Nasopharyngeal cancer: clinical guidelines

List of Abbreviations

IV – intravenous

EBRT – external beam radiotherapy

DNA – deoxyribonucleic acid

Malignant neoplasm – malignant neoplasm

LNs – lymph nodes

US – ultrasound examination

CT – computed tomography

RT – radiotherapy

PT – physical therapy

CRT – chemoradiotherapy

MRI – magnetic resonance imaging

PCR – polymerase chain reaction

RT-PCR – real-time polymerase chain reaction

PCT – polychemotherapy

PEG – percutaneous endoscopic gastrostomy

PET-CT – positron emission tomography combined with computed tomography

ESDD – level of evidence certainty

LoR – level of conviction of recommendation

5-FU – fluorouracil**

CCF – chronic cancer pain syndrome

TNM – (stands for tumor, node, and metastasis) international classification of cancer stages

CI – confidence interval

HR – hazard ratio

EBV – Epstein-Barr virus

ECOG – Eastern Cooperative Oncology Group performance status scale

AUC* (area under the curve) – pharmacokinetic parameter determining drug concentration. Required for calculating the drug dose based on creatinine clearance

ERAS – Enhanced recovery after surgery

IMRT – intensity-modulated radiation therapy (volumetric modulated arc therapy)

QUANTEC – quantitative analyses of normal tissue effects in the clinic

VMAT – volumetric modulated arc therapy

DCF – systemic antineoplastic treatment regimen including docetaxel**, cisplatin**, fluorouracil**

18F-FDG – fluorodeoxyglucose [18F]

Terms and Definitions

Superior wall – sphenoid bone, part of the occipital bone.

Posterior wall – first and second cervical vertebrae.

Anterior wall – choanae.

Lateral walls – pharyngeal openings of the auditory tubes.

Inferior wall – hard palate.

Nutritional status – state of the organism characterized by the relationship between the volume of nutrient intake and requirements, as well as the body's ability to digest, absorb, and metabolize nutrients.

Relapse-free survival – from the onset of remission until the occurrence of relapse.

Overall survival – from the start of treatment to the end of the study or patient death.

Complete response – absence of tumor signs according to laboratory and instrumental imaging examinations.

Progression – appearance of a new tumor lesion and/or growth of the primary tumor lesion or metastatic lesions by more than 25%.

Partial response – reduction in the size of tumor lesions by more than 50% with no new lesions.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Nasopharyngeal cancer – malignant tumor developing from the non-keratinizing epithelium of the nasopharynx [1].

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

Among the etiological factors for the development of nasopharyngeal cancer, the following should be highlighted:

– Epstein-Barr virus (EBV) infection;

– chronic inflammatory processes causing hyperplasia and metaplasia of the nasopharyngeal mucosa;

– influence of anatomical characteristics of certain races (peoples of Southeast Asia, Africa, and Indochina have a higher incidence) [2, 3].

1.3 Epidemiology of the Disease or Condition

The incidence of nasopharyngeal cancer in Russia in 2023 was 0.36 cases per 100,000 population, while the crude incidence rate in men was higher than in women, being 0.53 per 100,000 population and 0.2 per 100,000 population, respectively [4].

1.4 Features of Coding the Disease or Condition

Malignant neoplasm of the nasopharynx (C11):

C11.0 - Malignant neoplasm of the superior wall of the nasopharynx.

C11.1 - Malignant neoplasm of the posterior wall of the nasopharynx.

C11.2 - Malignant neoplasm of the lateral wall of the nasopharynx.

C11.3 - Malignant neoplasm of the anterior wall of the nasopharynx.

C11.8 - Lesions of the nasopharynx overlapping one or more of the above sites.

C11.9 - Malignant neoplasm of the nasopharynx, unspecified.

1.5 Classification of the disease or condition

Among malignant tumors of the nasopharynx, epithelial neoplasms predominate, accounting for about 70% of cancer cases. There are three histological variants of nasopharyngeal carcinoma: squamous cell keratinizing carcinoma, squamous cell non-keratinizing carcinoma (differentiated/undifferentiated), and basaloid squamous cell carcinoma.

ICD-O Coding, 3rd Edition, 1st Revision, 2017: [5]

Squamous cell carcinoma

8010/3 - Carcinoma, NOS

8012/3 - Large cell carcinoma

8020/3 - Undifferentiated carcinoma

8070/3 - Squamous cell carcinoma, NOS

8071/3 - Squamous cell carcinoma, keratinizing

8072/3 - Squamous cell carcinoma, large cell non-keratinizing

8073/3 - Squamous cell carcinoma, small cell non-keratinizing

8082/3 - Lymphoepithelial carcinoma

8083/3 - Basaloid squamous cell carcinoma

8085/3 - Squamous cell carcinoma, HPV-positive

8086/3 - Squamous cell carcinoma, HPV-negative

The extent of epithelial malignant tumors of the nasopharynx is presented in the TNM Classification of Malignant Tumors, 8th Edition.

The T category includes the following grades:

TX – primary tumor cannot be assessed.

T0 – no primary tumor identified, but Epstein-Barr virus (EBV)-positive regional lymph nodes are present.

Tis – carcinoma in situ (intraepithelial invasion or invasion of the lamina propria).

T1 – tumor confined to the nasopharynx, or tumor extending to the oropharynx or nasal cavity without parapharyngeal space involvement.

T2 – tumor with parapharyngeal space extension.

T3 – tumor invading the skull base and/or paranasal sinuses.

T4 – tumor with intracranial extension and/or involvement of cranial nerves, orbit, infratemporal fossa, or masticator space.

The N category indicates the presence or absence of regional lymph node (LN) metastases:

NX – regional lymph nodes cannot be assessed.

N0 – no regional lymph node metastasis.

N1 – unilateral cervical lymph node metastases above the supraclavicular fossa, measuring $\le$6 cm in greatest dimension, and/or unilateral or bilateral retropharyngeal metastases, measuring $\le$6 cm in greatest dimension.

N2 – bilateral cervical lymph node metastases, measuring $\le$6 cm in greatest dimension, above the supraclavicular fossa.

N3 – unilateral or bilateral lymph node metastases measuring >6 cm in greatest dimension and/or located below the lower border of the cricoid cartilage.

The M symbol characterizes the presence or absence of distant metastases: M0 – no distant metastases.

M1 – presence of distant metastases.

Table 1. Stage grouping

1.6 Clinical presentation of the disease or condition

The clinical presentation of nasopharyngeal cancer consists of local symptoms, signs of regional and distant metastasis, and may also be caused by a general tumor symptom complex. In most cases, the initial manifestations of nasopharyngeal cancer are masked as acute respiratory viral infections, rhinopharyngitis, or adenoidal hypertrophy. Often, the first clinical signs are enlarged lymph nodes in the neck, which prompt the patient to consult a doctor.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is established based on:

1) anamnesis data;

2) clinical presentation and physical examination, including a thorough clinical examination and palpation of regional lymph nodes (LNs);

3) cytological examination of tissue micropsherules (micro-specimens), upper respiratory tract discharge and touch preps, and punctates from enlarged or suspicious LNs;

4) pathological anatomical examination of biopsy (surgical) material;

5) instrumental examinations, including fibrolaryngoscopy, computed tomography (CT) / magnetic resonance imaging (MRI), positron emission tomography combined with computed tomography (PET-CT) with [18F]fluorodeoxyglucose ([18F]-FDG), as clinically indicated;

6) laboratory testing for Epstein-Barr virus DNA levels.

2.1 Complaints and Anamnesis

Level of evidence – 5 (grade of recommendation – C).

Comments: risk factors include harmful lifestyle habits (smoking, heavy alcohol consumption), occupational hazards, and chronic infections (chronic pharyngitis, otitis, rhinitis, Epstein-Barr virus). When determining smoking history, it is advisable to use the pack-years criterion, which accounts for the cumulative history based on smoking duration and intensity.

2.2 Physical Examination

Level of evidence – 5 (grade of recommendation – C).

2.3 Laboratory Diagnostics

Level of evidence – 4 (grade of recommendation – C).

Comments: EBV infection is associated with nasopharyngeal cancer according to the World Health Organization [6, 7]. Y.M. Lo et al. applied real-time PCR (RT-PCR) analysis, making the detection of circulating cell-free EBV DNA substantially more sensitive. To measure EBV DNA, primers targeting the BamHI-W region of the EBV genome—which is repeated 8–11 times—are used, increasing detection sensitivity compared to single-copy genes such as EBNA1, LMP2, or POL1. Using this method, viral DNA was identified in 96% (55 of 57) of patients with nasopharyngeal carcinoma and 7% (3 of 43) of healthy individuals. A second advantage of RT-PCR is the ability to quantify EBV DNA, which revealed differences in plasma viral load between patients with early (I/II) and advanced (III/IV) stages of nasopharyngeal cancer [6]. Blood viral DNA levels are used in several clinics to monitor residual disease. Studies have shown that in locally advanced cancer, a high initial blood EBV DNA level or one that remains elevated by the end of radiotherapy (RT) is associated with a poor prognosis after completion of RT or chemoradiotherapy (CRT) [8, 9, 10, 11, 12, 13].

Level of evidence – 5 (grade of recommendation – C).

2.4 Instrumental Diagnostics

Level of evidence – 5 (grade of recommendation – C).

Level of evidence – 5 (grade of recommendation – C).

Level of evidence – 5 (grade of recommendation – C).

Comments: to assess the local spread of nasopharyngeal cancer, MRI of the facial skull and neck with contrast enhancement should be performed when available [14]. For lesions directly adjacent to the skull base, facial skull CT can be used as a complementary method to assess bone destruction and detect bone erosions. To evaluate local spread and regional lymph node metastasis, neck CT or MRI must cover the entire area from the skull base to the thoracic inlet; if lymph node involvement below the cricoid cartilage is identified, the scan area should be extended to the level of the tracheal bifurcation. In cases of significant intracranial component size, brain MRI should be performed to further assess its extent and mass effect [2].

Level of evidence – 5 (grade of recommendation – C).

Comment: if chest CT is not feasible, targeted chest radiography is advisable.

Level of evidence – 5 (grade of recommendation – C).

Comment: [18F]fluorodeoxyglucose PET-CT has high sensitivity and specificity in detecting distant metastases in nasopharyngeal cancer patients and is advisable in locally advanced disease [15].

2.4.1 Planning of radiotherapy and chemoradiotherapy

Level of evidence – 2 (grade of recommendation – A).

Level of evidence – 4 (grade of recommendation – C).

Comment: if MRI—which provides superior soft-tissue and spatial visualization—is not feasible, RT and CRT planning should be performed using facial skull CT with intravenous bolus contrast enhancement or positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals with contrast ([18F]fluorodeoxyglucose PET-CT) [17].

2.4.2 Evaluation of antitumor treatment efficacy

Level of evidence – 5 (grade of recommendation – C).

Comment: in case of ambiguous MRI results, positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals with contrast ([18F]fluorodeoxyglucose PET-CT) should be performed for the differential diagnosis of post-radiation changes and disease recurrence [19].

Level of evidence – 2 (grade of recommendation – A).

Level of evidence – 5 (grade of recommendation – C).

Comment: cervical lymph nodes of groups I–IV measuring more than 2 cm in their maximal dimension and group V nodes measuring more than 1 cm, as well as lymph nodes with altered architecture on ultrasound, should be considered suspicious.

2.4.3 Follow-up monitoring

Level of evidence – 5 (grade of recommendation – C).

Level of evidence – 5 (grade of recommendation – C).

Level of evidence – 5 (grade of recommendation – C).

Level of evidence – 5 (grade of recommendation – C).

Comment: if CT is not feasible, targeted chest radiography is advisable.

Level of evidence – 5 (grade of recommendation – C).

Comment: if PET-CT with fluorodeoxyglucose [18F] or contrast-enhanced intravenous CT of the chest and abdomen is not feasible, targeted chest radiography and comprehensive abdominal ultrasound are advisable.

2.5 Other Procedures

No additional information available.

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

Specialized anti-tumor treatment for patients with nasopharyngeal cancer should be carried out taking into account the clinic's experience and equipment, as well as patient preferences in light of expected outcomes both in terms of anti-cancer efficacy and preservation of patients' quality of life.

3.1 Conservative Treatment

Level of evidence – 5 (grade of recommendation – C).

• For patients with stage T1, N0, M0 nasopharyngeal cancer, it is recommended to administer definitive radiation therapy to improve survival and reduce treatment toxicity [2].

Level of evidence – 5 (grade of recommendation – C).

• For patients with stage T2, N0, M0 nasopharyngeal cancer, it is recommended to administer definitive chemoradiotherapy to improve survival [2].

Level of evidence – 5 (grade of recommendation – C).

• For patients with stage T1, N1-3 or T2–T4, any N nasopharyngeal cancer, it is recommended to administer concurrent CRT followed by adjuvant chemotherapy (2 cycles) or induction chemotherapy (3 cycles) followed by concurrent CRT to improve survival [21, 22, 23]. After completion of CRT, the administration of adjuvant chemotherapy with #capecitabine** may be considered in locally advanced stage III–IVA nasopharyngeal cancer (excluding T3–4N0 and T3N1), including in patients who received induction CRT with #gemcitabine** and cisplatin**. Based on the results of a phase III study in an Asian patient population, the administration of adjuvant chemotherapy with #capecitabine** at 650 mg/m² twice daily for 1 year, initiated no later than 12–16 weeks after completion of CRT, led to an increase in 3-year event-free survival [91]. Another study evaluated a regimen of adjuvant chemotherapy with #capecitabine** following CRT, which also demonstrated an advantage over CRT regarding 3-year and 5-year relapse-free survival (#capecitabine** 1.0 g/m² twice daily on days 1–14, followed by a 1-week break, 8 cycles) (II-C) [92]. For induction therapy, the DCF regimen (docetaxel**, cisplatin**, fluorouracil**) followed by CRT is used, which in locally advanced T3–4N+ nasopharyngeal cancer improves 3-year relapse-free and overall survival compared with concurrent CRT [22, 23, 90].

In the presence of residual metastatic lymph nodes after completion of conservative therapy, surgical treatment is advisable. In case of complete regression of metastatic nodes following conservative treatment modalities, active surveillance is indicated.

Evidence level – 1 (recommendation grade – A).

Comment: a meta-analysis by Blanchard et al. [21], which included 19 studies and 4,806 patients, showed that adjuvant chemotherapy regimens following CRT are associated with improved overall survival (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.56–0.76 and HR 0.80; 95% CI 0.70–0.93, respectively) and progression-free survival (HR 0.62; 95% CI 0.53–0.72 and HR 0.81; 95% CI 0.71–0.92, respectively).

• For patients with nasopharyngeal cancer with any T, N, M1, it is recommended to administer chemotherapy including platinum-based regimens (L01XA: platinum compounds) [24], preferably in combination with camrelizumab immunotherapy in the first line of treatment, regardless of PD-L1 expression level and EBV status, to improve survival [25].

Evidence level – 3 (recommendation grade – B).

Comments: during chemotherapy, depending on the response, it may be appropriate to address the issue of administering RT/CRT, drug therapy, surgical treatment (in oligometastatic disease), or palliative care.

Local recurrence or residual tumor after radiotherapy

• For patients with local recurrence or residual tumor after radiation therapy, it is recommended to administer chemotherapy including platinum-based regimens (L01XA: platinum compounds) in the first line of treatment, preferably in combination with camrelizumab immunotherapy regardless of PD-L1 expression level and EBV status, to improve survival [25].

Evidence level – 2 (recommendation grade – B).

Comments: if the tumor is resectable, surgical intervention may be considered, along with a discussion of re-irradiation or concurrent chemoradiotherapy. If the tumor is unresectable, it is advisable to discuss the possibility of re-irradiation/concurrent chemoradiotherapy, drug therapy, or palliative care [2].

Re-irradiation is considered if the patient's performance status is 0–1 according to the ECOG scale and no earlier than 6 months (preferably no earlier than 2 years) after prior irradiation (Appendix G1))[26].

Local recurrence or residual tumor with distant metastases

• In the case of local recurrence or residual tumor with distant metastases, when the Eastern Cooperative Oncology Group (ECOG) performance status of a patient with nasopharyngeal cancer is 0–1, it is recommended to consider systemic drug treatment using chemotherapy, single-agent chemotherapy, or immunotherapy regimens (depending on prior primary treatment) to improve survival [2].

Level of evidence – 5 (grade of recommendation – C).

• In the case of local recurrence or residual tumor with distant metastases, when the ECOG performance status of a patient with nasopharyngeal cancer is 2, it is recommended to administer single-agent chemotherapy to improve survival or palliative care for symptom relief [2].

Level of evidence – 5 (grade of recommendation – C).

• In the case of local recurrence or residual tumor with distant metastases, when the ECOG performance status of a patient with nasopharyngeal cancer is 3, it is recommended to provide palliative care for symptom relief [2].

Level of evidence – 5 (grade of recommendation – C).

3.2 Principles of Radiotherapy

Introduction: all patients must be evaluated prior to treatment by a radiation oncologist, preferably specializing in head and neck tumors, who should take the following steps: review the adequacy of the biopsy material, staging, and imaging of the tumor process (CT, MRI) to determine the extent of tumor spread, rule out the presence of a synchronous primary tumor, assess the current performance status and the feasibility of radiation/chemoradiotherapy, and develop a prospective follow-up plan that will include sanitation of the oropharyngeal area, including dental examination, ensuring adequate nutrition, pain management, and wound healing, as well as other measures necessary for maximum patient rehabilitation. For patients undergoing radiation/chemoradiotherapy, a comprehensive anti-tumor therapy implementation plan must be developed in full and within optimal timeframes.

• Radiation therapy is strongly recommended as the primary or adjuvant treatment and should be performed in specialized institutions with appropriate equipment and experience in treating nasopharyngeal cancer [27].

Level of evidence – 4 (grade of recommendation – C).

Comment: a deep understanding of anatomy, the clinical situation, and imaging of specific disease manifestations is required. External beam RT using high-precision techniques—IMRT (intensity-modulated radiation therapy) or VMAT (volumetric modulated arc therapy)—is preferred. Proton therapy is considered in cases of significant dose limitations by normal tissues [23]. 3D conformal RT is also acceptable.

The optimal approach in clinical practice is the delivery of planned ionizing radiation doses to the target volume while minimizing the dose to organs at risk.

The volume of irradiation to radical doses should not be modified based on the clinical response obtained prior to radiation therapy (following induction polychemotherapy), except in cases of tumor progression. It is permissible to discuss reducing the volume by excluding vital structures free from tumor involvement at the time of radiation therapy planning, in the event that the maximum permissible dose load on them according to QUANTEC criteria (quantitative analyses of normal tissue effects in the clinic) is exceeded [2]. Anatomical changes during the course of RT (e.g., rapid tumor shrinkage, significant weight loss) may require repeat diagnostic imaging and re-planning (adaptation) of treatment [28, 29].

Standalone RT

• For patients with nasopharyngeal cancer, standalone RT is recommended for the primary lesion (high-risk area) at 66–70 Gy (1.8–2.2 Gy/fraction) and for the locoregional area (intermediate/low-risk area), including regional lymph nodes, at 50 Gy (2.0 Gy/fraction), or 54–63 Gy (1.6–1.8 Gy/fraction) to improve survival [30].

Level of evidence – 5 (grade of recommendation – C).

Concurrent CRT

• For patients with nasopharyngeal cancer, concurrent CRT is recommended for the primary lesion and clinically detectable regional metastases (high-risk area) at 70 Gy (2.0 Gy/fraction) daily from Monday to Friday for 7 weeks; for the locoregional area (intermediate/low-risk area), including regional lymph nodes, at 50 Gy (2.0 Gy/fraction), or 54–63 Gy (1.6–1.8 Gy/fraction) to improve survival [30].

Level of evidence – 5 (grade of recommendation – C).

Comments: the benefit of non-conventional dose fractionation regimens during concurrent CRT has not been confirmed [32].

• Palliative RT is recommended for patients with malignant neoplasms of the nasopharyngeal region to relieve or prevent locoregional symptoms when radical treatment with standard RT is not feasible. An individualized RT schedule may be chosen to minimize treatment toxicity, including a dose of 50 Gy (2.5 Gy/fraction) and 30 Gy (3 Gy/fraction) [33].

Level of evidence – 4 (grade of recommendation – C).

3.3 Principles of Systemic Chemotherapy

Note: the presented chemotherapy regimens are indicated for squamous cell and undifferentiated carcinoma. Chemotherapy regimens for other histological tumor types (e.g., sarcomas) can be found in the relevant clinical guidelines.

Induction CRT followed by sequential CRT

• For patients with nasopharyngeal cancer, induction systemic chemotherapy to improve survival is recommended using one of the following regimens: Docetaxel** 75 mg/m² IV on day 1 + cisplatin** 75 mg/m² IV on day 1 + fluorouracil** 1000 mg/m²/day IV 96-hour infusion on days 1–4, for a total of 2–3 chemotherapy courses at 3-week intervals. Total number of cycles: 3 [31, 143].

• #Gemcitabine** 1000 mg/m² IV on days 1 and 8 + cisplatin** 80 mg/m² IV on day 1, every 3 weeks. Total number of cycles: 3 [31].

• #Gemcitabine** 1000 mg/m² IV on days 1 and 8 + cisplatin** 40 mg/m² IV on days 1 and 8, every 3 weeks. Total number of cycles: 3 [90].

Concurrent CRT

• For patients with nasopharyngeal cancer, it is recommended during concurrent CRT to administer cisplatin** chemotherapy at a dose of 100 mg/m² with hyperhydration on days 1, 22, and 43 of RT (recommended cumulative dose during RT is 300 mg/m²). Following induction polychemotherapy (PCT), as an alternative to cisplatin**, the use of carboplatin** is recommended taking into account CRT tolerability and the patient's general condition. Carboplatin** is used at an AUC of 1.5–2.0 administered weekly starting from the first day of RT [31, 34, 88].

Level of evidence: 5 (strength of recommendation: C).

CRT followed by adjuvant chemotherapy

• For patients with nasopharyngeal cancer, CRT followed by adjuvant chemotherapy is recommended: cisplatin** 100 mg/m² once every 3 weeks + RT, or cisplatin** 40 mg/m² weekly + RT [146], followed by adjuvant chemotherapy according to one of the following regimens: (cisplatin** 80 mg/m² on day 1 + fluorouracil** 1000 mg/m⁴/day on days 1–4 every 4 weeks. Total number of cycles: 3 [89], for a total of 2–3 courses of chemotherapy [27]. For patients in whom cisplatin cannot be administered**, the option of substituting it with carboplatin** may be considered [147, 148].

• #Gemcitabine** 1000 mg/m² on days 1 and 8 + cisplatin** 80 mg/m² on day 1, every 4 weeks. Total number of cycles: 3.

• #Gemcitabine** 1000 mg/m² on days 1 and 8 + cisplatin** 30 mg/m² on days 1 and 8, every 3 weeks. Total number of cycles: 3.

• #Capecitabine** 650 mg/m² orally twice daily for one year [90, 92, 145].

Level of evidence: 2 (strength of recommendation: B).

Drug treatment for recurrent and metastatic malignant neoplasms

• For patients with recurrent and distant metastatic nasopharyngeal cancer, it is recommended:

  — chemoimmunotherapy, polychemotherapy, or monotherapy to increase overall survival, taking into account the patient's general condition [2].

Level of evidence – 5 (grade of recommendation – C).

— camrelizumab 200 mg IV infusion, day 1 + #gemcitabine** 1000 mg/m² IV infusion, days 1 and 8 + cisplatin** 80 mg/m² IV infusion, day 1, course duration 21 days. A total of 4–6 courses of therapy are administered, followed by administration of camrelizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity [93].

Evidence level – 2 (recommendation grade – B).

• If chemoimmunotherapy is not feasible or is contraindicated, depending on the patient's general condition and/or treatment goals, as a first-line treatment for patients with locally advanced or metastatic disease, as well as disease recurrence, who are not candidates for CRT, combination chemotherapy or monotherapy is recommended (the number of courses is determined by treatment tolerability and efficacy):

  — carboplatin** AUC 5-6 IV infusion, day 1 + #paclitaxel** 175 mg/m² IV infusion, day 1, course duration 21 days [31];

  — cisplatin** 75 mg/m² + #docetaxel** 75-100 mg/m² IV infusion, day 1, course duration 21 days [149, 150, 151];

  — cisplatin** 100 mg/m² IV infusion, day 1 + fluorouracil** 1000 mg/m²/day IV 96-hour infusion, days 1-4, course duration 21 days [36];

  — carboplatin** AUC 5 IV infusion on day 1 + fluorouracil** 1000 mg/m² IV 96-hour infusion on days 1–4, every 3 weeks [31];

  — #gemcitabine** 1000 mg/m² IV on days 1 and 8 + cisplatin** 80 mg/m² IV on day 1, every 3 weeks [37].

  — Monotherapy regimens:

  — cisplatin** 100 mg/m² IV infusion, day 1, course duration 21 days [38];

  — #paclitaxel** 80 mg/m² IV infusion, weekly [39];

  — #docetaxel** 100 mg/m² IV infusion, day 1, course duration 21 days [40];

  — fluorouracil** 1000 mg/m² IV infusion, days 1-4, course duration 21 days [38];

  — #methotrexate** 40 mg/m² IV infusion once a week [41];

  — #capecitabine** 1250 mg/m² enterally twice daily from days 1 to 14 with a 1-week break, course duration 21 days [42];

  — #gemcitabine** 1000 mg/m² on days 1, 8, and 15 once every 28 days [43].

Level of evidence: 2 (strength of recommendation: B).

• As second-line chemotherapy, it is recommended to use one of the regimens listed above, or pembrolizumab** therapy in cases of MSI or CPS > 1, or nivolumab** if the first-line regimen did not contain camrelizumab [44, 45, 46, 86, 87].

Level of evidence: 2 (strength of recommendation: B).

3.4 Other treatment

The procedure and recommendations for pain management in malignant neoplasms of the nasopharynx correspond to the guidelines presented in the rubricator "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care".

• For patients with locally advanced nasopharyngeal malignancies at risk of bleeding or with ongoing bleeding from the tumor and/or regional metastatic lymph nodes, it is recommended to perform selective external carotid angiography and, in the absence of contraindications, perform selective and superselective embolization of tumor vessels to reduce the risks of bleeding and fatal complications [47].

Level of evidence – 5 (grade of recommendation – C).

For patients with locally advanced forms of head and neck cancer, as well as those at risk of bleeding from tumor nodes in the head and neck region, it is necessary to:

Perform a clinical assessment of the tumor process and evaluate the risks of bleeding, tumor size, and tumor invasion into adjacent structures in the case of tumor ulceration, an existing cavity within the tumor area, tumor recurrence, proximity to carotid artery branches, presence of a non-healing wound, or active tumor bleeding.

• If the risk of bleeding from tumor nodes is confirmed, patients with nasopharyngeal cancer are recommended to undergo selective external carotid angiography and, in the absence of contraindications, selective and superselective embolization of tumor vessels to reduce the risks of bleeding and fatal complications [80-85].

Level of evidence – 4 (grade of recommendation – C).

3.4.1 Prevention and Management of Complications of Antineoplastic Drug Therapy

• When administering anti-tumor drug therapy with emetogenic side effects to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of nausea and vomiting [94, 95].

Evidence level – 1 (recommendation grade – A).

Comments. The principles of diagnosis, prevention, and treatment of nausea and vomiting during anti-tumor drug therapy are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [96].

• During anti-tumor drug therapy, patients with cancer are recommended to receive prevention and treatment for febrile neutropenia and infectious complications [97-99, 100].

Level of evidence – 5 (grade of recommendation – C).

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, as well as the principles of antibacterial therapy, is set forth in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [100].

• When administering anti-tumor drug therapy to patients with nasopharyngeal cancer, it is recommended to correct hepatotoxicity [101, 102, 103].

Level of evidence – 5 (grade of recommendation – C).

Comments. The principles of diagnosis, prevention, and treatment of hepatotoxicity are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [103].

• When administering anti-tumor drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of cardiovascular complications [104-107, 108].

Level of evidence – 5 (grade of recommendation – C).

Comments. The principles of diagnosis, prevention, and treatment of cardiovascular complications during anti-tumor therapy are set forth in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [108].

• When administering anti-tumor drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of dermatological reactions [109].

Evidence level – 1 (recommendation grade – A).

Comments. The principles of diagnosis, prevention, and treatment of skin complications are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [110].

• To maintain the body's metabolic reserves and increase its resistance to treatment (surgical, medical, radiation), patients with nasopharyngeal cancer are recommended to receive nutritional support.

Evidence level – 1 (recommendation grade – A).

Comments. The choice of nutritional support method is determined by the patient's various types of nutritional disorders. Placement of a nasogastric tube, nasointestinal, percutaneous endoscopic, laparoscopic, or laparotomic stoma, endoscopic stenting for tumor stenosis, or palliative radiation therapy may be indicated [111, 112]. The principles of nutritional support are presented in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [113].

• When administering anti-tumor drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of nephrotoxicity [114-116].

Evidence level – 2 (recommendation grade – B).

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of nephrotoxicity is presented in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [117].

• When administering anti-tumor drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of immune-mediated adverse events [118-121].

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

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of immune-mediated adverse events is set forth in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [122].

• When administering anti-tumor drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of mucositis [123, 124].

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

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of mucositis is outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [125].

• Patients with nasopharyngeal cancer are recommended to receive treatment for anemia, which occurs as a symptom of the malignant neoplasm and as an adverse event during anti-tumor drug therapy [126, 127].

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

Comments. The procedure and principles of prevention and treatment of anemia correspond to the principles set forth in the clinical guidelines "Anemia in Malignant Neoplasms" [144] and in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [128].

• During treatment, patients with nasopharyngeal cancer are recommended to receive treatment for anorexia-cachexia syndrome [129].

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

Comments. A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [130].

• When administering cyclic anti-tumor drug therapy incorporating continuous prolonged (over 6 hours) infusions of anti-tumor drugs (fluorouracil**) or in case of poor peripheral vein condition in patients with nasopharyngeal cancer, it is recommended to install a central venous port and infusion pumps to ensure safe, long-term infusion anti-tumor therapy [131].

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comments. The choice of central access option is determined by the planned duration of the entire course of treatment, patient preferences, and anatomical features. For prolonged (over 3 months) courses of therapy, implantation of a subcutaneous venous port system is most convenient. For shorter periods, a peripherally inserted central venous catheter can serve as an alternative. The principles of using central venous access are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Anti-Tumor Drug Therapy of the Russian Society of Clinical Oncology" [132].

• When administering antineoplastic drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of antineoplastic drug extravasation. When planning antineoplastic drug therapy, the choice of vascular access is important for the prevention of antineoplastic drug extravasation [133].

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

Comments. Algorithms for choosing vascular access, as well as for the prevention, diagnosis, and treatment of extravasation, are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy" by the Russian Society of Clinical Oncology [134].

• During antineoplastic treatment in patients with nasopharyngeal cancer, it is recommended to treat chronic pain syndrome [136].

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

Comments. Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy" by the Russian Society of Clinical Oncology [136].

• When administering antineoplastic drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of infusion reactions [137].

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

Comments. Algorithms for the prevention, diagnosis, and treatment of infusion reactions are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy" by the Russian Society of Clinical Oncology [138].

• When administering therapy to patients with nasopharyngeal cancer, it is recommended to monitor and treat the reactivation/exacerbation of chronic viral hepatitis [139].

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

Comments. Principles of monitoring and management tactics in cancer patients with chronic viral hepatitis are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy" by the Russian Society of Clinical Oncology [140].

• When administering antineoplastic drug therapy to patients with nasopharyngeal cancer, it is recommended to provide prevention and treatment of neurological complications [141].

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

Comments. Principles of diagnosis, prevention, and treatment of neurological complications of antineoplastic therapy are outlined in the "Clinical Guidelines for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy" by the Russian Society of Clinical Oncology [142].

3.5 Diet therapy

The need for prescription nutrition is determined by the patient's nutritional status, as well as the advisability of correcting comorbid conditions and preventing complications of the ongoing treatment; therefore, the principles of clinical nutrition and indications are presented in the section "Medical Rehabilitation and Sanatorium-Resort Treatment, Medical Indications and Contraindications for the Use of Rehabilitation Methods, Including Those Based on Natural Therapeutic Factors".

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Level of evidence – 5 (grade of recommendation – C).

• Nutritional and metabolic rehabilitation for at least 7 days is recommended to reduce the rate of postoperative complications and the length of hospital stay for patients with malignant neoplasms of the nasopharyngeal region [49].

Level of evidence – 5 (grade of recommendation – C).

Comment: nutritional support during the planning of surgical treatment is provided if at least one of the following factors is present: unintentional weight loss over the past 6 months (10% or more), body mass index < 20

kg/m², hypoproteinemia < 60 g/L or hypoalbuminemia < 30 g/L, or deterioration of oral intake over the past week. In the case of chemotherapy, indications include: body mass index < 20 kg/m²; loss of more than 5% of body weight over 6 months; hypoproteinemia < 60 g/L or hypoalbuminemia < 30 g/L; inability to maintain adequate oral nutrition; moderate to severe enteropathy.

• For patients with malignant neoplasms of the nasopharyngeal region receiving chemotherapy, it is recommended to start physical activity early to prevent the onset and progression of sarcopenia, reduce fatigue, improve the quality of life and psychological state of patients receiving adjuvant chemotherapy, and increase exercise tolerance [50].

Level of evidence – 3 (strength of recommendation – B).

Comment: performing a set of exercise therapy (physical therapy) including aerobic exercise and Tai Chi elements for 4 months during chemotherapy leads to an increase in vital capacity, blood oxygen saturation, muscle strength, range of motion in large joints, and a decrease in body mass index [51].

• To reduce fatigue and increase endurance in patients with malignant neoplasms of the nasopharyngeal region undergoing chemoradiotherapy, it is recommended to perform therapeutic exercise (physical therapy) in the form of moderate-intensity aerobic exercises combined with resistance exercises [52].

Level of evidence: 2 (strength of recommendation: B).

Comment: combining physical therapy with psychological support is used as a comprehensive treatment for fatigue associated with chemotherapy [53]. In addition, it is advisable to conduct a course of general medical massage (A21.01.001) for 6 weeks to reduce fatigue associated with combination treatment [54].

• Balance training exercises are recommended for patients with malignant neoplasms of the nasopharyngeal region receiving chemotherapy to correct polyneuropathy [55].

Level of evidence – 3 (strength of recommendation – B).

Level of evidence – 2 (strength of recommendation – A).

Evidence level – 2 (recommendation grade – B).

Evidence level – 1 (recommendation grade – A).

Comment: for the prevention of oral mucositis, it is advisable to use low-intensity laser therapy on the oral mucosa.

Evidence level – 3 (recommendation grade – B).

Level of evidence – 5 (grade of recommendation – C).

• From the onset of radiation dermatitis until complete subsidence of reactions, patients with nasopharyngeal cancer are recommended to be prescribed dermatoprotectors (A01AD11 Other agents), and local wound-healing agents (gels, ointments, etc.) for the treatment of acute radiation skin injuries [64].

Level of evidence – 5 (grade of recommendation – C).

Level of evidence – 5 (grade of recommendation – C).

In the post-radiation period, irradiated normal tissues are very vulnerable and must therefore be handled with care. Performing invasive diagnostic procedures and biopsies early on is not advisable unless absolutely necessary. Dietary selection and nutritional support are indicated [65, 66]. Trauma, alcohol, smoking, and irritating foods easily cause mucosal ulceration, which is often accompanied by exposure of the mandible bone and subsequent development of osteomyelitis. A common cause of radiation osteomyelitis is tooth extraction within the prior irradiation zone; therefore, one should resort to conservative methods whenever possible and perform tooth extractions only when necessary, under antibiotic coverage.

Rehabilitation during radiotherapy

The success of antineoplastic treatment and rehabilitation depends on the patient's baseline condition. Thus, risk factors for the early onset and development of severe side effects include exhaustion and a severe psychological state of the patient, advanced age, comorbidities, trauma to the oral and pharyngeal mucosa, presence of decayed teeth, severe pain syndrome, smoking, and alcohol intake. Preparation for treatment and adequate patient management are tasks of such importance that the participation of relevant allied specialists in a multidisciplinary team (palliative care physician, clinical nutritionist, dentist, etc.), as well as the scope of supportive care, are specified in international guidelines as a prerequisite for the successful treatment of head and neck tumors.

The management of nasopharyngeal cancer patients who are receiving or have received radiation therapy requires a comprehensive approach including at least three core components of supportive care: wound healing, pain management, and nutritional support, combined with establishing patient contact and treatment compliance at all stages. It should be noted that supportive care and rehabilitation methods are much more diverse and also imply detoxification therapy, management of hematological toxicity, antiulcer, antiemetic, and antibiotic therapy, etc. Thorough post-treatment monitoring of patients and management of potential delayed side effects of radiation therapy (xerostomia, bone and/or soft tissue necrosis, etc.) are also mandatory.

Adequate nutrition and maintenance of water balance are vital. Combating "iatrogenic" malnutrition resulting from radiotherapy (RT) and chemoradiotherapy (CRT) is a crucial task for the successful treatment of head and neck cancer patients. A balanced dietary intake, which reflects the maintenance of a stable body weight, plays a special role. It should be noted that nutritional support is carried out for therapeutic purposes, since the period of RT is characterized by the body's increased need for energy and plastic substrates. For patients without severe dysphagia receiving RT and CRT, oral enteral nutrition is the method of choice. Nutritional therapy should be initiated immediately upon identification of malnutrition or in the absence of adequate oral intake for 7 days.

Level of evidence – 5 (grade of recommendation – C).

Comments: enteral medical nutrition is initiated when oral dietary intake is inadequate (i.e., less than 60% of total energy requirements for 10 days). A loss of more than 10% of baseline body weight is an indication for prescribing enteral nutrition. The optimal option for nutritional support is sipping using high-protein formulas (taking into account comorbid conditions, including renal disease). If adequate oral nutrition is impossible, it should be provided via a nasogastric tube (estimated placement duration up to 3–4 weeks) or via gastrostomy. Parenteral nutrition may also be introduced if necessary. The calculation of the patient's basic requirements focuses on the total amount of energy consumed and the quantitative ratio of various substrates. The required calorie count is most often calculated taking into account energy expenditure with the goal of preventing the escalation of energy deficit [68, 69, 70]. The main goal of nutritional support is to replenish losses based on at least: protein/amino acids: at least 1.2 g/kg/day and up to 2 g/kg/day; energy: 25–30 kcal/kg/day [67]. For patients receiving RT and CRT, it is optimal to use formulas enriched with omega-3 fatty acids and dietary fiber, as well as combining nutritional support with physical exercise.

Level of evidence – 5 (grade of recommendation – C).

• All patients scheduled for RT/CRT are recommended to undergo an initial dental examination (consultation), a follow-up dental examination (consultation), and evaluation with subsequent support at all stages of treatment and rehabilitation [75, 76].

Level of evidence – 5 (grade of recommendation – C).

• All patients receiving/who have received RT/CRT with pain syndrome are recommended an initial/follow-up consultation with a palliative care physician to ensure treatment tolerance, adequate rehabilitation, and improved quality of life [77, 78, 79].

Level of evidence – 5 (grade of recommendation – C).

• Patients with malignant neoplasms of the nasopharynx receiving chemoradiotherapy are recommended early initiation of physical exercise to improve quality of life and treatment tolerance [52].

Level of evidence – 3 (strength of recommendation – B).

• It is recommended that patients with malignant neoplasms of the nasopharynx receiving chemoradiotherapy undergo low-level laser therapy to the gingival area (A22.07.008) for the prevention and treatment of oral/pharyngeal mucositis induced by CRT [61, 62].

Level of evidence: 2 (strength of recommendation: B).

5. Prevention and Dispensary Observation

For the prevention and early detection of nasopharyngeal tumors, attention should be paid to the following factors:

a) primary symptoms

In early stages, the disease is asymptomatic. Symptoms depend on the tumor location and the direction of its growth. Patients may be troubled by progressive difficulty in nasal breathing, nasal voice, popping or stuffiness in the ear, hearing loss, earache, headache, bleeding, exophthalmos, masticatory muscle trismus, ptosis, strabismus, swallowing and phonation disorders, soft palate sagging, immobility of one half of the larynx, deviation of the tongue to the side, and masses in the neck.

b) carcinogenic factors

Smoking (including secondhand smoke), contact with asbestos, wood dust, petroleum products, ionizing radiation exposure, Epstein-Barr virus.

Dispensary follow-up (Active surveillance)

Scope of examination

Comments: after 5 years from surgery, visits are conducted annually or upon the appearance of symptoms. In patients with a high risk of recurrence, the interval between examinations may be shortened.

Scope of examination:

1) medical history and physical examination;

2) CT of the head soft tissues with contrast and CT of the neck with contrast, or MRI of the head soft tissues with intravenous contrast and MRI of the neck with intravenous contrast;

3) Endoscopic endonasal revision of the nasal cavity and nasopharynx;

4) CT of the chest organs every 12 months;

5) Whole-body positron emission tomography with a tumor-tropic radiopharmaceutical no earlier than 1 year after the end of RT;

6) blood thyroid-stimulating hormone (TSH) level testing every 6–12 months if neck irradiation was performed, to assess thyroid function.

6. Organization of Medical Care

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

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

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

3) based on these clinical guidelines;

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

Primary specialized health care is provided by an oncologist and other specialist physicians at an outpatient oncological care center or in a primary oncological office, or in the outpatient department of an oncological dispensary (oncological hospital).

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

Consultation at an ambulatory cancer care center or at a primary oncology office or outpatient department of an oncological dispensary (cancer hospital) shall not exceed the timeframe established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation. The oncologist of the ambulatory cancer care center (in the absence of an ambulatory cancer care center, the oncologist of the primary oncology office or outpatient department of the oncological dispensary (cancer hospital)) arranges for the acquisition of biopsy (surgical) material, as well as the performance of other diagnostic tests necessary to establish a diagnosis, including the extent of the oncological process and the stage of the disease.

In the event of the impossibility of acquiring biopsy (surgical) material or performing other diagnostic tests within the medical organization that incorporates the outpatient oncological care center (primary oncological office), the attending physician shall refer the patient to an oncological dispensary (oncological hospital) or to a medical organization providing medical care to patients with oncological diseases.

The turnaround time for pathomorphological examinations required for the histological verification of malignant neoplasms shall not exceed the timeframe established in the state guarantee program for free medical care to citizens, approved by the Government of the Russian Federation.

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

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

An oncologist from an outpatient oncological care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to cancer patients, including one subordinate to a federal executive body (hereinafter referred to as a federal medical organization), to clarify the diagnosis (if establishing the diagnosis is impossible, including the extent of the oncological process and disease stage), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

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

digital images obtained from pathomorphological examination results to the pathologoanatomical bureau (department) of the fourth group (reference center)¹ via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

of digital images obtained from diagnostic imaging methods to the remote diagnostic imaging consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

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

Treatment tactics are established by a medical board (consilium) comprising oncologists, a radiation therapist, and a neurosurgeon (in cases of nervous system tumors) of the medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians when necessary.

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

To maintain records, information on a newly diagnosed case of oncological disease is sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established, to the oncological dispensary or an organization of a constituent entity of the Russian Federation that performs the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System. If the oncological disease is confirmed in the patient, information on the updated diagnosis is sent from the oncological dispensary or the organization of the constituent entity of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms to the medical organization providing follow-up dispensary monitoring of the patient.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.

Specialized, excluding high-tech, medical care in medical organizations subordinate to federal executive authorities is provided based on medical indications established by the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as stipulated in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care. In cases where several federal medical organizations participating in the implementation of the Program provide specialized medical care for diseases and conditions (group of diseases and conditions) matching the patient's diseases and conditions (group of diseases and conditions), the attending physician is obliged to inform the patient (the patient's legal representative) about the possibility of choosing a federal medical organization, including the potential waiting times for specialized medical care, which may exceed the waiting times established by the program of state guarantees of free medical care for citizens.

Waiting times for the provision of specialized (excluding high-tech) medical care shall not exceed the timeframes established in the program of state guarantees of free medical care to citizens, approved by the Government of the Russian Federation.

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

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

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

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

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

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

2) presence of complications of treatment (surgical intervention, RT, drug therapy, etc.) of the oncological disease.

Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

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

Indications for discharging a patient from a medical organization are:

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

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day hospital setting established by the multidisciplinary team of the medical organization providing cancer care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

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

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

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

7. Additional Information

Factors influencing the prognosis of the disease include:

- size and extent of the primary tumor;

- tumor grade;

- status of regional lymph nodes (pN) (neck lymph node metastases double patient survival);

- extranodal tumor extension.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Andrey P. Polyakov, MD, DSc, Professor, Head of the Department of Head, Neck and Microsurgery Tumors, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

2. Yuri V. Alyмов, MD, PhD, Oncologist at the Department of Surgical Treatment No. 5 (Endocrine Oncology), N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Executive Director of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

3. Anna V. Boyko, MD, DSc, Professor, Head of the Department of Radiation Therapy with Modification, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Larisa V. Bolotina, MD, DSc, Professor of the RAS, Head of the Chemotherapy Department, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health. Chair of the Head and Neck Tumors Group of Practical Guidelines of the Russian Society of Clinical Oncology, Board Member.

5. Artem R. Gevorkov, MD, PhD, Leading Research Fellow, Radiation Oncologist at the Department of Radiation Therapy with Modification, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

6. Igor A. Gulidov, MD, DSc, Professor, Honored Scientist of the Russian Federation, Head of the Department of Radiation Therapy, A. Tsyb Medical Radiological Research Center, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

7. Marina A. Yengibaryan, MD, DSc, Associate Professor, Researcher, Head of the Head and Neck Tumors Department, National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

8. Anna L. Kornitskaya, MD, PhD, Senior Researcher at the Chemotherapy Department of the Drug Treatment of Tumors Division, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

9. Mikhail A. Kropotov, MD, DSc, Head of the Head and Neck Tumors Department, A. Tsyb Medical Radiological Research Center, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

10. Svetlana I. Kutukova, MD, DSc, Associate Professor, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation, City Clinical Oncology Dispensary.

11. Denis E. Kulbakin, MD, DSc, Oncologist, Head of the Head and Neck Tumors Department, Cancer Research Institute of Tomsk National Research Medical Center.

12. Aleksandr V. Mordovsky, MD, PhD, Senior Researcher at the Department of Head, Neck and Microsurgery Tumors, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

13. Ali M. Mudunov, MD, DSc, Professor of the RAS, Head of the Head and Neck Tumors Department at Lapino 2 Clinical Hospital, President of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

14. Irina V. Novikova, MD, PhD, Senior Researcher at the Department of Head, Neck and Microsurgery Tumors, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

15. Zamira A. Radzhabova, MD, DSc, Associate Professor of the RAS, Head of the Head and Neck Tumors Department, N. Petrov National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Associate Professor at the Department of Additional Professional Education, N. Petrov National Medical Research Center of Oncology.

16. Igor V. Reshetov, MD, DSc, Academician of the RAS, Director of the L. Levshin Institute of Cluster Oncology, Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, President of the All-Russian Public Organization "Federation of Head and Neck Diseases Treatment Specialists".

17. Ilya S. Romanov, MD, DSc, Senior Researcher at the Oncoendocrinology Department, N. Blokhin National Medical Research Center of Oncology, Associate Professor at the Department of Oncology, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University.

18. Aleksandra M. Stepanova, MD, PhD, Deputy General Director for Science and Education, Federal Scientific and Clinical Center for Medical Rehabilitation and Balneology of the Federal Medical-Biological Agency of Russia.

19. Evgeny V. Khmelevsky, MD, DSc, Professor, Corresponding Member of the RAS, Head of the Department of Radiation Therapy, P. Herzen Moscow Oncology Research Institute, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

20. Evgeny L. Choynzonov, MD, DSc, Academician of the RAS, Director of the Cancer Research Institute of Tomsk National Research Medical Center, Head of the Head and Neck Tumors Department at the Cancer Research Institute of Tomsk National Research Medical Center, Head of the Department of Oncology, Siberian State Medical University of the Ministry of Health of the Russian Federation, member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

Medical Care Organization Section

1. Tigran G. Gevorkyan, Deputy Director, N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation.

2. Sergey A. Ivanov, MD, DSc, Professor, Corresponding Member of the RAS, Honored Doctor of the Russian Federation, Director of the A. Tsyb Medical Radiological Research Center, branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Chief freelance oncologist of the Central Federal District of the Ministry of Health of Russia.

3. Zhanna V. Khaylova, MD, PhD, Deputy Director for Organizational and Methodological Work, A. Tsyb Medical Radiological Research Center, branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Yuri I. Komarov, Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health.

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

Supportive Care Section

1. Gladkov Oleg Alexandrovich, Professor, MD, DSc, Director of EVIMED Medical Center LLC.

2. Karaseva Vera Vitalievna, MD, DSc, Associate Professor, Professor, Department of Oncology, Institute of Continuing Professional Education, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologists.

2. Surgeons.

3. Radiologists.

4. Medical geneticists.

5. Medical students, residents, and postgraduate students.

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

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

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, 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

No additional information available.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Guidelines for post-treatment follow-up

Post-treatment follow-up is essential for maintaining the patient's health. If complaints appear, or if symptoms present before treatment recur, you must consult a doctor immediately without waiting for the scheduled appointment date.

The purpose of these visits is to monitor not only the oncological disease, but also side effects, including delayed ones (e.g., hypothyroidism after radiation therapy to the neck area, nutritional status decline, assessment of speech and swallowing function, etc.).

Recommendations regarding lifestyle and nutrition should be individualized taking into account the extent of treatment received, the risks and severity of complications, and the patient's characteristics.

Benefits of quitting smoking and alcohol consumption

– Higher survival rates.

– Greater treatment efficacy.

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

– Accelerated recovery of general condition after treatment.

– Lower risk of recurrence.

– Lower risk of second malignancies.

– Lower risk of infections.

– Higher quality of life.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian name: WHO/ECOG performance status scale.

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

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

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655.

Type: rating scale.

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

Content:

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

Appendix G2. NRS 2002 Scale

Russian title: Nutritional Risk Screening.

Original title: Nutritional Risk Screening - 2002.

Source (official developer website, validation publication):

Kondrup J, Allison SP, Elia M, Vellas B, Plauth M. ESPEN guidelines for nutrition screening 2002. Clin Nutr. 2003; 22(4): 415-421. doi: 10.1016/s0261-5614(03)00098-0).

Type: rating scale.

Purpose: recommended for assessing the nutritional status of hospitalized patients.

Assessment tool, content:

Key (interpretation):

Final screening

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

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

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

No explanations provided.

Appendix G3. Malnutrition Universal Screening Tool (MUST)

Russian title: Malnutrition Universal Screening Tool.

Original title: Malnutrition Universal Screening Tool.

Source (official developer website, validated publication): Stratton R.J., Hackston A., Longmore D., et al. (2004) Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the 'malnutrition universal screening tool' ('MUST') for adults. Br J Nutr 92, 799 – 808).

Type: rating scale.

Purpose: recommended for assessing the nutritional status of outpatients.

Assessment tool, content:

Total score: __________/30

Result interpretation key (full scale from A to T):

> 23.5 points — normal nutritional status;

17–23.5 points — risk of malnutrition;

< 17 points — malnutrition.

No explanations provided.