Nasal cavity and paranasal sinus cancer: clinical guidelines

List of Abbreviations

BT – brachytherapy

Gy – Gray

EBRT – external beam radiotherapy

ZNO – malignant neoplasms

IT – immunotherapy

ICT – induction chemotherapy

CT – computed tomography

LAE – lymphadenectomy

RT – radiotherapy

LU – lymph node

PT – physical therapy

mAb – monoclonal antibody

MRI – magnetic resonance imaging

NPF – adverse prognostic factors

PCT – polychemotherapy

PEG – percutaneous endoscopic gastrostomy

PET-CT – positron emission tomography combined with computed tomography

UZ – ultrasound

US – ultrasound examination

FLS – fibrolaryngoscopy

PDT – photodynamic therapy

FS – photosensitizer

CCF – chronic cancer pain syndrome

CRT – chemoradiotherapy

CT – chemotherapy

EFGDS – esophagogastroduodenoscopy

AUC* (area under the curve) – pharmacokinetic parameter determining drug exposure, required for dose calculation based on creatinine clearance.

Cf-252 – californium-252 radionuclides

CTV – Clinical Target Volume

CPS – combined positive score

ECOG – Eastern Cooperative Oncology Group performance status scale

ENE – extranodal extension

GTV — Gross Tumor Volume; PTV — Planning Target Volume

IMRT – volumetric modulated arc therapy

Ir-192 – iridium-192 radionuclides

PD-L1 – programmed death-ligand 1 expressed by tumor cells

R — a symbol indicating the resection margin, R0 — clear resection margin, R1 — tumor at the resection margin

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

VMAT – intensity-modulated radiation therapy

Terms and Definitions

Adjuvant chemoradiotherapy — a type of chemoradiotherapy administered after complete removal of the primary tumor to eradicate potential micrometastases.

Adjuvant radiation therapy is a type of radiation therapy administered after complete removal of the primary tumor to eradicate potential micrometastases.

Superior wall of the nasal cavity: formed by the cribriform plate, anterior wall of the sphenoid sinus, and anterior ethmoid air cells.

Medial wall of the nasal cavity: formed by the nasal septum.

Posterior wall of the nasal cavity: formed by the choanae.

Chemotherapy cycle is the time period calculated from the first to the last day of cytostatic administration.

Lateral wall of the nasal cavity: formed by the medial wall of the maxillary sinus.

Anterior wall of the nasal cavity: formed by the piriform aperture.

Disease progression: appearance of a new tumor lesion and/or increase in the size of the primary tumor lesion or metastatic lesions by more than 25%.

Radical surgery (R0) is the removal of the affected organ within healthy tissue margins along with regional metastatic zones, leaving no residual manifestations of the tumor process.

Symptomatic treatment: a set of therapeutic measures aimed at relieving the most burdensome manifestations of the tumor process, treating complications, or correcting consequences associated with antitumor treatment.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Cancer of the nasal cavity and paranasal sinuses is a malignant tumor developing from the elements of the mucous membrane of the nasal cavity and paranasal sinuses.

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

The main etiological factors for the development of malignant tumors of the nasal cavity and paranasal sinuses are:

• Chronic inflammatory diseases (chronic sinusitis, vasomotor rhinitis, bronchial asthma, inverted papilloma)

• Adverse environmental factors

• Exposure to physical and chemical carcinogenic substances, especially in individuals with occupational hazards [1,2,6,11,12].

1.3 Epidemiology of the Disease or Condition

Malignant tumors of the nasal cavity and paranasal sinuses account for 1.4% of all malignant tumors. In 2021, 1,012 new cases of nasal cavity and paranasal sinus cancer were registered in Russia [1,2].

1.4 Features of Coding the Disease or Condition

ICD-10 Coding

Malignant neoplasm of nasal cavity and middle ear (C30):

C30.0 – Malignant neoplasm of nasal cavity

C30.1 – Malignant neoplasm of middle ear

Malignant neoplasm of accessory sinuses (C31):

C31.0 – Malignant neoplasm of maxillary sinus

C31.1 – Malignant neoplasm of ethmoidal sinus

C31.2 – Malignant neoplasm of frontal sinus

C31.3 – Malignant neoplasm of sphenoidal sinus

C31.8 – Overlapping lesion of accessory sinuses

C31.9 – Malignant neoplasm of accessory sinus, unspecified

1.5 Classification of the disease or condition

The extent of malignant tumors of the nasal cavity and paranasal sinuses is presented in the TNM classification (8th edition, 2017) (excluding mucosal melanoma of the nasal cavity and paranasal sinuses)

The T descriptor indicates the primary tumor and includes the following categories:

The pN descriptor indicates the presence or absence of regional lymph node (LN) metastases based on the routine pathomorphological examination of the surgical specimen:

The M category describes the presence or absence of distant metastases:

The M descriptor defines the presence or absence of distant metastases

M0 – no distant metastases.

M1 – presence of distant metastases.

Table 1 – Stage grouping

Histological grade

Gx – grade cannot be assessed

G1 – well differentiated

G2 – moderately differentiated

G3 – poorly differentiated

1.6 Clinical presentation of the disease or condition

Malignant tumors of the nasal cavity and paranasal sinuses are of epithelial origin in 70% of cases. Of these, 80% are squamous cell carcinoma, 6% are adenocarcinoma, 10% are esthesioneuroblastoma, and melanoma is rare. The most frequent initial clinical manifestations of the disease are nasal congestion, nasal discharge, pain syndrome, and exophthalmos when the tumor spreads into the orbital cavity.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is established based on:

• anamnestic data, specifically the presence of nasal congestion refractory to conservative treatment for 2–3 weeks;

• physical examination, including a thorough clinical inspection, palpation of the mass, adjacent tissues, and regional lymph nodes (LNs);

• cytological examination of scrapings, smears, punctate from the primary tumor, or punctate from enlarged or suspicious lymph nodes; (cytological examination of the primary tumor (cytological examination of upper respiratory tract discharge and imprints, cytological examination of smears from the upper respiratory tract mucosa, cytological examination of upper respiratory tract tissue micropreparation), cytological examination of lymph node biopsy specimens (enlarged or suspicious), cytological examination of lymph node tissue preparation)

• pathological examination of biopsy (surgical) material;

• instrumental examinations, including ultrasound examination (ultrasound) of the neck, (instrumental examinations, including ultrasound examination (ultrasound) of the neck, (ultrasound examination of soft tissues (one anatomical region),) computed tomography (CT) computed tomography (CT) of the facial skull and neck with intravenous bolus contrast enhancement / magnetic resonance imaging (MRI) of the neck, (MRI of the facial skull, neck with intravenous contrast enhancement), positron emission tomography combined with computed tomography (PET-CT) with 2-fluoro-2-deoxy-D-glucose [18F] (18F-FDG) (performance of positron emission tomography combined with computed tomography (PET-CT) with a tumorotropic radiopharmaceutical (fluorodeoxyglucose [18F]) with contrast enhancement), fibrolaryngoscopy (FLS) as indicated [5,7,9].

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

Comments: The routine pathomorphological report must reflect the following parameters:

1. Tumor size.

2. Depth of tumor invasion.

3. Histological structure of the tumor.

4. Tumor differentiation grade.

1. Presence of lymphovascular or perineural invasion (a negative result must also be stated).

2. Size and extent of the primary tumor (pT).

1. Status of regional lymph nodes (pN) (indicating the total number of examined and affected lymph nodes, and signs of extranodal tumor extension).

1. Involvement of resection margins (a negative result must also be stated) [5].

2.4 Instrumental Diagnostics

Comment: if the result of the pathomorphological examination of the biopsy (surgical) material of the upper respiratory tract tissues is positive (malignant tumor verified), it is necessary to determine the histological type of the tumor, and it is advisable to establish the degree of differentiation. In case of a doubtful result of the pathomorphological examination of the biopsy material of the upper respiratory tract tissues (tumor diagnosis not verified), it is mandatory to perform a repeat biopsy in a sufficient volume for pathomorphological examination of the biopsy (surgical) material of the upper respiratory tract tissues using immunohistochemical methods. In case of a repeatedly negative result of the pathomorphological examination of the biopsy material of the upper respiratory tract tissues (tumor diagnosis not verified), a repeat biopsy is advisable if there are convincing clinical and/or radiological signs of a malignant neoplasm

Comment: if chest CT cannot be performed, chest radiography may be recommended

Comment: if PET-CT or CT cannot be performed, for tumor staging and treatment planning, it is necessary to perform chest radiography and a comprehensive ultrasound examination of the abdominal organs.

2.4.2 Evaluation of antitumor treatment efficacy

2.4.3 Follow-up monitoring

Comment: if chest CT cannot be performed, chest radiography should be carried out

Comment: if PET-CT or contrast-enhanced chest and abdominal CT is not feasible, targeted chest radiography and comprehensive abdominal ultrasound are recommended

2.5 Other Procedures

1. Tumor dimensions;

2. Depth of tumor invasion;

3. Histological structure of the tumor;

4. Tumor grade (differentiation);

5. Presence of lymphovascular and perineural invasion (a negative result must also be stated);

6. pT;

1. pN (indicating the total number of examined and affected lymph nodes, signs of extranodal extension of the tumor);

1. Involvement of resection margins (a negative result must also be stated);

GPR CLOE 5Grade of Recommendations – C (Level of Evidence – 5)

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

General treatment concept

Nasal cavity and ethmoid sinus cancer

• For T1–T2, newly diagnosed, surgical treatment is recommended. Radiotherapy (RT) is recommended after surgery. Observation is recommended only for stage T1 and favorable prognostic signs ("clean" resection margins, no tumor abutment to the cribriform plate and medial orbital wall, high-grade well-differentiated tumors) [5-7,9,13,22,23]

GCP CLEL 4Level of Evidence – C (Level of Likelihood of Evidence – 4)

• For T3–T4a, newly diagnosed, frontline surgical treatment or RT/CRT or induction chemotherapy followed by surgery or concurrent CRT is recommended. Subsequently, postoperative RT or concurrent CRT is administered (in the presence of adverse prognostic factors: tumor cells in the resection margins and/or intracranial extension) [5-7,9,,18,19,22,26,27]

GCP CLEL 4Level of Evidence – C (Level of Likelihood of Evidence – 4)

• For newly diagnosed T4b N0-N3, M0, or if the patient refuses extensive surgery, or has absolute contraindications to surgical treatment, it is recommended to enroll the patient in clinical trials or choose a treatment method depending on the general condition assessed by the ECOG scale:

  ECOG 0-1 Concurrent CRT or induction chemotherapy followed by RT or concurrent CRT.

  ECOG 2 RT +/- chemotherapy (depending on general condition)

  ECOG 3 Palliative RT or single-agent chemotherapy or palliative care [5,16-20].

GPP BLeD 2Grading of Recommendations, Assessment, Development and Evaluation (GRADE) – B (Level of Evidence – 2)

Comment: In most cases, early-stage ethmoid labyrinth cancer is diagnosed during morphological examination of surgical specimens removed after interventions for presumed non-neoplastic processes (polypoid ethmoiditis, nasal polyps, etc.). Thus, morphological verification is usually the result of a non-radical intervention. Patients who underwent a non-radical initial surgery, which is essentially an extended biopsy, are subsequently indicated for the same therapeutic approaches as those with a newly established diagnosis.

If CT/MRI examinations were performed during the diagnostic stage, the non-radical surgery can be supplemented with a single course of radical RT, provided there is no extension of the process to the skull base (i.e., strictly formal T1, T2 stages). The required radical volume of surgery is achieved by resections of various volumes until "clean" margins are obtained. Metastases to regional cervical lymph nodes (N+) are extremely rare in cancer of the nasal cavity and ethmoid labyrinth, but if detected, they require neck dissection with appropriate subsequent adjuvant therapy.

• If the diagnosis is established after incomplete removal (polypectomy, etc.) and residual tumor persists, then surgical removal or RT or concurrent CRT is recommended. Postoperative RT or concurrent CRT is recommended in the presence of adverse prognostic factors: tumor cells at the resection margins, tumor abutment to the cribriform plate, medial orbital wall, intracranial or intraorbital extension, unfavorable histology (poorly differentiated tumors, adenoid cystic carcinoma), perineural or lymphatic invasion.

• If the diagnosis is established after non-radical removal, and no residual tumor is detected clinically and by special imaging methods, then RT or surgery is recommended. Postoperative RT is recommended. Observation is indicated only for stage T1 and favorable prognostic signs (R0 resection, centrally located, well-differentiated tumors, absence of perineural and lymphatic invasion) [5-7,18,22,23].

GCP CLEL 4Level of Evidence – C (Level of Likelihood of Evidence – 4)

Maxillary sinus cancer (excluding melanoma, sarcoma, and lymphoma)

• T1–T2, N0 (any histology except adenoid cystic carcinoma): Radical surgery followed by active surveillance is recommended. In case of perineural, vascular, or lymphatic invasion, RT or concurrent CRT is indicated. For positive margins, surgical resection followed by RT; for repeat non-radical surgery, concurrent CRT [5-7,9,13,22,23].

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

• T1–T2, N0, adenoid cystic carcinoma: Radical surgery followed by RT is recommended. Active surveillance is an option in case of R0 resection and absence of perineural invasion according to histological examination [5-7,9,13,22,23,25,26,28,31,32].

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

• T3–T4a, N0. Radical surgery is recommended. Postoperative RT to the primary tumor site or, in the presence of adverse prognostic factors (tumor cells at the resection margins), concurrent CRT is recommended [5-7,9,13,21-23].

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

• T1–T4a, N+: Surgical removal of the primary tumor and extended neck lymphadenectomy is recommended. Postoperative RT to the primary tumor and regional lymph nodes or, in the presence of adverse prognostic factors (tumor cells at the resection margins, extracapsular extension of the lymph node metastasis), concurrent CRT is recommended [3,5,7,9,10,13,18].

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

• For newly diagnosed T4b, N0-N3 M0, or if the patient refuses extensive surgery, it is recommended to enroll the patient in clinical trials or choose a treatment method depending on the general condition assessed by the ECOG scale:

  ECOG 0-1 Concurrent CRT or induction chemotherapy followed by RT or concurrent CRT.

  ECOG 2 RT +/- chemotherapy (depending on general condition)

  ECOG 3 Palliative RT or single-agent chemotherapy or palliative care [5,16-20].

GCR CLEL 2Grade of Recommendation — C (Level of Evidence — 2)

• Local recurrence or residual tumor without prior radiotherapy. Recommended management includes surgery or concurrent chemoradiotherapy or induction chemotherapy followed by concurrent CRT [5,7,9,13,16-22].

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

Comments: If adverse histological features (tumor invasion through the lymph node capsule, presence of perineural invasion, tumor emboli in blood vessels) are detected during routine postoperative histological examination, concurrent CRT is indicated. If resection margins are positive, re-operation or RT should be considered.

• Local recurrence or residual tumor after RT. Recommended management includes surgery with consideration of re-irradiation, or if surgery is not feasible, re-irradiation followed by salvage chemotherapy [5,7,9,13,16-22]

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

• In local recurrence or residual tumor with distant metastases (M1), it is recommended to include the patient in clinical trials or select a treatment method based on the general condition assessed by the ECOG scale:

  ECOG 0–1 Concurrent CRT or induction CT followed by RT or concurrent CRT.

  ECOG 2 RT ± concurrent CT (depending on general condition)

  ECOG 3 Palliative RT, monochemotherapy, or palliative care [5, 16, 22].

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

3.1. Radiotherapy

Introduction:

All patients before treatment should be evaluated by a radiation oncologist, preferably one specializing in head and neck tumors, who should take the following steps: review the adequacy of morphological verification, staging, and imaging of the tumor process (CT, MRI) to determine the extent of tumor spread, rule out a synchronous primary tumor, and assess current functional status and the feasibility of RT/CRT. For patients undergoing CT/CRT, the tactics for implementing antitumor therapy in full and within optimal timeframes must be elaborated.

Radiation therapy as primary or adjuvant treatment should be performed in specialized institutions with appropriate equipment and experience in treating cancers of the nasal cavity and paranasal sinuses.

A deep understanding of anatomy, clinical presentation, and imaging of specific disease manifestations is required. High-precision RT techniques are preferred, such as IMRT (intensity-modulated radiation therapy) or VMAT (volumetric modulated arc therapy). Proton therapy is considered in case of significant normal tissue dose constraints. 3D-conformal RT is also acceptable.

The optimal approach in clinical practice is delivering the planned doses of ionizing radiation to the target while minimizing the dose to organs at risk as much as possible. It is acceptable to discuss volume reduction by excluding vital structures free from tumor involvement at the time of RT planning if the maximum permissible dose limits for them according to QUANTEC criteria (quantitative analyses of normal tissue effects in the clinic) are exceeded. The target volume for radical doses should not be modified based on the clinical response obtained before RT (after induction systemic chemotherapy), except in cases of tumor progression. Anatomical changes during the course of RT (e.g., rapid tumor shrinkage, significant weight loss) may necessitate repeat diagnostic imaging and replanning (adaptation) of treatment.

• RT as a standalone option. Recommended: 70 Gy (1.8–2.0 Gy/fraction) to the primary tumor and clinically identified neck lymph node metastases, daily from Monday to Friday for 7 weeks; 50 Gy (2.0 Gy/fraction) to clinically uninvolved lymph nodes [58, 59].

LoE CGoR 5Level of evidence – C (grade of recommendation – 5)

• Postoperative RT: Recommended: to the primary site: total cumulative dose (TCD) 60–66 Gy (fraction dose 2 Gy). To neck lymph nodes: clinically identified lymph node metastases – 60–66 Gy (fraction dose 2 Gy); in the absence of clinical signs of involvement – 50 Gy (fraction dose 2.0 Gy) [5, 18, 27, 58, 59].

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

Comments: The preferred interval after surgery is <6 weeks and should not exceed 3 months.

• Concurrent postoperative chemoradiotherapy: Concurrent postoperative CRT is recommended for patients with cancer of the nasal cavity and paranasal sinus mucosa in the following regimen: RT to the primary lesion and clinically detected regional metastases (high-risk area) at a dose of 66–70 Gray (Gy) (2.0 Gy/fraction) daily from Monday to Friday for 6–7 weeks; to the locoregional area including regional lymph nodes (intermediate/low-risk area) – 46–54 Gy (1.8–2.0 Gy/fraction). Irradiation is carried out in two (46–54 Gy/66–70 Gy) or three (46–54/60/66–70 Gy) phases with sequential reduction of the irradiation volume [5, 18, 27, 58, 59, 70].

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

• Combined CRT with cisplatin** at a dose of 100 mg/m² with hyperhydration on days 1, 22, and 43 of RT, or on a weekly schedule (40 mg/m² IV with hyperhydration) is preferred. The recommended cumulative dose of cisplatin** per RT course is 300 mg/m² [5, 27, 71].

Comments: as alternative options, especially when an induction CT phase is included, the use of cetuximab** or carboplatin** is possible, taking into account the tolerability of CRT and the patient's performance status. It is also possible to use RT in combination with carboplatin** at a dose of 70 mg/m²  IV AUC 1.5–2 intravenously weekly, up to 7 administrations [5,18,19,27,72,75]

• In the presence of comorbidities that preclude concurrent CRT containing platinum compounds (chronic kidney disease, creatinine clearance <50–60 mL/min, patient age >65 years, severe concomitant renal, cardiovascular, neurological, hepatic pathology, and/or poor performance status (ECOG >1)), replacing platinum compounds with cetuximab** during RT is preferred [18, 19, 58, 59].

GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)

• Palliative RT is recommended for the relief or prevention of locoregional symptoms when radical treatment with standard RT is not feasible. An individually planned RT schedule may be chosen taking into consideration treatment toxicity minimization, including doses of 50 Gy (2.5 Gy/fraction) and 30 Gy (3 Gy/fraction) [73, 74].

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

3.2. Medical treatment

The choice of CT should be individualized based on patient characteristics (performance status, treatment goals).

• Induction CT followed by concurrent CRT is recommended according to the regimen: Docetaxel** + cisplatin** + fluorouracil**, for a total of 2–3 cycles of CT with a 3-week interval [75].

  In cases of sinonasal neuroendocrine tumor and poorly differentiated esthesioneuroblastoma, the following induction systemic chemotherapy regimens are recommended: carboplatin** AUC 5–6 + #etoposide** 100 mg/m² days 1–3, cisplatin** 75 mg/m² + #etoposide** 100 mg/m² days 1–3, #cyclophosphamide + doxorubicin** + #vincristine** + cisplatin** 50 mg/m² + doxorubicin** 50 mg/m² + #cyclophosphamide** 500 mg/m² on day 1 every 3 weeks [46, 49, 75].

GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)

• Concurrent CRT. Recommended chemotherapy regimens – Cisplatin** (preferred) or carboplatin** or cetuximab** + RT. RT to the primary lesion and clinically detected regional metastases – 70 Gy (2.0 Gy/fraction) daily from Monday to Friday for 6–7 weeks; to clinically uninvolved lymph nodes – 44–60 Gy (2.0 Gy/fraction); cisplatin** at a dose of 100 mg/m² with hyperhydration on days 1, 22, and 43 of RT (total dose during RT – 300 mg/m²) or weekly administration of carboplatin** 1.5–2.0 AUC or cetuximab** 400 mg/m² one week before the start of radiation therapy and 250 mg/m² weekly during RT [57, 58].

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

• Salvage chemotherapy (when surgery and RT are not feasible) For the treatment of recurrent, initially unresectable tumors or metastatic disease, when concurrent CRT is not possible, poly- or monochemotherapy is recommended to improve patient survival. Depending on the patient's performance status and/or treatment goals, the following drug combinations can be recommended (the number of cycles is determined by treatment tolerance and efficacy) [15–20, 75]:

¹ For patients with an ECOG performance status of 2.

² Suboptimal treatment regimens; can be used only in case of absolute contraindications to anti-EGFR mAbs.

³ In the 2nd and subsequent lines of therapy for platinum-resistant tumors. Can be prescribed regardless of PD-L1 expression level.

⁴ As first-line therapy in the presence of PD-L1 expression with CPS ≥1. In case of progression during or after platinum-based chemotherapy (L01XA: Platinum compounds) with a TPS ≥50%. The recommended duration of use corresponds to the design of registration trials.

⁵ As first-line therapy at CPS ≥1

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

3.3 Surgical Treatment

• For patients undergoing elective surgery, it is recommended to plan the surgical intervention with resection margins of the clinically apparent tumor free of malignant cells [5,7,21-30].

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

Comments: Surgical intervention should not be modified based on the clinical response obtained before treatment. Tumor involvement of the following structures is associated with a poor prognosis: (e.g., inoperability associated with the technical impossibility of obtaining clear resection margins) significant involvement of the pterygopalatine fossa, severe trismus due to tumor infiltration of the pterygoid muscles; macroscopic tumor extension to the skull base (e.g., erosion of the pterygoid plates or sphenoid bone, enlargement of the foramen ovale, etc.); potential invasion (encasement) of the common or internal carotid artery wall. Encasement is typically assessed radiologically (by CT and MRI) and is diagnosed if the tumor surrounds $\ge$270° of the carotid artery circumference; direct tumor extension from regional lymph nodes with skin involvement, direct extension to mediastinal structures, prevertebral fascia, or cervical vertebrae. It is recommended to perform en bloc resection of the primary tumor. Surgical resection must be planned based on the extent of the primary tumor determined during the clinical examination and careful interpretation of relevant radiographic images. In cases where the tumor is adjacent to a motor or sensory nerve, perineural invasion cannot be ruled out. In this situation, the nerve should be dissected in the proximal and distal directions and resected to obtain a clear resection margin. It has been confirmed that frozen section analysis (intraoperative histological examination) of the proximal and distal nerve margins is useful for obtaining tumor-free tissue. Simultaneous reconstruction of the resected nerve segment is preferred. Adequate resection is defined as a distance from the resection margin to the macroscopically visible tumor of $\ge$2 cm or a negative frozen section margin. In general, frozen section evaluation is usually performed intraoperatively if the macroscopically tumor-free zone at the resection margin is <2 cm, if the resection line cannot be determined due to an unclear tumor border, or if residual tumor is suspected. A detailed description of the resection margin must be included in the operative report. Margins can be assessed from the resected specimen or, alternatively, from the properly oriented tumor bed. A clear margin is defined as a distance from the invasive tumor front of $\ge$5 mm to the resection margin. A close margin is defined as a distance from the invasive tumor front to the resection margin of <5 mm. The primary tumor should be marked so that the pathologist can adequately assess specimen orientation. Neck dissection specimens must be oriented or sectioned sequentially to determine the level of lymph nodes included in the dissection zone. Reconstruction of surgical defects should be performed using conventional techniques at the surgeon's discretion.

• Whenever possible, primary closure is recommended; however, wide tumor-free resection margins should not be compromised. At the surgeon's discretion, plastic closure using local/regional flaps, free flaps, split-thickness skin grafts, or other flaps with/without maxillary reconstruction may be performed [5,7,21-30].

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

• In patients with locally advanced head and neck cancer, as well as in the presence of bleeding risk from tumor masses in the head and neck region, it is recommended to:

  Perform a clinical assessment of the tumor status and evaluate the risks of bleeding, tumor size, and tumor extension into adjacent structures in cases of tumor ulceration, cavitation within the tumor area, tumor recurrence, proximity to carotid artery branches, presence of a non-healing wound, or a prior tumor hemorrhage [5,23,66-69].

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

• If there is a confirmed risk of hemorrhage from tumor nodes, it is recommended to perform selective carotid angiography and, in the absence of contraindications, superselective intra-arterial embolization of tumor vessels to reduce the risk of bleeding and fatal complications [5,23,66-69].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All patients are recommended to undergo rehabilitation based on the general principles of patient rehabilitation following surgical interventions and/or chemotherapy [59,60 5].

LoE CGoR 5Level of evidence – C (grade of recommendation – 5)

5. Prevention and Dispensary Observation

During the first 1–2 years, physical examination and symptom review should be performed every 3–6 months; at 3–5 years, once every 6–12 months. After 5 years from surgery, visits are conducted annually or upon the appearance of symptoms. In patients at high risk of recurrence, the interval between examinations may be shortened.

Scope of examination:

1. Anamnesis and physical examination

2. Ultrasound of the cervical lymph nodes bilaterally, abdominal organs, and pelvis every 3–6 months depending on the risk of progression;

3. Chest radiography every 12 months.

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

Comments: the objective of follow-up is early detection of disease progression to enable early initiation of chemotherapy or surgical treatment for resectable metastatic lesions and recurrent tumors, as well as the detection of metachronous head and neck cancers.

6. Organization of Medical Care

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

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

2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

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

Primary specialized health care is provided by an oncologist and other 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 outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the 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 timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

The 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 an oncologist, and in the case of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96, also by a hematologist.

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.

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

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:

of digital images obtained from pathomorphological examinations to the pathomorphological 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.

For record-keeping purposes, information about a newly diagnosed case of an oncological disease shall be sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of the subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System.

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 medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated by paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as provided in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care.

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

Indications for discharging a patient from a medical organization are:

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

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in 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; degree of tumor differentiation;

• presence/absence of perivascular, perilymphatic, and perineural invasion; regional lymph node status (pN) (cervical lymph node metastases halve patient survival); extranodal extension of the tumor;

• cellular proliferation activity (Ki-67 index); resection margin status (R0-R1).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kropotov Mikhail Alekseevich, MD, PhD, Head of Surgical Department No. 10 for Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

2. Bolotin Mikhail Viktorovich, D.Sc. in Medicine, Senior Researcher at Surgical Department No. 11 of Upper Aerodigestive Tract Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

1. Agababyan Tatev Artakovna, Head of the Diagnostic Radiology Department, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Ph.D. in Medicine, Obninsk https://orcid.org/0000-0002-9971-3451

2. Alieva Sevil Bagaturovna, D.Sc. in Medicine, Leading Researcher at the Radiation Oncology Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

3. Alymov Yury Vladimirovich, Ph.D. in Medicine, Oncologist at the Surgical Treatment Department No. 5 (Endocrine Oncology) of the N.N. Trapeznikov Institute of Clinical Oncology, N.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»; ORCID: https://orcid.org/0000-0002-6851-9867

4. Artemyeva Anna Sergeevna, Ph.D. in Medicine, Pathomorphologist, Head of the Scientific Laboratory of Tumor Morphology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor at the Department of Additional Professional Education, N.N. Petrov National Medical Research Center of Oncology

5. Boyko Anna Vladimirovna, D.Sc. in Medicine, Professor, Head of the Radiotherapy Department with Modification, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

6. Bolotina Larisa Vladimirovna, D.Sc. in Medicine, Associate Professor of the RAS, Head of the Chemotherapy Department, P.A. 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.

7. Vinogradov Vyacheslav Vyacheslavovich, D.Sc. in Medicine, Professor, Head of the Scientific and Clinical Department of Otorhinolaryngology Oncology, Scientific and Clinical Center of Otorhinolaryngology of the Federal Medical-Biological Agency of Russia.

8. Vladimirova Lyubov Yuryevna, D.Sc. in Medicine, Professor, Head of the Department of Drug Treatment of Tumors, National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation

9. Gevorkov Artem Rubenovich, Ph.D. in Medicine, Senior Researcher, Radiation Oncologist at the Radiotherapy Department with Modification, P.A. 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»

10. Girshovich Mikhail Markovich, Ph.D. in Medicine, Radiation Oncologist, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health; https://orcid.org/0000-0002-7925-9570

11. Gulidov Igor Aleksandrovich, Head of the Radiotherapy Department, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health

12. Guz Alexander Olegovich, Ph.D. in Medicine, Oncologist, Head of the Head and Neck Tumors Department, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine

13. Daikhes Nikolay Arkadievich, Corresponding Member of the RAS, D.Sc. in Medicine, Professor, Director of the Scientific and Clinical Center of Otorhinolaryngology of the Federal Medical-Biological Agency of Russia.

14. Dronova Ekaterina Leonidovna, Radiologist, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

15. Engibaryan Marina Aleksandrovna, D.Sc. in Medicine, 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».

16. Ignatova Anastasia Valeryevna, Ph.D. in Medicine, Oncologist at the Surgical Treatment Department No. 5 of the N.N. Trapeznikov Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists», Assistant at the Department of General and Clinical Dentistry, Peoples' Friendship University of Russia (RUDN University). ORCID: https://orcid.0000-0002-6796-0968

17. Klimenko Veronika Viktorovna, Ph.D. in Medicine, Physician at the Clinical Diagnostic Department, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health; https://orcid.org/0000-0003-1079-4492

18. Kornietskaya Anna Leonidovna, Ph.D. in Medicine, Senior Researcher at the Chemotherapy Department of the Tumor Drug Treatment Division, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

19. Kostromina Ekaterina Viktorovna, Ph.D. in Medicine, Ultrasound Diagnostics Physician, Radiologist at the Diagnostic Radiology Department, Researcher at the Scientific Department of Diagnostic and Interventional Radiology, N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Associate Professor at the Department of Diagnostic Radiology and Medical Imaging, Faculty of Postgraduate Education, Saint Petersburg State Pediatric Medical University; https://orcid.org/0000-0002-4245-687X

1. Krasilnikova Larisa Anvarovna, Ph.D. in Medicine, Cytopathologist N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

2. Kutukova Svetlana Igorevna, D.Sc. in Medicine, Associate Professor, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation, City Clinical Oncology Dispensary

3. Kulbakin Denis Evgenyevich, D.Sc. in Medicine, Senior Researcher, Oncologist at the Head and Neck Tumors Department, Oncology Research Institute, Tomsk National Research Medical Center

20. Mordovsky Alexander Valentinovich – Ph.D. in Medicine, Researcher at the Microsurgery Department, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health

4. Mudunov Ali Muradovich, D.Sc. in Medicine, Professor of the RAS, President of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists»

5. Musin Shamil Ismagilovich, Ph.D. in Medicine, Head of Surgical Department No. 6, Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Bashkortostan

21. Podvyaznikov Sergey Olegovich, D.Sc. in Medicine, Professor, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Vice-President of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

22. Polkin Vyacheslav Viktorovich, Ph.D. in Medicine, Head of the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health

23. Polyakov Andrey Pavlovich, D.Sc. in Medicine, Associate Professor, Head of the Microsurgery Department, P.A. 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. Ponomareva Olga Igorevna, Radiologist at the Radiotherapy Department, N.N. Petrov National Medical Research Center of Oncology; https://orcid.org/0000-0002-7004-9630

7. Radzhabova Zamira Ahmed-Gadzhievna, D.Sc. in Medicine, Associate Professor of the RAS, Head of the Head and Neck Tumors Department, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor at the Department of Additional Professional Education, N.N. Petrov National Medical Research Center of Oncology https://orcid.org/0000-0002-6895-0497

24. Reshetov Igor Vladimirovich, D.Sc. in Medicine, Academician of the RAS, Head of the Department of Oncology, Radiotherapy and Reconstructive Surgery, I.M. Sechenov First Moscow State Medical University, President of the All-Russian Public Organization «Federation of Specialists in the Treatment of Head and Neck Diseases»

25. Romanov Ilya Stanislavovich, D.Sc. in Medicine, Senior Researcher at the Oncoendocrinology Department, N.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

26. Rubtsova Natalya Aleftinovna, D.Sc. in Medicine, Head of the Diagnostic Radiology Department, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center of the Russian Ministry of Health. Chief freelance specialist in diagnostic radiology and instrumental diagnostics of the Ministry of Health of the Russian Federation for the Central Federal District of the Russian Federation.

27. Rudyk Andrey Nikolaevich, Ph.D. in Medicine, Oncologist at Oncological Department No. 5 (Head and Neck Tumors), Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan named after Professor M.Z. Sigal, Acting Head of the Department of Maxillofacial Surgery and Surgical Dentistry, Associate Professor at the Department of Oncology, Radiology and Palliative Medicine, Kazan State Medical Academy – Branch of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Associate Professor at the Department of Surgical Diseases of Postgraduate Education, Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan.

28. Oksana A. Saprina, PhD in Medicine, Oncologist, Surgical Department No. 11 for Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

8. Tatiana Yu. Semiglazova, MD, PhD, Professor, Head of the Research Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

29. Aleksandra M. Stepanova, Head of the Rehabilitation Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

9. Natalia S. Sukortseva, Assistant at the Department of Oncology, Reconstructive Surgery and Radiotherapy, Oncologist at University Clinical Hospital No. 1 of Sechenov University

10. Elena V. Tkachenko, PhD in Medicine, Head of the Short-Term Antitumor Drug Therapy Department, Researcher at the Research Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, https://orcid.org/0000-0001-6375-8335

11. Natalia A. Falaleeva, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

12. Aleksandr A. Fedenko, MD, PhD, Professor of the RAS, Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

13. Evgeny V. Khmelevsky, MD, PhD, Professor, Head of the Radiotherapy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Radiation Oncologist at the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

14. Malika M. Khodjibekova, MD, PhD, Radiologist at the Department of Radionuclide Diagnostics, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

15. Evgenia V. Tsurlina, PhD in Medicine, Endocrinologist at the Department of Functional Diagnostics, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

30. Evgeny L. Choynzonov, MD, PhD, Academician of the RAS, Director of the Cancer Research Institute of Tomsk National Research Medical Center, Head of the Department of Head and Neck Tumors at the Cancer Research Institute of Tomsk National Research Medical Center, Head of the Department of Oncology at Siberian State Medical University of the Russian Ministry of Health, Member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists»

31. Lilia P. Yakovleva, PhD in Medicine, Oncologist, Head of the Center for Diagnosis and Treatment of Head and Neck Tumors, Moscow Center for Research and Practice in Medical Oncology of the Moscow Healthcare Department

Section: Organization of Medical Care

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

32. Sergey A. Ivanov, MD, PhD, Professor of the RAS, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

33. Aleksey A. Nevolskikh, MD, PhD, Deputy Director for Medical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

2. Zhanna V. Khaylova, PhD in Medicine, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Oncologists;

2. Surgeons;

3. Radiologists;

4. Chemotherapists;

5. Medical geneticists;

6. Medical students, residents, and postgraduate students.

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

Table 2. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 3. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Methods used for formulating recommendations: expert consensus.

Economic analysis

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review

• Internal expert review

Description of the guideline validation method:

The draft of these recommendations was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Feedback was received from primary care oncologists regarding the clarity of the guidelines and their perceived importance as a working tool in daily practice.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and the resulting changes to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and peer review: The draft recommendations were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Updates to clinical guidelines: updates are carried out at least once every three years, taking into account new information on the diagnosis and management of patients with head and neck tumors. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicines, medical devices, and the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its reliability. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Appendix A3. Reference Materials

No information available

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Recommendations for chemotherapy complications – contact your chemotherapist.

1) If body temperature rises to 38°C and above:

• Start taking antibiotics: as recommended by the chemotherapist

2) For stomatitis:

• Diet – mechanical and thermal sparing;

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

• Treat the oral cavity as recommended by the chemotherapist

1) For diarrhea:

• Diet – exclude fatty, spicy, smoked, sweet, dairy products, and fiber.

Lean meat, flour products, fermented dairy products, and rice broth are permitted. Drink plenty of fluids.

• Take medications as recommended by the chemotherapist

4) For nausea:

• Take medications as recommended by the chemotherapist

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

Appendix G1. ECOG/WHO Scale for assessing the general condition of the patient

Russian name: ECOG Performance Status Scale.

Original name (if any): The ECOG Scale of Performance Status.

Source (official developer website, validation publication): https://ecog-acrin.org/resources/ecog-performance-status/ [119].

Type: rating scale.

Purpose: Assessment of the patient's general condition.

Content (template) and Key (interpretation).

Score

Appendix G2. G.A. Lavnikova Tumor Regression Grading Scale

Russian title: G.A. Lavnikova's scale for assessing tumor therapeutic pathomorphosis

Original title: G.A. Lavnikova's scale for assessing tumor therapeutic pathomorphosis

Source (official developer website, validation publication): https://cr.minzdrav.gov.ru/scale/eb218f32-ee25-4f18-bfb6-c3b6917a8e97

Lavnikova G.A. (1979) Histological method for quantitative assessment of therapeutic tumor damage. Moscow: Methodological recommendations, 13 p.

Type: rating scale.

Purpose: assessment of therapeutic pathomorphosis of the tumor.

Content (template) and Key (interpretation).

Score

Grade I – more than 50% of the tumor parenchyma is preserved;

Grade II – 20–50% of the tumor parenchyma is preserved;

Grade III – up to 20% of the tumor parenchyma is preserved as individual foci;

Grade IV – complete absence of tumor parenchyma

Notes: none.