Oral cavity malignant neoplasms: 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 – symbol denoting the resection margin; R0 – clear resection margin; R1 – tumor involvement at the resection margin

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

VMAT – intensity-modulated radiation therapy

Terms and Definitions

Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgery/chemotherapy (CT)/radiotherapy (RT)).

Stage I rehabilitation – rehabilitation during specialized treatment of the primary disease (including surgery/CT/RT) in specialized departments of medical organizations.

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

Stage III rehabilitation – rehabilitation during the early and late recovery periods and residual manifestations in rehabilitation, physiotherapy, exercise therapy, reflexology, manual therapy, psychotherapy, and medical psychology departments (units) providing outpatient care, in day care facilities, as well as by mobile teams at home (including sanatorium-resort settings), and speech therapy (defectology) offices.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Oral cavity cancer - malignant tumor developing from the squamous epithelium of the mucosa of the buccal mucosa, palate, gingiva, floor of the mouth, and tongue [1].

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

The etiological factors of oral cancer include the following:

• bad habits: smoking, especially combined with heavy alcohol consumption, chewing various mixtures (betel nut, etc.).

• precancerous conditions: leukoplakia, erythroplakia, chronic ulcers and fissures of the lips, cheilitis.

• chronic oral infection;

• chronic trauma to the oral mucosa (from broken teeth and roots, poorly fitted dentures) [1, 2].

1.3 Epidemiology of the Disease or Condition

The incidence of malignant neoplasms of the oral cavity is 6.52 per 100,000 population. In 2021, 9,503 cases of oral cancer were registered in the Russian Federation. Over recent decades, incidence and mortality rates have shown a steady upward trend [3].

1.4 Features of Coding the Disease or Condition

ICD-10 coding:

C02 Malignant neoplasm of other and unspecified parts of tongue

●                    C02.0 Dorsal surface of tongue (anterior 2/3 of dorsal surface)

●                    C02.1 Border of tongue; tip of tongue

●                    C02.2 Ventral surface of tongue (anterior 2/3 of ventral surface)

● C02.3 Anterior two-thirds of tongue, unspecified part

● C02.8 Overlapping lesion of tongue

● C02.9 Tongue, unspecified

C03 Malignant neoplasm of gum

● C03.0 Upper gum

● C03.1 Lower gum

● C03.9 Gum, unspecified

C04 Malignant neoplasm of floor of mouth

● C04.0 Anterior floor of mouth (anterior to the canine-premolar contact point)

● C04.1 Lateral floor of mouth

● C04.8 Overlapping lesion of floor of mouth

● C04.9 Floor of mouth, unspecified

C05 Malignant neoplasm of palate

● C05.0 Hard palate

C06 Malignant neoplasm of other and unspecified parts of mouth

● C06.0 Cheek mucosa

● C06.1 Vestibule of mouth

● C06.2 Retromolar area

● C06.8 Overlapping lesion of mouth

● C06.9 Mouth, unspecified

ICD-O-3 coding, 4th edition, 2010: Oral cavity tumors

Malignant epithelial tumors

● 8070/3 Squamous cell carcinoma, NOS

● 8051/3 Verrucous carcinoma, NOS

● 8083/3 Basaloid squamous cell carcinoma

● 8052/3 Papillary squamous cell carcinoma

● 8074/3 Squamous cell carcinoma, spindle cell

● 8075/3 Squamous cell carcinoma, adenoid

● 8560/3 Adenosquamous carcinoma

8082/3 Lymphoepithelial carcinoma

1.5 Classification of the disease or condition

Over 90% of malignant tumors of the oral mucosa are squamous cell carcinomas, while adenocarcinomas (from minor salivary glands) and sarcomas are less common [1].

The extent of epithelial malignant tumors of the oral cavity is presented in the TNM Staging Classification for Malignant Tumors, 8th edition, by the American Joint Committee on Cancer (AJCC).

*Note: Superficial erosion of bone or tooth socket alone (in primary tumors originating on the alveolar ridge mucosa) is insufficient to classify a tumor as T4.

Table 1. Stage grouping

1.6 Clinical presentation of the disease or condition

In the early period, painless nodules, indurations, superficial ulcers, or fissures are observed that do not respond to conservative treatment. Patients may also complain of discomfort during eating, such as a burning or tingling sensation. In the advanced period, pain is observed in almost 100% of cases and can vary in intensity, radiating to the ear or temporal region. Due to secondary infection and tumor breakdown, halitosis appears. The tumor is characterized by three growth patterns: exophytic, endophytic (ulcerative, infiltrative, or ulcero-infiltrative), or mixed. The exophytic form presents as mushroom-like, plaque-like growths on the mucosa with clear borders. In the endophytic form, the ulcer may be surrounded by a tumor ridge, and the tumor may spread deep into the tissues as an infiltrate without clear borders. In the neglected period, massive destruction of surrounding tissues is observed, involving bone structures, the vestibule of the mouth, skin, and muscles [4].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is established based on:

• anamnestic data, specifically the presence of a neoplasm unresponsive 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, and punctate from enlarged or suspicious LNs;

• pathological examination of biopsy (surgical) material;

• instrumental examinations, including ultrasound examination (ultrasound) of oral cavity tissues, neck ultrasound, computed tomography (CT) / magnetic resonance imaging (MRI), positron emission tomography combined with computed tomography (PET-CT) with 18F-fluorodeoxyglucose (18F-FDG), and fibrolaryngoscopy (FLS) as indicated [5, 6].

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

2.4 Instrumental Diagnostics

• If there is clinical suspicion of an oral cavity MN, to verify the tumor process prior to treatment initiation, it is recommended to perform imprint smears, scrapings (obtaining scrapings from erosive and ulcerative elements of the skin and mucous membranes) or biopsies (oral mucosal biopsy) from the surface of erosions, ulcerations, fissures, or fine-needle aspiration biopsy of oral cavity tissues for soft tissue indurations without signs of ulceration. If the cytological examination (cytological examination of oral tissue micropreparation) is inconclusive, an oral mucosal biopsy is required for pathomorphological examination (including immunohistochemical examination) (Pathological examination of biopsy (surgical) material of oral tissues using immunohistochemical methods) to confirm the diagnosis [1, 4, 6, 7].

Level of Evidence CGrade of Evidence 5 Level of Evidence – C (Grade of Evidence – 5)

Comment: In case of a positive result of the pathomorphological examination of biopsy material (malignant tumor verified), it is necessary to determine the histological type of the tumor, and it is advisable to establish the tumor grade. In case of a doubtful result of the pathomorphological examination of biopsy material (neoplasm diagnosis not verified), it is mandatory to perform a repeat biopsy of the neoplasm in a sufficient volume for additional special methods of vital pathomorphological examination (immunohistochemical typing). In case of a negative result of the pathomorphological examination of biopsy material, a repeat biopsy is advisable if there are convincing clinical and/or radiological signs of a malignant neoplasm.

• Patients are recommended to undergo an endoscopic examination of the upper aerodigestive tract (esophagogastroduodenoscopy, fibrolaryngoscopy) if indicated [1, 4, 6, 7].

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

• All patients with a verified diagnosis of malignant neoplasm of the oral cavity, to assess the extent of the tumor process, are recommended to undergo computed tomography of the facial skull with intravenous bolus contrast enhancement + computed tomography of the neck with intravenous bolus contrast enhancement and/or magnetic resonance imaging of the facial skull with intravenous contrast enhancement + magnetic resonance imaging of the neck with intravenous contrast enhancement (from the skull base to the superior thoracic aperture) [8].

GCR CGrade of Recommendation – C (Level of Evidence – 5)

Comment: if there are symptoms of cranial nerve involvement, MRI is the preferred method for assessing perineural invasion [6]. CT has higher diagnostic performance for assessing cortical bone destruction [6]. If adequate assessment of primary tumor invasive growth by MRI and CT is impossible due to low informativeness caused by artifacts from metal structures after dental prosthetics, an ultrasound of the oral cavity tissues may be performed.

• All patients with malignant neoplasms of the oral cavity, prior to treatment initiation, are recommended to undergo computed tomography of the chest organs for staging purposes [8].

GCR CGrade of Recommendation – C (Level of Evidence – 5)

Comment: if chest CT cannot be performed, all patients with malignant neoplasms of the oral cavity should undergo chest radiography prior to treatment initiation for tumor staging

• To assess the status of regional lymph nodes, all patients with malignant neoplasms of the oral cavity are recommended to undergo ultrasound of the neck lymph nodes [6, 8].

GCR CGrade of Recommendation – C (Level of Evidence – 5)

• If there are signs of metastatic lymph node involvement detected by imaging methods, it is necessary to perform an ultrasound-guided lymph node biopsy [6, 8].

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

• For the diagnosis of distant metastases in patients with locally advanced malignant neoplasms of the oral cavity and regional lymph node metastasis (stage III-IV or T1-T2 ≥N1), it is recommended to perform positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals with fludeoxyglucose [18F], or computed tomography (CT) of the chest organs with intravenous bolus contrast enhancement + computed tomography (CT) of the abdominal organs with intravenous bolus contrast enhancement [6, 9, 10].

GCR BLOE 2 Grade of Recommendation – B (Level of Evidence – 2)

Comment: If PET-CT or CT cannot be performed, patients with locally advanced malignant neoplasms of the oral cavity and regional lymph node metastasis should undergo targeted chest X-ray and abdominal ultrasound (comprehensive) for the purpose of diagnosing distant metastases and planning the treatment algorithm[1, 6, 7, 8].

• Patients with locally advanced malignant neoplasms of the oral cavity and regional lymph node involvement (stage III-IV or T1-T2 ≥N1), in the presence of clinical suspicion of brain metastasis, are recommended to undergo contrast-enhanced brain MRI [6, 8].

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

Comment: if brain MRI cannot be performed, contrast-enhanced brain CT is recommended [6].

2.5 Other Procedures

2.5.1. Radiation and Chemoradiotherapy Planning

Comment: if it is not possible to perform MRI of the soft tissues of the head and neck, which provides higher tissue and spatial visualization, patients with malignant neoplasms of the oral cavity should undergo CT of the facial skull and neck with intravenous bolus contrast enhancement or whole-body positron emission tomography with tumorotropic radiopharmaceuticals for RT and CRT planning.

2.5.2. Evaluation of antitumor treatment efficacy

• Following RT/CRT, to evaluate the response of the primary tumor and regional metastasis zones to the treatment, it is recommended to perform whole-body positron emission tomography with tumorotropic radiopharmaceuticals using [18F]fluorodeoxyglucose or contrast-enhanced MRI of the soft tissues of the head and neck 2–3 months after treatment completion [8].

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

2.5.3 Follow-up

• Patients are recommended to undergo an endoscopic examination of the upper aerodigestive tract (fibrolaryngoscopy, esophagogastroduodenoscopy) in the presence of symptoms [1, 4, 6, 7].

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

• All patients with malignant neoplasms of the oral cavity are recommended to undergo ultrasound of the neck lymph nodes bilaterally every 3 months during the first year after treatment, and every 3–6 months during the second year. For years 3–5, follow-up examinations are performed once every 6 months. After 5 years — once a year [6, 8].

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

• All patients with malignant neoplasms of the oral cavity are recommended to undergo chest CT every 12 months to monitor distant metastasis sites [6, 8].

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

Comment: if chest CT is not feasible, targeted chest X-ray should be performed in all patients with malignant neoplasms of the oral cavity to monitor distant metastasis sites

• All patients with malignant neoplasms of the oral cavity are recommended to undergo a comprehensive abdominal ultrasound every 3 months during the first year after treatment, and every 3–6 months during the second year. For years 3–5, follow-up examinations are performed once every 6 months, and thereafter once a year [6, 8].

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

• Patients with malignant neoplasms of the oral cavity are recommended to undergo CT of the facial skull and neck or MRI of the soft tissues of the head and neck when clinically indicated, as well as when an adequate physical examination of the area of interest is not feasible, in order to assess local control of the tumor process [6, 8].

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

• In the presence of symptoms indicative of disease recurrence or a confirmed disease recurrence, in order to assess the extent of the tumor process and determine treatment tactics, it is recommended to perform PET/CT with [18F]fluorodeoxyglucose1 or CT of the chest and abdominal organs with IV bolus contrast enhancement [10].

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

Comment: if PET/CT or contrast-enhanced CT of the chest and abdomen cannot be performed, patients with malignant neoplasms of the oral cavity presenting with symptoms of disease recurrence should undergo targeted chest radiography and comprehensive abdominal ultrasound to assess the extent of the tumor process and determine treatment tactics.

• For unresectable processes in patients with malignant neoplasms of the oral cavity, it is recommended to determine PD-L1 protein expression using the immunohistochemical method in a tumor tissue sample, along with TPS (%) and CPS, for palliative treatment planning [6, 8].

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

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

3.1. Principles of surgical treatment and treatment tactics based on disease stage

Introduction:

All patients diagnosed with oral mucosa cancer must initially be examined and evaluated by a medical oncologist specializing in the treatment of head and neck tumors.

This examination allows to:

• Obtain sufficient biopsy material for diagnosis verification.

• Adequately assess the patient's functional status, evaluate the extent of the tumor process, determine the need for additional examination, and rule out the presence of second primary tumors in the oral cavity and oropharynx.

• Assess the primary extent of the tumor process to understand tumor dissemination at the pre-treatment stage in case a non-surgical treatment modality is chosen, which may subsequently fail to achieve a complete response and necessitate surgical intervention.

• Determine potentially feasible surgical options.

For patients undergoing surgical treatment, the surgical plan should be determined taking into account the extent of the tumor process and is feasible only if the surgeon can achieve an R0 resection. In this case, an adequate lymph node dissection plan and a reconstructive plastic stage of the operation should be initially planned to achieve maximum radicality of the surgical intervention and ensure functional and social rehabilitation of the patient [1, 6, 7, 8].

• In patients with oral cavity tumors T1-2, N0, surgery is recommended as the primary treatment method. As an alternative technique (in the presence of absolute contraindications to surgery or patient refusal), external beam radiotherapy (EBRT) (medical service — conformal external beam radiotherapy, including IMRT, IGRT, VMAT, stereotactic) or brachytherapy (BT) (medical service — interstitial radiotherapy of oral cavity tumors) is recommended as a monotherapy option to increase patient survival and reduce complication rates [1, 6, 7, 8].

  Level of Recommendation — C (Level of Evidence — 5).

3.1.1. Surgical treatment

¹When the depth of tumor invasion is greater than 4 mm.

²When the tumor is centrally located or crosses the midline.

³When the depth of tumor invasion is between 2 and 4 mm.

LoR CLoE 5Level of Recommendation — C (Level of Evidence — 5).

Comment: Further treatment tactics are determined depending on the presence/absence of adverse prognostic factors (APFs) according to the routine pathomorphological examination of the biopsy (surgical) material of tumors, tumor-like soft tissue lesions of the oral cavity, and lymph nodes. In the absence of affected lymph nodes (pN0) and the absence of adverse prognostic factors (APFs) in the primary tumor according to the morphological examination of the resected material, active surveillance is recommended [1, 6, 7, 8].

In pN1 following selective neck dissection of levels I–III lymph nodes and the absence of other APFs, re-operation to complete neck dissection of levels I–V lymph nodes or postoperative EBRT is indicated. Another indication for postoperative EBRT is the presence of at least one of the following APFs: pT3–4, perineural, perivascular, or perilymphatic invasion, pN2–3a. When 2 or more APFs are combined, concurrent chemoradiotherapy should be considered [1, 6, 7, 8].

In the presence of only the R1 APF, re-resection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of ENE+ (pN3b) either isolated or in combination with other APFs is an indication for concurrent CRT [1, 6, 7, 8].

• 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 process status and evaluate the risks of bleeding, tumor size, and tumor extension to adjacent structures in cases of tumor ulceration, an existing cavity within the tumor area, tumor recurrence, proximity to carotid artery branches, presence of a non-healing wound, or a prior tumor bleeding episode [6, 120–125].

LoR CLoE 5Level of Recommendation — C (Level of Evidence — 5).

• If there is a confirmed risk of bleeding from tumor nodes, it is recommended to perform angiography of the mass and, in the absence of contraindications, superselective intra-arterial embolization of the tumor vessels to reduce the risk of hemorrhage and fatal complications [120–125].

LoR CLoE 5Level of Recommendation — C (Level of Evidence — 5).

• Radiotherapy for T1–T2, N0. Radiotherapy (medical service — conformal external beam radiotherapy, including IMRT, IGRT, VMAT, stereotactic) is recommended to be administered using a radical program. (For principles of radiotherapy, see below)

• In patients with oral cavity tumors T3-4aN0M0 , surgery as the first-line treatment is recommended, with mandatory ipsilateral or bilateral supraomohyoid neck lymph node dissection as clinically indicated (for centrally located tumors or those crossing the midline).

• In patients with oral cavity tumors T1–4aN1-3M0 , surgery as the first-line treatment is indicated, with mandatory ipsilateral or bilateral lymph node dissection as clinically indicated (for centrally located tumors or those crossing the midline) [1, 6, 7, 8].

LoR CLoE 5Level of Recommendation — C (Level of Evidence — 5).

Comment: Further treatment strategy is determined based on the presence or absence of adverse prognostic factors (APFs) according to routine pathomorphological examination of biopsy (surgical) specimens of tumors, tumor-like soft tissue lesions of the oral cavity, and lymph nodes.

In cases of pN1 and the absence of other APFs, postoperative radiotherapy is indicated. Another indication for postoperative radiotherapy is the presence of at least one of the following APFs: pT3-4, perineural, perivascular, or perilymphatic invasion, or pN2-3a. When 2 or more APFs are combined, chemoradiotherapy should be considered [1, 6, 7, 8].

In the presence of only the R1 APF, re-resection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of ENE+ (pN3b) either isolated or in combination with other APFs is an indication for concurrent CRT [1, 6, 7, 8].

• As an alternative treatment approach for patients with oral cavity tumors T3-4aN0M0, T1–4aN1-3M0 (in the presence of absolute contraindications to surgery or patient refusal), chemoradiotherapy is recommended to improve treatment outcomes and patient survival [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

• In patients with oral cavity tumors T4bN0-3M0 or unresectable N+, or other stages with absolute contraindications for surgical treatment, it is recommended to choose the treatment method depending on the general condition, assessed using the scale developed by the Eastern Cooperative Oncology Group to improve treatment outcomes and reduce the number of complications (ECOG) [1, 6, 7, 8]:

• ECOG 0-1: Chemoradiotherapy or induction polychemotherapy (IPCT) followed by radiotherapy/chemoradiotherapy, with subsequent consideration of surgical intervention.

• ECOG 2: Radiotherapy +/- concurrent chemotherapy (depending on general condition).

• ECOG 3: Palliative radiotherapy or monochemotherapy or palliative care.

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

3.1.2. Assessment of resectability.

• Tumor characteristics that determine an unfavorable clinical, oncological, and functional prognosis, or T4b tumors (unresectability is defined as the inability to achieve an R0 resection) [1, 6, 7, 8].

Note: none of the listed conditions is an absolute contraindication to surgery; careful patient selection with evaluation of the feasibility of total tumor removal is required.

• involvement of the pterygoid muscle or pterygopalatine fossa, clinically manifested as trismus or peripheral neuropathy;

• spread of the tumor process to the skull base (involvement of the pterygoid process of the sphenoid bone, sphenoid bone, or tumor extension into the foramen ovale);

• spread of the tumor to the upper nasopharynx, the orifice of the Eustachian tube, or the lateral wall of the nasopharynx;

• massive metastatic neck disease with breakdown and skin involvement;

• spread of the tumor to mediastinal lymph nodes, the prevertebral fascia, and the cervical spine;

• intradermal metastases;

• spread of the tumor to major blood vessels.

3.1.3. Removal of the primary tumor.

• The resection of advanced oral cavity tumor processes is highly variable and depends on the extent of the primary tumor. It is recommended to remove the primary tumor in accordance with the principles of adequate radicality, taking into account the functional characteristics of the affected organs and tissues, in order to increase survival and improve quality of life [1, 6, 7, 8].

  Level of Recommendation — C (Level of Evidence — 5).

• Removal of the oral cavity tumor is recommended to be performed en bloc, maintaining an adequate margin from the tumor edge to increase survival [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

• Removal of the primary tumor should be planned based on physical examination and a detailed analysis of radiological imaging results.

• Segmental or marginal mandibulectomy is necessary in a number of cases. The extent of resection is recommended to be determined based on the extent of the tumor process (tumor infiltration on clinical examination — spread of the infiltrate to the alveolar ridge of the mandible, tumor fixation relative to the mandible, radiologically confirmed bone invasion). The final extent of mandibular resection should be determined intraoperatively when the surgeon assesses the extent of the tumor process [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

• If involvement of the mandibular canal is clinically or radiologically established, segmental resection of the mandible is recommended to adhere to the principles of adequate radicality and increase survival [1, 6, 7, 8].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

• Transoral robotic surgery (TORS) and laser-assisted resection of the primary tumor to improve functional outcomes and quality of life are recommended for carefully selected patients based on the oncological principles of open malignant tumor surgery and the surgeon's experience [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

3.1.4. Resection margin.

• Following surgical resection, pathomorphological examination of biopsy (surgical) specimens of tumors, tumor-like soft tissue lesions of the oral cavity, and lymph nodes is recommended for final verification of the tumor process and assessment of resection margins. A "clear" resection margin is undoubtedly prognostically favorable for the patient. An R+ resection causes a high risk of rapid disease progression and also determines the aggressiveness and tactics of the patient's postoperative treatment. Clinical studies have reliably confirmed the relationship between close and positive resection margins and the development of locoregional recurrence. Pathomorphological evaluation of resection margins must be performed assessing both superficial-peripheral compartments and deep layers of the resected tissues [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

• When resecting the primary tumor in patients with malignant neoplasms of the oral cavity, a 1.5 cm margin from the edge of the tumor infiltrate is recommended to adhere to the principles of adequate radicality and increase survival. This margin is not always fully achievable along all resection borders because margin dimensions are sometimes limited by the proximity of major blood vessels [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

• The pathomorphological report of the resected oral cavity tumor is recommended to reflect resection margins in order to determine the patient's postoperative treatment strategy. A resection margin is considered clear when the distance between the tumor and the specimen edge is 5 mm or more. A close resection margin is present when the distance between the specimen edge and the tumor tissue is less than 5 mm. The presence of tumor cells, both macro- and microscopically, at the edge of the resected specimen constitutes a positive resection margin [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

• The morphological report of the resected oral cavity tumor and lymph nodes, for the purpose of final verification of the tumor process and determination of the patient's postoperative treatment strategy, is recommended to reflect the following parameters:

• size and extent of the primary tumor;

• depth of primary tumor invasion;

• histological structure of the tumor;

• tumor differentiation grade;

• presence of perivascular, perilymphatic, and perineineural invasion (a negative result must also be explicitly stated);

• regional lymph node status (pN) indicating the total number of examined and metastatic lymph nodes, and the presence of extranodal tumor extension (ENE+/-);

• microscopic evaluation of resection margins (status) R0-1 (R0 — clear resection margin, R1 — tumor at the resection margin) indicating the distance to the closest resection margin in millimeters (mm);

• tumor regression grade (TRG) (if prior treatment was administered) [1, 6, 7, 8].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

3.1.5. Control of the regional lymphatic basin.

• A thorough assessment of regional metastatic zones is an essential component in the management and follow-up of this category of patients. Based on the results of lymph node dissection, it is recommended to perform final staging of the tumor process using the N descriptor in order to determine the postoperative treatment strategy for a patient with malignant neoplasms of the oral cavity. The most important predictor of metastasis is the depth of invasion of the primary tumor: when the thickness of the oral mucosa tumor is less than 2 mm, lymph node dissection is not indicated. When the depth of invasion is greater than 4 mm, ipsilateral selective lymph node dissection is mandatory. If the depth of invasion is in the range of 2 to 4 mm, the need for lymph node dissection is determined individually, taking into account the clinical situation; sentinel lymph node biopsy may be performed [6].

The type of lymph node dissection depends on the cN status:

• cN0 – selective neck dissection levels I–III

• cN+ – neck dissection levels I–V (for ipsilateral metastatic lymph node, ipsilateral neck dissection levels I–V is performed; for contralateral metastatic lymph node or midline tumor location, bilateral neck dissection levels I–V is performed).

LoR CLoE 5Level of Recommendation — C (Level of Evidence — 5).

• In patients with oral cavity tumors with N2c, it is recommended to perform bilateral radical neck dissection (levels I–V) to improve treatment outcomes and patient survival [1, 6, 7, 8].

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

• In tumor processes with a central location having lymphatic drainage to both sides of the neck (cancer of the tip of the tongue, oral mucosa with a midline location in the anterior oral cavity, cancer of the base of the tongue, and central soft palate), it is recommended to perform bilateral neck dissection of equal extent on both sides to comply with the principles of adequate radicality and to increase survival [1, 6, 7, 8].

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• In advanced tumor processes with an ipsilateral location that extend to the midline of the tongue, the anterior-central floor of the mouth, or with close proximity (less than 5 mm) to the midline, it is recommended to perform bilateral neck dissection to comply with the principles of adequate radicality and to increase survival. In the absence of clinical lymph node involvement on the contralateral side, it is recommended to perform selective/modified neck dissection to increase survival [1, 6, 7, 8].

LoR CLoE 5Level of Recommendation — C (Level of Evidence — 5).

3.1.6. Sentinel lymph node biopsy.

• Sentinel lymph node biopsy is a viable alternative to selective neck dissection in limited (T1–T2) tumor processes with clinically negative regional lymph nodes and is recommended in such spread to clarify the extent and final staging of the tumor process. The efficacy rate of this method is 95%. Patients who are found to have metastatic involvement upon sentinel lymph node biopsy require neck dissection of levels I–V to comply with the principles of adequate radicality and to increase survival. In the absence of sentinel lymph node involvement, lymph node dissection is not indicated. Sentinel lymph node biopsy requires appropriate technical equipment of the clinic and surgical experience [1, 6, 7, 8, 11].

GCR BLEL 2Grade of Recommendations — B (Level of Evidence – 2).

3.2. Principles of radiation therapy.

Introduction:

All patients must be evaluated prior to treatment by a radiation oncologist, preferably one specializing in head and neck tumors, who should take the following steps: review the adequacy of pathological verification, staging, and imaging of the tumor process (CT of the facial bones and neck with intravenous bolus contrast enhancement, MRI of the head and neck soft tissues) to determine the extent of tumor spread, rule out a synchronous primary tumor, assess current performance status and feasibility of RT/CRT, and develop a prospective patient management plan that will include oropharyngeal sanitation, including dental examination, provision of adequate nutrition, pain management, wound healing, and other measures necessary for adequate and timely patient rehabilitation. For patients undergoing CT/CRT, the antineoplastic therapy strategy must be worked out in full and within optimal timeframes.

Radiation therapy as primary or adjuvant treatment should be performed in specialized centers with appropriate equipment and experience in treating oral cavity cancer [6, 7, 8, 13].

A deep understanding of anatomy, clinical presentation, and imaging of specific disease manifestations is required. It is preferable to perform RT using high-precision techniques: IMRT (intensity-modulated radiation therapy), VMAT (volumetric modulated arc therapy). Proton therapy is considered in cases of significant normal tissue dose constraints. 3D conformal RT is also acceptable.

The optimal approach in clinical practice is the delivery of planned ionizing radiation doses to the target while minimizing the dose to organs at risk. It is acceptable to discuss volume reduction by excluding vital structures free from tumor involvement at the time of RT planning, if the dose limits for them are exceeded according to QUANTEC criteria (Quantitative Analyses of Normal Tissue Effects in the Clinic) [28]. The irradiation volume to radical doses should not be modified based on the clinical response obtained prior to RT (after induction chemotherapy), except for tumor progression. Anatomical changes during the course of RT (e.g., rapid tumor shrinkage, significant weight loss) may require repeat diagnostic imaging and treatment replanning (adaptation).

3.2.1. Definitive EBRT.

• In patients with malignant neoplasms of the oral cavity with contraindications to surgery, unresectable tumor process, or refusal of surgery, and having indications for definitive EBRT described in the previous section, RT is recommended to the primary tumor and clinically apparent regional metastases (high-risk area) at a dose of 66–70 Gy (2.0–2.2 Gy/fraction) daily Monday through Friday for 6–7 weeks, and to the locoregional area including regional LNs (intermediate/low-risk area) at 46–54 Gy (1.8–2.0 Gy/fraction) to improve survival rates [1, 8, 9]. Irradiation is performed in two (46–54 Gy / 66–70 Gy) or three (46–54 / 60 / 66–70 Gy) phases with sequential reduction of the irradiation volume.

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

Comment: In specialized institutions with appropriate equipment and experience in treating oropharyngeal cancer, accelerated radiation therapy to a total dose of 66–70 Gy (2.0 Gy/fraction, 6 fractions per week) is permissible. In case of 3D conformal radiation therapy, treatment according to the conventional fractionation schedule is strongly recommended (fraction dose of 2 Gy to a total dose of 50 Gy to the locoregional area and up to a total dose of 70 Gy to the primary tumor and clinically apparent regional metastases, respectively).

• In patients with T1–2, N0 oral cavity tumors, as an alternative to EBRT, monotherapy brachytherapy with sentinel LN biopsy (if depth of invasion is greater than 4 mm) or active surveillance is recommended [14, 15, 16].

• Low-dose-rate (LDR) brachytherapy (0.4–0.5 Gy/h):

– Consider an LDR boost of 20–35 Gy combined with external beam radiation therapy (EBRT) at a dose of 50 Gy or 60–70 Gy over several days when using LDR as sole therapy.

• High-dose-rate (HDR) brachytherapy:

– Consider an HDR boost of 21 Gy at 3 Gy/fraction combined with EBRT at a dose of 40–50 Gy or 45–60 Gy at 3–6 Gy/fraction when using HDR as sole therapy.

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

Comments: Cf-252, Ir-192, Co-60 sources can be used for brachytherapy.

The technique of interstitial therapy is based on classical systems for interstitial brachytherapy (Paris, Manchester, or New York systems). In preparation for BT, three-dimensional (3D) planning is used, employing computers and software to calculate and display isodoses and integrate them with computed tomography images of the irradiated tissues. The source placement must be parallel and equidistant, at a distance of 1 to 1.5 cm.

GTV (Gross Tumor Volume) represents the palpable or instrumentally visualized tumor volume. CTV (Clinical Target Volume) includes the gross tumor volume and tissues with a probability of microscopic tumor invasion, in most cases 0.5–1 cm. PTV (Planning Target Volume) does not differ from CTV with proper placement. The cross-sections of the irradiated volumes are square, rectangular, or elliptical in shape.

When performing BT with Cf-252 as a monotherapy for primary tumors, the total dose is 7–9 Gy in terms of the neutron component. The dose rate of neutron radiation ranges from 0.04 to 0.27 Gy/h. Dosimetric planning of interstitial neutron therapy using Cf-252 sources includes two main elements: selecting the source placement scheme based on the target dimensions and calculating the dose distribution generated by the combination of these sources. For the optimal implementation of Cf-252 BT dosimetric planning, various standard or individual fixation devices can be used [14, 15, 16].

When performing BT with Ir-192, a remote afterloading system for contact radiotherapy is used, allowing high dose rate (HDR) irradiation or pulsed dose rate (PDR) irradiation, where Ir-192 is used as the radioactive agent.

During monotherapy HDR BT, the fractional dose (FD) is 3–6 Gy/fraction up to a total dose (TD) of 45–60 Gy. During combined modality radiotherapy with HDR BT, the FD is 3 Gy/fraction up to a TD of 21–30 Gy, following EBRT with a TD of 40–50 Gy. The interval between EBRT and BT should be as short as possible (1–2 weeks) depending on recovery from acute toxicity; BT is administered twice a day with an interval of 6 hours.

Adjuvant high-dose-rate Ir-192 brachytherapy is performed 1–2 months after surgery. Postoperative BT as monotherapy is 45–60 Gy; in combined treatment, the Ir-192 TD is 22–29 Gy combined with EBRT to a TD of 47–60 Gy. [15]

3.2.2. Chemoradiotherapy.

• For patients with locally advanced malignant neoplasms of the oral cavity who have contraindications to surgery, an unresectable tumor process, or refusal of surgical treatment as described in the previous section, it is recommended to administer CRT for radical treatment using the following regimen: radiotherapy to the primary tumor and clinically apparent 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) to improve survival rates [1, 6, 7, 8]. Irradiation is carried out in two (46–54 Gy / 66–70 Gy) or three (46–54 / 60 / 66–70 Gy) phases with a sequential reduction in the irradiation volume.

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

Comment: The benefit of non-traditional dose fractionation schedules during concurrent CRT has not been confirmed [17].

• Preferred is 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 with hyperhydration). The recommended total dose of cisplatin per course of RT is 300 mg/m² [1, 6, 7, 8].

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• As alternative options, especially in the presence of an induction CRT phase, it is recommended to use cetuximab** or carboplatin**, taking into account the tolerability of CRT and the patient's performance status [6, 18, 19].

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• Also as alternative options, it is recommended to use RT combined with #carboplatin** at a dose of 70 mg/m2 and #fluorouracil** at a dose of 600 mg/m2 on days 1–4 every 3 weeks (taking into account the high toxicity of the regimen) [6, 32].

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• In the presence of comorbid conditions preventing concurrent platinum-based CRT (chronic renal failure, creatinine clearance <50–60 mL/min, patient age >65 years, pronounced concurrent renal, cardiovascular, neurological, hepatic pathology, and/or weakened patient condition (ECOG >1)), it is recommended to replace platinum compounds (L01XA: Platinum compounds) with cetuximab** during RT [1, 6, 8; 20; 21; 22, 23].

GCR ALEL 2Grade of recommendation — A (Level of evidence — 2)

3.2.3. Postoperative EBRT

• Postoperative EBRT is recommended for pT3-4 and N2-3 oral cavity tumors, as well as for selected patients with pT1-2, N0-1 stages (in the presence of adverse features) to increase patient survival [1, 2, 8; 9, 24].

  Grade of recommendation — C (Level of evidence — 4)

Comments: The preferred interval after surgery is <6 weeks and should not exceed 3 months. With R0, a dose of at least 60 Gy (2.0 Gy/fraction) is delivered to the area of the excised primary tumor and regional metastases. With R1/R2, the recommended total radiation dose is 66 Gy (2.0 Gy/fraction). To the locoregional area, including unchanged regional lymph nodes, the total dose is 50–54 Gy (1.8–2.0 Gy/fraction) or 54–63 Gy (1.6–1.8 Gy/fraction), taking into account the risk of subclinical spread and the RT method.

Postoperative CRT is performed in case of ENE+ or R1/R2.

Comment: Concurrent CRT is discussed individually in the presence of two or more specified adverse factors, taking into account the patient's age and performance status) [20, 21, 25].

• Palliative RT is recommended to relieve or prevent locoregional symptoms when radical treatment with standard RT is not feasible. An individualized RT plan may be chosen to minimize treatment toxicity, including doses of 50 Gy (2.5 Gy/fraction) and 30 Gy (3 Gy/fraction) [1, 2, 8; 9, 26].

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

3.3. Systemic therapy

3.3.1. Principles of systemic therapy

The choice of chemotherapy should be individualized based on patient characteristics (general condition, treatment goals) [6].

• For patients with malignant neoplasms of the oral cavity who have not previously received chemotherapy and have no distant metastases, to improve survival within concurrent CRT, it is recommended to use the agents [6, 7, 8, 19, 23, 27, 30, 31, 32].

  Preferred regimens:

• Cisplatin** 100 mg/m² — day 1, 21, 43

• Cisplatin** 40 mg/m² — IV weekly

• Carboplatin** AUC 5-6 — day 1 + fluorouracil** 1000 mg/m²/day days 1–4, interval 21 days

Other regimens:

• Cetuximab** 400 mg/m2 — one week prior to RT, then 250 mg/m2 weekly during RT

• Cisplatin** 100 mg/m² — day 1, interval 21 days + #Fluorouracil** 1000 mg/m²/day days 1–4 [6, 32].

• #Cisplatin** 20 mg/m^{2 —} day 1, interval 7 days + #paclitaxel** 30 mg/m^{2 —} day 1, interval 7 days [31].

• #Fluorouracil** 800 mg/m²/day on RT days + #hydroxycarbamide** 1 g bid [6, 31, 32].

GCR CLEL 5Grade of recommendation — C (Level of evidence — 5).

Comments: The standard chemoradiotherapy (CRT) regimen is cisplatin** 100 mg/m2 every 3 weeks concurrently with radiotherapy (RT) for 3 cycles. This regimen provides the best response. However, this regimen is associated with the development of toxic reactions [28, 43]. Modifying the regimen with #cisplatin** at a dose of 40 mg/m2 weekly (combined with RT) helps reduce toxicity [6, 32]. The use of carboplatin** AUC 1.5–2.0 weekly during RT is recommended if there are contraindications to cisplatin** treatment or following prior induction polychemotherapy with cisplatin**. An alternative option may be the concurrent administration of cetuximab** with RT (400 mg/m2 one week prior to RT, followed by 250 mg/m2 weekly during RT), which increases overall survival and improves locoregional control compared to RT without increasing toxicity. However, substituting cisplatin** with cetuximab** should only be done if there are contraindications to cisplatin** and following induction polychemotherapy using cisplatin**[32]

• For patients with stage III-IV malignant neoplasms of the oral cavity with comorbid conditions that preclude concurrent CRT with cisplatin** (chronic renal failure, severe heart disease, etc.), to improve survival within concurrent CRT, it is recommended to use the following agents [6, 7, 8, 32, 37]:

  Carboplatin** AUC 2.0 - day 1 weekly

  Cetuximab** 400 mg/m² one week prior to RT and 250 mg/m² weekly during RT

GPP CLoE 5Level of Evidence/Grade of Recommendation – C (level of evidence - 5).

• In patients with oral cavity malignant neoplasms who have indications for postoperative CRT (according to pathomorphological prognostic factors), the use of Cisplatin** 100 mg/m² on days 1, 22, and 43 is recommended [6, 7, 8, 27]

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

3.3.2. Induction chemotherapy (ICT)

• Induction chemotherapy (ICT) is recommended for patients with locally advanced oral cavity malignant neoplasms with unresectable tumor process and ECOG 0-1 to reduce tumor size, decrease the incidence of distant metastasis, and improve survival [6, 7, 8].

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• The decision on applying a bi- and trimodal approach (induction CT, CRT / surgery) is recommended to be made by a multidisciplinary team before initiating treatment. This approach can be implemented in specialized centers that have all the necessary departments whose specialists are involved in each stage of treatment [6, 7, 8].

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• The recommended induction chemotherapy regimen for squamous cell carcinomas of the head and neck: Docetaxel** 75 mg/m² - day 1 + cisplatin** 75 mg/m² - day 1 + #fluorouracil** 1000 mg/m2/day on days 1-4, interval 21 days. Total number of cycles – 3 [30, 32]

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

After completing 2-3 cycles of ICT, a follow-up examination is recommended to assess the efficacy of ICT. Subsequent management strategy (CRT/ surgery for selected cases) is determined by a multidisciplinary board. Any subsequent local treatment step should be initiated 3-4 weeks after completing ICT [6, 7, 8].

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

3.4. Treatment of recurrent or residual tumor

• In patients with oral cavity tumors in the case of local recurrence or residual tumor with resectability of the oral cavity tumor, surgical intervention with achievement of R0 status is recommended, along with a discussion of RT or concurrent CRT [1, 6, 7, 8].

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

Comment:further management strategy after surgical treatment for recurrence or progressive growth is determined based on the presence/absence of adverse prognostic factors (APFs) according to the pathomorphological examination of the surgical specimen. The absence of APFs does not require additional treatment; active surveillance is recommended. The presence of R1 and ENE+ alone or in combination with APFs is an indication for CRT. An indication for postoperative external beam radiotherapy (EBRT) is the presence of at least one or more of the following APFs: pT3-4, perineural, perivascular, or perilymphatic invasion, pN1-3a. If EBRT was previously performed or contraindications exist, polychemotherapy is administered.

• In patients with unresectable oral cavity tumors, the choice of treatment method is recommended to be based on the general condition (ECOG) to reduce the risk of recurrence and improve treatment outcomes [1, 6, 7, 8]:

• ECOG 0-1 - Administration of CRT or induction polychemotherapy followed by EBRT/CRT, with subsequent consideration of surgical intervention.

• ECOG 2 - Administration of EBRT +/- concurrent CT (depending on general condition)

• ECOG 3 - Palliative EBRT, or monochemotherapy, or palliative care.

Level of Recommendation — CLevel of Evidence — 5Level of Recommendation — C (Level of Evidence — 5).

• In patients with isolated local or regional recurrence without signs of multiple regional or distant metastasis, who received RT/CRT as the first-line treatment with a time interval of 12 months or more, and an ECOG status of 0-2, a repeat course of RT/CRT may be administered, taking into account the radiation dose received during the first course of irradiation [12].

  Grade of Recommendations — C (Level of Evidence — 3).

• For patients with any T, any N, M1, or local recurrence/residual tumor with distant metastases, with the absence or presence of recurrence/residual tumor at the primary site and regional metastasis zones in the presence of distant metastases, the choice of treatment method is recommended based on general condition (ECOG) to increase patient survival and reduce the risk of complications [1, 6]:

• ECOG 0–1 - Systemic therapy based on platinum agents. Optimal regimens are considered to be those with the addition of monoclonal antibodies (mAbs) cetuximab** (L01XC06) or pembrolizumab** to cytostatics (L01XC Monoclonal antibodies). In the 1st line of therapy, regimens based on the immunotherapy drug pembrolizumab** may be used. According to the updated prescribing information, the combination regimen with cytostatics (L01 Antineoplastic agents) can be prescribed only in the presence of a CPS expression ≥ 1. Upon progression (recurrence or metastatic process) during or within 6 months following prior platinum-based therapy for patients in satisfactory general condition (ECOG 0–1) who have not previously received a pembrolizumab**-containing regimen, the administration of mAbs blocking the PD1 receptor must be considered. Although the use of nivolumab** in head and neck cancer (HNC) has no regulatory limitations based on ligand expression levels, a pre-planned exploratory analysis revealed a significant improvement in overall survival in patients with PD-L1 expression ≥ 1 %. For PD-L1 < 1 %, no overall survival benefit was observed. A similar correlation was found in the trial evaluating pembrolizumab**. According to the updated prescribing information, pembrolizumab** upon progression on platinum therapy (L01XA: Platinum compounds) can be prescribed if PD-L1 TPS expression is ≥ 50 %. Prior cetuximab** therapy does not reduce the efficacy of nivolumab** and pembrolizumab**. No additional tumor cell characterization is required to prescribe cetuximab**-containing regimens. Among other antineoplastic agents, any previously unused drugs may be used. A slight advantage is more pronounced regarding the objective response rate when using taxanes (L01CD: Taxanes). The objective response rate with monotherapy ranges from 15 % to 35 %. A platinum-based doublet (cisplatin** + fluorouracil**) demonstrates a higher objective response rate compared to monotherapy with comparable overall survival, but at the cost of higher toxicity. Surgical treatment for distant metastases is possible if R0 resection can be achieved, or EBRT/CRT can be directed to the area of distant metastasis in the absence of recurrence/residual tumor in the primary site and regional metastasis zones. If impossible, palliative care.

• ECOG 2 - Monochemotherapy or palliative care.

• ECOG 3 - Palliative care.

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• For the treatment of recurrent, initially unresectable tumors, or metastatic tumor processes when CRT cannot be administered, poly- or monochemotherapy is recommended to improve patient survival [5] (Table 1). Taking into account the patient's general condition and/or treatment goals, the following drug combinations may be recommended (the number of cycles is determined by treatment tolerability and efficacy) [1, 6, 7, 8, 32]: Table 1. Recommended regimens of antineoplastic drug therapy for oral cavity tumors

¹For 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.

⁴As first-line therapy in the presence of PD-L1 CPS > 20. In case of progression during or after platinum-based chemotherapy, with a TPS level ≥ 50%. The recommended duration of use corresponds to the design of registration trials.

⁵ As first-line therapy at a CPS expression of ≥ 1.

⁶The regimen corresponds to clinical trials; in case of poor tolerability, the dose should be reduced.

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

For patients with progression of the metastatic phase of the disease after the use of the monoclonal antibody (L01XC) cetuximab**, immuno-oncology drugs: (L01XC18) pembrolizumab** and (L01XC17) nivolumab** it is recommended to consider prescribing #afatinib** (L01EB epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors) 40 mg/day orally until disease progression or unacceptable toxicity (efficacy in squamous cell carcinoma of the head and neck has been evaluated only in foreign studies) to improve progression-free survival [33].

GCP ALOE 2Grade of Recommendation — A (Level of Evidence — 2)

3.5. Clinical nutrition and dietary management

Nutritional support when planning surgical treatment is carried out in the presence of at least one of the specified factors: unintentional weight loss over the past 6 months (loss of 10% or more), body mass index <20 kg/m¹, hypoproteinemia <60 g/L or hypoalbuminemia <30 g/L, deterioration of food intake over the past week. In the case of chemotherapy, indications are: 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 feed adequately via the mouth; moderate to severe enteropathy [57].

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 oral cavity [34].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

• Patients with malignant neoplasms of the oral cavity who have indications for nutritional support are recommended to use ready-to-use specialized formulas enriched with protein, omega-3 fatty acids, arginine, and ribonucleic acids at a dose of at least 400–600 mL/day to improve treatment tolerance and reduce the rate of complications [34, 35].

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

Comments: Adequate nutrition and maintenance of water balance are vital. Combating "iatrogenic" nutritional deficiency is a crucial task in the successful treatment of patients with head and neck tumors. The preferred method is oral nutrition (sipping). If oral intake is impossible, feeding the severely ill patient via the mouth and/or nasogastric tube, parenteral or mixed nutrition is performed. The calculation of the patient's basic needs is focused on the total amount of energy consumed and the quantitative ratio of various substrates. The caloric content of the diet should be 25–30 kcal/kg of body weight per day, and the protein dose should be 1.0–1.5 g/kg of body weight per day. Replenishment of the daily requirement for vitamins and trace elements is necessary [35, 36, 37, 38, 39].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In patients with an expected life expectancy of less than a few months, it is recommended to reduce the invasiveness of nutritional interventions; when planning nutritional support, preference should be given to dietary counseling and sip feeding (oral nutritional supplements) [43].

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

• In patients with an expected survival of less than a few weeks, care and comfort-oriented symptomatic therapy are recommended, including the relief of thirst and hunger [43].

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

• The patient's required daily caloric intake during therapy should be 25–30 kcal/kg of body weight per day, and the required protein intake should be 1.2–2 g of protein per 1 kg of body weight per day [43].

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

• A multimodal approach is recommended, aimed at alleviating symptoms that affect food intake, ensuring adequate energy and nutrient intake, minimizing catabolic changes, supporting physical activity, and providing psychological and social support in patients with malignant tumors of the oral cavity in order to correct malnutrition [43].

  Level of Evidence C (reliability of evidence level – 5).

• It is recommended to conduct dietary counseling as a first step to increase the intake of energy, protein, and other essential nutrients [43].

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

• The enteral route of nutrient delivery is preferred. Parenteral nutrition is recommended in the complete absence of gastrointestinal function, or if it is not possible to meet the required energy and protein needs via enteral nutrition (sip feeding or tube feeding) [43].

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

Comments: Telerehabilitation is a complex of rehabilitation, assistive measures, and training programs provided to the patient remotely via telecommunication and computer technologies. It allows patients to independently perform restorative treatment programs under the remote control and guidance of a specialist physician. Tele-support tools may include phone calls or messages, email, mobile applications, web platforms, and videoconferencing. Telerehabilitation technologies can be used at all stages of antitumor treatment: during preoperative preparation, in the delayed and late postoperative periods after discharge from the hospital, and to improve tolerance to chemoradiotherapy, but it is particularly relevant after the transition from inpatient to outpatient rehabilitation. Advantages of telerehabilitation: ensuring continuity between inpatient and outpatient treatment (including under conditions of viral load), the possibility of reducing the duration and frequency of hospitalizations, organizing control over complications and adverse events of antitumor treatment, increasing treatment accessibility for the patient by reducing the effort and cost of transportation, monitoring the patient's condition in the postoperative period, and maintaining the necessary intensity of rehabilitation sessions using an economical way to organize individual and group exercise therapy classes to restore impaired functions during antitumor treatment.

Prerehabilitation:

Prehabilitation:

• Patients with oral cavity and pharyngeal cancer who are at high risk of malnutrition should receive nutritional support for 10–14 days before surgical treatment [55].

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

• If nutritional disorders are expected within 7 days after surgery, additional enteral sip feeding as part of prehabilitation is mandatory [55].

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

• Prophylactic placement of a nasogastric tube or percutaneous endoscopic gastrostomy (PEG) (gastrostomy using video-endoscopic technologies) is recommended to maintain patients' functional status and prevent treatment-associated complications in the presence of the following indications [8]:

• documented significant weight loss (5% of baseline body weight over the previous month or 10% of baseline body weight over the previous 6 months);

• existing dehydration, dysphagia, anorexia, or pain that limits the patient's ability to eat or drink adequately;

• significant comorbid and morbid conditions that may be aggravated by dehydration, a hypocaloric diet, or the inability to swallow required medications;

• aspiration syndrome, especially in the elderly or in patients with cardiopulmonary insufficiency;

• patients who are likely to have prolonged swallowing disorders, including those anticipated during radiation therapy.

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

Comment: To maintain swallowing function during and after antineoplastic therapy in patients with preserved swallowing and no risk of aspiration, a natural diet is indicated. It should be taken into account that changes in swallowing function may appear throughout the entire course of treatment and after its completion, and must be monitored throughout the patient's life [8].

Stage I rehabilitation for surgical treatment

• In patients with oral cavity malignancies in the early postoperative period, it is recommended to manage pain syndrome using a combination of analgesic therapy and physiotherapy, exercise therapy, positioning therapy, clinical and psychological correction methods, transcutaneous electrical nerve stimulation (TENS), and acupuncture point stimulation with other physical factors to improve functional outcomes [60].

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

• For patients who have undergone head and neck surgery for oral cavity malignancies, general medical massage is recommended in the postoperative period to improve quality of life [61].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

• For patients with oral cavity malignancies in the preoperative and early postoperative periods, a speech therapist consultation is recommended for prescribing a set of special exercises to restore swallowing function and train the patient in speech production [62].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

• There are several restrictions for speech therapy rehabilitation: it is not recommended to perform active functional training in patients with oral cavity malignancies in the early postoperative period, during the primary healing stage, and in the presence of fistulas in order to reduce the risk of complications. Violation of the functional training regimen is unacceptable [63].

GCR BLEL 3Grade of Recommendation — B (Level of Evidence — 3).

• To restore swallowing function in patients with oral cavity malignancies, exercises aimed at increasing the range of motion and muscle strength, as well as enhancing voluntary control over the timing and coordination of the swallow (exercise therapy for aphasia and dysarthria), are recommended [63, 64].

GCR BLEL 2Grade of Recommendation — B (Level of Evidence — 2).

Comments: Postural support is also important, i.e., finding a suitable posture during swallowing. Additionally, phonopedic techniques (e.g., sliding into falsetto), swallowing maneuvers (e.g., effortful swallow), and selection of swallowing textures are used.

• For patients with oral cavity malignancies to improve respiratory function, especially after tracheostomy placement, the following are recommended: coordinating inhalation and exhalation, taking an inhalation sufficient for speech production, finding an optimal body position, pausing, and breathing exercises aimed at coordinating phonatory breathing [65].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments: Breathing exercises are structured on the principle of progressing from simple to complex. First, patients are asked to blow light objects off the palm and table, the sequence of inhalation and exhalation phases is practiced, the exhalation phase is extended, and then phonatory exhalation is added along with diaphragmatic breathing practice. During functional training, exercises are performed for all articulatory organs: lips, cheeks, tongue, floor of the mouth, hard palate, soft palate muscles, pharyngeal muscles, and extrinsic neck muscles.

• For patients with oral cavity malignancies to establish compensatory mechanisms of speech production, dynamic and static articulation exercises with a gradual increase in load are recommended [66].

GCR BLOE 3Grade of Recommendation B (Level of Evidence - 3).

Comments: They begin with exercises that activate lip movements, then move on to exercises for the lower jaw and articulation gymnastics for the tongue, relying on phantom sensations of the missing organ.

• To eliminate resonance disorders in the postoperative period manifested by hypernasality and nasal emission, exercises promoting activation of the velum and palatal arches, development of plasticity and extensibility of soft palate tissues with simultaneous contraction of the posterior pharyngeal wall muscles and soft palate muscles, are recommended. The goal of these exercises is to ensure the maximum possible velopharyngeal closure [66].

GCR BLOE 3Grade of Recommendation B (Level of Evidence - 3).

• Low-level laser therapy (intravenous laser blood irradiation) may be prescribed to improve postoperative wound healing. It is safe and does not increase the rate of progression and local recurrence [71].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Stages II and III rehabilitation for surgical treatment

Comments: These include static, dynamic, and resistance exercises. To restore function, movements are performed not only in the jaw-lowering and elevating plane, but also lateral, forward, backward, and circular movements.

Comments: The highest efficacy of lymphedema therapy after combined treatment of head and neck tumors is observed with the use of complete decongestive therapy.

• Complete decongestive therapy, including exercise therapy, compression therapy, medical massage of the neck, scalp, and face, and skin care for a severely ill patient, is recommended as the "gold standard" in the treatment of lymphedema of all localizations in patients with oral cavity malignancies [75].

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• Low-frequency general magnetotherapy combined with complete decongestive therapy is recommended for patients with oral cavity malignancies for the treatment of lymphedema [76].

GCR CLEL 4Grade of Recommendation — C (Level of Evidence — 4).

• The use of low-level laser therapy in combination with complete decongestive therapy is recommended for patients with oral cavity malignancies to accelerate the reduction of edema severity [77].

LEL 5Grade of Recommendation — C (Level of Evidence — 5).

• Low-level laser therapy targeting the masticatory muscles and the temporomandibular joint may be used to correct trismus in patients with head and neck cancer [82].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comments: Currently, spa-resort treatment may be prescribed to patients with oral tumors under clinical dispensary observation group III who have received radical anti-tumor treatment, have completely finished it, and have no signs of tumor recurrence or metastases. To refer a patient for medical rehabilitation, an oncologist at a specialized oncological outpatient clinic must issue a medical certificate valid for 1 month, signed by the head of the department. This certificate indicates the primary diagnosis and the clinical dispensary observation group, confirmed by the results of a follow-up comprehensive examination. 1–2 months after completing the course of medical rehabilitation in a sanatorium-resort setting, the patient must appear for an examination by the oncologist at the outpatient clinic where they are registered. 3–6 months after completing radical treatment, patients may be sent to local sanatoriums or resorts in the climatic zone of their permanent residence at any time of the year. For residents of northern regions, southern resorts are recommended during the winter period and no earlier than 6–12 months after the end of radical treatment. It is not recommended to refer patients to resorts with an unfavorable clinical weather class characterized by pronounced interseasonal and intraday sharp changes in weather factors, resorts with thermal springs, or climates with high background temperatures, high humidity, and high ultraviolet radiation intensity.

Rehabilitation during chemotherapy

Antineoplastic treatment of head and neck cancer causes psychological distress, anxiety, and depression, which impairs patients' quality of life [86].

• For patients with malignant neoplasms of the oral cavity 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 [87].

GCR BLEL 3Grade of Recommendation — B (Level of Evidence — 3).

Comments: Performing a therapeutic exercise program incorporating aerobic load 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 [88].

• To reduce fatigue and increase endurance in patients with malignant neoplasms of the oral cavity during chemoradiotherapy, it is recommended to perform therapeutic exercises in the form of moderate-intensity aerobic workouts combined with resistance training [89].

GOM BLOE 2Grade of Recommendation - B (Level of Evidence - 2).

Comment: Combining therapeutic exercise with psychological support is used as a comprehensive treatment for chemotherapy-induced fatigue [90]. In addition, a 6-week course of medical massage is advisable to reduce fatigue associated with combination therapy [91].

• Balance training exercises are recommended for patients with malignant neoplasms of the oral cavity to correct polyneuropathy [92].

GCR BLOE 3Grade of Recommendation B (Level of Evidence - 3).

Comment: Percutaneous electrical nerve stimulation for 20 minutes a day for 4 weeks has also proven effective in treating chemotherapy-induced peripheral neuropathy [95].

• The use of local cryotherapy is recommended for the prevention of chemotherapy-induced alopecia [98].

FoR BLoE 3Level of recommendation evidence - B (level of data reliability - 3).

Rehabilitation during radiotherapy

• During radiation therapy, oral inhalations with alkaline-oil solutions are recommended to prevent the development of mucositis [106].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments:Regular oral rinsing with isotonic solution removes food debris and accumulated secretions. Oils (olive, peach, sea buckthorn, or rosehip) can be used for oral applications or nasal drops. In the presence of pain syndrome, topical anesthetics and systemic analgesics are used [97]. Opioids are most commonly required, with particular attention to transdermal formulations [107].

From the onset of radiation dermatitis until complete resolution of reactions, the use of regenerants and reparants (gels, dioxomethyltetrahydropyrimidine**), as well as topical ultraviolet-protecting agents, is indicated. The skin must be protected from friction and irritation. To combat xerosis, a cream with urea and an oil solution of vitamin A are used. For bioloid dermatitis, it is advisable to use a cream containing vitamin K.

In the post-radiation period, irradiated normal tissues are highly vulnerable and must be handled with care. In the early stages, invasive diagnostic procedures and biopsies should be avoided unless absolutely necessary. A customized diet is indicated, combined with proton pump inhibitors if necessary [108]. 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 frequent cause of radiation osteomyelitis is tooth extraction in the previously irradiated area; therefore, one should resort to conservative methods whenever possible and perform tooth extractions only when necessary, accompanied by antibiotic therapy.

• A combination of nutritional support and physical rehabilitation during radiation therapy is indicated to improve body composition and physical functions in patients with head and neck cancer [100].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comments: although there is insufficient evidence regarding the efficacy of interventions such as baking soda rinses, saline rinses, and oral hygiene education, these methods may be used given their safety profile. Although there is insufficient evidence supporting the use of professional dental care for the prevention of oral mucositis, most experts agree that dental examination and treatment prior to chemoradiotherapy are desirable to reduce the risk of local and systemic infections from odontogenic sources.

Comments: exercises incorporating active and movement-based techniques aimed at stimulating active swallowing, normal physiological and phonational breathing, as well as restoring the functional activity of the masticatory, facial, and tongue muscles, are indicated.

5. Prevention and Dispensary Observation

In the 1st year, physical examination and history taking are recommended every 1–3 months; in the 2nd year, every 2–6 months; and at 3–5 years, every 4–8 months. 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:

• medical history and physical examination;

• thyroid-stimulating hormone level testing every 6–12 months if neck irradiation was performed, to assess thyroid function [1, 4, 6, 7, 8].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comment: the goal of follow-up is the early detection of disease progression for the prompt initiation of chemotherapy or surgical treatment of resectable metastatic lesions and recurrent tumors, as well as the detection of metachronous head and neck tumors.

• All diagnostic imaging modalities, including dynamic monitoring, can be found in the instrumental diagnostics section.

• Patients with oral cavity malignancies are recommended to be under the care of a dentist before, during, and after specialized treatment to assess oral cavity status, risk of caries and periodontal disease, extraction of "problematic" teeth, prevention of radiation-induced osteonecrosis, elimination of potential infection sources, and patient motivation for oral hygiene maintenance. "Problematic" teeth must be extracted at least 2 weeks prior to the start of specialized treatment [1, 4, 6, 7, 8, 86, 87, 88, 89, 90].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comment: Radiation therapy to the head and neck region can cause xerosis and salivary gland dysfunction, significantly increasing the risk of dental caries and associated adverse consequences such as dentoalveolar infection and osteoradionecrosis. Radiation therapy also affects tooth structure, increasing the likelihood of demineralization in the setting of xerosis, post-irradiation microflora alterations, and adherence to a caries-associated diet. Moreover, oral infections impair post-surgical repair processes and necessitate intensified antibiotic regimens. Radiation-associated caries and other dental tissue changes can develop within the first 3 months after completion of radiation therapy.

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, which is approved by the authorized federal executive body;

2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of 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 body.

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:

• digital images obtained from pathomorphological studies to the pathoanatomical bureau (department) of the fourth group (reference center) [1] via information interaction, including the use of telemedicine technologies during 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. presence of oncological disease complications requiring emergency and urgent specialized medical care;

2. presence of complications from cancer treatment (surgical intervention, radiation therapy, drug therapy, etc.).

Indications for hospitalization in a medical organization in a planned form are:

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

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

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 a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

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

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

4. need to transfer the patient to another medical organization in the relevant medical specialty.

   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.

[1]

7. Additional Information

Factors influencing the prognosis of the disease include:

● size and extent of the primary tumor;

● depth of invasion of the primary tumor;

● tumor differentiation grade;

● presence/absence of perivascular, perilymphatic, and perineural invasion;

● regional lymph node status (pN) (neck lymph node metastases double patient mortality/halve survival);

● extranodal tumor extension;

● margin status (R0–1).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Polyakov Andrey Pavlovich, MD, PhD, Associate Professor, Head of the Microsurgery Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia, member of the All-Russian Public Organization "Russian Society of Specialists in Head and Neck Tumors"

2. Polkin Vyacheslav Viktorovich, PhD, Head of the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb MRRC – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia

3. Agababyan Tatev Artakovna, Head of the Diagnostic Radiology Department, A.F. Tsyb MRRC — branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia, PhD, Obninsk https://orcid.org/0000-0002-9971-3451

4. Aliyeva Sevil Bagaturovna, MD, PhD, Leading Researcher, Radiation Oncology Department, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, member of the All-Russian Public Organization "Russian Society of Specialists in Head and Neck Tumors".

5. Alymov Yury Vladimirovich, PhD, Oncologist at the Department of Surgical Treatment Methods No. 5 (Endocrine Oncology), N.N. Trapeznikov Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, Executive Director of the All-Russian Public Organization "Russian Society of Specialists in Head and Neck Tumors"; ORCID: https://orcid.org/0000-0002-6851-9867

6. Artemyeva Anna Sergeevna, PhD, Pathomorphologist, Head of the Scientific Laboratory of Tumor Morphology, N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health of Russia, Associate Professor at the Department of Additional Professional Education, N.N. Petrov National Medical Research Center of Oncology

7. Boyko Anna Vladimirovna, MD, PhD, Professor, Head of the Radiation Therapy Department with Modification, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia.

8. Bolotin Mikhail Viktorovich, PhD, Researcher, Department of Surgical Treatment No. 11 of Upper Aerodigestive Tract Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, member of the All-Russian Public Organization "Russian Society of Specialists in Head and Neck Tumors".

9. Bolotina Larisa Vladimirovna, MD, PhD, Associate Professor of the RAS, Head of the Chemotherapy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia. Chairperson of the Head and Neck Tumor Group of the Practical Guidelines of the Russian Society of Clinical Oncology, Board Member.

10. Vinogradov Vyacheslav Vyacheslavovich, MD, PhD, Professor, Head of the Scientific and Clinical Department of Otorhinolaryngology, Scientific and Clinical Center of Otorhinolaryngology of the Federal Medical-Biological Agency of Russia.

11. Vladimirova Lyubov Yuryevna, MD, PhD, 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

12. Gevorkov Artem Rubenovich, PhD, Senior Researcher, Radiation Oncologist at the Radiation Therapy Department with Modification, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia, member of the All-Russian Public Organization "Russian Society of Specialists in Head and Neck Tumors"

13. Girshovich Mikhail Markovich, PhD, Radiation Oncologist, N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health of Russia; https://orcid.org/0000-0002-7925-9570

14. Gulidov Igor Alexandrovich, Head of the Radiation Therapy Department, A.F. Tsyb MRRC – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia

15. Guz Alexander Olegovich, PhD, Oncologist, Head of the Head and Neck Tumors Department, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine

16. Daikhes Nikolay Arkadyevich, Corresponding Member of the RAS, MD, PhD, Professor, Director of the Scientific and Clinical Center of Otorhinolaryngology of the Federal Medical-Biological Agency of Russia.

17. Dronova Ekaterina Leonidovna, Radiologist, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, member of the All-Russian Public Organization "Russian Society of Specialists in Head and Neck Tumors".

18. Yengibaryan Marina Alexandrovna, MD, PhD, 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 Specialists in Head and Neck Tumors".

19. Ignatova Anastasia Valeryevna, PhD, Oncologist at the Department of Surgical Treatment Methods No. 5, N.N. Trapeznikov Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, member of the All-Russian Public Organization "Russian Society of Specialists in Head and Neck Tumors", Assistant at the Department of General and Clinical Dentistry, RUDN University. ORCID: https://orcid.org/0000-0002-6796-0968

20. Klimenko Veronika Viktorovna, PhD, Physician at the Clinical Diagnostic Department, N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health of Russia; https://orcid.org/0000-0003-1079-4492

21. Korniyetskaya Anna Leonidovna, PhD, Senior Researcher, Chemotherapy Department of the Drug Treatment of Tumors Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of Russia.

22. Ekaterina V. Kostromina, Cand. of Sci. (Med.), Ultrasound Diagnostics Physician, Radiologist at the Department of Radiology, Researcher at the Research Department of Diagnostic and Interventional Radiology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor at the Department of Radiology and Medical Visualization, Faculty of Postgraduate and Additional Professional Education, St. Petersburg State Medical University; https://orcid.0000-0002-4245-687X

23. Larisa A. Krasilnikova, Cand. of Sci. (Med.), Cytopathologist, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

24. Mikhail A. Kropotov, Dr. of Sci. (Med.), Head of Surgical Department No. 10 (Head and Neck Tumors), N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

25. Svetlana I. Kutukova, Dr. of Sci. (Med.), Associate Professor, Academician I.P. Pavlov First St. Petersburg State Medical University of the Ministry of Health of the Russian Federation, City Clinical Oncology Dispensary of St. Petersburg

26. Denis E. Kulbakin, Dr. of Sci. (Med.), Senior Researcher, Oncologist at the Head and Neck Tumors Department, Cancer Research Institute of Tomsk National Research Medical Center

27. Aleksandr V. Mordovskiy, Cand. of Sci. (Med.), 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

28. Ali M. Mudunov, Dr. of Sci. (Med.), Professor of the Russian Academy of Sciences, Head of Surgical Treatment Department No. 10 for Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, President of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists"

29. Shamil I. Musin, Cand. of Sci. (Med.), Head of Surgical Department No. 6, Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Bashkortostan

30. Podvyaznikov Sergey Olegovich, MD, PhD, Professor, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Vice President of the National Association of Head and Neck Oncologists.

31. Olga I. Ponomareva, Radiologist at the Radiotherapy Department, N.N. Petrov National Medical Research Center of Oncology; https://orcid.0000-0002-7004-9630

32. Zamira A.-G. Radzhabova, Dr. of Sci. (Med.), Associate Professor of the Russian Academy of Sciences, 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.0000-0002-6895-0497

33. Reshetov Igor Vladimirovich, MD, PhD, Academician of the Russian Academy of Sciences, Head of the Department of Oncology, Radiotherapy and Reconstructive Surgery, I.M. Sechenov First Moscow State Medical University, President of the Federation of Specialists in the Treatment of Head and Neck Diseases

34. Ilya S. Romanov, Dr. of Sci. (Med.), 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, N.I. Pirogov Russian National Research Medical University

35. Natalia A. Rubtsova, Dr. of Sci. (Med.), Head of the 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 Radiation and Instrumental Diagnostics of the Russian Ministry of Health in the Central Federal District of the Russian Federation.

36. Andrey N. Rudyk, Cand. of Sci. (Med.), Oncologist at Oncology Department No. 5 (Head and Neck Tumors), Professor M.Z. Sigal Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan, 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 RMACPE of the Russian Ministry of Health, Associate Professor at the Department of Surgical Diseases of Postgraduate Education, Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan.

37. Tatiana Yu. Semiglazova, Dr. of Sci. (Med.), 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

38. Stepanova, Alexandra M., Head of the Rehabilitation Department at the P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health

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

40. Elena V. Tkachenko, Cand. of Sci. (Med.), Head of the Short-Term Antineoplastic 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

41. 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

42. Aleksandr A. Fedenko, Dr. of Sci. (Med.), Professor of the Russian Academy of Sciences, 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

43. Evgeny V. Khmelevsky, Dr. of Sci. (Med.), 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.

44. Malika M. Khodzhibekova, Dr. of Sci. (Med.), Radiologist at the Radionuclide Diagnostics Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

45. Evgenia V. Tsurlina, Cand. of Sci. (Med.), Endocrinologist at the Functional Diagnostics Department, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

46. Choynzonov, Evgeny L., Dr. of Sci. (Med.), Academician of the Russian Academy of Sciences, Director of the Cancer Research Institute of the Tomsk National Research Medical Center, Head of the Head and Neck Tumors Department at the Cancer Research Institute of the Tomsk National Research Medical Center, Head of the Department of Oncology at the Siberian State Medical University of the Russian Ministry of Health, Member of the All-Russian Public Organization "Russian Society of Head and Neck Cancer Specialists"

47. Liliya P. Yakovleva, Cand. of Sci. (Med.), Oncologist, Head of the Center for Diagnostics and Treatment of Head and Neck Tumors, A.S. Loginov Moscow Clinical Scientific Center of the Russian Ministry of Health

    Section: Organization of Medical Care

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

2. Ivanov, Sergey A., Dr. of Sci. (Med.), Professor of the Russian Academy of Sciences, Director of the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health

3. Nevolskikh, Alexey A., Dr. of Sci. (Med.), Deputy Director for Clinical Work at the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Zhanna V. Khaylova, Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological 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. Medical students, residents, and postgraduate students

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)

Table 4. Grade of Recommendation (GoR) grading scale for prevention, diagnostics, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The clinical practice guidelines update mechanism provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based medicine data on the diagnostics, treatment, prevention, and rehabilitation of specific diseases, or when justified additions/comments to previously approved Clinical Practice Guidelines are available, but not more frequently than once every 6 months.

Appendix A3. Reference Materials

Information is not available.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Guidelines for post-treatment follow-up

Follow-up after completed treatment is essential for maintaining patient health. Typically, during the first 1–2 years, follow-up visits with an oncologist are recommended every 3–6 months, and at 3–5 years, every 6–12 months. After 5 years from surgery, visits are conducted annually or upon the appearance of symptoms. Nevertheless, the frequency of doctor visits may be increased depending on the disease characteristics and associated risks, and is determined individually in each specific case. If new complaints arise or symptoms present before treatment recur, it is necessary to consult a doctor immediately without waiting for the scheduled visit 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 neck radiation therapy, nutritional status decline, assessment of speech and swallowing functions, 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

• Higher 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 primary tumors

• Lower risk of infections

• Higher quality of life

In case of CT/CRT complications, contact your oncologist or radiation oncologist.

If body temperature rises to 38 °C or higher:

• start antibiotic therapy as prescribed by a doctor.

For stomatitis:

• diet with mechanical and thermal sparing;

• frequent mouth rinsing (every hour) using chamomile, oak bark, or sage decoctions, apply sea buckthorn (peach) oil to the oral mucosa;

• treat the oral cavity as recommended by a doctor.

For diarrhea:

• diet: exclude fatty, spicy, smoked, sweet, dairy foods, and fiber. Lean meat, flour products, fermented dairy products, and rice water are permitted. Drink plenty of fluids;

• take medications as recommended by a doctor.

  For nausea:

• take medications as recommended by a doctor

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

Not applicable.