Nasopharyngeal cancer: clinical guidelines

List of Abbreviations

5-HT₃ – 5-HT3 serotonin receptor antagonists

ALT − alanine aminotransferase

AST – aspartate aminotransferase

ESBL – extended-spectrum beta-lactamases

EBV – Epstein-Barr virus

GGT – gamma-glutamyl transferase

ZNO – malignant neoplasms

CT – computed tomography

LDH – lactate dehydrogenase

RT – radiotherapy

MRSA – methicillin-resistant Staphylococcus aureus

MRI – magnetic resonance imaging

NPC – nasopharyngeal carcinoma

PD – progressive disease

CR — complete response

PCR – polymerase chain reaction

PCT – polychemotherapy

SFD – single focal dose

SD – stable disease

GFR – glomerular filtration rate

TFD – total focal dose

FN – febrile neutropenia

PR — partial response

Echo-CG – echocardiography

AJCC (American Joint Committee on Cancer) – American Joint Committee on Cancer

AUC (area under curve) – area under the plasma concentration-time curve

CTV (Clinical Target Volume) – clinical target volume

GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie) – Society of Pediatric Oncology and Hematology

GTV (Gross Tumor Volume) – gross tumor volume

IMRT (Intensity Modulated Radiotherapy) – intensity-modulated radiotherapy

LN (lymph node) – regional lymph nodes

NK₁ – neurokinin-1 receptors (other antiemetic drugs)

PTV (Planning Target Volume) – planning target volume

UICC (Union for International Cancer Control) – Union for International Cancer Control

Terms and Definitions

Overall survival – the time from the date of NPC diagnosis until death from any cause or until the date of last patient follow-up.

Event-free survival – the time from the date of NPC diagnosis until an adverse event, defined as progression, relapse (if complete response was achieved), development of a secondary malignancy, death from any cause, or the date of last patient follow-up.

Complete response – disappearance of all target lesions. Any previously enlarged lymph node must have a short axis of less than 10 mm.

Partial response – at least a 30% decrease in the sum of diameters of target lesions.

Disease progression – appearance of any new tumor lesion; an increase of >20% in any measurable lesion.

Disease relapse – appearance of any new tumor lesions in patients who previously achieved a complete response according to the response evaluation criteria in patients with NPC.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Nasopharyngeal cancer (nasopharyngeal carcinoma) – a malignant epithelial neoplasm of the nasopharynx [1].

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

In childhood and adolescence, EBV is the etiological factor in the vast majority of cases—serological evidence is present in 98% of patients, with the majority having EBV DNA in tumor cells and viral antigens on their surface [2, 3]. In some cases, the detection of circulating EBV DNA can provide certain assistance in differential diagnosis, prognostic assessment (which significantly worsens with increasing viral load), and subsequent monitoring of the antitumor effect during treatment [2, 3]. The presence of genetic factors is also important. Genetic predisposition to NPC development may be indicated by the association of certain HLA variants (e.g., the A2Bsin2 haplotype) with a higher incidence of this tumor [1, 2].

1.3 Epidemiology of the Disease or Condition

Malignant tumors of the nasopharynx account for 1 to 3% of all pediatric malignancies [1, 4]. Among all nasopharyngeal malignancies, nasopharyngeal carcinoma accounts for 26.4%. Undifferentiated carcinoma is the predominant type (97%) among malignant epithelial neoplasms of the nasopharynx [1].

The incidence of NPC varies significantly by region (ranging from 1–2 cases per 1 million population in Europe and the USA to 20 cases per 1 million population in China, Southeast Asia, North Africa, and parts of the Mediterranean) and by ethnicity (representatives of different ethnic groups within the same country or region may have different rates) [1, 2].

NPC is extremely rare in children under 10 years of age, whereas in the 10–14 age group the incidence rises to 0.8 per million per year, and in the 15–19 age group to 1.3 per million per year [5].

1.4 Features of Coding the Disease or Condition

Malignant neoplasms of the nasopharynx (C11):

C11.0 – Malignant neoplasm of superior wall of nasopharynx

C11.1 – Malignant neoplasm of posterior wall of nasopharynx

C11.2 – Malignant neoplasm of lateral wall of nasopharynx

C11.3 – Malignant neoplasm of anterior wall of nasopharynx

C11.8 – Overlapping lesion of nasopharynx

C11.9 – Malignant neoplasm of nasopharynx, unspecified

1.5 Classification of the disease or condition

1.5.1 International Histological Classification of NPC

The WHO classification distinguishes several morphological types of NPC, which in its original 1978 version were designated as squamous cell keratinizing carcinoma (type I), non-keratinizing carcinoma (type II), and undifferentiated carcinoma (type III) [6]. The updated classification (2005) introduced subtype IIa – differentiated non-keratinizing squamous cell carcinoma, and subtype IIb – undifferentiated non-keratinizing squamous cell carcinoma. The 2005 classification also introduced a new, previously undescribed, extremely rare subtype – basaloid squamous cell carcinoma (type IV) [7].

NPC Classification (WHO 2005)

I. Squamous cell keratinizing carcinoma.

IIa. Differentiated non-keratinizing squamous cell carcinoma.

IIb. Undifferentiated non-keratinizing squamous cell carcinoma.

III. Undifferentiated carcinoma.

IV. Basaloid squamous cell carcinoma.

1.5.2 International Clinical Classification of NPC

Staging of NPC in children and adolescents, as in the adult population, is performed using the TNM system. According to the 8th edition of the UICC/AJCC Classification of Malignant Tumours published in 2016, clinical staging of patients has changed; primarily, stage IV was modified by combining IVA and IVB into a single IVA, and IVC into IVB [8].

Primary tumor (T):

Tx – Primary tumor cannot be assessed.

T0 – No primary tumor identified, but EBV-associated NPC tumor cells are present in enlarged lymph nodes.

T1 – Tumor confined to the nasopharynx, oropharynx, or nasal cavity without parapharyngeal extension.

T2 – Tumor with extension to the parapharyngeal space, involvement of adjacent soft tissues.

T3 – Tumor extension into bone structures (skull base, cervical vertebra) and/or paranasal sinuses.

T4 – Intracranial tumor extension, cranial nerve involvement, hypopharynx, orbit involvement, or extensive soft tissue infiltration.

Regional lymph nodes (N):

Nx – Regional lymph nodes cannot be assessed.

N0 – No regional lymph node metastasis;

N1 – Unilateral cervical, unilateral or bilateral retropharyngeal lymph nodes ≤6 cm in greatest dimension, above the caudal border of the cricoid cartilage.

N2 – Bilateral cervical lymph nodes ≤6 cm in greatest dimension, above the caudal border of the cricoid cartilage.

N3 – Lymph node(s) >6 cm in dimension and/or extending below the caudal border of the cricoid cartilage (regardless of lateralization).

Distant metastases (M):

M0 – No distant metastasis.

M1 – Distant metastasis present.

Table 1. Clinical classification of NPC (8th edition of the UICC/AJCC classification)

1.6 Clinical presentation of the disease or condition

The leading clinical symptom is unilateral or bilateral lymphadenopathy, which manifests prior to symptoms originating from the nasopharyngeal tumor.

Local symptoms include epistaxis, nasal congestion, and various types of nasal discharge. Due to Eustachian tube orifice obstruction, patients present with otalgia and recurrent otitis media. Headache is a manifestation of tumor-induced systemic toxicity and reactive inflammation. When the tumor invades the pterygoid and/or masticator muscles, trismus occurs [1, 3, 9].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended methods for diagnosing the disease and related conditions have limited evidence bases (according to the grades of recommendation and levels of evidence scales) due to a lack of dedicated clinical trials. Despite this, they are necessary components of patient evaluation for establishing a diagnosis and selecting treatment strategy, as more effective and evidence-based methods have not yet been developed.

All children with suspected tumors should be referred to pediatric oncology centers equipped with the necessary diagnostic facilities.

Criteria for establishing the diagnosis/condition: the diagnosis is established based on pathognomonic data:

1) anamnesis data;

2) physical examination;

3) laboratory tests;

4) instrumental examination;

5) data from post-mortem pathological examination of surgical material.

2.1 Complaints and Anamnesis

• All patients with suspected or confirmed NPC at the initial visit are recommended to undergo a detailed medical history taking [1, 3].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: history taking should include a detailed family history, a thorough account of the patient's development from birth to the time of examination, and an oncological history detailing benign or malignant tumors in family members.

• All patients with suspected or confirmed NPC at the initial visit, as well as at every visit (examination, consultation) by a pediatric oncologist (B01.009.001, B01.009.002), before each subsequent course of chemotherapy, when assessing response to therapy during treatment, and during follow-up, are recommended a detailed symptom assessment [3, 10, 11].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: conditionally, all symptoms of malignant nasopharyngeal tumors can be divided into 4 main groups: nasal, auricular, neurological, and metastatic. The first two groups are considered early symptoms that are strictly nasopharyngeal, as they result from tumor growth within the nasopharynx. Neurological symptoms and regional metastases indicate the spread of the process beyond the organ and involvement of regional lymph node basins. In nasopharyngeal carcinoma, metastatic lymph node involvement appears within the first months of the disease. Undifferentiated nasopharyngeal carcinoma is characterized by a rapid, aggressive course with infiltrative growth and involvement of surrounding anatomical structures. As the tumor grows, mucous and purulent nasal discharges appear, and with the addition of a secondary infection and in advanced stages of the disease, a putrid odor, blood admixture, and necrotic masses develop. Ulceration and breakdown of the tumor cause periodic spontaneous epistaxis.

2.2 Physical Examination

• All patients with suspected or confirmed NPC at the initial visit, as well as at every visit (examination, consultation) by a pediatric oncologist (B01.009.001, B01.009.002), before each subsequent course of chemotherapy, when assessing response to therapy during treatment, and during follow-up, are recommended a physical examination, height and weight measurements, abdominal palpation, and auscultation of the heart and lungs [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with NPC at the initial visit, as well as at every visit (examination, consultation) by a pediatric oncologist (B01.009.001, B01.009.002), before each subsequent course of chemotherapy, when assessing response to therapy during treatment, and during follow-up, are recommended an assessment of the patient's general condition (Appendix G1, G2) [12, 13].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with suspected or confirmed NPC at the initial visit, as well as at every visit (examination, consultation) with a pediatric oncologist (B01.009.001, B01.009.002), to assess treatment efficacy at the treatment response evaluation stage and at each subsequent visit, are recommended to perform palpation of the cervical and supraclavicular lymph nodes to detect altered lymph nodes and their dynamics during treatment [1, 3, 14].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: the initial examination of the patient is aimed at assessing the patient's general status, the presence of intoxication syndrome, the potential presence of metastases, and determining the scope of the initial workup.

The examination should include:

• anthropometric measurements (weight, height, and body surface area), nutritional status assessment (percentiles), and physical development assessment;

• assessment of skin and mucous membranes;

• assessment of the musculoskeletal system (detection of pain syndrome, identification of extremity dysfunction);

• assessment of cardiovascular system function;

• assessment of pulmonary system function;

• abdominal palpation;

• assessment of the size of cervical and supraclavicular lymph nodes.

Comments: cervical lymph node involvement is observed in 90% of all NPC cases; in advanced stages of the disease, super- and subclavicular lymph nodes may also be involved. Distant metastases in children and adolescents with NPC account for no more than 25-30% of cases.

Comments: The otolaryngological examination includes:

• Examination of the external nose – detection of deformities in the external nose area or the projection of paranasal sinuses is possible;

• Anterior rhinoscopy – tumor masses may be detected in the posterior and upper parts of the nasal cavity;

• Posterior rhinoscopy – allows detection of tumor masses in the nasopharynx partially or completely obstructing the choanae;

• Oropharyngeal examination – tumor growth into the oropharynx causes anterior displacement and asymmetry of the soft palate, a nasal voice tone, and airway obstruction when large;

• Otoscopy – the otoscopic picture corresponds to chronic secretory otitis media or tubotympanitis.

2.3 Laboratory Diagnostics

• All patients with suspected or confirmed NPC at the initial visit, as well as at every visit (examination, consultation) by a pediatric oncologist (B01.009.001, B01.009.002), before each subsequent course of chemotherapy, when assessing response to therapy during treatment, and during follow-up, are recommended to undergo the following laboratory tests to clarify the patient's condition, plan therapeutic tactics, determine the need for its modification, and identify the need for supportive and concomitant care [11]:

  • complete blood count (CBC) with differential;

  • general clinical blood chemistry test including the following parameters: determination of LDH activity, ALT, AST, GGT in the blood, measurement of total bilirubin in the blood, determination of alkaline phosphatase activity in the blood, measurement of total protein in the blood, measurement of albumin in the blood, measurement of creatinine in the blood, measurement of urea in the blood, measurement of uric acid in the blood, measurement of potassium, sodium, chlorides, and total calcium in the blood (other biochemical blood parameters may be included at the physician's discretion);

  • coagulogram (exploratory hemostasis screening)

  • general (clinical) urinalysis;

  • determination of the glomerular filtration rate.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Serological testing for EBV is performed at initial diagnosis and during follow-up, as patients' blood shows elevated titers of anti-EBV antibodies, as well as elevated titers of viral capsid antigen (VCA) and the diffuse (D) component of the early antigen (EA) complex (D-EA). IgG VCA and D-EA titers generally rise and fall in accordance with disease activity.

2.4 Instrumental Diagnostics

• All patients with suspected or confirmed NPC during the initial workup, when assessing response to therapy during treatment and during follow-up, as well as when a relapse/disease progression is suspected, are recommended to undergo magnetic resonance imaging of the soft tissues of the head with intravenous contrast and magnetic resonance imaging of the neck with intravenous contrast [1, 16].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: initial imaging is critical for assessing tumor size, volume, and precise extent; its relationship with blood vessels (including tumor-feeding vessels), nerves, and adjacent structures; bone changes, and vascularity (contrast-enhanced imaging). Imaging of the primary tumor site should include evaluation of regional lymph nodes.

For reliable assessment, scanners with a magnetic field strength of 1.0T to 3.0T must be used.

• All patients with suspected or confirmed NPC during the initial workup, when assessing response to therapy during treatment and during follow-up, as well as when a relapse/disease progression is suspected, are recommended to undergo computed tomography of the soft tissues of the head with contrast to assess skull bone destruction [1].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• For all patients with suspected or confirmed NPC during initial examination, when assessing the response to therapy during treatment and follow-up, as well as when disease recurrence is suspected, it is recommended to perform computed tomography (CT) of the chest organs with intravenous bolus contrast enhancement to rule out metastatic lung lesions [1].

GOR CLE 5Grade of recommendation C (level of trustworthiness – 5)

Comment: CT of the chest organs is mandatory for all patients. Given that CT is performed to rule out metastatic lung lesions, it is advisable to conduct the study with i.v. bolus contrast enhancement.

• For all patients with suspected or confirmed NPC during initial examination, when assessing the response to therapy during treatment and follow-up, as well as when disease recurrence/progression is suspected, it is recommended to perform an ultrasound examination of the cervical lymph nodes — ultrasound examination of the lymph nodes (one anatomical region) of the neck [11].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: Epipharyngoscopy allows for a detailed examination of all walls of the nasopharynx, identification of the direction of tumor growth, and, most importantly, targeted biopsy for morphological confirmation of the diagnosis. Undifferentiated nasopharyngeal carcinoma is characterized by an exophytic growth pattern with surface ulceration; the tumor is most often localized on the lateral walls of the nasopharynx, infiltrating and spreading along them into the oropharynx and even the laryngopharynx, while isolated involvement of the nasopharyngeal dome is less common. When the neoplasm grows anteriorly, tumor masses are visualized during endoscopic examination in the nasal cavity.

Comments: Endoscopic examination and biopsy of the nasopharyngeal tumor (biopsy of the nasopharyngeal mucosa under endoscopic guidance) in younger patients is performed under sedation, which requires a preliminary consultation and support by an anesthesiologist-resuscitologist.

Endoscopic examination and biopsy of the nasopharyngeal tumor (biopsy of the nasopharyngeal mucosa under endoscopic guidance) in older children and adolescents, if the patient's general condition is not severe, can be performed on an outpatient basis using local topical anesthesia.

Comments: Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals allows for the evaluation of distant metastases and the dynamics of the tumor process during therapy.

2.5 Other Procedures

Comments: Biopsy of the nasopharyngeal tumor (biopsy of the nasopharyngeal mucosa under endoscopic guidance) and/or biopsy of the altered cervical lymph node (lymph node biopsy) is necessary to obtain material for histological and immunohistochemical examination. Morphological verification of the diagnosis is required for all patients.

Comments: Morphological examination completes the comprehensive diagnosis. Given that the appearance of metastatic lymph nodes in the neck is quite frequently the first symptom of nasopharyngeal carcinoma, material for examination is obtained via puncture or biopsy of a cervical lymph node (puncture and biopsy of a lymph node). In the absence of metastases, a biopsy of the nasopharyngeal tumor (biopsy of the nasopharyngeal mucosa under endoscopic guidance) is performed using one of the aforementioned methods.

2.6 Examinations During Treatment

Whenever possible, examinations during therapy should be performed using the same methods as those used in the initial evaluation.

• For all patients with verified NPC receiving therapy according to treatment regimen No. 1 (see 3.1), it is recommended after 2, 4, 6, and 7 courses of polychemotherapy to perform MRI of the soft tissues of the head and neck with intravenous contrast enhancement, CT of the chest cavity with intravenous bolus contrast enhancement, Epstein-Barr virus DNA quantitative PCR assay in peripheral and cord blood, and positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals after 4 and 7 courses of polychemotherapy in the case of initial distant metastatic lesions or suspected appearance during treatment [1, 16, 19].

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

• For all patients with verified NPC receiving therapy according to treatment regimens No. 2 and No. 3 (see 3.2 and 3.3), it is recommended no earlier than 15 days from the start of the last course (3 or 4) of induction chemotherapy to perform MRI of the soft tissues of the head with intravenous contrast enhancement and MRI of the neck with intravenous contrast enhancement, CT of the chest cavity with intravenous bolus contrast enhancement, Epstein-Barr virus DNA quantitative PCR assay in peripheral and cord blood ± positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement in the case of initial distant metastatic lesions or suspected appearance during treatment [1, 16, 19].

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

Comment: the scope of follow-up examinations is determined individually for each patient based on the clinical situation and tumor spread at the physician's discretion.

2.7 Evaluation of Response to Therapy

Tumor response criteria to therapy (RECIST 1.1) [20] see 7.3

PR − at least a 30% decrease in the sum of diameters of target lesions.

CR − disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

PD − at least a 20% increase in the sum of diameters of target lesions (>5 mm); appearance of one or more new lesions; unequivocal progression of existing non-target lesions.

SD − neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

2.8 Examinations Prior to Treatment Completion

• Examinations before completion of therapy are recommended to be performed after the completion of the radiotherapy phase [3, 11].

The scope of examinations after completion of therapy includes:

• Detailed physical and neurological examination (consultations with subspecialists as indicated).

• Monitoring of laboratory parameters (complete blood count, general clinical blood chemistry, urinalysis, coagulogram [evaluation of the hemostatic system]).

• Echocardiography.

• Electrocardiography.

• Other studies as indicated (e.g., electroencephalography, pure-tone audiometry, fundus biomicroscopy, cerebrospinal fluid cytology, hormonal status).

• Instrumental examinations: brain MRI with contrast enhancement, neck MRI with intravenous contrast enhancement, brain CT with intravenous contrast enhancement, neck CT with intravenous bolus contrast enhancement, chest CT with intravenous bolus contrast enhancement, abdominal ultrasound (comprehensive), abdominal CT, targeted chest X-ray, positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement in case of initial distant metastatic lesions or suspected development during treatment).

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

Comment: brain MRI with contrast enhancement, neck MRI with intravenous contrast enhancement, brain CT with intravenous contrast enhancement, neck CT with intravenous bolus contrast enhancement 6 weeks after completion of radiotherapy, positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals no earlier than 3 months after completion of radiotherapy

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

When choosing management tactics and administering therapy, it should be taken into account that the patient may have atypical disease manifestations, as well as a combination of a specific disease with other pathologies, which may dictate changes in the algorithm for choosing the optimal diagnostic and treatment strategy for the attending physician.

Therapy for patients with NPC is based on a multidisciplinary approach and should be carried out under the supervision of specialized centers with experience in treating this group of patients. The mainstay of therapy for primary patients with verified NPC is systemic chemotherapy and radiotherapy.

These clinical guidelines present several regimens of induction chemotherapy and chemoradiotherapy that have demonstrated efficacy in NPC in children and adolescents.

3.1 Treatment Regimen No. 1 – Chemotherapy + Radiation Therapy

Induction Phase of Treatment

Indications for starting induction chemotherapy:

o Histological verification of the diagnosis;

o White blood cell count above 2×10⁹, platelet count above 75×10⁹;

o Absence of chronic diseases in the stage of decompensation, severe organ dysfunctions;

o Absence of infectious complications;

o Absence of a history of allergic reactions to #vinblastine**, #cyclophosphamide**, doxorubicin**, #bleomycin**.

Table 2 – Induction chemotherapy regimen [22]:

Upon reaching a cumulative dose of #bleomycin** of 300 mg/m², this drug is discontinued.

Table 3 – Consolidation chemotherapy regimen [22]:

#Dactinomycin is not administered during radiotherapy. The maximum single dose of #dactinomycin is 2.5 mg. Intervals between courses are 21–28 days. Before starting the 5th and subsequent courses, a comprehensive set of diagnostic examinations should be performed (see examination at the treatment efficacy control stage).

Radiation Therapy

Comment: RT to the primary lesion and lymph nodes should expediently be started after 6 neoadjuvant courses of systemic chemotherapy

3.2 Treatment Regimen No. 2 – Chemotherapy + Chemoradiotherapy

Induction Phase of Treatment

Indications for starting induction chemotherapy:

o Histological verification of the diagnosis;

o White blood cell count above 2×10⁹ and granulocytes above 0.75×10⁹, platelets above 75×10⁹;

o Absence of chronic diseases in the stage of decompensation, severe organ dysfunctions;

o Absence of uncontrolled infectious complications;

o Absence of urinary system disorders.

o Absence of a history of allergic reactions to #fluorouracil** and cisplatin**.

Table 4 – Induction chemotherapy regimen [24, 25]

Chemoradiotherapy

• All patients with a verified diagnosis of NPC and stage I are recommended to undergo radiotherapy without prior induction treatment with cytostatic agents (TDF = 66.6 Gy) and prophylactic irradiation of regional lymph nodes (TDF = 45 Gy) [28].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with a verified diagnosis of NPC and stage II, III, IVA are recommended to undergo radiotherapy targeting the primary tumor area and neck lymph nodes. Primary tumor and retropharyngeal lymph nodes: GTV is the tumor prior to treatment initiation. CTV = GTV + 1 cm with correction for anatomical barriers of tumor spread. Daily dose (FDD) 1.8 Gy, TDF 54 Gy. In case of local progression during systemic chemotherapy, the TDF should be 66.6 Gy. In the presence of residual tumor after completion of neoadjuvant systemic chemotherapy, irradiation of the residual tumor (GTV_boost) with a PTV margin up to 59.4 Gy is performed. Neck lymph nodes: neck lymph node levels IB–V FDD 1.8 Gy, TDF 45 Gy, affected node groups up to TDF 54 Gy, residual affected lymph nodes (if present after completion of neoadjuvant systemic chemotherapy) with a CTV margin of 5 mm up to TDF 59.4 Gy [10]

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with a verified diagnosis of NPC and stage II, III, IVA are recommended cisplatin** 20 mg/m² intravenously over 1 h during the first 3 and last 3 days of radiotherapy [25–27].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

3.3 Treatment Regimen No. 3 – Chemotherapy + Chemoradiotherapy

Induction Phase of Treatment

Indications for starting induction chemotherapy:

o Histological verification of the diagnosis;

o White blood cell count above 2×10⁹ and granulocytes above 0.75×10⁹, platelets above 75×10⁹;

o Absence of chronic diseases in the stage of decompensation, severe organ dysfunctions;

o Absence of uncontrolled infectious complications;

o Absence of urinary system disorders.

o Absence of a history of allergic reactions to #gemcitabine** and cisplatin**.

Table 5 – Induction chemotherapy regimen [27, 28]

Comment: the addition of #pembrolizumab** to the treatment regimen is possible subject to approval by a Federal Consilium

Table 6 – Induction chemotherapy regimen [29, 30]

Chemoradiotherapy

• All patients with a verified diagnosis of NPC and stage I are recommended to undergo radiotherapy without prior induction treatment with cytostatic agents (TDF = 66.6 Gy) and prophylactic irradiation of regional lymph nodes (TDF = 45 Gy) [28].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with a verified diagnosis of NPC are recommended radiation therapy to the primary tumor site and neck lymph nodes. Primary tumor and retropharyngeal lymph nodes: GTV is the tumor prior to treatment. CTV = GTV + 1 cm with correction for anatomical barriers of tumor spread. RD 1.8 Gy, TD 54 Gy. In case of local progression during chemotherapy, the TD should be 66.6 Gy. In the presence of residual tumor after completion of neoadjuvant chemotherapy, irradiation of the residual tumor (GTV_boost) with a margin for PTV up to 59.4 Gy. Neck lymph nodes: level IB–V neck lymphatic collectors, RD 1.8 Gy, TD 45 Gy, involved lymph node collectors up to a TD of 54 Gy, residual involved lymph nodes (if present after completion of neoadjuvant chemotherapy) with a CTV margin of 5 mm up to a TD of 59.4 Gy [10].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with a verified diagnosis of NPC stages II, III, IVA are recommended cisplatin** 20 mg/m² intravenously over 1 h during the first 3 and last 3 days of radiotherapy [25, 26].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

3.4 Maintenance Therapy

• All patients with a verified diagnosis of NPC and stage I are recommended observation without subsequent maintenance therapy after completion of radiation therapy [25, 27].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

• All patients with a verified diagnosis of NPC and stage II, III, IVA, and VIB are recommended maintenance therapy with #interferon beta-1b** for 6 months after completion of radiation therapy [25, 27].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Table 8 – Maintenance therapy regimen [23, 25]

3.4 Second-Line Chemotherapy

• All patients with confirmed progression or relapse of NPC are recommended to contact federal centers to select the optimal second-line therapy regimen [33].

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

3.6 Surgical Treatment

• All patients diagnosed with NPC presenting with significantly enlarged metastatic neck lymph nodes causing compression of adjacent structures and life-threatening conditions are recommended to contact federal centers to consider surgical treatment in the volume of neck lymph node dissection [34].

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

3.7 Prevention of complications arising during specialized treatment (supportive care)

3.7.1 Nutritional Support

• All patients under 18 years of age with oncological disease NPC are recommended to undergo nutritional status assessment during treatment and rehabilitation, with nutritional correction if disorders are identified (see Appendix A3.1) [35, 36].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3.7.2 Prevention and Treatment of Antineoplastic Therapy-Induced Nausea and Vomiting

• All patients under 18 years of age with oncological disease NPC are recommended to assess the emetogenicity level of medications and perform treatment and prevention of nausea and vomiting using medicinal products (see Appendix A3.2) during the treatment period to manage and prevent antineoplastic therapy-induced nausea and vomiting [37].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

3.7.3 Blood Transfusion Support

• All patients under 18 years of age with oncological disease NPC are recommended to receive blood transfusion support with blood products in the event of anemia syndrome, bleeding, or high risk of hemorrhagic syndrome during the treatment period (see Appendix A3.3) [38].

LCR CLEL 4 Level of Clinical Recommendation C (Level of Evidence – 4)

3.7.4 Specifics of venous access in ensuring successful diagnostic and therapeutic procedures

• All patients under 18 years of age with NPC are recommended the placement of an implantable infusion/injection port/catheter*** during the [intensive care/rehabilitation] period (see Appendix A 3.4) [39]

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: the presence of a central venous catheter providing the ability to monitor CVP, frequent blood sampling, and a high rate of fluid administration is absolutely necessary at the initial stages of therapy and in high-risk patients receiving intensive high-dose chemotherapy.

3.7.5 Prevention and Treatment of Infections

• All patients with NPC are recommended the appropriate and rational prescription of systemic antibacterial drugs in the event of infectious complications [40, 41].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

The scope, duration, and nature of rehabilitation measures depend on the patient's age at the time of the initial diagnosis, the timing of rehabilitation, the scope of treatment performed, and comorbid conditions. The initiation of rehabilitation measures depends on the stage and risk group, and starts during the primary polychemotherapy phase and continues after its completion across all stages of follow-up monitoring. Rehabilitation measures are carried out under the supervision of a pediatric oncologist at the medical institution where the patient received all the main stages of therapy. Rehabilitation is divided into medical, psychological, social, etc. The program involves educators (preschool and school education), social workers, psychologists, and physicians of various specialties (rehabilitologists, neurologists, endocrinologists, cardiologists, orthopedists, etc.). Rehabilitation is carried out in regional centers based at outpatient clinics and in specialized medical and rehabilitation centers. The frequency of rehabilitation is 2–3 times a year and can be increased depending on the patient's psychosomatic status [42, 43].

5. Prevention and Dispensary Observation

• All patients with an established diagnosis of NPC are recommended a follow-up examination (consultation) by a pediatric oncologist at established intervals after completion of treatment [22, 45].

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

Table 9 – Follow-up examinations for NPC patients after completion of therapy [19, 39]

^* For stage I and II disease, PET-CT with fluorodeoxyglucose [18F] is optional

6. Organization of Medical Care

Indications for planned hospitalization in a specialized pediatric oncology department:

1) Need for tumor biopsy: nasopharyngeal tumor biopsy (nasopharyngeal mucosal biopsy under endoscopic guidance) and/or biopsy of an altered cervical lymph node (lymph node biopsy) for morphological verification of the diagnosis

2) Administration of chemotherapy courses

3) Administration of radiation therapy

Indications for emergency hospitalization in a specialized pediatric oncology department:

1) Development of febrile neutropenia

2) Development of grade 3–4 stomatitis

3) Development of grade 2–4 toxicity requiring inpatient correction

Indications for discharge from the specialized pediatric oncology department inpatient unit:

1) Absence of signs of grade 2–4 chemoradiotherapy toxicity

2) Absence of indications for chemoradiotherapy (interval between chemotherapy courses, between treatment stages)

3) Refusal by parents/legal representatives/patient older than 14 years to undergo specialized treatment

4) Indications for palliative therapy in case of ineffectiveness of specialized treatment and absence of signs of grade 2–4 chemoradiotherapy toxicity

5) Diagnostic procedures at the diagnosis stage and between chemotherapy courses can be performed on an outpatient basis. Chemotherapy for older children and adolescents can be provided in a day hospital setting. Radiation therapy can be administered on an outpatient basis or in a day hospital setting if there is no need for anesthetic support and prior to the development of complications requiring antibacterial, infusion, or other supportive therapy. If complications develop, the child is transferred to inpatient care. Chemotherapy and radiation therapy in preschool and early school-age children should be performed in specialized inpatient units.

7. Additional Information

7.1 Adverse Prognostic Factors in NPC:

1. Presence of distant metastatic lesions;

2. Administration of chemotherapy with dose reduction of chemotherapeutic agents;

3. Refusal of radiation therapy;

4. Extension of intervals between chemotherapy courses beyond 28 days;

5. Onset of infectious complications;

6. Tumor invasion into the lateral pterygoid muscle.

7.2 Principles of Radiation Therapy in NPC

Technical requirements for external beam radiation therapy equipment

Medical linear accelerator with a photon energy of 6–10 MeV, equipped with a multileaf collimator and, highly preferably, image guidance system(s): cone-beam computed tomography (CBCT), portal imaging. Scanning-beam proton therapy using patient setup verification methods before the irradiation session may be used.

Head and body immobilization devices (thermoplastic masks, vacuum mattresses, etc.).

X-ray computed tomography scanner for simulation, featuring a flat tabletop with attachment capabilities and indexable immobilization systems.

A 3D radiation treatment planning system, highly preferably with the capability for dose calculation using intensity-modulated radiation therapy (IMRT/VMAT) techniques in both static and dynamic modes.

Pre-radiation preparation

CT-simulation must be performed using an X-ray computed tomography scanner adapted for radiation therapy needs.

Marker placement is performed using individual immobilization devices: thermoplastic masks and, potentially, a vacuum mattress.

The scan area must include the entire head, neck, and mediastinum down to the level of the tracheal bifurcation. Scanning is performed with a slice thickness of 1-3 mm.

The Field Of View (FOV) must be adequate to include all body parts and immobilization systems.

It should be taken into account that simulation and radiation therapy in patients under 5 years of age may require general anesthesia.

Planning is performed on a native CT topometry series. The use of IMRT [46] or scanning-beam proton therapy techniques is preferred.

7.3 Criteria for Tumor Response to Therapy (RECIST 1.1) [20]

Modern criteria for tumor response to therapy are the RECIST 1.1 criteria (2009).

RECIST 1.1 criteria are a set of criteria used to assess tumor response to ongoing therapy. The core of the assessment is determining tumor size using diagnostic imaging methods (radiography, CT, MRI, ultrasound) and endoscopic methods.

Tumor lesions

According to RECIST 1.1 criteria, tumor lesions are subdivided into two types:

1) measurable lesions — lesions that can be detected and have a longest diameter of:

≥10 mm on CT (brain CT with intravenous contrast, neck CT with intravenous bolus contrast, chest CT with intravenous bolus contrast) with 5 mm slice reconstruction;

≥20 mm on CT (brain CT with intravenous contrast, neck CT with intravenous bolus contrast, chest CT with intravenous bolus contrast) with 10 mm slice reconstruction;

≥20 mm on targeted chest radiography;

2) non-measurable lesions — lesions that are detected and have a longest diameter on CT (brain CT with intravenous contrast, neck CT with intravenous bolus contrast, chest CT with intravenous bolus contrast) with 10 mm slice thickness of <20 mm, and on CT (brain CT with intravenous contrast, neck CT with intravenous bolus contrast, chest CT with intravenous bolus contrast) with 5 mm slice thickness of <10 mm.

Non-measurable lesions include: small lesions (<10 mm), leptomeningeal metastases, pleural effusion, ascites, pericardial effusion, cysts, lymphangitic carcinomatosis of the skin or lungs, bone metastases, inflammatory breast changes, lesions with cystic and necrotic transformation, organ enlargement (hepatosplenomegaly), and peritoneal implants.

Assessment algorithm

First and foremost, measurable lesions are assessed quantitatively.

The next step is to select target lesions that will be used for monitoring during therapy. A target lesion remains classified as a target lesion throughout all follow-up scans, even if its size decreases to the limit of measurement error of the imaging method.

Target and non-target lesions

Target lesions:

• measurable lesions, up to a maximum of 5 lesions per organ, with a total of up to 10 lesions; lesions reflecting the affected organ must meet the criteria for a target lesion;

• selected based on their size (longest diameter) and suitability for precise repeated measurement;

• lesions in mobile organs (e.g., gastrointestinal tract, ovaries) may be unsuitable for evaluation;

• only axial dimensions are recorded.

Non-target lesions:

• may include both measurable and non-measurable lesions;

• measurable lesions include all lesions that exceed the maximum allowable number of target lesions (up to 5 lesions per organ, no more than 10 lesions total in the body);

• non-target lesions do not necessarily need to be measurable;

• ideally, should include all lesions not classified as target lesions.

Response evaluation criteria:

• PR — at least a 30% decrease in the sum of diameters of lesions.

• CR — disappearance of all lesions. Any lymph nodes that were previously enlarged must have a short axis of less than 10 mm.

• PD — an increase of 20% or more in the sum of diameters of target lesions (>5 mm); the appearance of one or more new lesions; unequivocal progression of non-target lesions.

• SD — everything else.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Listed in alphabetical order

Clinical Oncologists

Svetlana R. Varfolomeeva, Doctor of Medical Sciences, Professor, President of RODOG, Director of the Research Institute of Pediatric Oncology and Hematology named after Acad. L.A. Durnov at the National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Professor at the Department of Pediatric Oncology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Tatyana V. Gorbunova, Doctor of Medical Sciences, Deputy Chief Physician of the Research Institute of Pediatric Oncology and Hematology named after Acad. L.A. Durnov at the National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

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

Liliya L. Rabaeva, Candidate of Medical Sciences, Head of the Department of Older Children's Oncology and Hematology and Neurooncology at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

2. Radiation Therapists

Aleksey V. Nechesnyuk, Candidate of Medical Sciences, Head of the Department of Radiation Therapy at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

3. Surgical Group

Nikolay S. Grachev, Doctor of Medical Sciences, Professor, Chief Executive Officer of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

Raisa S. Oganesyan, Pediatric Surgeon at the Department of Pediatric Oncology, Head, Neck and Skull Base Surgery, and Neurosurgery at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

Vladimir G. Polyakov, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director, Head of the Department of Head and Neck Tumors at the Research Institute of Pediatric Oncology and Hematology named after Acad. L.A. Durnov at the National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health, Head of the Department of Pediatric Oncology at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Chief Freelance Pediatric Oncologist of the Russian Ministry of Health

4. Supportive Care Group

A.Yu. Vashura, Candidate of Medical Sciences, Clinical Nutritionist, Head of the Department of Scientific Foundations of Nutrition and Nutritional-Metabolic Therapy at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

Pavel A. Zharkov, Doctor of Medical Sciences, Head of the Laboratory of Hemostasis Pathology at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

N.A. Klimova, Head Nurse of the Department of Pediatric Hematology/Oncology at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

I.V. Korovina, Clinical Nutritionist at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

O.V. Pimenova, Director of Nursing at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

A.V. Satsuk, Candidate of Medical Sciences, Head of the Department of Advanced Training for Mid-Level Medical Personnel, Epidemiologist at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Senior Researcher at the Laboratory of Nosocomial Infection Prevention, Central Research Institute of Epidemiology of Rospotrebnadzor.

G.G. Solopova, Candidate of Medical Sciences, Deputy Chief Physician for Infection Control, Head of the Department of Infection Control, Hematologist at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

L.F. Sorokina, Nurse at the Department of Pediatric Oncology, Head, Neck and Skull Base Surgery, and Neurosurgery at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

Trachtman P.E., MD, PhD, Professor, Transfusiologist, Head of the Department of Transfusion Medicine, Hematopoietic Stem Cell Harvesting and Processing, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

Shchemelinskaya Yu.L., Epidemiologist, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

Shchukin V.V., PhD, Head of the Department of Anesthesiology and Intensive Care with Operating Suite, Anesthesiologist-Intensivist, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatric oncologists;

2. Medical students, residents, postgraduate students.

Table 10 – Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 11 – Scale for assessing levels of evidence (LE) for methods of prevention, treatment, medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, therapeutic, rehabilitation interventions)

Table 12 – Scale for assessing grades of recommendation (GR) for methods of prevention, diagnosis, treatment, medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, diagnostic, therapeutic, rehabilitation 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 Recommendations for Assessing and Correcting Nutritional Status

A3.1.1 Medical Nutrition Therapy

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 patients upon admission to a medical organization providing inpatient medical care. Medical nutrition is prescribed by the attending physician or the physician on duty of the medical organization in accordance with the nosological form of the disease according to the primary and/or comorbid diagnosis. All patients with protein-energy malnutrition or a high risk of developing it (regardless of nutritional status) are indicated for nutritional support [35, 47].

A3.1.2 Nutritional Screening and Monitoring (Assessment of Nutritional Status)

All patients with NCD upon admission to the hospital and subsequently 1 to 4 times a month are indicated for nutritional status assessment in order to identify protein-energy malnutrition or the risk of its development [48, 49]. Detecting nutritional disorders in the early stages of their development, especially before the initiation of antitumor therapy, allows for timely initiation of nutritional correction. Criteria for protein-energy malnutrition, obesity, and nutritional risk factors can be found in the appendix. Primary screening is performed either by assessing anthropometric parameters and identifying risk, or by using standard scales/tools for nutritional screening [50]. Nutritional screening consists of the initial and subsequent regular assessment of 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 specifics of the ongoing treatment [51].

To conduct nutritional screening, it is necessary to use special validated questionnaires/tools; their use is particularly relevant at the stage of initial admission to the hospital and/or at the (subsequent) stage of admission to the clinical department [35].

Most screening tools are focused on combining data on the primary diagnosis, clinical status, anthropometric indices, body weight dynamics, and nutritional status, and integrating these data into a composite score with subsequent division of patients into 2 or 3 cohorts: those who do not require nutritional correction (support); those who require repeat screening over time (the "alarm" group); and those who require 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 should be remembered that existing screening tools are not designed to answer the question of the volume and method of required nutritional support and do not carry prognostic information for a specific patient, since their use is aimed solely at medical triage. In addition, there is no universal screening tool for pediatrics

For the primary (general) assessment of nutritional status and identification of nutritional risk, it is necessary to take into account anthropometric parameters, changes in body weight over a specific period (3, 6, or 12 months), nutritional data (regimen, habitual diet, dietary habits, possible eating disorders, presence of intolerance/allergies to food components), endocrine status (data on identified endocrine disorders in the child), and data on identified gastrointestinal disorders [51].

As a mandatory minimum of basic anthropometric parameters for the initial and regular assessment of nutritional status, the following must be used: body weight, height (body length), body mass index [35, 48].

As additional anthropometric parameters, in case of the need for a detailed anthropometric study for the initial and regular assessment of nutritional status, the following are used: measurement of circumferences, lengths, skinfold thickness, handgrip dynamometry [35, 48]

To correlate the obtained anthropometric data (height, body weight, body mass index, arm circumference) with normative values for the pediatric population, reference values (scales) are used, either local (domestic) references or globally used growth charts: centile values/percentiles, or the magnitude of deviation of the obtained value from the population mean (SDS or z-score) [48]

Commonly used "by default" in the Russian Federation are WHO growth charts, 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 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 identified nutritional disorders upon initial screening are recommended a more detailed examination of nutritional status: dietary analysis, body composition assessment, laboratory parameter evaluation, as well as a detailed physical examination and interview to identify nutritional-metabolic disorders and their predictors [51]

Patients receiving nutritional support require nutritional monitoring – interview, anthropometry, body composition analysis, laboratory parameters (general clinical biochemical blood test, coprological examination) [35, 52].

A3.1.3 Nutritional Support

All patients with protein-energy malnutrition or a high risk of developing it (regardless of nutritional status) are indicated for nutritional support (NS) [35].

When choosing the form, method, type, and volume of nutritional support, one must be guided, first of all, by the principle of an individual patient-oriented approach – in accordance with the clinical situation and logic [35].

The calculation of the volume of nutritional support must be carried out by calculating nutritional requirements or total energy expenditure (TEE) [35, 36].

Calculation of total energy expenditure (TEE) is performed using the formula: TEE = REE × AF, where REE is resting energy expenditure, AF is activity factor.

The gold standard for determining REE is indirect calorimetry. If indirect calorimetry is impossible, REE can be calculated using a formula (e.g., Schofield) [53]. To avoid overfeeding in the initial stages of nutritional support in children with chronic protein-energy malnutrition and/or with an alleged history of inadequate nutrient intake for 3 or more consecutive months, an AF of 0.85–1.4 is used to calculate TEE. The exact volume of nutritional intervention is determined depending on the specific clinical situation.

When choosing the route of nutritional support, the priority is the use of enteral nutrition (EN) [54, 55].

EN is the most physiological, providing intraluminal trophism of the gastrointestinal mucosa, preventing microbial translocation from the intestinal lumen into the blood, and is more cost-effective than parenteral nutrition.

In cases where the patient cannot/does not want/is not ready to take the prescribed volume of the formula in the required regimen independently, it is indicated to use a nasogastric (nasojejunal) tube or gastrostomy for enteral nutrition [35, 55].

If tube feeding is currently or potentially required for more than 6 weeks, gastrostomy placement is indicated [35]

In cases where there is a demonstrated need for prolonged enteral nutrition and a predicted risk of nutritional deficiency (including during chemoradiotherapy), preventive gastrostomy placement is possible, 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 anti-tumor treatment is still to be continued, gastrostomy placement is necessary, bypassing the stage of tube feeding and even sipping [56].

In patients with gastrointestinal dysfunction or those who have not received regular enteral nutrition for a prolonged period (more than 3 weeks), starting enteral nutritional support with an isocaloric formula is indicated, with a subsequent transition to a hypercaloric formula if necessary (monitoring tolerance) [47]

All patients in whom the estimated nutritional requirements cannot be met enterally and/or in cases where EN cannot meet the basal energy expenditure requirements are indicated for parenteral nutrition. Among these patients, special attention should be paid to children with existing protein-energy malnutrition, especially moderate and severe grades [35, 36].

The key indication for prescribing parenteral nutrition (PN) is the inability to meet the patient's estimated nutritional requirements (at least at the level of basal energy expenditure) via the enteral route – whether current or potentially anticipated in the short term.

Parenteral nutrition should be initiated gradually, stepwise increasing the volume (and rate) of daily infusion starting from one-third/half of the calculated target volume and, under the monitoring of blood biochemistry parameters (primarily glucose, direct bilirubin, urea) and acid-base balance, over several days (the rate of reaching the target volume is determined individually based on the clinical situation) bringing the volume up to the target. Discontinuation of parenteral nutrition should also be performed gradually, stepwise, in the reverse order [35, 47].

A3.1.3 Reference and informational tables for assessing nutritional status and its correction.

Table 13 – Interpretation of nutritional status based on Z-score according to WHO reference data [48]

Notes: nutritional status in pediatric oncology is assessed using cumulative data (clinical, laboratory, instrumental), taking into account nutritional risk; anthropometric parameters serve as a criterion-based guide in determining nutritional status and cannot be the sole determining factor [35]; *– in determining nutritional status, the parameter with the minimum SDS is used; SDS – standard deviation score; obesity – simple; hypothalamic; in neuroendocrine diseases; iatrogenic; monogenic; syndromic.

Table 14 – High-risk factors for the development of nutritional status disorders [35]

Table 15 – Main screening tools for detecting the risk of nutritional disorders in pediatrics [57]

Table 16 – Recommended requirements of children for basic nutrients and energy (per kg of body weight per day) in the calculation of dietotherapy and enteral nutrition [47]

Notes: Requirements are provided as a guide for calculating and prescribing enteral nutrition; they do not cancel or replace a patient-oriented approach in prescribing nutritional support: in each specific case, the clinical picture, possible metabolic and organ dysfunctions should be taken into account, and nutrient intake adjusted considering the child's capabilities and tolerance.

Appendix A3.2 Prevention and treatment of nausea and vomiting induced by anti-tumor therapy

A3.2.1 Determination of Emetogenic Level and CINV Prophylaxis Option

To select an adequate CINV prophylaxis regimen, the first step is to determine the emetogenic level (risk of CINV development) of the anti-tumor therapy regimen planned for the patient. The emetogenicity level influences the choice of drugs for CINV prophylaxis, their doses, and duration of use [37]. Appendix A 3.2.6 (Table 17) presents the general classification of chemotherapy emetogenicity according to ASCO (American Society of Clinical Oncology) [58] and COG (Children's Oncology Group) guidelines [37]

A3.2.2 Prevention of Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy

For optimal prophylaxis 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, use a four-drug regimen including a serotonin 5HT3-receptor antagonist, other antiemetic drugs (A04AD), #dexamethasone**, and #olanzapine** [59–62]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

If the anti-tumor therapy regimen includes a systemic corticosteroid (H02) at a dose equal to or exceeding the dose indicated for antiemetic use, additional administration (to the anti-tumor therapy regimen) of a systemic corticosteroid (H02) for CINV prophylaxis 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.

For optimal prophylaxis of delayed CINV, carried out for 3 days after the completion of chemotherapy administration, use a combination of #dexamethasone** and #olanzapine** [62, 63]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

In the absence of the possibility of prescribing other antiemetic drugs (A04AD), use a combination consisting of any serotonin 5HT3-receptor antagonist, #dexamethasone**, and #olanzapine** [60, 62, 64]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

In the absence of the possibility of prescribing #dexamethasone**, palonosetron** is used as the preferred serotonin 5HT₃-receptor antagonist in combination with other antiemetic drugs (A04AD) (if prescription is possible) and #olanzapine** [37, 65]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

A3.2.3 Prevention of Nausea and Vomiting Induced by Moderately Emetogenic Chemotherapy

For optimal prophylaxis of acute CINV occurring on the day(s) of chemotherapy administration, use a two-drug regimen including a serotonin 5HT3-receptor antagonist and #dexamethasone** [37, 61]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

If the anti-tumor therapy regimen includes a systemic corticosteroid (H02) at a dose equal to or exceeding the dose indicated for antiemetic use, additional administration (to the anti-tumor therapy regimen) of a systemic corticosteroid (H02) for CINV prophylaxis on that day is not required.

For optimal prophylaxis of delayed CINV, carried out for 1 day after the completion of cytostatic administration (according to the ATC classification L: Antineoplastic and immunomodulating agents), use #dexamethasone** [37, 61]. Regimens and doses are presented in Appendix A3.2.6 (Table 17).

In the absence of the possibility of prescribing #dexamethasone**, use a combination consisting of any serotonin 5HT3-receptor antagonist and other antiemetic drugs (A04AD) [37, 61]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

In the absence of the possibility of prescribing both #dexamethasone** and other antiemetic drugs (A04AD), palonosetron** is used as the preferred serotonin 5HT3-receptor antagonist [37, 61]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

A3.2.4 Prevention of Nausea and Vomiting Induced by Low- and Minimally Emetogenic Chemotherapy

CINV prophylaxis during low- and minimally emetogenic chemotherapy includes single-agent prophylaxis with a serotonin 5HT3-receptor antagonist for low-emetogenic therapy, or its complete absence in the case of chemotherapy with minimal emetogenic activity [37]. Regimens and doses are presented in Appendix A3.2.7 (Table 18).

A3.2.5 Management of Breakthrough and Refractory Emesis

For patients with breakthrough and refractory vomiting during cytostatic therapy, it is recommended to:

1. If breakthrough CINV occurs during cytostatic therapy (and consequently prophylaxis) classified as minimal, low, or moderate emetogenicity, drugs designated for the next, higher level of prophylaxis must be used.

2. If the patient is already receiving prophylaxis intended for highly emetogenic therapy, in the event of breakthrough CINV, the addition of #olanzapine** should be considered (if it was not previously used due to unsuitable age or body weight). If #olanzapine** cannot be used, metoclopramide** may be administered as an alternative.

3. If a patient experiences refractory CINV and is not yet receiving the maximum level of prophylaxis, an escalation of antiemetic therapy must be performed. If refractory CINV occurs despite the maximum level of prophylaxis, replacing the currently used 5-HT3 serotonin receptor antagonist with palonosetron or administering additional doses of 5-HT3 serotonin receptor antagonists is possible. If these prophylactic approaches fail, it is recommended to persistently add #olanzapine**, metoclopramide**, or other agents that have proven effective in treating breakthrough vomiting in the patient [66].

A3.2.6 Table 17 – Emetogenic potential of antineoplastic agents

A3.2.7 Table 18 – Doses and Regimens of Antiemetics

Appendix A3.3 Blood Transfusion Support

Order of the Russian Ministry of Health No. 1170n dated October 28, 2020, "On Approval of the Rules of Medical Care Delivery to the Population in the Profile of 'Transfusiology'", registered with the Ministry of Justice of the Russian Federation on November 27, 2020, No. 61123, regulates the procedure for blood transfusion support for patients in need of this type of medical care.

Red Blood Cell Components

In children with malignant neoplasms receiving chemotherapy and/or radiation therapy who present with severe anemia (Hb <70 g/L, Ht <25%) with symptoms and signs of anemic hypoxia and without bleeding, red blood cell transfusions are recommended [67]. Transfusions may not be required for well-compensated patients recovering from induced aplasia. However, in the event of upcoming intensive chemotherapy in the absence of clinical manifestations of anemia, red blood cell transfusions may be justified. The decision to administer transfusions should be based primarily on clinical rather than laboratory data [67]. In stable pediatric patients with malignant neoplasms without bleeding, red blood cell transfusions are recommended at a dose of 10–15 mL per kg of body weight [68]. Pediatric patients with oncological diseases are recommended to receive transfusions of leukoreduced blood components [68]. The use of leukoreduced blood components has been shown to reduce the incidence of febrile non-hemolytic transfusion reactions, as well as significantly lower the likelihood of patient HLA alloimmunization and the transmission of certain transfusion-transmitted infections (cytomegalovirus, Epstein-Barr virus).

Platelet Concentrate

In children with malignant neoplasms and hypoproliferative thrombocytopenia caused by the underlying disease and/or its treatment, prophylactic platelet transfusions are recommended under the following conditions [68]:

• stable neonates with a platelet count drop to ≤25×10⁹/L;

• stable patients with a platelet count drop to ≤10×10⁹/L;

• febrile patients with a platelet count drop to ≤15×10⁹/L;

• patients at high risk of bleeding with a platelet count drop to ≤20×10⁹/L;

• prior to minor surgical procedures in non-critical sites with a platelet count drop to ≤20×10⁹/L;

• prior to lumbar puncture, with a platelet count drop to ≤40×10⁹/L;

• prior to percutaneous liver biopsy, if the platelet count is ≤50×10⁹/L;

• during surgical interventions in critical sites (e.g., central nervous system), if the platelet count is ≤75-100×10⁹/L;

• prior to other surgical interventions with a platelet count of ≤50×10⁹/L

Patients receiving anticoagulants (antithrombotic drugs), patients with disseminated intravascular coagulation (DIC), sepsis, etc., are at an increased risk of bleeding.

Platelet transfusions in children with hypoproliferative thrombocytopenia and hemorrhagic syndrome are recommended in the presence of [68]:

• minor hemorrhagic syndrome and a platelet count drop to ≤10×10⁹/L;

• moderate hemorrhagic syndrome and a platelet count drop to ≤20×10⁹/L;

• severe hemorrhagic syndrome and a platelet count drop to ≤30×10⁹/L;

• bleeding in a critically important location (e.g., CNS) and a platelet count drop to ≤100×10⁹/L

Platelet transfusions in children with malignant neoplasms are recommended at the following dose [68]:

• neonates 10-15 mL/kg

• children with a body weight of more than 10 kg: 10 mL/kg

Donor Plasma

Donor plasma transfusions are recommended for children with oncological diseases presenting with clinically significant bleeding combined with an activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) exceeding 1.5 times the upper limit of normal [68].

Donor plasma transfusions are recommended for children with malignant neoplasms at a dose of 15 mL/kg of body weight [68].

Cryoprecipitate (Coagulation Factor VIII**)

• Cryoprecipitate transfusions (coagulation factor VIII**) in children with oncological diseases are recommended when the fibrinogen concentration drops below 1–1.5 g/L.

• Cryoprecipitate transfusions (coagulation factor VIII**) for acquired fibrinogen deficiency caused by various etiologies are recommended when its serum concentration drops below 1 g/L.

• Cryoprecipitate transfusions (coagulation factor VIII**) when blood concentration drops below 1.5 g/L are recommended for patients experiencing severe intraoperative bleeding and for patients with sepsis who develop hemorrhagic syndrome.

• Cryoprecipitate transfusions (coagulation factor VIII**) are recommended at a dose of 1 unit per 5 kg of the patient's body weight [69].

Appendix A3.4 Features of venous access in ensuring successful diagnostic and therapeutic measures

3.4.1 General features of venous access.

The manufacturer's instructions and documentation provided with the venous access device allow key information regarding the device, possible flow rates and pressure limits during infusion, and priming volume to be provided to all personnel involved in daily patient care or performing diagnostic procedures [70]. This documentation must be promptly and permanently accessible to the personnel working with the patient.

3.4.2 Recommendations for Device Selection

The choice of venous access device should be based on the patient's needs and take into account:

• Diagnosis, management plan, and expected duration of intravenous treatment;

• Patient age;

• Possible patient preferences regarding the type or location of the device;

• The condition of the patient's veins;

• Available resources for device installation and maintenance.

There is insufficient evidence to definitively favor one device over another for every patient category. It is advisable to use a catheter with the fewest possible lumens [71].

In the presence of contraindications to catheter insertion via the superior vena cava basin veins, femorally inserted central catheters are used.

For continuous use (daily or at least once a week), it is recommended to use external catheters such as PICC, CICC, and FICC; for intermittent use (less than once a week), fully implantable systems (ports) should be used [70].

3.4.3 Recommendations for Device Insertion

Central venous access devices are inserted according to urgent and elective indications in an aseptic operating room. A detailed description is available in the FAR clinical guidelines.

The choice of vein depends on the condition of the patient's venous system. It is preferable to use devices that allow high flow rates and contrast agents [72, 73]. Every effort should be made to ensure that the ratio of catheter diameter to vein diameter does not exceed 1/3.

The use of multi-lumen catheters, although indicated for certain specific categories of patients, is associated with an increased risk of infection [74, 75].

The catheter material must be chosen based on high flow and pressure resistance characteristics, as well as device durability.

Catheter insertion via a surgical vein cutdown is not recommended in patients with oncohematological diseases [76]. Cyanoacrylate tissue adhesive is used for polyurethane catheters, whereas it is not used in practice for silicone catheters [77].

3.4.4 Venous access care and removal.

Venous access care is performed in compliance with asepsis and antisepsis rules; periodic dressing changes, flushing of the venous access, its "locking" in case of intermittent treatment, and removal according to indications are indicated [78, 79].

Appendix A3.5 Prevention and Treatment of Infections

3.5.1 Standard Definitions Used [81-83]

Neutropenia is defined as a granulocyte count of less than 0.5×10⁹/L, or less than 1.0×10⁹/L with an anticipated decline over the next few days.

Febrile status is a single elevation of body temperature ≥38.3°C or a body temperature ≥37.8°C persisting for one hour or more.

Hypothermia – a drop in body temperature below 36°C. This indicator is an important sign of an infectious process, especially in young children and patients receiving glucocorticosteroids.

Fever of unknown origin – a condition characterized by fever in the absence of clinical and radiological manifestations of infection and microbiological data.

Bacteremia is the identification of a microorganism from a blood culture taken during a febrile episode that is not a contaminant. False bacteremia includes the identification of so-called contaminating microorganisms—skin commensals such as coagulase-negative staphylococci, Propionibacterium spp., Micrococcus spp., etc.—in the case of a single isolation.

Proven infection is one in which a microorganism is identified from sterile body fluids (blood, cerebrospinal fluid, urine, biopsy material) in the presence of symptoms of an inflammatory reaction, or a pathogen is isolated from non-sterile substrates (skin, mucous membranes, gastrointestinal tract) with a corresponding local clinical presentation of the infection.

Probable infection is one in which there is no identification of a microorganism from the studied media, but there are clinical and/or radiological signs of infection with a rapid response to anti-infective therapy.

Febrile neutropenia is a symptom complex combining the development of fever or hypothermia in a patient with criteria for neutropenia. It is the most anticipated infectious complication and develops in the vast majority of high-risk patients, and less frequently in standard-risk patients.

Patients with febrile neutropenia (FN) belong to the standard-risk group. In this group, the expected duration of neutropenia is less than 7 days.

3.5.2 Patients with NPC Suspected of Having Febrile Fever Are Indicated For:

1. Performing blood cultures (microbiological examination of blood for sterility) [80–83].

2. Determination of antimicrobial susceptibility of microorganisms isolated from the blood and/or antifungal susceptibility of fungi isolated from the blood in case of a positive blood culture result, in order to prescribe adequate treatment [80–83].

3. Performing an ultrasound examination of the abdominal organs and kidneys in case of abdominal pain and/or bowel movement retention for more than 3 days; computed tomography of the chest organs in the presence of respiratory symptoms such as cough, dyspnea, desaturation, chest pain; and computed tomography of the paranasal sinuses in case of signs of sinusitis [84].

4. Performing virological testing of nasopharyngeal and oropharyngeal swabs for respiratory viruses, including the novel coronavirus infection COVID-19 [85–87].

5. Performing a microbiological examination of an oropharyngeal swab in the presence of symptoms of mucositis/gingivitis, as well as PCR for herpes simplex virus [85–87].

6. Determination of Clostridium difficile toxins A and B in stool samples, as well as determination of a group of "enteric" viruses: rotavirus, norovirus, adenovirus (by PCR or immunochromatography) in the presence of diarrhea [88, 89].

7. Monitoring of Aspergillus spp. galactomannan antigen determination if the duration of FN is 7 days or more [90–92].

8. Determination of Aspergillus spp. galactomannan antigen in bronchoalveolar lavage (BAL) fluid when pneumonia is detected [90–92].

9. Determination of Candida spp. mannan antigen in the blood and determination of antibodies to Candida spp. in the blood to exclude disseminated/invasive candidiasis in the presence of liver lesions [93, 94].

3.5.3 Antibiotic Therapy

When febrile neutropenia develops, after blood collection for blood culture, immediate intravenous administration of systemic antibacterial drugs (J01) is indicated—for stable patients, the maximum allowable interval should not exceed 60 minutes, and in case of hemodynamic instability, 30 minutes [80, 95, 96]. All other necessary examinations should be carried out after the initiation of starting therapy.

When FN develops, it is necessary to initiate broad-spectrum empirical antibiotic therapy with activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. The choice of starting therapy depends on the risk group, the patient's somatic status, local epidemiological data and recommendations, as well as screening results and the patient's prior infection history [80, 96, 97]. For patients in the standard-risk group, the administration of 3rd generation cephalosporins (J01DD) is indicated [97, 98].

Appropriate options for empirical antibiotic therapy:

• #Piperacillin+[Tazobactam] (4.5 g every 6 hours or 300 (400) mg/kg/day divided into 3-4 administrations or by continuous infusion +/- #amikacin** 15-20 mg/kg/day in a single administration) [99];

• cefepime** (2 g x 3 times or 100-150 mg/kg/day divided into 3 administrations +/- #amikacin** 15-20 mg/kg/day in a single administration) [99];

• cefoperazone+[sulbactam]** (4 g x 2 times or 160 mg/kg/day calculated by cefoperazone divided into 3 administrations +/- #amikacin** 15-20 mg/kg/day in a single administration) [99];

• ceftazidime** (2 g x 3 times daily or 100-150 mg/kg/day divided into 3 doses);

1. In clinics with a low detection rate of ESBL-producing Enterobacteriaceae, the following may be prescribed:

• cefepime** (2 g x 3 times daily or 100-150 mg/kg/day divided into 3 doses);

• ceftazidime** (2 g x 3 times daily, intravenously, or 100-150 mg/kg/day divided into 3 doses).

The administration of vancomycin** in addition to the baseline drug in first-line therapy is indicated in the development of ulcerative-necrotizing stomatitis, soft tissue lesions, suspected catheter-related infection (prior to microbiological confirmation), in patients after high-dose cytarabine** chemotherapy, as well as in cases of prior patient colonization with methicillin-resistant Staphylococcus aureus (MRSA);

2. For severe infections, carbapenems may be prescribed in 1st-line therapy (intra-abdominal infection, perirectal soft tissue infection, etc.):

• #Imipenem+[Cilastatin]** (0.5-1.0 g every 6-8 hours or 80-100 mg/kg/day divided into 3-4 administrations + #amikacin 15-20 mg/kg/day in a single administration) [99];

• #Meropenem** (2.0 g every 8 hours or 100-120 mg/kg/day divided into 3 administrations + #amikacin** 15-20 mg/kg/day in a single administration) [99];

3. If anaerobic infection is suspected (gingivitis, perioral cellulitis, intra-abdominal or perirectal infection), antibiotics with anti-anaerobic activity must be prescribed (#piperacillin+[tazobactam], #imipenem + [cilastatin]**, #metronidazole**, #clindamycin**).

4. In the event of Clostridium infection or diarrhea when C. difficile toxin detection in stool is not feasible – #metronidazole** (0.5 g every 8 hours, intravenously, or 10 mg/kg every 8 hours. In severe enterocolitis, oral administration of vancomycin** at a total daily dose of 500 mg is possible [100].

5. In case of allergy to beta-lactam antibacterial drugs (penicillins), fluoroquinolones may be prescribed as an alternative regimen:

#Levofloxacin** (750 mg/day or 10 mg/kg BID for children under 5 years, then 10 mg/kg/day as a single dose) [101]

Modification of antimicrobial therapy is carried out based on clinical symptoms, instrumental examinations, and microbiological studies. If the fever persists while the patient's clinical condition remains stable, it is acceptable to wait for a clinical response to initial antibacterial therapy for 48–72 hours, as fever is not the sole indicator of infection severity. In patients with persistent febrile neutropenia and negative blood culture, the susceptibility of Gram-negative bacteria colonizing the intestinal mucosa is taken into account when modifying therapy. Reserve drugs include colistimethate sodium, polymyxin B**, #tigecycline**, #ceftolozane+[tazobactam]**, ceftazidime+[avibactam]** (in some situations combined with aztreonam**).

Recommended doses:

• #Colistimethate sodium – loading dose of 118,000 IU/kg (maximum 720 mg) over 4 hours, followed by 75,000 IU/kg every 12 hours (maximum 320 mg BID) [102]

• Polymyxin B** (2.5 mg/kg/day in 2 divided doses; in children under 1 year, 4 mg/kg/day in 2 divided doses)

• #Tigecycline** – loading dose of 2 mg/kg (100 mg), followed by 1.2 mg/kg (50 mg) every 12 hours [103]

• #Ceftazidime+[avibactam]** 2.5 g TID or 120–150 mg/kg/day based on ceftazidime in 3 divided doses – each infusion lasting 2–3 hours [104]

• If administration of #ceftazidime+[avibactam]** in combination with aztreonam** is necessary, the drugs must be administered simultaneously via parallel infusions.

When signs of sepsis and septic shock develop, systemic antibacterial drugs should be prescribed: carbapenems combined with aminoglycosides and vancomycin**, and reserve drugs for patients with known colonization. In the event of severe infectious complications and/or sepsis, antibacterial drugs are prescribed at maximum doses, preferably as prolonged infusions due to impaired clearance and fluid redistribution in the body [45-48].

When infections associated with Gram-positive flora develop, the choice of antibacterial drugs should be based on susceptibility data and maximal efficacy for the specific clinical situation:

For bloodstream infections, endocarditis, or device-related infections, preference should be given to bactericidal drugs – vancomycin**, daptomycin** (8–10 mg/kg/day as a single dose), ceftaroline fosamil** (600 mg TID or 12 mg/kg TID);

For pneumonia – drugs with greater penetration into lung tissue – linezolid** (600 mg BID or 10 mg/kg TID in children under 12 years), vancomycin**;

For soft tissue infections – linezolid**, daptomycin**, #tigecycline**, vancomycin**

3.5.4 Empirical Antifungal Therapy

If fever persists for 96–120 hours despite ongoing first- and second-line empiric antibacterial therapy and absence of infection foci, initiate empiric antifungal therapy [105–107]:

• Caspofungin** 70 mg on the first day, then 50 mg intravenously once daily or 70 mg/m² on the first day and then 50 mg/m²/day)

• Amphotericin B [liposomal] (3 mg/kg/day as a single dose)

• Alternative agents include other systemic antifungals (micafungin** 100 mg once daily IV or 2–4 mg/kg/day (in infants in the first month of life, the dose may be increased up to 10 mg/kg/day); anidulafungin** (drug of choice for patients with hepatic impairment) 200 mg on the first day, then 100 mg once daily, or 3 mg/kg on the first day, then 1.5 mg/kg/day);

• Amphotericin B [lipid complex] (5 mg/kg/day as a single dose).

Appendix B. Physician Action Algorithms

Regimen No. 1. Algorithm for the management of a patient with NPC

Appendix C. Patient Information

What is nasopharyngeal carcinoma?

Nasopharyngeal carcinoma is a malignant epithelial neoplasm of the nasopharynx. In 98% of cases, nasopharyngeal carcinoma is associated with the Epstein-Barr virus. In pediatric oncology, nasopharyngeal cancer is extremely rare. However, despite its rarity, nasopharyngeal carcinoma is one of the few epithelial malignancies that occur quite frequently in children and adolescents.

Symptoms of nasopharyngeal carcinoma

Due to its location, nasopharyngeal carcinoma very rarely causes symptoms in the early stages; when they do occur, they are most often non-specific. Conventionally, all symptoms can be divided into four main groups: nasal, otologic, neurological, and metastasis-associated symptoms.

The first two groups are considered early symptoms and are strictly nasopharyngeal, as they result from tumor growth within the nasopharynx. Early symptoms are almost indistinguishable from acute respiratory infections. A warning sign may be a prolonged, recurrent course and lack of response to symptomatic and pathogenetic therapy. Neurological symptoms and regional metastases indicate the spread of the process beyond the nasopharynx and involvement of regional lymph node chains.

1. Early symptoms – symptoms of an acute respiratory infection (nasal and otologic):

• Prolonged recurrent rhinitis;

• Cough;

• Low-grade fever.

• Nasal congestion;

• Nasal discharge;

• Frequent nosebleeds;

• Nasal tone of voice (rhinolalia);

2. Late symptoms (neurological):

• Headaches;

• Hearing loss;

• Enlarged cervical lymph nodes;

• Deformity of the oropharynx, face, and neck;

• Cranial nerve and ophthalmological disorders;

• Putrid odor;

• Necrotic masses from the nasal passages.

Diagnostics

Early diagnosis of nasopharyngeal carcinoma includes laboratory and instrumental examinations and consultations with specialists. As part of laboratory diagnostics, it is advisable to evaluate a complete blood count, which typically shows leukocytosis, decreased hemoglobin and erythrocyte levels, and to perform serological testing for the Epstein-Barr virus.

The next diagnostic stage is an X-ray examination, specifically a lateral view of the nasopharynx and an anteroposterior view of the paranasal sinuses. If a suspicious radiological picture is identified, contrast-enhanced computed tomography or magnetic resonance imaging of the head must be performed.

Another important diagnostic step is an otolaryngologist consultation followed by epipharyngoscopy.

In the vast majority of cases (80%), nasopharyngeal carcinoma involves regional lymph nodes. In nasopharyngeal cancer, metastatic lesions of the cervical lymph nodes appear within the first months of the disease. In most cases, the initial signs of nasopharyngeal cancer leading to diagnosis are precisely these enlarged cervical lymph nodes. The affected cervical lymph nodes are palpated along the anterior border of the sternocleidomastoid muscle as firm, painless conglomerates. In nasopharyngeal carcinoma, both unilateral and bilateral cervical lymphadenopathy is detected. Enlarged cervical lymph nodes combined with the aforementioned complaints constitute a definitive indication for a more in-depth examination of the child.

Distant metastases in primary nasopharyngeal carcinoma in children occur in only 10% of all verified cases of nasopharyngeal cancer. Most frequently, distant metastases localize in the skeletal bones and liver, and less commonly in the lungs and non-regional lymph nodes.

The diagnosis is established based on histological examination and following an evaluation that includes examination of the primary nasopharyngeal tumor and assessment of regional and distant metastases. Morphological confirmation of the tumor is performed based on the results of a biopsy of the affected lymph node and/or the nasopharyngeal tumor.

Clinical forms

- Localized form (tumor is confined to the nasopharynx and adjacent structures);

- Locally advanced form (tumor is in the nasopharynx with cervical lymph node involvement);

- Metastatic form (distant metastases are present, e.g., in the lungs, liver, skeletal bones, etc.)

Treatment

Due to the localization of the tumor process (nasopharynx) and its locally advanced nature (involvement of cervical lymph nodes), surgical treatment is rarely applicable for the majority of patients with nasopharyngeal carcinoma even at the initial diagnostic stage. Histological types of nasopharyngeal carcinoma occurring in children and adolescents exhibit high chemo- and radiosensitivity; therefore, the current standard of care is systemic chemotherapy followed by chemoradiotherapy.

Prognosis

Modern treatment protocols, which include induction chemotherapy followed by chemoradiotherapy, achieve cure in the majority of patients with localized and locally advanced disease stages (over 80%). The prognosis for patients with distant metastases is significantly less favorable. However, novel therapeutic approaches (immunotherapy) are currently emerging that offer hope for improved treatment outcomes in this patient group as well. Undoubtedly, the key to a favorable prognosis is the coordinated teamwork of physicians and parents.

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

Appendix G1. Karnofsky Performance Scale

Name in Russian: Karnofsky Scale.

Original title: Karnofsky Performance Status.

Source (official developer website, validation publication):

Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [12].

Type: rating scale.

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

Table 19. Karnofsky Performance Scale

Notes: Assessment of the patient's general performance status is performed in all patients with NPC during the initial appointment, as well as at every subsequent appointment (examination, consultation) with a pediatric oncologist (B01.009.001, B01.009.002), prior to each subsequent cycle of chemotherapy, when evaluating response to therapy during treatment, and during follow-up.

Appendix G2. ECOG Performance Status 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 [13]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Table 20. ECOG Performance Status Scale

Notes: Assessment of the patient's general performance status is performed in all patients with NPC during the initial appointment, as well as at every subsequent appointment (examination, consultation) with a pediatric oncologist (B01.009.001, B01.009.002), prior to each subsequent cycle of chemotherapy, when evaluating response to therapy during treatment, and during follow-up.