions (distortion product otoacoustic emission testing) in the frequency range up to 8–10 kHz.

— Tympanometry.

— Recording of short-latency and tone-specific auditory brainstem responses (auditory steady-state response [ASSR] testing) for young children in the absence of otoacoustic emissions and when pure-tone audiometry cannot be performed.

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

Comments: the scope of possible acoustic examination depends on the equipment available at the hospital.

Preferred timeframe for audiological testing:

— Baseline testing before starting treatment.

— 4–6 weeks after completion of treatment (the last administration of #carboplatin**).

— 1–2 times a year for 3–5 years after completion of treatment for patients with normal hearing.

If hearing loss is detected, the patient is referred to an otorhinolaryngologist (audiologist-otorhinolaryngologist) to determine an individual follow-up, treatment, and rehabilitation program.

2.5 Other Procedures

• In patients with suspected WT, it is recommended to perform a biopsy followed by pathomorphological examination of the biopsy (surgical) specimen if other renal/extrarenal tumors cannot be ruled out based on imaging data and clinical presentation, specifically in the following cases [33; 58; 59]:

— an unusual clinical presentation is observed: Age >6 years (risk of renal tumors of another etiology); presence of urinary tract infection or septicemia (suspected abscess); psoas muscle infiltration (suspected neuroblastoma); presence of lung metastases in patients under 2 years of age, extrahepatic and extrapulmonary metastases (suspected renal malignant solid tumor);

— unusual imaging findings are present: multiple calcifications (suspected neuroblastoma); extensive lymphadenopathy (suspected malignant solid tumor); renal parenchyma not visualized; almost completely extrarenal process.

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

Comments: core-needle biopsy should not be used if the patient is 6 months of age or younger, in which case primary surgery is indicated, nor in the presence of a purely cystic tumor (primary surgery should be considered due to the high risk of tumor capsule rupture during biopsy). Open biopsy is not recommended. An open renal tumor biopsy at the postsurgical staging stage is interpreted as stage 3 and requires local radiation therapy (see section 3.3 Radiation Therapy).

In patients with the cystic variant of the tumor, there is a high risk of tumor capsule rupture during the biopsy procedure.

Summary recommendations for diagnostic puncture biopsy of renal neoplasms in patients without genetic predisposition are presented in Table 3 [60].

Table 3. Summary recommendations for diagnostic puncture biopsy of renal neoplasms in patients without genetic predisposition [60]

Comments: central review (reference pathology) should be performed within 2 weeks of surgery to decide on adjuvant therapy tactics.

• All patients with renal malignancies are recommended a dietary consultation with subsequent diet modification and possible prescription of clinical nutrition formulas to ensure adequate and timely nutritional support (see section 7.2) [61].

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

• If a patient with a renal malignancy presents with dysmorphic stigmata and congenital malformations, especially of the urogenital tract, aniridia, macrosomia, hemihypertrophy, as well as when bilateral involvement is suspected, it is recommended to consult a geneticist (initial geneticist consultation/examination), since genetic syndromes occur in 5–10% of WT cases and predominantly represent a combination of tumor with genitourinary malformations, nephropathy, or macrosomia [10; 11; 12; 39; 41].

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

• All patients with a renal malignant solid tumor are recommended a geneticist consultation to determine the indications and scope of molecular genetic testing, since in 30% of cases renal malignant solid tumors develop against the background of predisposition syndromes (types 1 and 2 hereditary cancer predisposition syndromes) [16; 17; 18].

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

• All patients with renal malignancies and comorbidities that may influence the choice of anticancer treatment strategy are recommended an initial consultation (examination) with the appropriate specialist (pediatric cardiologist, neurologist, ophthalmologist, etc.) prior to therapy initiation [41; 44].

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

Comments: patients with suspected genetic syndromes should be evaluated by subspecialists depending on the target organs (e.g., patients with suspected WAGR syndrome and aniridia should be evaluated by an ophthalmologist) [41].

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

Renal malignancy therapy is based on chemotherapy and surgery. Only a very small proportion of patients require radiation therapy. The choice of treatment strategy depends on the histological tumor type, risk group, disease stage, and patient age [33; 64].

• Patients with renal malignancies younger than 7 months or older than 16 years, as well as patients with cystic tumor variants, are recommended surgical intervention as the first step of treatment [33; 6433].

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

Comments: In children under 7 months of age, congenital mesoblastic nephroma is most frequently observed, which can be cured by surgery alone.

In patients older than 16 years, renal cell carcinoma must be ruled out, requiring primary surgery in all feasible cases.

In patients with the cystic variant of the tumor, there is a high risk of tumor capsule rupture during the biopsy procedure.

• All patients under 18 years of age with malignant renal tumors who develop anemia, bleeding, or high risk of hemorrhagic syndrome during treatment are recommended to receive blood transfusion support with blood products [62].

LGR CLEL 5 Level of Evidence – C (Level of Likelihood of Evidence – 5)

• All patients under 18 years of age with malignant renal tumors throughout treatment, for the purpose of treating and preventing nausea and vomiting caused by antineoplastic therapy, are recommended to assess the emetogenic level of medicinal products, and to carry out treatment and prevention of nausea and vomiting using medicinal products (see Section 5.1) [63].

GCR ALEL 2Grade of Recommendation – A (Level of Evidence – 2)

3.1 Neoadjuvant Chemotherapy

• All patients with verified malignant renal tumors for whom surgery was not indicated at the first stage of treatment are recommended to undergo preoperative (neoadjuvant) chemotherapy [33; 64; 65].

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

• For localized malignant renal tumors (stages I-III), neoadjuvant chemotherapy is recommended in the AV regimen for 4 weeks: #vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4; #dactinomycin 45 mcg/kg/day, IV bolus on weeks 1, 3 (see Appendix A3.1) [33; 64; 66].

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

Comments: the maximum single dose of #vincristine** is 2 mg. #Dactinomycin is not used in children weighing less than 5 kg and under 3 months of age. Dose reductions of the drugs depending on age are presented in Tables 15 and 16. Surgical treatment is performed at weeks 5–6. In case of delayed surgery, administration of additional #vincristine** is recommended [9; 38].

• For metastatic malignant renal tumors (stage IV), neoadjuvant chemotherapy is recommended in the AVD regimen for 6 weeks: #vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, and 6; dactinomycin 45 mcg/kg/day, IV bolus on weeks 1, 3, and 5; doxorubicin** 50 mg/m²/day, 2–6 hour infusion on weeks 1, 5 (see Appendix A3.1) [33; 64; 6633].

For Wilms tumor – Level of Evidence – C (Level of Likelihood of Evidence – 4).

For malignant rhabdoid tumor of the kidney (MRTK), clear cell sarcoma of the kidney (CCSK), and congenital mesoblastic nephroma (CMN) – Level of Evidence – C (Level of Likelihood of Evidence – 5).

Comments: The maximum single dose of #vincristine** is 2 mg. #Dactinomycin is not used in children weighing less than 5 kg and under 3 months of age. Dose reductions of the drugs depending on age are presented in Tables 15 and 16. Surgical treatment is performed at weeks 7–8. In case of delayed surgery, administration of additional #vincristine** is recommended [9; 38].

• Patients in whom the diagnosis of MRTK or CCSK was established based on core-needle biopsy results are indicated to initiate neoadjuvant chemotherapy within treatment regimens corresponding to the histological type (see Section 3.3) [16; 33; 51].

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

Comments: Dose reductions of the drugs depending on age are presented in Table 16. Surgical treatment is performed after 1–2 courses of therapy.

3.2 Surgical Treatment

3.2.1 Recommendations for Surgical Treatment of the Primary Tumor

• All patients with unilateral malignant renal tumors after neoadjuvant therapy are recommended to undergo nephroureterectomy [33; 65; 67; 68; 69];

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

• Patients in whom the diagnosis of MRTK or CCSK was established based on core-needle biopsy results are indicated to undergo surgical treatment after 1–2 courses of neoadjuvant chemotherapy within treatment regimens corresponding to the histological type [16; 33; 51];

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

• For patients with a suspected diagnosis of congenital mesoblastic nephroma of the kidney, total nephrectomy is the preferred treatment method for localized disease and should be performed according to the general surgical treatment recommendations given above. Perirenal fat must always be removed since congenital mesoblastic nephroma tends to infiltrate surrounding tissues. In case of incomplete tumor resection or incomplete removal of perirenal fat, repeat resection must be performed. Metastasectomy is recommended in exceptional cases in the presence of solitary metastases [33].

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

Comments: when performing nephrectomy, follow these principles:

— Midline or transverse laparotomy as the surgical approach.

— Abdominal cavity exploration is performed prior to nephrectomy. The liver, lymph nodes, and peritoneum must be examined for metastatic lesions and intra-abdominal metastases. Any tumor-suspicious neoplasm is excised or biopsied if unresectable. This also applies to lymph node biopsy, even if they appear grossly uninvolved.

— It is advisable to begin nephrectomy by ligating the renal vessels. The renal artery is ligated first to prevent tumor rupture due to its fragility and potential dissemination via perinephric perforating veins. The steps of mobilization are recorded in the operative report. If the tumor is large and vascular access is difficult, it is first dissected from surrounding tissues, and the vessels are ligated whenever possible.

— Transection of the ureter is performed as close to the urinary bladder as possible;

— It is advisable to remove the renal tumor along with the surrounding adipose tissue and affected structures;

— Thorough examination of the contralateral retroperitoneal space is required in bilateral cases;

— Thorough inspection of the renal vein and inferior vena cava (IVC) during surgery is required – a short renal vein thrombus is resected along with the vein. Thrombi of the infrahepatic IVC segment are removed via venotomy. In the presence of a large thrombus and IVC wall infiltration, radical removal is impossible, and this area must be included in the radiation field in the postoperative period [65; 68].

• All patients with malignant renal tumors are recommended to undergo lymph node biopsy followed by pathomorphological examination for correct staging and prescription of adequate subsequent therapy [33; 65; 69; 70].

For Wilms tumor (NB) – Level of Evidence – C (Level of Likelihood of Evidence – 4).

For malignant rhabdoid tumor of the kidney (MRTK), clear cell sarcoma of the kidney (CCSK), and congenital mesoblastic nephroma (CMN) – Level of Evidence – C (Level of Likelihood of Evidence – 5).

Comments: lymph nodes of the renal hilum, renal artery at its origin from the aorta (regional nodes), and upper and lower para-aortic (extraregional) nodes must be sent for pathomorphological examination even if they appear unchanged. Lymph nodes must be removed without compromising their integrity. Each removed lymph node must be labeled with a description of its exact location and sent to the pathologist separately. At least 7 lymph nodes must be taken for examination.

• All patients with malignant renal tumors are recommended to undergo nephroureterectomy using video-endoscopic technologies provided the following criteria are met [33; 65; 67; 71; 74; 75]:

— space-occupying lesions in the kidney not exceeding the volume of a healthy kidney, without enlarged contralateral lymph nodes visible on MRI/CT;

— resection must be performed in accordance with oncological principles and include lymph node biopsy;

— presence of centrally located tumors with a clear boundary with the "normal" renal parenchyma surrounding the tumor;

— extraction of the tumor must be performed using a retrieval bag without damaging the tumor capsule through an adequate opening in the abdominal wall, both to prevent tumor dissemination and to ensure adequate staging;

— if organ-preserving surgery is feasible, it must be performed via laparotomy.

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

Comments: Minimally invasive and organ-preserving surgeries should be performed in federal centers with experience in such procedures [65; 72]!

In all possible cases of laparoscopic radical nephrectomy, it is necessary to obtain the opinion of a specialist from a reference surgical center, who also confirms the need to refer the patient for laparoscopic surgery to a center whose staff has relevant experience.

Contraindications to laparoscopic nephrectomy [33]:

— Tumor infiltrating extrarenal structures or extending beyond the ipsilateral border of the spinal column;

— Thrombus in the renal vein or vena cava;

— Tumor location at the renal periphery where organ-preserving surgery is impossible;

— Tumor unresponsive to chemotherapy due to the risk of tumor capsule rupture;

— Lack of sufficient experience in performing laparoscopic nephrectomy.

• Performing a nephron-sparing surgery is recommended for unilateral nephroblastoma without genetic predisposition, provided the following criteria are met [33; 65; 67; 72; 73]:

— A tumor confined to a single renal pole or located at the periphery of the kidney;

— Tumor volume of less than 300 ml at the time of diagnosis (the risk of regional lymph node metastasis is about 2%);

— No evidence of initial tumor capsule rupture;

— No involvement of the renal pelvis;

— No invasion into surrounding organs;

— No thrombus in the renal vein or vena cava;

— No multifocal nature of the tumor;

— Nephron-sparing surgery is only possible while adhering to oncological principles of a safe surgical margin from the tumor edge;

— The remaining renal parenchyma is expected to be sufficient for adequate function;

— It is necessary to preserve at least 66% of the renal parenchyma after tumor resection to prevent hyperperfusion. Preoperative radioisotope scanning is required to determine the functional reserve of the kidney.

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

Comments: Renal resection is also possible in cases of unilateral renal lesions; however, the advantages of this surgical method (percentage of remaining renal parenchyma, risk of local recurrence) must be carefully evaluated.

The benefits of nephron-sparing surgery can be achieved in the presence of urological and nephrological disorders in the contralateral kidney, as well as in the presence of genetic syndromes associated with the risk of Wilms tumor (which increases the risk of a potential operation on the contralateral kidney in the event of a metachronous tumor).

Enucleation (tumor resection without a rim of unchanged renal parenchyma) is not considered adequate local therapy. In cases of incomplete resection with microscopic residual tumor, subsequent local therapy depends on several factors and must be discussed with a multidisciplinary team of specialists. However, total nephrectomy for unfavorable subtypes of renal tumors (specifically, clear cell sarcoma of the kidney and rhabdoid tumor of the kidney) appears to be necessary.

Positive lymph nodes on pathological examination following nephron-sparing surgery indicate the need for radiation therapy, but not necessarily nephrectomy.

Following renal resection, careful short-term and long-term functional monitoring should be performed: renal Doppler ultrasound 2 days after surgery. After 6 months, the functional reserve of the preserved renal tissue should be evaluated by renoscintigraphy. It is necessary to assess creatinine clearance and rule out renal hypertension and signs of renal failure. This information is important for determining the presence or absence of potential delayed renal function benefits from nephron-sparing surgery.

Nephroblastomatosis in the renal parenchyma within the specimen obtained during nephron-sparing surgery may contribute to the development of metachronous nephroblastoma in the remaining kidney. Close follow-up of these patients should be maintained.

3.2.2 Recommendations for Surgical Treatment of Metastases

• Metastasectomy is recommended for all patients with malignant renal tumors after nephrectomy and after 1–2 cycles of postoperative chemotherapy [65; 71].

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

• Surgical removal of metastases is recommended for all patients with malignant renal tumors with lung metastases, if feasible [33; 65; 71].

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

Comments: thoracoscopy is applicable only for subpleural localization of metastases. Thoracotomy is preferred. Wedge resection with achievement of "clear" resection margins is preferred. If radical removal cannot be achieved via wedge resection, segmentectomy or lobectomy may be performed. Pneumonectomy is not justified.

Liver metastases

• Wedge resection is recommended for all patients with malignant renal tumors presenting with isolated liver metastases [40; 65; 71].

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

Comments: metastases in other sites must be radically resected without mutilating operations.

3.3 Postoperative Therapy

Postoperative treatment depends on the histological type and tumor volume after neoadjuvant chemotherapy, the stage of the disease, and is based on SIOP (nephroblastoma, clear cell sarcoma of the kidney) and EU-RHAB (rhabdoid tumor of the kidney) recommendations [16; 33; 64].

3.3.1 Adjuvant Therapy for Localized Nephroblastoma

Postoperative chemotherapy should be initiated within 2 weeks after surgery. For the scope of postoperative therapy in localized disease, see Table 4.

Table 4. Scope of postoperative therapy for localized disease

TN – total necrosis; A – #Dactinomycin; V – Vincristine**; D – Doxorubicin** (cumulative dose 250 mg/m²); HR – block chemotherapy; RT – radiotherapy.

* – excluding stromal and epithelial subtypes (treatment does not depend on tumor size: AV1 for stage I and AV2 for stage II); ⁺ – flank – half of the abdominal cavity

• Adjuvant therapy is recommended for the following categories of patients with localized WT (for treatment regimens, see Appendix A3.1) [33; 40; 64]:

— Stage I, intermediate risk group – AV1 regimen, 4 weeks of chemotherapy: vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4; #dactinomycin 45 mcg/kg/day, IV bolus – week 2.

— Stage I, high risk group – AVD regimen - 27 weeks of chemotherapy: vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27; #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26; doxorubicin** 50 mg/m²/day, IV drip 2-6 hour infusion – weeks 2, 8, 14, 20, 26;

— Stages II/III, low and intermediate risk groups – AV-2 regimen: vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27; #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26 or AVD – 27 weeks of chemotherapy: vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27; #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26; doxorubicin** 50 mg/m²/day, IV drip 2-6 hour infusion – weeks 2, 8, 14, 20, 26 (see comments);

— Stages II/III, high risk group – HR-1 regimen - 34 weeks of chemotherapy: course 1 – cyclophosphamide** + doxorubicin** (6 courses total): cyclophosphamide** 450 mg/m²/day IV drip over 1 hour – days 1, 2, 3, in weeks 1, 7, 13, 19, 25, 31; doxorubicin** 50 mg/m²/day IV drip over 2-6 hours – day 1, in weeks 1, 7, 13, 19, 25, 31; course 2 – #etoposide** + #carboplatin** (6 courses total): #etoposide** 150 mg/m²/day IV drip over 1 hour – days 1, 2, 3, in weeks 4, 10, 16, 22, 28, 34; #carboplatin** 200 mg/m²/day IV drip over 1 hour – days 1, 2, 3, in weeks 4, 10, 16, 22, 28, 34.

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

Comments: adjuvant therapy is not performed for stage I patients from the low-risk group (total necrosis). The presence of the totally necrotic type must be confirmed by histological material review at a reference center.

Most patients with stage II/III, low- and intermediate-risk disease receive therapy according to the AV-2 regimen; in patients with focal anaplasia, mixed, or regressive histological tumor types and a tumor volume after neoadjuvant chemotherapy of >500 ml, doxorubicin** is added to the AV-2 regimen (treatment according to the AVD regimen, as for high-risk stage I tumors).

The maximum single dose of vincristine** is 2 mg. The first administration of vincristine** is given after the restoration of bowel motility in the postoperative period, within up to 21 days from the last administration of neoadjuvant chemotherapy. #Dactinomycin is not used in children weighing less than 5 kg and under 3 months of age. Drug dose reductions depending on age are presented in Tables 15 and 16.

Cyclophosphamide** is administered with Mesna**, the doses of which are calculated according to the State Register of Medicines instructions, namely, for this dose of chemotherapy – 90 mg/m²/day IV bolus immediately before cyclophosphamide** administration and 360 mg/m²/day IV drip over 24 hours – days 1, 2, 3 in weeks 1, 7, 13, 19, 25, 31.

3.3.2 Adjuvant Therapy for Generalized Nephroblastoma [33]:

Postoperative chemotherapy is administered depending on the histological type of the tumor and the response of the primary focus and metastases to preoperative treatment – see Table 5.

Table 5. Evaluation of metastases before surgery

* For target lesions measuring 3–5 mm, the only response options are complete response (CR) and non-complete response (non-CR).

Abbreviations: CR – complete response, PR – partial response, VGPR – very good partial response, PD – progressive disease, SD – stable disease.

Postoperative chemotherapy for pulmonary lesions measuring less than 3 mm:

• In patients with generalized nephroblastoma with baseline pulmonary lesions measuring less than 3 mm, if the lesions disappear (on CT) after preoperative chemotherapy, treatment is recommended to be carried out in accordance with the local stage and histological subtype [33; 64].

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

• In patients with generalized nephroblastoma with baseline pulmonary lesions measuring less than 3 mm, if the pulmonary lesions persist, it is recommended to perform their complete surgical resection (if possible), or at least a resection of the largest lesion for subsequent pathoanatomical examination and decision-making on further treatment tactics (for treatment regimens, see Appendix A3.1) [33; 64]:

— if pathoanatomical examination of the removed metastases reveals no viable tumor tissue or total necrosis, treatment is carried out in accordance with the local stage and histological subtype;

— if histology reveals a persistent viable tumor or total necrosis, treatment is given according to the AVD 250 program (see Appendix A3.1). If micrometastases persist at week 10 of postoperative treatment, total irradiation of both lungs is indicated;

— if diffuse anaplasia is detected, total lung irradiation is indicated provided that metastases are histologically confirmed;

— if biopsy is not feasible, continuation of chemotherapy according to the histological subtype (at least AV2), regardless of the stage. Assessment of the dynamics of pulmonary lesions at week 10 of postoperative therapy.

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

• In patients with generalized nephroblastoma with baseline pulmonary lesions measuring less than 3 mm, in case of an increase in the size of metastases on CT, it is recommended to resect at least one node for subsequent pathoanatomical examination of the surgical material and decision-making on further treatment tactics (for treatment regimens, see Appendix A3.1) [33; 64]:

— If histological examination of the removed metastases reveals no viable tumor tissue or total necrosis, treatment is carried out in accordance with the local stage and histological subtype (minimum AV2);

— If histology reveals a persistent viable tumor or total necrosis, treatment is given according to the AVD program. If micrometastases persist at week 10 of postoperative treatment, total irradiation of both lungs is indicated;

— If diffuse anaplasia is detected, total lung irradiation is indicated provided that metastases are histologically confirmed;

— If biopsy is not feasible, continuation of chemotherapy according to the histological subtype (at least AVD), regardless of the stage. Follow-up examination at week 10.

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

Postoperative chemotherapy in the presence of pulmonary lesions greater than 3 mm:

• Patients with generalized nephroblastoma with baseline pulmonary metastases greater than 3 mm, group A (metastases (lesions) absent or completely resected) with low- and intermediate-risk histological subtypes, are recommended the following therapeutic approaches depending on the size of metastases and tumor histological subtype (for treatment regimens, see Appendix A3.1) [33; 64]:

— A1. Pulmonary nodules greater than 3 mm but less than 5 mm at diagnosis with low- or intermediate-risk histology: treatment with the AVD 150 regimen. If histological examination reveals viable tumor tissue, total lung irradiation is indicated;

— A2. Pulmonary nodules greater than 5 mm at diagnosis and with low- or intermediate-risk histology: treatment with the AVD 250 regimen. If histological examination reveals viable tumor tissue, lung irradiation is indicated;

— A3. Complete surgical resection of nodules with no histological confirmation of metastases (no viable tumor or total necrosis detected): treatment according to the local stage and in accordance with the histological subtype.

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

• Patients with generalized nephroblastoma with baseline pulmonary metastases greater than 3 mm, group B (local stage I/II/III with low-risk histology and multiple unresectable lesions or incompletely resected lesions) are recommended the following therapeutic approaches depending on the results of the surgical intervention and pathoanatomical examination (for treatment regimens, see Appendix A3.1) [33; 64]:

— If metastases are not histologically proven (viable metastases and total necrosis excluded), treatment according to the local stage;

— If histology shows no viable tumor tissue, but total necrosis is detected, treatment with the AVD 250 regimen, 27 weeks of chemotherapy: vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27; #dactinomycin 45 mcg/kg/day, IV bolus on weeks 2, 5, 8, 11, 14, 17, 20, 23, 26; doxorubicin** 50 mg/m²/day, IV drip 2–6 hour infusion on weeks 2, 8, 14. Dynamics assessment via chest CT is performed at week 10. If lesions persist, complete surgical resection is recommended. Total lung irradiation is not performed;

— If histological examination reveals viable tumor tissue, treatment with the AVD 250 regimen, 27 weeks of chemotherapy: vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27; #dactinomycin 45 mcg/kg/day, IV bolus on weeks 2, 5, 8, 11, 14, 17, 20, 23, 26; doxorubicin** 50 mg/m²/day, IV drip 2–6 hour infusion on weeks 2, 8, 14, with lung irradiation;

— If pulmonary lesions cannot be resected, treatment with the AVD 250 regimen. If pulmonary lesions are still identified during examination at week 10 of postoperative chemotherapy, repeat biopsy. Additionally, lung irradiation, as the pulmonary nodules may have non-low-risk histology.

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

Comment: age-based drug dose reductions are presented in Table 16. If irradiation of the tumor bed and lungs is necessary, it is advisable to perform radiation therapy simultaneously to prevent overlap of irradiation fields. Therefore, radiation therapy may be postponed up to week 10. #Dactinomycin is not used in children weighing less than 5 kg and under 3 months of age. Age-based drug dose reductions are presented in Table 16.

• Patients with generalized nephroblastoma with baseline pulmonary metastases greater than 3 mm, group C (local stage I/II/III with intermediate-risk histology and multiple unresectable lesions or incompletely resected lesions) are recommended the following therapeutic approaches depending on the results of the surgical intervention and pathoanatomical examination (for treatment regimens, see Appendix A3.1) [33; 64]:

— If metastases are not histologically proven (no viable metastases or total necrosis) – treatment in accordance with the local stage, but if multiple pulmonary nodules disappeared after preoperative AVD chemotherapy, and the remaining nodules are considered non-malignant – continuation of therapy with the AVD 250 regimen;

— If no viable tumor tissue is found histologically, but total necrosis is present – treatment with the AVD 250 regimen for 27 weeks. If pulmonary nodules persist at week 10 of postoperative chemotherapy – repeat resection or lung irradiation. If viable tumor tissue is detected – lung irradiation;

— If viable tumor tissue is detected histologically in the excised nodes, switch to HR2 treatment, 34 weeks of chemotherapy: Course 1 – cyclophosphamide** + doxorubicin** (4 courses in total): cyclophosphamide** 450 mg/m²/day IV infusion over 1 hour – days 1, 2, 3, in weeks 1, 7, 19, 31; doxorubicin** 50 mg/m²/day IV infusion over 2–6 hours – day 1, in weeks 1, 7, 19, 31; Course 2 – #etoposide** + #carboplatin** (8 courses in total): #etoposide** 150 mg/m²/day IV infusion over 1 hour – days 1, 2, 3, in weeks 4, 10, 13, 16, 22, 25, 28, 34; #carboplatin** 200 mg/m²/day IV infusion over 1 hour – days 1, 2, 3, in weeks 4, 10, 13, 16, 22, 25, 28, 34, with total lung irradiation, regardless of lung status at week 10 of treatment;

— If pulmonary nodules cannot be resected – administer HR2 therapy and lung irradiation if lesions persist at week 10;

— If metastatic lesions in sites other than the lungs and liver cannot be radically resected, they must be irradiated, regardless of the response to chemotherapy;

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

Comments: Dose reductions of drugs according to age are presented in Tables 15 and 16. Cyclophosphamide** is administered concurrently with the administration of Mesna** 90 mg/m²/day IV bolus immediately before cyclophosphamide** administration and 360 mg/m²/day IV infusion over 24 hours – days 1, 2, 3 in weeks 1, 7, 13, 19, 25, 31. This mesna administration schedule and doses are calculated in accordance with the State Register of Medicines instructions, specifically for this chemotherapy dose.

Patients with localized stage III disease receive radiation therapy to the corresponding half of the abdominal cavity. Radiation therapy may be delayed until week 10 (assessment of persistent lesions) to be combined with total lung irradiation if necessary (to avoid overlapping radiation fields).

• Patients with generalized NB with baseline pulmonary metastases > 3 mm of group D (with high-risk histology regardless of the degree of dissemination) are recommended to consult with experts from a federal specialized center for individualized patient therapy selection [33; 64].

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

3.3.3 Adjuvant therapy for patients with NB after primary surgery without neoadjuvant (preoperative) chemotherapy

• Patients with low histological risk NB who, for one reason or another, underwent primary surgery without preoperative chemotherapy are not recommended to receive postoperative chemotherapy [33; 76; 77; 78; 79; 80].

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

Comments: in case of stage III, consultation with a federal/national center is required to obtain further recommendations.

• For patients with neuroblastoma of intermediate histological risk (excluding focal anaplasia), stage I, who for various reasons underwent primary surgery without preoperative chemotherapy, it is recommended to administer postoperative chemotherapy according to Regimen 1 (intensive VCR): vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (10 doses in total) – see Appendix A3.1 [76; 77; 78; 79; 80].

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

Comments: Maximum single dose of vincristine** is 2 mg. First administration of vincristine** – after recovery of bowel motility in the postoperative period, within up to 14 days from surgery. Infants and children weighing <12 kg should receive the full dose of vincristine** if this single drug is used and there are no signs of toxicity. In case of toxic events, the subsequent dose should be reduced by 50%, after which doses can be cautiously increased (if well tolerated).

• For patients with neuroblastoma of intermediate histological risk (focal anaplasia), stage I and intermediate histological risk, stage II, who for various reasons underwent primary surgery without preoperative chemotherapy, it is recommended to administer postoperative chemotherapy according to Regimen 2 (AV): vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, then weeks 14, 17, 20, 23, and 26 (16 doses in total); #dactinomycin 45 mcg/kg/day, IV on weeks 2, 5, 8, 11, 14, 17, 20, 23, and 26 (9 doses in total) – see Appendix A3.1 [33].

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

Comments: Maximum single dose of vincristine** is 2 mg. First administration of vincristine** – after recovery of bowel motility in the postoperative period, within up to 14 days from surgery. Infants and children weighing <12 kg receive therapy in age-appropriate dosages (Drug dose reductions according to age are presented in Tables 15 and 16). The use of #dactinomycin must be discussed in this group with the federal center.

• Patients with intermediate histological risk stage III NB who for one reason or another underwent primary surgery without preoperative chemotherapy are recommended to receive postoperative chemotherapy according to Regimen 3 (AVD): vincristine** 1.5 mg/m²/day, IV bolus – at weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, then weeks 13, 16, 19, 22, 25, and 28 (16 doses in total); #dactinomycin 45 mcg/kg/day, IV bolus – 2/3 of the dose at week 2, then full dose at weeks 10, 16, 22, 28 (5 doses in total); doxorubicin** 50 mg/m²/day, IV infusion 4–6 hour infusion – at weeks 7, 13, 19, 25) – see Appendix A3.1 [33].

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

Comments: Maximum single dose of vincristine** is 2 mg. First administration of vincristine** – after recovery of bowel motility in the postoperative period, within up to 14 days from surgery. Infants and children weighing <12 kg receive therapy in age-appropriate dosages (Drug dose reductions according to age are presented in Tables 15 and 16). The use of #dactinomycin must be discussed in this group with the federal center..

• Patients with stage IV NB who for one reason or another underwent primary surgery without preoperative chemotherapy are recommended to receive therapy according to the following schedule [33]:

— postoperative chemotherapy according to the "preoperative" chemotherapy regimen, AVD regimen for 6 weeks – see Appendix A3.1;

— evaluation of response of metastases at week 6 using chest CT;

— subsequent chemotherapy depending on whether complete remission of metastases was achieved via chemotherapy +/- surgery, in accordance with the main recommendations for adjuvant therapy for generalized NB, see Appendix A3.3.

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

Comments: Tumors with a predominance of the blastema component after primary surgery belong to the intermediate risk group.

• Patients with stages I–IV NB with "diffuse anaplasia" histological type, high-risk group, regardless of the local stage of the process are recommended to receive postoperative chemotherapy in accordance with the adjuvant therapy recommendations for the high-risk group (for patients with localized stage – HR-1 regimen – 34 weeks of chemotherapy; for patients with generalized stage – HR-2 regimen – 34 weeks of chemotherapy) – see Appendix A3.1 [33].

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

Comments: Abdominal radiation therapy is prescribed to patients with local abdominal stages II and III. Lung radiation therapy is performed in all patients with stage IV tumors with pulmonary metastases, regardless of the response of metastases to chemotherapy/surgery.

3.3.4 Adjuvant Therapy for Renal Malignant Rhabdoid Tumor

All patients with malignant renal rhabdoid tumor, regardless of the form and stage of the process, are indicated for adjuvant chemotherapy according to the EU-RHAB recommendations [16].

• All patients are indicated for: 9 courses of intensive chemotherapy at 14-day intervals: Course 1 – #doxorubicin** (3 courses in total): #doxorubicin** 37.5 mg/m²/day IV infusion over 24 hours – days 1, 2, in weeks 1, 7, 13; Course 2 – #ifosfamide** + #carboplatin** + #etoposide** (3 courses in total): #ifosfamide** 2000 mg/m²/day IV infusion over 1 hour – days 1, 2, 3, in weeks 3, 9, 15; #carboplatin** 500 mg/m²/day IV infusion over 1 hour – day 1, in weeks 3, 9, 15; #etoposide** 100 mg/m²/day IV infusion over 1 hour – days 1, 2, 3, in weeks 3, 9, 15; Course 3 – #vincristine** + #cyclophosphamide** + #dactinomycin (3 courses in total): #vincristine** 1.5 mg/m²/day IV bolus – days 1, 8, in weeks 5, 11, 17; #dactinomycin 25 mcg/kg/day IV bolus – days 1, 2, in weeks 5, 11, 17; #cyclophosphamide** 1500 mg/m²/day IV infusion over 1 hour – day 1, in weeks 5, 11, 17 – therapy regimens – see Appendix A3.1.

• For patients with localized disease where radical surgery is not feasible (stage III) with a macroscopically residual tumor remaining after 9 courses of intensive chemotherapy, a consultation at Federal National Centers is recommended to determine indications for metronomic chemotherapy, 6 courses of 28 days each [50]: #cyclophosphamide** 25 mg/m²/day orally – days 1–28 continuously, weeks 1, 5, 9, 13, 17, 21; #vinorelbine** 25 mg/m²/day IV over 5–10 minutes, weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23 – see Appendix A3.1.

• For patients with metastatic disease after 9 courses of intensive chemotherapy, a consultation at Federal National Centers is recommended to determine indications for metronomic chemotherapy, 6 courses of 28 days each [50]: #cyclophosphamide** 25 mg/m²/day orally – days 1–28 continuously, weeks 1, 5, 9, 13, 17, 21; #vinorelbine** 25 mg/m²/day IV over 5–10 minutes, weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23 – see Appendix A3.1.

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

Comments:

The maximum single dose of #vincristine** is 2 mg. The first administration of #vincristine** is given after the recovery of bowel motility in the postoperative period, within up to 21 days from the last administration of neoadjuvant chemotherapy.

The dose of #dactinomycin in children under 1 year of age and/or weighing less than 10 kg is reduced by 1/3. If well tolerated, the dose of the drug may be increased to the target dose in subsequent courses. Dose reductions of drugs depending on age are presented in Tables 15 and 16.

#Ifosfamide** is administered with concurrent Mesna** at 400 mg/m²/day IV bolus immediately before #ifosfamide** administration on days 1, 2, and 3 in weeks 3, 9, and 15; and at 1600 mg/m²/day IV infusion over 24 hours on days 1, 2, and 3 in weeks 3, 9, and 15. This mesna administration schedule and dosages are calculated in accordance with the State Register of Medicines (GRLS) instructions specifically for this chemotherapy dose.

#Cyclophosphamide** is administered with concurrent Mesna** at 500 mg/m²/day IV bolus immediately before #cyclophosphamide** administration on day 1 in weeks 5, 11, and 17; and at 1500 mg/m²/day IV infusion over 24 hours on days 1 and 2 in weeks 5, 11, and 17. This mesna administration schedule and dosages are calculated in accordance with the State Register of Medicines (GRLS) instructions specifically for this chemotherapy dose.

Metronomic chemotherapy begins 2 weeks after the last course of intensive chemotherapy. If oral administration of #cyclophosphamide** tablets is not feasible, #cyclophosphamide** may be administered at a dosage of 87.5 mg/m²/day as an intravenous infusion over 1 hour on days 1 and 4 in weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. In case of intravenous administration of #cyclophosphamide**, prophylaxis of hemorrhagic cystitis is performed on the days of its administration by administering Mesna** at a dosage of 30 mg/m²/day IV bolus or orally at 0, 4, and 8 hours from the start of #cyclophosphamide** infusion. This mesna administration schedule and dosages are calculated in accordance with the State Register of Medicines (GRLS) instructions specifically for this chemotherapy dose.

3.3.5 Adjuvant Therapy for Renal Clear Cell Sarcoma

All patients with renal CCS, regardless of the form and stage of the process, are indicated for adjuvant chemotherapy according to SIOP recommendations [33].

• All patients with CCSK with stage I–IV disease are indicated for: 12 courses of intensive chemotherapy at 21-day intervals: Course 1 – cyclophosphamide** + doxorubicin** (3 courses total): cyclophosphamide** 450 mg/m²/day IV infusion over 1 hour on days 1, 2, 3 in weeks 1, 13, 25; doxorubicin** 50 mg/m²/day IV infusion over 4–6 hours on day 1 in week 1; Course 2 – #etoposide** + #carboplatin** (6 courses total): #etoposide** 150 mg/m²/day IV infusion over 1 hour on days 1, 2, 3 in weeks 4, 16, 28; #carboplatin** 200 mg/m²/day IV infusion over 1 hour on days 1, 2, 3 in weeks 4, 16, 28; Course 3 – ifosfamide** + doxorubicin** (3 courses total): ifosfamide** 2000 mg/m²/day IV infusion over 1 hour on days 1, 2, 3 in weeks 7, 19, 31; doxorubicin** 50 mg/m²/day IV infusion over 4–6 hours on day 1 in weeks 7, 19, 31; – see Appendix A3.1 [33].

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

Comments:

Ifosfamide** is administered with concurrent Mesna** at 400 mg/m²/day IV bolus immediately before ifosfamide** administration on days 1, 2, 3 in weeks 7, 19, 31; and at 1600 mg/m²/day IV infusion over 24 hours on days 1, 2, 3, 4 in weeks 7, 19, 31. This mesna administration schedule and dosages are calculated in accordance with the State Register of Medicines (GRLS) instructions specifically for this chemotherapy dose.

Cyclophosphamide** is administered with concurrent Mesna** at 90 mg/m²/day IV bolus immediately before cyclophosphamide** administration on days 1, 2, 3 in week 1; and at 360 mg/m²/day IV infusion over 24 hours on days 1, 2, 3 in week 1. This mesna administration schedule and dosages are calculated in accordance with the State Register of Medicines (GRLS) instructions specifically for this chemotherapy dose.

Doxorubicin** 50 mg/m2/day IV infusion over 4–6 hours – day 1 in week 1 immediately before the first dose of cyclophosphamide**. (Total of 5 courses; the maximum cumulative dose of doxorubicin** must not exceed 250 mg/m2 in stage I–III disease (for stage IV, the maximum cumulative dose of doxorubicin** is 300 mg/m2); if the cumulative dose of doxorubicin** exceeds 300 mg/m2, it is necessary to replace the doxorubicin** dose with #vincristine** 1.5 mg/m2 IV bolus on day 1; maximum #vincristine** dose is 2 mg/m2).

3.3.6 Adjuvant Therapy for Renal Congenital Mesoblastic Nephroma

Management of patients with SRT is indicated according to SIOP recommendations.

3.4 Radiation Therapy

3.4.1 Radiation Therapy for Localized Forms of Nephroblastoma

For localized NB, stage II (diffuse anaplasia) and stage III (intermediate and high histological risk groups), following organ-sparing surgeries, consultation at a specialized federal/national medical center is advisable to determine the indications and scope of radiation therapy.

Summary recommendations for abdominal radiation therapy are presented in Table 6 [33; 64].

Table 6. Summary recommendations for abdominal radiation therapy in NB

Comments: #dactinomycin and doxorubicin** are not administered for 1 week before RT and 2 weeks after RT.

• Local postoperative irradiation or irradiation of half of the abdomen (flank) is recommended 2–4 weeks after surgery for the following groups of patients with localized NB [33; 64]:

— Intermediate histological risk NB, stage III (affected para-aortic lymph nodes, presence of residual tumor after surgery, tumor rupture): local irradiation at a total dose (TD) of 14.4 Gy to half of the abdomen, with a 10.8 Gy boost to the macroscopic residual tumor;

— High histological risk NB (except blastemal type), stage II: local irradiation at a TD of 25.2 Gy to half of the abdomen, with a 10.8 Gy boost to the macroscopically residual tumor;

— High histological risk NB, stage III (all histological subtypes): local irradiation at a TD of 25.2 Gy to half of the abdomen, with a 10.8 Gy boost to the macroscopically residual tumor.

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

Comments: if RT to the lungs is planned, abdominal irradiation can be postponed so that RT to the abdomen and lungs can be delivered in a single field.

• In patients with bilateral NB, radiation therapy is recommended in accordance with the local stage [33; 64].

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

• Postoperative whole-abdomen irradiation is recommended 2–4 weeks after surgery in the following groups of patients with localized neuroblastoma [33; 64]:

— diffuse intra-abdominal dissemination (stage III due to macroscopic peritoneal metastases): whole-abdomen irradiation at a total dose (TD) of 19.5 Gy; a boost up to a TD of 25 Gy (histological intermediate-risk group) or 30.6 Gy (histological high-risk group) is possible for limited areas of macroscopic metastasis;

— massive pre- or intraoperative tumor rupture (stage III due to tumor rupture): whole-abdomen irradiation at a dose of 15 Gy (histological intermediate-risk group) or 19.5 Gy (histological high-risk group);

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

Comments: in children under 2 years of age, a dose reduction to 12 Gy is provided.

• In patients with localized neuroblastoma, stage II (diffuse anaplasia) and stage III (intermediate and high histological risk groups) after organ-sparing surgical interventions, it is recommended to contact federal/national centers to determine the indications and scope of radiation therapy [33; 64].

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

Comments: it is necessary to keep in mind functional asplenia and consider vaccination prior to spleen irradiation, as well as antibiotic prophylaxis in cases where the mean radiation dose to the spleen exceeds 10 Gy [81].

3.4.2 Radiation Therapy for Localized Forms of Malignant Rhabdoid Tumor [16]

Summary recommendations for abdominal radiation therapy are presented in Table 7.

Table 7. Summary recommendations for abdominal radiation therapy

Comments: in patients with renal malignant renal tumors before and after radiation therapy: #dactinomycin is excluded 2 weeks before and 2 weeks after RT; #doxorubicin** is excluded 2 weeks before and 4 weeks after RT. During RT, the dosage of #cyclophosphamide** may be reduced by 35% with subsequent dose escalation to 100% depending on previous tolerance. In the ICE regimen: the dosage of #ifosfamide** is calculated as 1500 mg/m²/day on days 1 and 2, the drug is not administered on day 3; the dosage of #carboplatin** is reduced by 50% – 250 mg/m²/day on day 1; the dosage of #etoposide** is reduced by 30% – 75 mg/m²/day on days 1 and 2, the drug is not administered on day 3.

• Local postoperative irradiation or irradiation of half of the abdomen (flank) is recommended 2–4 weeks after surgery in all patients with renal malignant renal tumors [16; 33; 64]:

— Patients ≥12 months old are indicated for local irradiation at a TD of 19.8 Gy to half of the abdomen, with a boost of 10.8 Gy to the macroscopically residual tumor;

— Patients <12 months old are indicated for local irradiation at a TD of 10.8 Gy to half of the abdomen, with a boost of 10.8 Gy to the macroscopically residual tumor;

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

• Postoperative whole-abdomen irradiation is recommended 2–4 weeks after surgery in the following groups of patients with renal malignant renal tumors [16; 64]:

— Patients ≥12 months old with diffuse intra-abdominal dissemination or massive tumor rupture: whole-abdomen irradiation at a TD of 19.5 Gy; a boost of 10.8 Gy is possible for limited areas of macroscopic metastasis;

— Patients <12 months old with diffuse intra-abdominal dissemination or massive tumor rupture: whole-abdomen irradiation at a TD of 10.5 Gy; a boost of 10.8 Gy is possible for limited areas of macroscopic metastasis;

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

Comments: if RT to the lungs is planned, abdominal irradiation can be postponed so that RT to the abdomen and lungs can be delivered in a single field.

3.4.3 Radiation therapy for localized forms of clear cell sarcoma of the kidney.

• Local postoperative irradiation or irradiation of half of the abdomen (flank) is recommended 2–4 weeks after surgery in the following groups of patients with localized clear cell sarcoma of the kidney [33]:

3.4.4 Radiation Therapy for Metastases

In the presence of low histological risk neuroblastoma, as well as if the patient is under 2 years of age with lung metastases or if neuroblastoma metastases are represented by viable tumor tissue (after chemotherapy and surgery), in generalized neuroblastoma, stage II (diffuse anaplasia) and stage III (intermediate and high histological risk groups) stages, after organ-sparing surgical interventions, consultation at a specialized federal/national medical center is advisable to determine the indications and scope of radiation therapy [33; 64].

All cases of renal malignant renal tumors with primary lung metastases, regardless of response to chemotherapy or surgical treatment, should receive RT in the volume of total lung irradiation at a TD of 15 Gy [16].

Summary recommendations for radiation therapy of neuroblastoma and renal MRT metastases are presented in Table 8.

Table 8. Summary recommendations for radiation therapy of metastases [16; 33; 51; 64].

WLI – whole-lung irradiation

Comments: for patients with NB, #dactinomycin and doxorubicin** are withheld for 1 week before RT and 2 weeks after RT.

In patients with renal MRT before and after radiation therapy: #dactinomycin is omitted for 2 weeks before and 2 weeks after RT; #dactinomycin** is omitted for 2 weeks before and 4 weeks after RT. During RT, the dosage of #cyclophosphamide** may be reduced by 35% with a subsequent dose escalation up to 100% depending on prior tolerance. In the ICE regimen: the dosage of #ifosfamide** is calculated as 1500 mg/m²/day on days 1 and 2, the drug is not administered on day 3; the dosage of #carboplatin** is reduced by 50% – 250 mg/m²/day on day 1; the dosage of #etoposide** is reduced by 30% – 75 mg/m²/day on days 1 and 2, the drug is not administered on day 3.

• In patients with generalized NB, it is recommended to perform whole-lung irradiation in the following cases [33; 64]:

— absence of complete clearance of lung metastases based on chest CT results at week 10 of postoperative therapy;

— if NB metastases consist of viable tumor tissue (after chemotherapy and surgery) of the histological intermediate-risk group, RT is indicated in the volume of whole-lung irradiation at a total dose of 12 Gy;

— all cases of NB with primary lung metastases, regardless of response to chemotherapy or surgical treatment, of the histological high-risk group, must receive RT in the volume of whole-lung irradiation at a total dose of 15 Gy;

— if both abdominal and whole-lung irradiation are required, it is recommended to perform chest and abdominal irradiation simultaneously during a single planning session (from a single field) to avoid treatment interruptions or field overlap;

— in case of stage III (macroscopically residual tumor) with a high probability of local recurrence, such as cases with a histological variant of diffuse anaplasia, abdominal irradiation may be performed after surgery, and lung irradiation – later, from a separate field.

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

• All patients after initial nephrectomy with a histological tumor type of "diffuse anaplasia", in the presence of metastatic lung lesions, are recommended to undergo whole-lung radiation therapy regardless of the response of metastases to chemotherapy/surgery [33; 64].

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

• All cases of renal MRT with primary lung metastases, regardless of response to chemotherapy or surgical treatment, must receive RT in the volume of whole-lung irradiation at a total dose of 15 Gy [16; 33].

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

• All cases of renal CCS with primary lung metastases, regardless of response to chemotherapy or surgical treatment, must receive RT in the volume of whole-lung irradiation at a total dose of 12 Gy [33; 51].

• Liver irradiation in patients with generalized renal malignant tumor is recommended in the following cases [16; 33; 64]:

— Presence of liver metastases that persisted after chemotherapy and cannot be radically resected;

— For patients with NB of the intermediate-risk histological group at a total dose of 14.4 Gy to the whole liver and a boost to residual metastases up to 25.2 Gy;

— For patients with NB of the high-risk histological group and renal MRT at a total dose of 19.8 Gy to the whole liver and a boost to residual metastases up to 30.6 Gy.

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

Comments: The total dose to the entire liver should not exceed 20 Gy.

• In patients with generalized Wilms' tumor or renal clear cell sarcoma with distant hematogenous metastasis to organs other than the liver and lungs, radiation therapy is recommended in the following cases [16; 33; 64]:

— brain metastases, regardless of the response to chemotherapy, at a total dose of 15.0 Gy during whole-brain radiotherapy for intermediate-risk histological Wilms' tumor with a boost up to 25.2 Gy, and at a total dose of 25.2 Gy during whole-brain radiotherapy for high-risk histological Wilms' tumor and renal clear cell sarcoma with a boost up to 30.6 Gy;

— Bone metastases, regardless of the response to chemotherapy. The radiation dose to bone metastases is 30 or 30.6 Gy.

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

Comments: given the rarity of hematogenous metastases outside the liver and brain, this situation requires discussion with a federal/national center.

3.5 Management of patients with bilateral tumors (stage V), as well as unilateral nephroblastoma with a genetic predisposition to bilateral involvement

The treatment strategy for bilateral nephroblastoma is based on 3 points:

1. Preoperative chemotherapy to reduce tumor volume as much as possible;

2. Nephron-sparing surgery, whenever possible;

3. Postoperative chemotherapy according to the highest stage and worst histology [33; 64].

• Patients with bilateral nephroblastoma are recommended the following treatment strategy [33; 51; 64; 82-85]:

— the duration of preoperative chemotherapy should not exceed 12 weeks;

— initial treatment: neoadjuvant VA regimen, 6 weeks – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6; #dactinomycin 45 mcg/kg/day, IV bolus – weeks 1, 3, 5 (see Appendix A3.1);

— first response evaluation using contrast-enhanced abdominopelvic MRI (CT);

— if feasible based on the response evaluation – surgical treatment (nephron-sparing surgery) on at least one kidney;

— in case of partial remission – continuation of chemotherapy with the same program – 6 weeks in the VA regimen (see Appendix A3.1);

— in the absence of response or in case of progression, if nephron-sparing surgery is not possible, it is recommended to change the chemotherapy regimen to #carboplatin**/#etoposide**: #etoposide** 150 mg/m²/day IV drip over 1 hour on days 1, 2, 3, weeks 1 and 4; #carboplatin** 200 mg/m²/day IV drip over 1 hour on days 1, 2, 3, weeks 1 and 4 (see Appendix A3.1) – 2 cycles

— second response evaluation: contrast-enhanced abdominopelvic MRI (CT) after another 6 weeks of VA or 2 cycles of #carboplatin**/#etoposide**;

— discussion of the feasibility of the 2nd stage of surgery;

— postoperative treatment according to the highest stage and worst histology (see Section 3.3. Postoperative therapy).

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

Comments: in patients with generalized disease, preoperative therapy is administered according to the AVD regimen. (see Section 3.1. Neoadjuvant chemotherapy for the metastatic form of the disease). Consultation at a federal/national center is required to determine the subsequent patient management strategy.

• Patients with unilateral nephroblastoma and contralateral nephroblastomatosis are recommended the following treatment strategy [33; 51; 64; 82-85]:

— Neoadjuvant VA regimen, 6 weeks – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6; #dactinomycin 45 mcg/kg/day, IV bolus – weeks 1, 3, 5 (see Appendix A3.1);

— First response evaluation: contrast-enhanced abdominopelvic MRI (CT) after 6 weeks of chemotherapy;

— If feasible – surgical treatment (nephron-sparing surgery) on at least one kidney;

— In case of partial remission – continuation of chemotherapy with the same program – 6 weeks in the VA regimen (see Appendix A3.1);

— In the absence of response or in case of progression, if nephron-sparing surgery is not possible, it is recommended to change the chemotherapy regimen to #carboplatin**/#etoposide**: #etoposide** 150 mg/m²/day IV drip over 1 hour on days 1, 2, 3, weeks 1 and 4; #carboplatin** 200 mg/m²/day IV drip over 1 hour on days 1, 2, 3, weeks 1 and 4 (see Appendix A3.1) – 2 cycles;

— Second response evaluation: contrast-enhanced abdominopelvic MRI (CT) after another 6 weeks of VA or 2 cycles of #carboplatin**/#etoposide**;

— Discussion of the feasibility of the 2nd stage of surgery;

— Postoperative treatment according to the highest stage and worst histology (see Section 3.3. Postoperative therapy).

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

• Patients with unilateral or bilateral nephroblastomatosis are recommended the following treatment strategy [33; 51; 64; 82-85]:

— Neoadjuvant VA regimen, 6 weeks: – vincristine** 1.5 mg/m²/day, IV bolus - weeks 1, 2, 3, 4, 5, 6; #dactinomycin 45 mcg/kg/day, IV bolus – weeks 1, 3, 5 (see Appendix A3.1);

— First response evaluation: contrast-enhanced abdominopelvic MRI (CT) after 6 weeks of VA;

— Further therapy depends on the response to induction chemotherapy and is detailed in the flowchart of the treatment algorithm for patients with unilateral or bilateral nephroblastomatosis, see Appendix B5 [33; 64].

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

Comments: in patients with unilateral nephroblastoma and contralateral nephroblastomatosis with stage IV disease, preoperative therapy is administered according to the AVD regimen (see Section 3.1. Neoadjuvant chemotherapy for the metastatic form of the disease). Consultation at a federal/national center is required to determine the subsequent patient management strategy.

• Patients with unilateral nephroblastoma and a tumor predisposition syndrome are recommended the following treatment strategy [33; 51; 64; 82-85]:

— Neoadjuvant VA regimen, 6 weeks – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6; #dactinomycin 45 mcg/kg/day, IV bolus – weeks 1, 3, 5 (see Appendix A3.1);

— First response evaluation: contrast-enhanced abdominopelvic MRI (CT) after 6 weeks of chemotherapy;

— If feasible – surgical treatment (nephron-sparing surgery) on at least one kidney;

— In case of partial remission – continuation of chemotherapy with the same program – 6 weeks in the VA regimen (see Appendix A3.1);

— In the absence of response or in case of progression, if nephron-sparing surgery is not possible, it is recommended to change the chemotherapy regimen to #carboplatin**/#etoposide** – #etoposide** 150 mg/m²/day IV drip over 1 hour on days 1, 2, 3, weeks 1 and 4; #carboplatin** 200 mg/m²/day IV drip over 1 hour on days 1, 2, 3, weeks 1 and 4 (see Appendix A3.1) – 2 cycles;

— Second response evaluation: contrast-enhanced abdominopelvic MRI (CT) after another 6 weeks of VA or 2 cycles of #carboplatin**/#etoposide**;

— Discussion of the feasibility of the 2nd stage of surgery;

— Postoperative treatment according to local stage and risk group (see Section 3.3. Postoperative therapy).

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

Comments: these patients are at high risk of developing metachronous bilateral tumors, and they should benefit from a treatment strategy that involves nephron-sparing surgery whenever possible. Therefore, treatment options intended for bilateral disease are applicable to them.

3.5.1 Surgical Treatment for Bilateral Nephroblastoma

Treatment of such patients requires an individualized approach. Surgical treatment should be performed by an experienced surgical team after consultation at a federal/national center [82-85].

• For bilateral nephroblastoma, nephron-sparing surgery is recommended following tumor response to chemotherapy: upon reduction in size or imaging signs of necrosis within the tumors [33; 82-85];

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

Comments: surgical treatment should be performed in departments experienced in nephron-sparing surgery. The goal of treatment is the maximum preservation of functioning renal parenchyma. The first surgical stage is performed on the less affected kidney, and the second surgical stage is performed on the more affected kidney. A total nephrectomy on one side and partial nephrectomy (resection) on the other are permitted, provided that a sufficient volume of functional renal tissue is preserved. If necessary, multiple surgeries may be performed to achieve complete resection.

3.5.2 Radiation Therapy in Patients with Bilateral Nephroblastoma

Recommendations regarding radiation doses and target volumes are similar to those for unilateral disease. According to indications, radiation therapy may be initiated concurrently with the start of adjuvant therapy (see Section 3.4 Radiation therapy) [33; 64].

3.6 Nutritional Screening and Monitoring

Medical nutrition is an integral component of the treatment process and preventive measures, and includes dietary rations that have a established chemical composition and energy value, consist of specific products, including specialized medical nutrition products, dry protein composite mixtures and vitamin-mineral complexes subjected to appropriate technological processing, as well as enteral clinical nutrition products (medical liquid formulas).

• Medical nutrition is recommended for prescribing to cancer patients upon admission to a medical organization for inpatient medical care. Medical nutrition is prescribed by the attending physician or the on-duty physician of the medical organization in accordance with the nosological form of the disease according to the primary and/or concomitant diagnosis [61].

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

Comments: The diet type depends on the patient's condition, gastrointestinal and metabolic disorders, primary or concomitant pathology, and is regulated by Appendix No. 3 "To the Procedure for Providing Patients with Therapeutic Nutrition" approved by Order of the Russian Ministry of Health No. 1008n dated September 23, 2020.

• All patients with protein-energy malnutrition or a high risk of developing it (regardless of nutritional status) are recommended to receive nutritional support (NS) [61, 86, 87].

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

Comments: the presence of protein-energy malnutrition or a high risk of its development in children with malignancies during antitumor treatment leads to associated risks of increased disability, increased duration and scope of primary and supportive treatment, low success rate of the ongoing treatment, increased mortality, and overall financial costs for treatment and rehabilitation measures—during active antitumor treatment and after its completion. Occult PEM (e.g., masked by an excess of fat mass during long-term systemic glucocorticosteroid therapy) is accompanied by the same risks. Therefore, given the high probability of worsening nutritional problems during treatment, it is advisable to prescribe nutritional support to patients in addition to their existing diet or replacing it.

Nutritional screening and monitoring (assessment of nutritional status)

Comments: detecting nutritional disorders in the early stages of their development, especially before the initiation of antitumor therapy, allows for timely nutritional correction. Primary screening is carried out either by assessing anthropometric parameters and identifying risk, or by using standard scales/tools for nutritional screening [90]. Nutritional screening consists of the initial and subsequent regular assessment of the nutritional status and the risk of developing protein-energy malnutrition, including occult malnutrition, in every patient from the moment of hospital admission. The frequency should be determined by the specific clinical situation and the characteristics of the treatment administered [91].

Comment: most screening tools (questionnaires) are aimed at combining data on the primary diagnosis, clinical status, anthropometric parameters, changes in body weight, nutritional status, and integrating these data into a total score with subsequent division of patients into 2 or 3 cohorts: do not need nutritional correction (support); require repeated dynamic screening ("at-risk" group); need nutritional correction (support). A clinical department (or institution) has the right to use the tool, or combination of tools, that it considers most appropriate for conducting nutritional screening among its patients. It must be remembered that existing screening tools are not designed to answer the question of the volume and method of necessary nutritional support, nor do they carry prognostic information for a specific patient, as their application is aimed solely at medical triage. In addition, there is no universal screening tool in pediatrics

• If there is a need for a detailed anthropometric study for the initial and regular assessment of nutritional status, it is recommended to use the following as additional anthropometric parameters: measurement of basic anthropometric circumferences, lengths, skinfold thickness (plimentry), and handgrip dynamometry (measurement of hand muscle strength) [61; 88; 92].

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

Comment: The WHO growth charts are frequently used "by default" in the Russian Federation, for the convenience of working with which there are freely available programs (WHO anthro and WHO anthro plus) that quickly allow calculating key anthropometric parameters in correlation with WHO reference data. However, it is also possible to use other reference data to correlate patient data with standards—in this case, it is necessary to indicate which specific references were used.

• Patients with nutritional disorders or patients with a high nutritional risk identified during initial screening are recommended to undergo a more detailed examination of nutritional status: dietary analysis, evaluation of laboratory parameters, as well as a detailed physical examination and interview to identify nutritional-metabolic disorders and their predictors [91-93].

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

• All patients receiving nutritional support are recommended to undergo nutritional monitoring, which includes an interview, anthropometry, and, if necessary, tissue body composition analysis (determining the percentage of water, muscle, and fat tissue using a bioelectrical impedance analyzer), and laboratory parameters (general therapeutic biochemical blood test, coprological examination) [61; 89; 93]

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

Nutritional support

Nutritional support is carried out by prescribing specialized enteral nutrition products. Enteral nutrition food products or therapeutic nutritional formulas are liquid or dry (reconstituted to ready-to-use) dietary therapeutic or dietary prophylactic food products intended for oral consumption directly or administration via a tube when it is impossible to supply the body with nutrients and energy in the usual way [94]. Therapeutic formulas are specially developed food products with a specified chemical composition, energy value, physical properties, and proven therapeutic effect that meet the physiological needs of the body and take into account the metabolic disorders of a sick person [95]. When choosing the form, method, type, and volume of nutritional support, it is recommended to be guided primarily by the principle of an individual patient-oriented approach—in accordance with the clinical situation and logic [61; 96]

• In obese patients (with excess fat mass), latent protein-energy malnutrition may develop, defined by a deficiency of fat-free body mass and a critical reduction of its skeletal muscle compartment; therefore, it is recommended to correct this type of deficiency. Obesity in itself is not a contraindication for enteral or parenteral nutritional support [92; 96; 97].

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

• The volume of nutritional support should be calculated by determining nutritional needs or total energy expenditure (TEE) [61; 98].

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

Comment: total energy expenditure (TEE) is calculated using the formula: TEE = BEE × CF, where BEE is basal energy expenditure and CF is the conversion factor. The gold standard for determining BEE is indirect calorimetry. If indirect calorimetry is unavailable, BEE can be calculated using a formula (e.g., Schofield) [98]. To avoid hyperalimentation during the initial stages of nutritional support in children with chronic protein-energy malnutrition and/or an estimated history of nutrient intake deficiency for 3 or more consecutive months, a CF of 0.85–1.4 is used to calculate TEE. The exact volume of nutritional intervention is determined based on the specific clinical situation.

• When choosing the route of nutritional support, it is recommended to prioritize enteral nutrition (EN) [87; 99].

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

Comment: EN is the most physiological method, providing intraluminal trophism of the gastrointestinal mucosa, preventing microbial translocation from the intestinal lumen into the bloodstream, and being more cost-effective than parenteral nutrition

• If the patient cannot, does not want to, or is not ready to independently consume the prescribed volume of the formula in the required regimen, it is recommended to use a nasogastric (nasojejunal) tube or gastrostomy for enteral nutrition [87; 96; 99].

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

Comment: lack of appetite, refusal to eat and EN formulas, swallowing disorders, and the inability to meet nutrient and energy needs orally are indications for EN via a nasogastric tube. The presence of pathological conditions in which the patient must not take food naturally (acute pancreatitis, gastric outlet stenosis, high proximal fistulas) indicates the use of EN via a nasojejunal tube.

• If there is a current or potential need for tube feeding lasting for more than 6 weeks, recommendations include gastrostomy placement [99].

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

Comment: when long-term enteral nutrition is required and there is a predicted risk of nutritional deficiency (including during chemoradiotherapy), preventive gastrostomy placement can be performed, bypassing the tube-feeding stage

• In cases where a child has severe chronic protein-energy malnutrition with a high risk of its further worsening, especially if they are yet to undergo further antitumor treatment, it is recommended to place a gastrostomy, bypassing the tube feeding and even sipping stages [96; 100].

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

• Patients with gastrointestinal disorders are recommended to start enteral nutritional support with a specialized therapeutic enteral nutrition formula with a caloric density of 1 kcal/ml (isocaloric formula) and, if necessary, subsequently transition to a therapeutic enteral nutrition formula with a caloric density of more than 1 kcal/ml (hypercaloric), under the control of tolerance [87].

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

Comment: formulas are divided by energy density into isocaloric (1 kcal/ml for children over one year and 0.67–0.69 kcal/ml for children under one year) and hypercaloric (more than 1 kcal/ml for children over one year and 1 kcal/ml for children under one year). It is advisable to initiate nutritional support, especially in children with a history of or current gastrointestinal disorders and/or those who have never received enteral nutrition before, using isocaloric formulas.

• In the presence of malabsorption/severe gastrointestinal disorders (but no contraindications to EN) or severe food allergy (or cow's milk protein allergy), it is recommended to prescribe a semi-elemental/oligomeric (или, по показаниям, elemental) specialized therapeutic enteral nutrition formula [87; 101].

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

Comment: formulas are classified by chemical composition into polymeric (based on intact protein) and oligomeric (containing protein hydrolysates) or semi-elemental. Elemental formulas do not contain intact protein; their protein component is represented by amino acids. Typically, elemental formulas are prescribed for diagnosed cow's milk protein allergy.

• For all patients whose estimated nutritional needs cannot be met enterally and/or in cases where EN cannot cover basal energy expenditure, it is recommended to prescribe parenteral nutrition (if there are no contraindications to parenteral nutrition). Among these patients, special attention should be paid to children with existing malnutrition, especially moderate and severe grades [98; 102].

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

Comments: the key indication for prescribing parenteral nutrition (PN) is the inability to meet the estimated nutritional requirements (at least at the level of basal energy expenditure) enterally – either currently or potentially in the short term.

• Parenteral nutrition should be initiated gradually, stepwise increasing the volume (and rate) of daily infusion starting from one-third to one-half of the calculated target volume. Under the monitoring of general clinical blood biochemistry parameters (primarily glucose, direct bilirubin, urea) and acid-base balance and blood gases, the volume should be brought to the target over several days (the rate of reaching the target volume is determined individually based on the clinical situation). Discontinuation of parenteral nutrition should also be performed gradually, stepwise, in reverse order [61; 87; 100].

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

Comments: initiating parenteral nutrition immediately at full volume is highly discouraged, as is a one-time discontinuation ("starting the next day") of total parenteral nutrition. It is especially dangerous to prescribe full parenteral nutrition to patients with a prolonged lack of alimentation due to the possible development of refeeding syndrome. The volume of PN should be gradually (stepwise) increased with parallel monitoring of blood acid-base balance, electrolytes, glucose, urea, and direct bilirubin. If necessary, the volume and composition of PN must be adjusted.

Table 3.6.1. Interpretation of nutritional status based on Z-scores according to WHO reference data [115, 119]

Notes: nutritional status in pediatric oncology is assessed based on cumulative data (clinical, laboratory, instrumental), taking nutritional risk into account. Anthropometric indicators provide a guideline for determining nutritional status and cannot be the sole defining factor [119]; *– the indicator with the minimum SDS is used in determining nutritional status; SDS – standard deviation score

Table 3.6.2. High-risk factors for nutritional status disorders in children with malignant neoplasms [119]

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All patients with neuroblastoma at all stages of treatment, as well as after the completion of medical treatment, are recommended comprehensive rehabilitation, and, if necessary, supportive care to improve treatment outcomes and the patient's quality of life, depending on comorbid pathology and complications of the primary therapy [63].

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

Comments: there are no special rehabilitation methods for renal malignancies. Patient rehabilitation must be comprehensive, covering not only medical but also social and psychological aspects of the patient's adaptation to normal life. Such rehabilitation requires, in addition to medical care, the mandatory participation of psychologists. Rehabilitation programs are developed individually depending on the identified complications of drug therapy, comorbid conditions, and social and psychological problems. Rehabilitation in the event of complications of the disease and treatment is carried out within the framework of the corresponding nosologies. The pediatric oncologist at the patient's place of residence is guided by the recommendations provided by the specialists of the treatment center.

5. Prevention and Dispensary Observation

Methods for the prevention of neuroblastoma, renal malignant neoplasms and renal CCS do not currently exist, as the majority of cases are sporadic in nature.

• Patients who have received/are receiving treatment for neuroblastoma, renal malignant neoplasms, and renal CCS are recommended to undergo regular scheduled screening examinations due to the risk of relapse and second malignancies (see Table 9, Table 10, Table 11) [16; 33; 64].

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

Table 9. Laboratory and instrumental diagnostics during the follow-up stage of neuroblastoma, GCT

Table 10. Laboratory and instrumental diagnostics during the follow-up stage of renal malignant neoplasms

Table 11. Laboratory and instrumental diagnostics during the follow-up stage of renal CCS [33].

5.1 Prevention and treatment of nausea and vomiting induced by antineoplastic therapy

• In all patients with malignant renal tumors, to determine the emetogenicity level and the CINV prevention option to select an adequate CINV prevention regimen at the first stage, it is necessary to determine the emetogenicity level (risk of CINV) of the antineoplastic therapy regimen planned for the patient. The emetogenicity level influences the choice of drugs for CINV prevention, their doses, and duration of administration [63].

GOM ALOE 1Level of Evidence – A (Level of Data Reliability – 1)

Comments: Appendix A3.4 provides the general classification of chemotherapy emetogenicity according to ASCO (American Society of Clinical Oncology) and COG (Children's Oncology Group) guidelines [63; 103].

• In all patients with malignant renal tumors receiving highly emetogenic chemotherapy for optimal prevention of acute CINV occurring on the day(s) of chemotherapy administration, for children aged 5 years and older and/or weighing 15 kg or more, it is indicated to use a four-drug regimen including a 5-HT3 serotonin receptor blocker, an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics), #dexamethasone**, and #olanzapine** [104–106]. Regimens and doses are presented in Appendix A3.4.

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

Comments: If the antineoplastic therapy regimen includes a glucocorticoid at a dose equal to or exceeding the dose indicated for antiemetic purposes, additional administration of a glucocorticoid (to the antineoplastic regimen) for CINV prevention on that day is not required. The use of #olanzapine** in children under 5 years of age and/or weighing less than 15 kg has not been studied and cannot be recommended.

• In all patients with malignant renal tumors receiving highly emetogenic chemotherapy for optimal prevention of delayed CINV, administered for 3 days after the completion of chemotherapy drug administration, it is indicated to use a combination of #dexamethasone** and #olanzapine** [104; 107]. Regimens and doses are presented in Appendix A3.4.

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

Comments: if it is not possible to prescribe an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics), a combination consisting of any 5-HT3 serotonin receptor blocker, #dexamethasone**, and #olanzapine** may be used [103; 104; 106]. Regimens and doses are presented in Appendix A3.4.

If it is not possible to prescribe #dexamethasone**, palonosetron is used as the preferred 5-HT₃ serotonin receptor blocker in combination with an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics) (if available) and #olanzapine** [63; 108]. Regimens and doses are presented in Appendix A3.4

• In all patients with malignant renal tumors receiving moderately emetogenic chemotherapy for optimal prevention of acute CINV occurring on the day(s) of chemotherapy administration, it is indicated to use a two-drug regimen including a 5-HT3 serotonin receptor blocker and #dexamethasone** [63; 105]. Regimens and doses are presented in Appendix A3.4.

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

Comments: if the antineoplastic therapy regimen includes a glucocorticoid at a dose equal to or exceeding the dose indicated for antiemetic purposes, additional administration of a glucocorticoid (to the antineoplastic regimen) for CINV prevention on that day is not required.

• In all patients with malignant renal tumors receiving moderately emetogenic chemotherapy for optimal prevention of delayed CINV administered within 1 day after the completion of cytostatic administration (according to the ATC classification L: Antineoplastic and immunomodulating agents), it is indicated to use #dexamethasone** [63; 105]. Regimens and doses are presented in Appendix A3.4.

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

Comments: if #dexamethasone** cannot be prescribed, a combination consisting of any 5-HT3 serotonin receptor blocker and an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics) should be used [63; 105]. Regimens and doses are presented in Appendix A3.4.

If neither #dexamethasone** nor an NK₁ receptor antagonist (according to the ATC classification A04AD: Other antiemetics) can be prescribed, palonosetron is used as the preferred 5-HT3 serotonin receptor blocker [63; 105]. Regimens and doses are presented in Appendix A3.4.

• All patients with malignant renal tumors receiving low- and minimal-emetogenicity chemotherapy require optimal prevention with single-agent therapy including a 5-HT3 serotonin receptor blocker for low-emetogenicity therapy, or no prophylaxis at all in the case of chemotherapy with minimal emetogenic activity [63]. Regimens and doses are presented in Appendix A3.4.

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

• In all patients with malignant renal tumors with breakthrough and refractory vomiting during cytostatic therapy, it is recommended [63; 109]:

1. to use drugs provided for the next, higher level of prophylaxis if breakthrough CINV occurred during cytostatic therapy (and, accordingly, prophylaxis) classified as minimal, low, or moderate emetogenicity;

2. to consider adding #olanzapine** (if not previously used due to inappropriate age or body weight) if the patient is already receiving prophylaxis intended for highly emetogenic therapy. If #olanzapine** cannot be used, metoclopramide** may be used as an alternative;

3. to escalate antiemetic therapy if the patient experiences refractory CINV and is not yet receiving the maximum level of prophylaxis.

GCR BLOE 1Grade of Recommendation – B (Level of Evidence – 1)

Comments: If refractory CINV is observed despite the maximum level of prophylaxis, the currently used 5-HT3 serotonin receptor blocker may be switched to palonosetron, or additional doses of 5-HT3 serotonin receptor blockers may be administered. If these prophylactic approaches fail, it is recommended to permanently add #olanzapine**, metoclopramide**, or other drugs that have proven effective in treating breakthrough vomiting in the patient [105; 109]

6. Organization of Medical Care

Admission to a 24-hour hospital in the specialty "pediatric oncology/hematology" is carried out according to the following indications:

• suspected malignant renal tumor (initial diagnostics);

• established histological diagnosis for the administration or continuation of surgical treatment or staged therapy;

• established histological diagnosis for follow-up examination to assess the status of the primary disease and therapy toxicity

Requirements for the patient's hospital stay and therapy conditions:

• Air purifiers or central ventilation in hospital wards are preferred;

• A healthcare facility treating patients with malignant tumors, including malignant renal tumors, must have an intensive care unit or ward equipped with all necessary medications and equipment for managing patients with severe respiratory and cardiovascular failure, septic and other types of shock, hemorrhagic syndrome, renal failure, etc. It is necessary to have the capability to perform extracorporeal detoxification (hemodialysis) and mechanical ventilation;

Requirements for the availability of specialists and medical diagnostic facilities of related specialties:

• The healthcare facility treating a patient with a malignant renal tumor must include an anesthesiology and resuscitation department (ward) and a surgery department capable of performing thoracic and abdominal surgeries of any complexity. In addition, an endocrinologist, neurologist, ophthalmologist, and ENT specialist must be on staff. Cytological, immunological, bacteriological, biochemical, and stat laboratories are mandatory;

• If the above conditions are absent or if certain therapeutic procedures cannot be performed, patients must be referred to specialized higher-level medical institutions (federal, national centers);

The indication for discharging a patient from the hospital is the completion of all ongoing therapy or one of the treatment stages with a satisfactory somatic status.

The patient is referred to the local pediatrician (if available, a pediatric hematologist/oncologist) at their place of residence after completing a treatment phase or the entire treatment protocol. The local pediatrician (hematologist/oncologist) follows the recommendations provided by the specialists of the center where the main stages of treatment were performed.

Follow-up care (dispensary observation) by the pediatrician and pediatric oncologist/hematologist is carried out until the patient is transferred to adult care.

7. Additional Information

7.1 Stages of Pathological Examination of Surgical Specimens

Surgical material must be sent for examination immediately after the procedure in an intact state. The surgeon is strictly prohibited from opening any of the specimens or excised fragments.

Stages of the pathomorphological examination:

1. Macroscopic description with mandatory notation of all visible external damage: capsular ruptures, visible tumor on the renal surface. It is prohibited to strip the fibrous capsule of the kidney (it must remain intact with the entire volume of perirenal adipose tissue).

2. Measurement and weighing.

3. All lymph nodes, in addition to those isolated by the surgeon, must be dissected out and labeled separately with indication of their anatomical location.

4. The renal vein, renal artery, and ureter are described additionally. Their resection margins (the most distally located transversely sectioned fragment) are labeled separately.

5. Peripherally inking the entire specimen, including the sinus. In some cases, edema of the perirenal adipose tissue or the capsule of the kidney/tumor prevents the marking ink from adhering to the sample surface. In such cases, pre-fixation in 10% formalin for 15–20 minutes followed by ink marking is recommended.

6. Longitudinal bisection of the kidney through the tumor from pole to pole after the marking ink has dried completely. Description of the tumor topography relative to the capsule and sinus. Mandatory indication of macroscopically visible foci of necrosis expressed as a percentage of the tumor cut surface area.

7. Measurement of the tumor in three dimensions (for subsequent calculation of tumor volume and blastemal component volume).

8. Isolation of multiple visually distinct fragments for the biobank and genetic testing. These fragments are bisected – one part is sent to the laboratories, and the other is submitted for routine tissue processing (this allows identification of components in each sampled specimen, which is reported to the geneticists).

9. The kidney, cut in half, is fixed in 10% buffered formalin for 12 to 48 hours. For large kidneys, making multiple parallel cuts in addition to the central cut is permissible to improve fixation. To reduce preparation time and accelerate diagnosis, fixation of a longitudinal slice up to 1–1.5 cm thick in 20% buffered formalin for a maximum of up to 12 hours can be used.

10. Selection of fragments for histological examination:

    - at least one longitudinal slice must be selected for histological examination and submitted for routine processing in its entirety;

    - the section through the kidney must pass through the renal sinus;

    - fragments up to 3 mm thick are sampled from the slice to prevent suboptimal tissue processing;

    - fragment size must correspond to the area of the histological cassettes used (thus, using mega-cassettes speeds up the review phase and saves time for both the physician and the laboratory technician);

11. For histological examination, the following must be sampled (in addition to the above, if not already present):

    - macroscopically distinct tumor foci;

    - all suspicious foci marked separately by the surgeon (marked with an ink color different from the main one);

    - renal sinus lymph nodes;

    - soft tissues of the renal sinus, ureteral resection margin, and hilar vessels;

    - each tumor nodule separated from the main tumor mass (in multifocal disease);

    - portions of the tumor/renal capsule suspicious for tumor invasion;

    - at least two fragments of visually intact renal parenchyma (to potentially detect remnants of nephrogenic rests).

12. To review the material in other laboratories, it is necessary to provide macrophotographs of the kidney before and after the first cut, a photograph of the slice selected for examination, and a block map. All fragments isolated for examination are laid out according to their anatomical location in the kidney, assigned sequential numbers, and photographically documented.

13. Histological type and stage are assigned according to the SIOP protocol, pathomorphology section.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Clinical oncologists:

Belogurova Margarita Borisovna (Head), MD, Prof., Member of the Russian Association of Pediatric Oncology and Hematology (RODOG), Head of the Department of Chemotherapy (Antineoplastic Drug Therapy) and Combined Treatment of Tumors in Children, Saint Petersburg City Clinical Oncological Center named after N.P. Napalkov, Professor of the Department of Pediatrics, Albrecht Federal Scientific Center of Rehabilitation and Prosthetics

Varfolomeeva Svetlana Rafaelevna, MD, Prof., Deputy Director for Scientific and Clinical Work – Director of the Durnov Research Institute of Pediatric Oncology and Hematology, Blokhin National Medical Research Center of Oncology, President of RODOG

Grachev Nikolay Sergeevich, MD, Prof., General Director Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Kachanov Denis Yurievich, MD, Member of RODOG, Head of the Department of Clinical Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Deputy Director of the Institute of Oncology, Radiology and Nuclear Medicine, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Kirgizov Kirill Igorevich, PhD, Member of RODOG, Deputy Director for Scientific Work of the Durnov Research Institute of Pediatric Oncology and Hematology, Acting Head of the Department, Leading Researcher of the Department of Pediatric Bone Marrow Transplantation and Hematopoietic Stem Cells, Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Novichkova Galina Anatolievna, MD, Prof., Chief freelance pediatric specialist oncologist-hematologist of the Ministry of Health of the Russian Federation

Rubanskaya Marina Vladimirovna, PhD, Head of Pediatric Oncology Department No. 1 (chemotherapy of thoracoabdominal tumors), Durnov Research Institute of Pediatric Oncology and Hematology (NII DOIG), Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Sagoyan Garik Barisovich, pediatric oncologist, Senior Researcher of Pediatric Oncology Department No. 1 (chemotherapy of thoracoabdominal tumors), Durnov Research Institute of Pediatric Oncology and Hematology (NII DOIG), Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Smirnova Lilia Andreevna, pediatric oncologist of the Department of Clinical Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Suleymanova Amina Magomedovna, pediatric oncologist, Senior Researcher of Pediatric Oncology Department No. 1 (chemotherapy of thoracoabdominal tumors), Durnov Research Institute of Pediatric Oncology and Hematology (NII DOIG), Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Teleshova Margarita Viktorovna, Member of RODOG, pediatric oncologist of the Department of Clinical Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

2. Surgical group:

Merkulov Nikolay Nikolaevich, Member of RODOG, pediatric surgeon of the Department of Oncology and Pediatric Surgery, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Rubansky Mikhail Alexandrovich, PhD, Member of RODOG, pediatric oncologist of Surgical Department No. 2, Durnov Research Institute of Pediatric Oncology and Hematology, Blokhin National Medical Research Center of Oncology

3. Radiation therapists:

Grigorenko Vasily Andreevich, Head of the Radiotherapy Department, Durnov Research Institute of Pediatric Oncology and Hematology, Blokhin National Medical Research Center of Oncology

Kanestri Francesca Yanisovna, radiation therapist of the Radiotherapy Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Nechesnyuk Alexey Vladimirovich, PhD, Head of the Radiotherapy Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

4. Laboratory of Pathological Anatomy

Anna M. Mitrofanova, member of RODOG, physician at the Department of Pathology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

5. Prevention and management of nausea and vomiting:

Nikolay V. Zhukov, MD, PhD, Head of the Department of Interdisciplinary Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health.

Dmitry V. Litvinov, MD, PhD, Chief Medical Officer, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health.

Liliya L. Rabaeva, MD, PhD, pediatric oncologist at the Department of Older Children Hematology/Oncology and Neurooncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health.

6. Nutritional support:

Andrey Yu. Vashura, MD, PhD, nutritionist, Head of the Department of Scientific Foundations of Nutrition and Nutritional-Metabolic Therapy, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health

Irina V. Korovina, nutritionist, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Pediatric oncologists;

2. Pediatricians;

3. Medical geneticists;

4. Medical students, residents, postgraduate students.

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

Methodology for evidence collection

Methods used for collecting/selecting evidence: search for publications in specialized peer-reviewed journals with an impact factor >0.3.

Search in electronic databases.

The evidence base for the recommendations includes publications from the Cochrane Library, PubMed, and MEDLINE databases. The search depth was 30 years.

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• Systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• evaluation of the significance of evidence in accordance with the evidence rating scheme (Tables 12–14).

Table 12. Scale for assessing levels of evidence reliability (LER) for diagnostic methods (diagnostic interventions)

Table 13. Scale for assessing levels of evidence reliability (LER) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 14. Scale for assessing grades of recommendation strength (GRS) 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 three years, as well as upon the emergence of new evidence-based medicine data on 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

Appendix A3.1. Drug Treatment Regimens for Renal Malignant Tumors

AV neoadjuvant chemotherapy regimen in patients with localized nephroblastoma [33; 64]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1–4;

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – weeks 1, 3.

AVD neoadjuvant chemotherapy regimen in patients with metastatic nephroblastoma [33; 64]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, and 6;

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – weeks 1, 3, and 5;

DOX – doxorubicin** 50 mg/m²/day, 2–6 hour infusion – weeks 1, 5.

AV1 adjuvant chemotherapy regimen in patients with localized nephroblastoma, stage I, intermediate-risk group [33; 40; 64]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus on weeks 1–4;

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – week 1.

AVD adjuvant chemotherapy regimen in patients with localized nephroblastoma, stage I, high-risk group [33; 64]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus – weekly for 8 weeks (8 doses), and then on the first day of weeks 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27 (20 doses in total)

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26;

DOX – doxorubicin** 50 mg/m²/day, IV drip 2–6 hour infusion – weeks 2, 8, 14, 20, 26.

Note: doxorubicin** – 5 doses in total, total cumulative dose: 250 mg/m².

AV-2 adjuvant chemotherapy regimen in patients with localized nephroblastoma, stage II/III, intermediate-risk group (except for tumors with focal anaplasia, mixed, or regressive histology when tumor volume after neoadjuvant chemotherapy completion is >500 ml) [33; 64]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27;

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26.

AVD 250 adjuvant chemotherapy regimen in patients with localized nephroblastoma, stage II/III, intermediate-risk group (for tumors with focal anaplasia, mixed, or regressive histology when tumor volume after neoadjuvant chemotherapy completion is >500 ml) [33; 64]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27;

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26;

DOX – doxorubicin** 50 mg/m²/day, IV drip 2–6 hour infusion – weeks 2, 8, 14.

Note: maximum single dose of vincristine** is 2 mg. The first administration of vincristine** is after the recovery of bowel motility in the postoperative period, within up to 21 days from the last neoadjuvant chemotherapy administration; #dactinomycin is not used in children weighing less than 5 kg; taking into account preoperative chemotherapy, the cumulative dose of doxorubicin** is 250 mg/m2; during radiation therapy, doxorubicin** is not administered, and the dose of #dactinomycin is reduced by 1/3.

HR-1 adjuvant chemotherapy regimen in patients with localized nephroblastoma, stage II/III, high-risk group [33; 64]:

CYCLO – cyclophosphamide** 450 mg/m²/day IV drip over 1 hour – days 1, 2, 3, on weeks 1, 7, 13, 19, 25, 31;

DOX – doxorubicin** 50 mg/m²/day IV drip over 2–6 hours – day 1, on weeks 1, 7, 13, 19, 25, 31;

VP16 – #etoposide** 150 mg/m²/day IV drip over 1 hour – days 1, 2, 3, on weeks 4, 10, 16, 22, 28, 34;

CARBO – #carboplatin** 200 mg/m²/day IV drip over 1 hour – days 1, 2, 3, on weeks 4, 10, 16, 22, 28, 34;

– Echocardiography: at baseline, before weeks 19 and 31, and at the end of treatment;

– glomerular filtration rate (GFR) (measured during every third course or more frequently if signs of renal dysfunction are present).

Note: the first course must be started no later than 21 days after the end of preoperative chemotherapy. Doxorubicin** is administered on day 1 after cyclophosphamide**                               

AVD 150 regimen – 27 weeks of chemotherapy [33; 64]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27;

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26;

DOX – doxorubicin** 50 mg/m²/day, IV drip 2–6 hour infusion – week 2.

Note: maximum single dose of vincristine** is 2 mg. The first administration of vincristine** is after the recovery of bowel motility in the postoperative period, within up to 21 days from the last neoadjuvant chemotherapy administration; #dactinomycin is not used in children weighing less than 5 kg and under 3 months of age; taking into account preoperative chemotherapy, the cumulative dose of doxorubicin** is 150 mg/m²; during radiation therapy, doxorubicin** is not administered, and the dose of #dactinomycin is reduced by 1/3.

AVD 250 regimen – 27 weeks of chemotherapy [33; 64]:  

VCR – vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, 27;

ACT – #dactinomycin 45 mcg/kg/day, IV bolus – weeks 2, 5, 8, 11, 14, 17, 20, 23, 26;

DOX – doxorubicin** 50 mg/m²/day, IV drip 2–6 hour infusion – weeks 2, 8, 14.

Note: maximum single dose of vincristine** is 2 mg. The first administration of vincristine** is after the recovery of bowel motility in the postoperative period, within up to 21 days from the last neoadjuvant chemotherapy administration; #dactinomycin is not used in children weighing less than 5 kg; taking into account preoperative chemotherapy, the cumulative dose of doxorubicin** is 250 mg/m²; during radiation therapy, doxorubicin** is not administered, and the dose of #Dactinomycin is reduced by 1/3.

HR-2 regimen – 34 weeks of chemotherapy [33; 64]:

CYCLO – cyclophosphamide** 450 mg/m²/day IV drip over 1 hour – days 1, 2, 3, on weeks 1, 7, 19, 31;

DOX – doxorubicin** 50 mg/m²/day IV drip over 2–6 hours – day 1 (after cyclophosphamide**), on weeks 1, 7, 19, 31;

VP16 - #etoposide** 150 mg/m²/day IV drip over 1 hour – days 1, 2, 3, on weeks 4, 10, 13, 16, 22, 25, 28, 34;

CARBO – #carboplatin** 200 mg/m²/day IV drip over 1 hour – days 1, 2, 3, on weeks 4, 10, 13, 16, 22, 25, 28, 34.

Regimen 1 (intensive VCR) [33]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (10 doses in total)

Note: the maximum single dose of vincristine** is 2 mg. Infants and children weighing <12 kg should receive the full dose of vincristine

Regimen 2 (AV) [33]:

VCR – vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, then weeks 14, 17, 20, 23, and 26 (16 doses in total);

ACT-D – #dactinomycin 45 mcg/kg/day, IV on weeks 2, 5, 8, 11, 14, 17, 20, 23, and 26 (9 doses in total)

Note: the maximum single dose of vincristine** is 2 mg.

Regimen 3 (AVD) [33]:   

VCR – vincristine** 1.5 mg/m²/day, IV bolus on weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, then weeks 13, 16, 19, 22, 25, and 28 (16 doses in total);

ACT-D – #dactinomycin 45 mcg/kg/day, IV bolus – 2/3 of the dose on week 2, then the full dose on weeks 10, 16, 22, 28 (5 doses in total);

DOX – doxorubicin** 50 mg/m²/day, IV infusion as a 4-6 hour infusion – on weeks 7, 13, 19, 25)

*Note: 2/3 of the #dactinomycin dose on week 2 is due to the upcoming radiation therapy

VA regimen (for bilateral renal tumors) [33]:

Vincristine** 1.5 mg/m²/day, IV bolus – weeks 1, 2, 3, 4, 5, 6;

#Dactinomycin 45 mcg/kg/day, IV bolus – weeks 1, 3, 5.

Total duration of the course – 6 weeks.

#Carboplatin**/#Etoposide regimen (for bilateral renal tumors) [33]:

VP16 – #etoposide** 150 mg/m²/day IV infusion over 1 hour on days 1, 2, 3, weeks 1 and 4;

CARBO – #carboplatin** 200 mg/m²/day IV infusion over 1 hour on days 1, 2, 3, weeks 1 and 4. 2 such cycles are administered.

EU-RHAB and metronomic therapy regimen for patients with renal SRT [16; 50]:

Intensive chemotherapy:

Course 1 (DOX) – #doxorubicin** (3 courses in total):

#doxorubicin** 37.5 mg/m²/day IV infusion over 24 hours – days 1, 2, in weeks 1, 7, 13;

Course 2 (ICE) – #ifosfamide** + #carboplatin** + #etoposide** (3 courses in total):

#ifosfamide** 2000 mg/m²/day IV infusion over 1 hour – days 1, 2, 3, in weeks 3, 9, 15;

#carboplatin** 500 mg/m²/day IV infusion over 1 hour – day 1, in weeks 3, 9, 15;

#etoposide** 100 mg/m²/day IV infusion over 1 hour – days 1, 2, 3, in weeks 3, 9, 15;

Course 3 (VCA) – #vincristine** + #cyclophosphamide** + #dactinomycin (3 courses in total):

#vincristine** 1.5 mg/m²/day IV bolus – days 1, 8, in weeks 5, 11, 17;

#dactinomycin 25 mcg/kg/day IV bolus – days 1, 2, in weeks 5, 11, 17;

#cyclophosphamide** 1500 mg/m²/day IV infusion over 1 hour – day 1, in weeks 5, 11, 17.

Vnr/Cyclo metronomic chemotherapy regimen for patients with renal SRT [50]:

#cyclophosphamide** 25 mg/m²/day orally – days 1-28 continuously, weeks 1, 5, 9, 13, 17, 21;

#vinorelbine** 25 mg/m²/day IV over 5-10 minutes, weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23.

SIOP intensive therapy regimen for patients with renal CCS [33]:

Course 1 (CYCLO/DOX) – cyclophosphamide** + doxorubicin** (3 courses in total): cyclophosphamide** 450 mg/m2/day IV infusion over 1 hour – days 1, 2, 3 in week 1; doxorubicin** 50 mg/m2/day IV infusion over 4-6 hours – day 1 in weeks 1, 13, 25;

Course 2 (VP16/CARBO) – #etoposide** + #carboplatin** (6 courses in total): #etoposide** 150 mg/m2/day IV infusion over 1 hour – days 1, 2, 3 in weeks 4, 16, 28; #carboplatin** 200 mg/m2/day IV infusion over 1 hour – days 1, 2, 3 in weeks 4, 16, 28;

Course 3 (IFO/DOX) – ifosfamide** + doxorubicin** (3 courses in total): ifosfamide** 2 g/m2/day IV infusion over 1 hour – days 1, 2, 3 in weeks 7, 19, 31; #doxorubicin** 50 mg/m2/day IV infusion over 4-6 hours – day 1 in weeks 7, 19, 31.

SIOP therapy regimen for patients with MRT [33]:

#Dactinomycin 45 mcg/kg 9 doses

#Vincristine** 1.5 mg/m2 20 doses

Appendix A3.2 Therapy toxicity, rules for the administration of chemotherapeutic agents, and age-based dosages [33]

Hematological Toxicity:

Neutropenia: absolute neutrophil count (ANC) must be greater than 1000/mm³ to start a course with #Dactinomycin, #Doxorubicin**, #Cyclophosphamide**, #Ifosfamide**, or #Carboplatin**. Treatment with #Vincristine** can be continued regardless of the ANC if the patient is in good clinical condition.

Thrombocytopenia: the platelet count must be >100,000/mm³ to start a treatment course. An ongoing treatment course should be interrupted if the platelet count drops below 50,000/mm³. In case of a sudden drop in platelet count, the patient should be monitored for signs of veno-occlusive disease (VOD) or sepsis/catheter-related infection. Platelet transfusions are always indicated in case of bleeding.

Isolated anemia is treated with blood transfusions if necessary (hemoglobin <70 g/L). The development of anemia is not a reason for modifying the treatment regimen.

Febrile neutropenia – temperature (rectal measurement) >38.5°C or temperature >38.0°C measured four times within 24 hours with an interval of more than 4 hours, and a neutrophil count <500/mcL.

Isolated Gastrointestinal Complications:

Vomiting lasting for several hours may occur primarily after the administration of #Dactinomycin or #Doxorubicin**. Symptomatic treatment is usually sufficient, and therapy modification is required only in rare cases.

Diarrhea, with or without vomiting, may occur primarily following whole-abdomen irradiation in young children. In this case, a temporary suspension of treatment for a few days or sometimes even discontinuation of radiation therapy may be required.

Constipation is a common occurrence during #Vincristine** therapy. Laxatives must be prescribed, and it should be ensured that the patient has a loose stool. In case of paralytic ileus, the drugs should be discontinued and resumed at half the dose.

Liver Complications:

Liver complications may occur during treatment with #Dactinomycin, #Vincristine**, or #Doxorubicin**. Risk factors, mainly associated with #Dactinomycin, include right-sided nephroblastoma and whole-abdomen or right-flank irradiation. Careful monitoring of patients with symptoms of liver dysfunction is required.

In patients with veno-occlusive disease (VOD), #Dactinomycin should not be used until the primary pathological phenomena have resolved; half of the initial dose should be used during the first of the subsequent chemotherapy courses. If symptoms recur during #Dactinomycin therapy, the drug should be discontinued permanently. #Vincristine** therapy may exacerbate liver disease.

Cardiotoxicity:

There are no standard guidelines for dose modification of #Doxorubicin**. Echocardiographic monitoring must be performed prior to each administration of #Doxorubicin**. The interruption of #Doxorubicin** treatment should be considered if the patient's shortening fraction is less than 28% or if a >10% decrease is observed between two consecutive administrations of #Doxorubicin**. In such cases, chemotherapy should be continued with #Vincristine** and #Dactinomycin only. After 3 weeks, repeat the echocardiogram and, if the parameter has improved, resume #Doxorubicin** therapy, but repeat the echocardiogram before each administration of this drug. A decrease in the shortening fraction by more than 20% from the baseline value is an indication for withholding #Doxorubicin** treatment until the parameter recovers to its initial value. Beware of developing anemia, which can affect the shortening fraction value.

Cardiotoxicity is more common in patients who have received chest radiation therapy and have stage III left-sided nephroblastoma.

Neurotoxicity:

The main side effects of #Vincristine** are muscle weakness and hyporeflexia. Jaw pain, pain on swallowing (odynophagia), and hoarseness may occur. In the event of peripheral nerve paralysis, foot drop, or severe neuritis, one or two #Vincristine** injections should be skipped, and the next dose should be reduced to 2/3 of the initial dose.

An EEG should be performed to confirm the presence of developed abnormalities typical of #Ifosfamide** therapy.

Bladder and Renal Toxic Effects:

If the administration guidelines are not followed, #Cyclophosphamide** and #Ifosfamide** can cause hemorrhagic cystitis. Regular use of Mesna* is recommended. In cases of macroscopically detectable and recurrent hematuria, chemotherapy should be interrupted. To increase diuresis, the administration of infusion hyperhydration (3 L/m2) and a diuretic (Furosemide**, Mannitol**) should be considered.

If serum creatinine levels rise or tubulopathy develops, dose modification should be considered.

As a rule, in the case of #Ifosfamide**, the following measures can be taken:

1. Administration of #Ifosfamide** over 24 hours instead of a short infusion;

2. A reduction of the #Ifosfamide** dose by approximately 1/3;

3. Use of #Cyclophosphamide** instead of #Ifosfamide**.

Gonadal Toxic Effects

Gonadal toxicity (gonadotoxicity) occurs mainly following the use of alkylating agents and abdominal irradiation. In all cases, fertility counseling and fertility preservation measures must be considered. This is particularly relevant for patients who have undergone whole-abdomen irradiation (following seeding).

Severe Intolerance to Preoperative Therapy

If the following complications occur during preoperative chemotherapy, nephrectomy should be performed after toxic effects have resolved, provided the surgery is feasible and associated with an acceptable level of risk; otherwise, the use of alternative chemotherapeutic agents prior to surgery may be considered. In most cases, postoperative chemotherapy should still be administered in accordance with the tumor stage and histological type. Exceptions are low-risk, low-stage tumors and/or cases where continuing chemotherapy is impossible due to the specific clinical situation. Alternative chemotherapeutic agents should be discussed with the national coordinator. In some cases (e.g., treatment with #Dactinomycin), therapy with the same drug may be continued at a reduced dose, whereas for other drugs where cumulative dose is a key toxicity factor (e.g., #Doxorubicin**), complete discontinuation is required:

a. Severe thrombocytopenia (platelets <50x109/L) with or without bleeding, associated with VOD: abdominal pain with diarrhea, ascites, edema, significant hepatomegaly, oliguria, fever, and jaundice

b. Or cutaneous erythema with desquamation corresponding to Stevens-Johnson syndrome

c. Severe neurological complications such as intolerable paresthesia with paralysis, convulsions, or amaurosis.

Dose reductions or timing adjustments should be made according to the following criteria [33]:

1. Administration of #dactinomycin, #doxorubicin**, #cyclophosphamide**, #etoposide**, and #carboplatin** should be delayed until recovery of counts: neutrophils >1.0x10⁹/L, platelets >100x10⁹/L [64];

2. Administration of #dactinomycin should be delayed: if bilirubin is >1.5 times the upper limit of normal (ULN); if ALT is >5 times ULN; in the presence of clinical signs of veno-occlusive disease [64];

3. Administration of #doxorubicin** should be delayed: if bilirubin is >2 times ULN; if ALT is >5 times ULN; in the presence of mucositis grade 1 or higher [64];

4. If the next cycle is delayed by more than 1 week, a 33% dose reduction of the drugs should be discussed [64];

5. Chemotherapy doses are calculated based on the patient's weight and are presented in Tables 15 and 16 [64].

Table 15. Chemotherapy doses for children with neuroblastoma and renal CCS according to their weight [33; 64]:

Table 16. Chemotherapy doses for children with renal MRT according to their weight [16]:

Appendix A3.3. Scope of Postoperative Therapy for Generalized Nephroblastoma [33]

LR – low risk

IR – intermediate risk

HR – high risk

Appendix A3.4 Prevention and treatment of nausea and vomiting induced by antineoplastic therapy

Tab. A3.4.1. Emetogenicity level of antineoplastic agents [110]

Tab. A3.4.2. Doses and regimens of antiemetic drugs [63; 106; 111]                     

Appendix B. Physician Action Algorithms

Appendix B1. Algorithm for Primary Diagnosis of Renal Malignant Tumors

Appendix B2. Algorithm for Patient Management with Nephroblastoma

Appendix B3. Algorithm for Managing Patients with Bilateral Nephroblastoma [33]

Appendix B4. Management algorithm for patients with unilateral nephroblastoma and contralateral nephroblastomatosis [33]

Appendix B5. Management algorithm for patients with bilateral or unilateral nephroblastomatosis [33]

Appendix B6. Management algorithm for patients with unilateral tumor and tumor predisposition syndrome [33]

Appendix B7. Algorithm for Audiological Examination

Appendix C. Patient Information

Nephroblastoma (Wilms tumor) is a highly malignant solid renal tumor. It is also referred to as nephroblastoma (derived from the Greek words "nephros", meaning kidney, and "blastoma", meaning tumor). The tumor is named after the Heidelberg German surgeon Max Wilms. At the turn of the past century, Max Wilms studied this disease and was the first to describe it in detail.

Nephroblastoma originates from embryonic tissue that begins to develop during the prenatal period. It may contain several cell types, which is why nephroblastoma is called a "mixed tumor", with the primary component being renal precursor cells.

In 90% of patients, the tumor presents in a localized form; however, approximately 10% of children already have metastases at diagnosis, which may involve regional lymph nodes, as well as the lungs, liver, and rarer sites. In some children (about 5%), nephroblastoma affects both kidneys simultaneously. Typically, in these children, the tumor arises from renal precursor cells that failed to regress within the required timeframe, a condition known as nephroblastomatosis (immature embryonic renal tissue). Children with certain developmental anomalies and/or hereditary cancer syndromes develop nephroblastoma more frequently than other pediatric oncology patients.

Nephroblastoma is the most common pediatric renal tumor, with a peak incidence between the ages of 2 and 5 years. However, nephroblastoma also occurs in younger infants and adolescents.

The tumor is associated with alterations in specific genes and chromosomes, the most studied being Wilms tumor gene 1 [WT1 gene].

Nephroblastoma is frequently observed in children with pre-existing congenital tumor syndromes, such as WAGR syndrome (incorporating several developmental anomalies), Beckwith-Wiedemann syndrome (characterized by body and internal organ enlargement), and Denys-Drash syndrome (genital malformations). Children with these conditions exhibit developmental disorders and an increased risk of cancer. A family history of nephroblastoma also increases a child's likelihood of developing the disease. "Familial" cases are relatively rare (approximately 1%), and in these children, the tumor typically affects both kidneys or presents as multifocal nephroblastoma. However, in the majority of cases, nephroblastoma is sporadic.

Affected children present with abdominal enlargement, and the tumor is often an incidental finding on ultrasound. Symptoms may include abdominal pain and hematuria. Additionally, the child may experience weight loss and fever. The presence of specific genetic syndromes and developmental anomalies helps raise suspicion for nephroblastoma.

Following clinical and radiological confirmation that the tumor originates from the kidney, preoperative therapy is initiated in the majority of cases. Histological verification prior to treatment is reserved for cases with significant diagnostic uncertainty regarding nephroblastoma. In a subset of patients (children under 6 months and older than 7–10 years), histological examination of the tissue is performed prior to therapy due to the risk of non-nephroblastoma tumors.

Once the definitive diagnosis is established (following surgery after preoperative chemotherapy), physicians formulate a treatment plan. The managing multidisciplinary team develops an individualized treatment program (so-called risk-adapted therapy) that accounts for specific factors known as risk factors (prognostic factors), which influence disease prognosis.

The most critical prognostic factors in children with nephroblastoma include: the stage of the disease (how far the tumor has spread throughout the body by the time of diagnosis and the extent to which it can be surgically resected), the histological variant of nephroblastoma (which indicates tumor growth pattern and grade of malignancy), and the tumor response to chemotherapy.

Treatment for children with nephroblastoma is multimodal, primarily consisting of surgery and chemotherapy. Most commonly, treatment begins with a course of chemotherapy to reduce tumor size, thereby increasing resectability. In some children, treatment begins directly with surgery. The goal of surgery is to remove the tumor and any potential metastases. As a rule, chemotherapy is continued (or initiated) postoperatively. Depending on the postoperative tumor stage and/or the presence of residual metastases, radiation therapy to the tumor bed may be administered additionally. In all major medical centers, children and adolescents with nephroblastoma are treated according to standardized protocols. The objective of all programs is to maximize long-term survival while minimizing long-term sequelae on the child's developing body.

The chances of curing a child of nephroblastoma are very favorable. Thanks to high-precision modern diagnostic methods and standardized multimodal therapy protocols, approximately 90% of patients achieve recovery. However, for any individual child, the prognosis depends primarily on the histological variant of nephroblastoma and the extent of disease dissemination at diagnosis (disease stage). Children with high-grade malignant tumors have a less favorable prognosis. Nevertheless, even children with advanced-stage nephroblastoma can achieve favorable recovery odds under specific conditions. It is important to understand that every child is unique and statistics cannot predict individual outcomes, though discussing the prognosis for a specific disease variant with the attending physician is essential.

Clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK) are rare, aggressive renal tumors in early childhood, and differential diagnosis is most commonly performed with nephroblastoma. CCSK is characteristic of children aged 2 to 3 years and is extremely rare in infants under 6 months of age. RTK most frequently occurs in children during the first years of life and may be associated with a genetic predisposition syndrome. Clinical symptoms are non-specific and similar to those of nephroblastoma. Given their malignant potential, these tumor types require more intensive chemotherapy. Treatment for patients with these neoplasms invariably includes intensive multi-agent chemotherapy, aggressive local control using surgical resection, and radiation therapy.

Congenital mesoblastic nephroma (CMN) is a rare renal tumor predominantly affecting infants in the first months of life. The majority of tumors require surgical resection alone, followed by active surveillance. However, in cases of incomplete surgical resection, locally advanced recurrences may occur. Reports of metastatic disease are exceedingly rare.

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

Appendix G1. Toxicity (The Common Terminology Criteria for Adverse Events, Version 3.0 and 5.0)

Russian title: Toxicity grading scale according to CTC AE criteria

Original title (if applicable): Common Terminology Criteria for Adverse Events

Source (official developer website, validation publication): Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Publish Date: November 27, 2017 (http://ctep.cancer.gov).

Appendix G2. ECOG Scale

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649–65 [49]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Appendix G3. Karnofsky Scale, Lansky Modification

Original title: Lansky Performance Scale

Source: Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR (1987). "The measurement of performance in childhood cancer patients". Cancer. 60 (7): 1651–6 [55]

Type: rating scale

Purpose: clinical assessment of the patient's general condition depending on age (Karnovsky scale for patients 16 years and older, Lansky scale for patients under 16 years of age)

Content and interpretation: