Malignant tumors of the salivary glands: clinical guidelines

List of Abbreviations

Gy – Gray

EBRT – external beam radiotherapy, MN – malignant neoplasm, LN – lymph nodes

wk – week

US – ultrasound, CT – computed tomography

PT – physical therapy

FNAB – fine-needle aspiration biopsy, RT – radiation therapy

MRI – magnetic resonance imaging

PEG – percutaneous endoscopic gastrostomy

PET-CT – positron emission tomography combined with computed tomography

LoE – level of evidence, GoR – grade of recommendation, CRT – chemoradiotherapy

CT – chemotherapy

AJCC – American Joint Committee on Cancer

ECOG – Eastern Cooperative Oncology Group performance status scale

ENE – extranodal extension

NaF – sodium fluoride

R0 – tumor-free resection margin, R1 – microscopic residual tumor

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

Terms and Definitions

Major salivary glands – parotid gland, submandibular gland, sublingual gland.

Complex antitumor treatment – specialized treatment of cancer patients, including a combination of three modalities (surgery, radiation therapy, and chemotherapy).

Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgery/chemotherapy/radiation therapy).

Stage I rehabilitation – rehabilitation during the period of specialized treatment of the underlying disease (including surgery/chemotherapy/radiation therapy) in departments of medical organizations specialized in the underlying disease.

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 rehabilitation periods, and the period of residual effects of the disease in departments (offices) of rehabilitation, physiotherapy, therapeutic exercise, reflexology, manual therapy, psychotherapy, medical psychology, speech therapy (speech-language pathology) offices providing outpatient medical care, day hospitals, and mobile teams at home (including in sanatorium-resort organizations).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Malignant salivary gland tumors – malignant neoplasms of the salivary glands differing in their morphological structure [1].

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

The main etiological factors in the development of malignant salivary gland tumors are:

• inflammatory diseases;

• dietary factors;

• hormonal and genetic disorders;

• smoking [1].

1.3 Epidemiology of the Disease or Condition

Salivary gland neoplasms account for 1–5% of all malignant tumors and 3% of head and neck tumors. The peak incidence occurs at the age of 15–39 years [2][3].

1.4 Features of Coding the Disease or Condition

Malignant neoplasm of other and unspecified parts of mouth (C06)

C06.9 – Malignant neoplasm of minor salivary gland, unspecified site

Malignant neoplasm of parotid gland (C07).

Malignant neoplasm of other and unspecified major salivary glands (C08).

C08.0 – Malignant neoplasm of submandibular gland. C08.1 – Malignant neoplasm of sublingual gland.

C08.8 – Lesion of major salivary glands overlapping one or more of the above sites.

C08.9 – Malignant neoplasm of major salivary gland, unspecified.

1.5 Classification of the disease or condition

International Histological Classification of Salivary Gland Tumors (World Health Organization classification, 5th edition, 2022).

Non-neoplastic epithelial lesions (formations):

- nodular oncocytic hyperplasia

- lymphoepithelial sialadenitis

Benign epithelial tumors:

- pleomorphic adenoma – 8940/0 (metastasizing pleomorphic adenoma – 8940/3)

- basal cell adenoma – 8147/0

- Warthin tumor – 8561/0

- oncocytoma – 8290/0

- myoepithelioma of salivary glands – 8982/0

- canalicular adenoma – 8149/0

- cystadenoma of salivary glands – 8440/0

- ductal papillomas – 8503/0

- papillary sialadenoma (papilliferum) – 8406/0

- lymphadenoma – 8563/0

- sebaceous adenoma – 8410/0

- intercalated duct adenoma and hyperplasia – no code

- striated duct adenoma – no code

- sclerosing polycystic adenoma – no code

- keratocystoma – no code

Malignant epithelial tumors:

- mucoepidermoid carcinoma – 8430/3

- adenoid cystic carcinoma – 8200/3

- acinic cell carcinoma – 8550/3

- secretory carcinoma – 8502/3

- microsecretory adenocarcinoma – no code

- polymorphous adenocarcinoma – 8525/3

- hyalinizing clear cell carcinoma – 8310/3

- basal cell adenocarcinoma – 8147/3

- intraductal carcinoma – 8500/2

- salivary duct carcinoma – 8500/3

- myoepithelial carcinoma – 8982/3

- epithelial-myoepithelial carcinoma – 8562/3

- mucinous adenocarcinoma – 8480/3

- sclerosing microcystic adenocarcinoma – no code

- carcinoma ex pleomorphic adenoma – 8941/3

- carcinosarcoma of salivary glands – 8980/3

- sebaceous adenocarcinoma – 8410/3

- lymphoepithelial carcinoma – 8082/3

- squamous cell carcinoma – 8070/3

- sialoblastoma – 8974/1

- salivary gland carcinoma, NOS – 8140/3

Mesenchymal tumors specific to salivary glands:

- sialolipoma – no code

In accordance with the WHO (2022) and CAP (College of American Pathologists) recommendations, a three-tier grading system (high-, intermediate-, low-grade carcinoma) is applicable to the following histotypes:

- mucoepidermoid carcinoma;

- polymorphous adenocarcinoma (classic and cribriform variants);

- adenocarcinoma, NOS;

- squamous cell carcinoma.

A two-tier grading system (low/high grade) is used for intraductal carcinoma of the salivary glands.

For adenoid cystic carcinoma, the proportion of the solid component is indicated: in general, the presence of more than 30% solid structures is associated with a more aggressive clinical course. In accordance with current international guidelines, the presence and proportion (any amount) of the solid component should be indicated as an indicator of high-grade transformation of adenoid cystic carcinoma. In addition to adenoid cystic carcinoma, high-grade transformation has been described for the following histological variants of salivary gland carcinomas:

- acinic cell carcinoma – high-grade transformation manifests as a combination with low-grade adenocarcinoma (cribriform, solid, trabecular architecture) and/or undifferentiated areas;

- hyalinizing clear cell carcinoma – transformation is considered to be present when there is increased mitotic activity, pronounced atypia, and necrosis;

- rare cases of epithelial-myoepithelial carcinoma transformation have been described.

Grading of other salivary gland carcinomas is not recommended, since the histotype (nosological entity) itself is associated with the clinical course. Tumors can be grouped by their behavior; indolent clinical course is characteristic of: secretory carcinoma, microsecretory carcinoma, basal cell adenocarcinoma, sclerosing microcystic adenocarcinoma, lymphoepithelial carcinoma, sialoblastoma. Tumors with an aggressive clinical behavior include: salivary duct carcinoma, myoepithelial carcinoma, carcinoma ex pleomorphic adenoma, carcinosarcoma of salivary glands.

TNM Staging Classification of Malignant Tumors

The extent of malignant salivary gland tumors is presented in the TNM Classification of Malignant Tumors, 8th edition, published by the American Joint Committee on Cancer.

The main group of salivary gland neoplasms consists of tumors of epithelial origin (95%), with 80–90% of cases developing in the major salivary glands and 10% in the minor salivary glands. The grade of the tumor plays a significant role in prognosis.

The T category includes the following grades:

TX – primary tumor cannot be assessed. T0 – no evidence of primary tumor.

T1 – tumor 2 cm or less in greatest dimension without extraparenchymal extension.

T2 – tumor more than 2 cm, but not more than 4 cm in greatest dimension without extraparenchymal extension.

T3 – tumor more than 4 cm in greatest dimension and/or extraparenchymal extension.

T4a – tumor invades skin, mandible, ear canal, and/or facial nerve.

T4b – tumor invades pterygoid plates, skull base, or internal carotid artery.

The symbol cN indicates the presence or absence of regional lymph node (LN) metastases based on clinical and instrumental examinations.

The pN category indicates the presence or absence of regional lymph node metastases based on routine pathological examination of the surgical specimen.

The symbol M indicates the presence or absence of distant metastases:

M0 – no distant metastases;

M1 – presence of distant metastases.

Table 1. Stage grouping

1.6 Clinical presentation of the disease or condition

The clinical course of salivary gland tumors is largely determined by their location, extent, and morphological structure. The tumor typically presents as a firm, elastic, painless nodule, mobile upon palpation and not fixed to the skin. Tumors located in the pharyngeal process of the parotid gland have specific clinical features. The tumor is not palpable externally; only a slight swelling in the parotid region is detected. Examination of the pharyngeal wall reveals a deformation that varies in degree depending on the size of the lesion. Tumor growth is always directed toward the oral cavity; it does not spread outwardly due to the obstruction by the mandible. In advanced cases, skin infiltration, restricted mobility of the lesion, and occasional tenderness upon palpation are frequently observed. Facial nerve palsy is an extremely unfavorable prognostic sign indicating local disease progression [4].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is established based on:

1. anamnestic data, specifically the presence of a neoplasm;

2. physical examination, including a thorough clinical inspection, palpation of the lesion, adjacent tissues, and regional lymph nodes;

3. cytological examination of material obtained via fine-needle aspiration biopsy (FNAB), core-needle biopsy, incisional or excisional biopsy (of the primary tumor, enlarged or suspicious lymph nodes);

4. pathological examination of salivary gland biopsy (surgical) material;

5. instrumental examinations, including ultrasound (US) of the soft tissues of the face and oral floor, neck ultrasound, computed tomography (CT) / magnetic resonance imaging (MRI), and positron emission tomography combined with computed tomography (PET-CT) [5].

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

• 1. tumor size (greatest dimension, or in three mutually perpendicular dimensions)

• 2. histological variant (nosological entity) of the tumor

• 3. grade of differentiation (if applicable) or presence of high-grade transformation

• 4. presence or absence of lymphovascular and/or perineural invasion

• 5. pT

• 6. pN (indicating the total number of examined and involved lymph nodes, and the presence or absence of extranodal tumor extension)

• 7. resection margin status (positive/negative, minimum distance from tumor to the resection margin)

GCR CLoE 4Guidelines Recommendation Grade C (Level of Evidence – 4)

2.4 Instrumental Diagnostics

– 1)

– 4)

2.5 Other Procedures

– 1)

Comment: if the cytological examination is uninformative, it is advisable to perform a pathomorphological examination of biopsy (surgical) material from the salivary gland tissues (using core-needle biopsy, core biopsy, incisional, or excisional biopsy). If the result of the pathomorphological examination of the salivary gland biopsy (surgical) material is positive (malignant tumor verified), it is necessary to determine the histological type of the tumor and establish the tumor differentiation grade, if such a classification is applicable to the specific histotype. If the result of the pathomorphological examination of the salivary gland biopsy (surgical) material is equivocal (neoplasm diagnosis not verified), it is mandatory to repeat the biopsy of the neoplasm in a sufficient volume to perform additional special pathomorphological methods on the salivary gland biopsy (surgical) material using immunohistochemical techniques. If the result of the pathomorphological examination of the salivary gland biopsy (surgical) material is negative, a repeat biopsy is advisable if there are convincing clinical and/or radiological signs of a malignant neoplasm

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

The prescription and use of medications indicated in the clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions presented in the instructions, and dose adjustments are also possible taking into account the patient's condition.

3.1. Choice of treatment method

Below are the principles of treatment for epithelial malignant neoplasms of the salivary glands. The principles of treatment for non-epithelial malignant tumors (sarcomas, lymphomas) of the salivary glands do not differ from those for other localizations of these nosologies (see the relevant clinical guidelines for the provision of medical care to patients with malignant neoplasms of lymphoid, hematopoietic, and related tissues, as well as malignant neoplasms of other types of connective and soft tissues).

Comments: The minimum surgical volume for suspected malignant tumor of the parotid glands is a subtotal resection of the parotid gland.

• For stages T1–T2, N0, complete surgical removal of the primary tumor is recommended. If routine pathomorphological examination of the salivary gland surgical material reveals adenoid cystic carcinoma, low-grade mucoepidermoid carcinoma, or adverse histological features (positive margins, perineural invasion), postoperative external beam radiotherapy (EBRT) is recommended [16,18].

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

• For stages T1–2, N+M0, complete surgical removal of the primary tumor combined with cervical lymphadenectomy, followed by postoperative EBRT, is recommended [16,19].

GCR CLEL 3Grade of Recommendation – C (Level of Evidence – 3)

• For stages T3–4a, N0 M0, complete surgical removal of the primary tumor is recommended; in cases of adenoid cystic carcinoma, ductal carcinoma, and adenocarcinoma, this should be combined with cervical lymphadenectomy, and postoperative EBRT is recommended [16].

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

• For stages T3–4a, N0 M0, if routine pathomorphological examination of the surgical material reveals adverse histological features (poorly differentiated tumor, positive margins, perineural invasion, vascular embolization), it is recommended to consider concurrent chemoradiotherapy (CRT) [7].

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

• For stages T3–4a, N + M0, complete surgical removal of the primary tumor combined with cervical lymphadenectomy, followed by postoperative EBRT, is recommended [16].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

• For stages T3–4a, N + M0, if routine pathomorphological examination of the salivary gland surgical material reveals adverse histological features (poorly differentiated tumor, positive margins, perineural invasion, tumor emboli in vessels), it is recommended to consider concurrent CRT [7,13]

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

• If radical surgery cannot be performed as a first-line treatment, RT or concurrent CRT is recommended for all patients, taking into account the patient's general condition [7].

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

• For stage T4b, RT or concurrent CRT is recommended, taking into account the patient's general condition [16].

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

Comments: if radical surgery or radical treatment is not feasible, systemic drug therapy may be administered.

• For locoregional recurrence of the disease without prior radiotherapy (RT), complete surgical removal is recommended, addressing the question of RT/CRT. If radical surgery cannot be performed, RT/CRT or systemic therapy should be considered [7].

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

• For locoregional recurrence after RT, complete surgical removal is recommended, addressing the question of re-irradiation/CRT. If radical surgery cannot be performed, re-irradiation should be considered [7].

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

3.2. Principles of RT

• If RT is administered as a standalone treatment, external beam radiotherapy is recommended for soft tissue involvement in the following regimen: primary tumor site and clinically detectable regional metastases (lymph nodes ≥1 cm in size or with central necrosis) – total dose (TD) 66–70 Gy. Prophylactic irradiation of the regional neck areas (levels Ib–III) on the affected side in the absence of clinically detectable metastases is performed for all poorly differentiated or locally advanced (T3–T4) tumors, with the exception of acinic cell and adenoid cystic carcinoma. If involved lymph nodes are present, levels Ib–V lymph nodes are included in the irradiation field. Elective irradiation of the contralateral neck, including levels I–III, is performed in the presence of metastases in multiple regional neck lymph nodes on the affected side and for malignant submandibular salivary gland tumors up to a TD of 50 Gy.

Radiotherapy is administered at a fractional dose of 2 Gray (Gy)/fraction, 5 times a week for 6–7 weeks; [1-4, 96]

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

• As postoperative irradiation in the presence of one or more adverse histological features (poorly differentiated tumor, positive or close resection margins, perineural invasion, vascular embolization, regional lymph node metastases, T3–4a, adenoid cystic carcinoma, breach of the tumor capsule integrity during removal), external beam radiotherapy is recommended in the following regimen: to the tumor bed, with an additional volume in the presence of perineural invasion including the facial nerve canal up to the geniculate ganglion, and the lingual and hypoglossal nerves down to the skull base – TD 50–66 Gy. Prophylactic postoperative radiotherapy to regional areas (levels I–III) is performed for all malignant submandibular salivary gland tumors (except for acinic cell and adenoid cystic tumors in stage T1) – TD 50 Gy. In all other cases, the need for prophylactic irradiation depends on the stage, histological subtype, and tumor localization. In the presence of clinically detectable metastases, levels I–V lymph nodes are included in the radiation volume – TD 50–60 Gy. The recommended interval between surgery and the start of postoperative RT is 6–8 weeks.

Radiotherapy is administered at a fractional dose of 2 Gray (Gy)/fraction, 5 times a week for 5–6.5 weeks; [1-4, 96]

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

3.3. Principles of drug therapy

The choice of drug therapy must be individualized based on patient characteristics (general condition, tumor morphology, and its receptor status).

• As concurrent chemoradiotherapy, it is recommended to prescribe cisplatin** + RT adhering to the following regimen: RT to the primary tumor (70 Gy) and lymph nodes (50 Gy) – a fraction of 2 Gy/day daily (Monday – Friday) for 7 weeks; Cisplatin** at a dose of 100 mg/m² with hyperhydration on days 1, 22, and 43 of RT (total dose during RT – 300 mg/m²) [25].

GGR BLEL 2Grading of recommendations – B (level of evidence – 2)

In case of distant metastases and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–3, drug therapy, watchful waiting (in case of slow tumor progression), selective metastectomy, or antiandrogen therapy in the presence of androgen receptor overexpression is recommended [7,13].

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

For recurrent unresectable tumors or incurable distant metastases, the preferred recommended chemotherapy regimens are:

o #paclitaxel** 175 mg/m² IV on day 1 (3-hour infusion) + carboplatin** AUC 5–6 IV on day 1, every 3 weeks [26,89];

o Doxorubicin** 50 mg/m² on day 1 + #bleomycin** 30 mg IV on days 1–5 + cisplatin** 20 mg/m² on days 1–5 every 3 weeks [27].

o Doxorubicin** 60 mg/m² IV on day 1 + #bleomycin** 10 mg IV on days 1–5 + #vincristine** 1.4 mg/m² IV on days 1 and 8, every 3 weeks [28].

o Cisplatin** 50 mg/m² IV + doxorubicin** 50 mg/m² IV + #cyclophosphamide** 500 mg/m² IV on day 1 every 4 weeks [90].

GGR CLEL 4Grading of recommendations – C (level of evidence – 4)

For recurrent unresectable tumors or incurable distant metastases, additional recommended chemotherapy regimens are:

o doxorubicin** 60 mg/m² on day 1 + cisplatin** 40 mg/m² on day 1 every 3 weeks [28];

GSI CLoE 5Grade of Recommendation – C (Level of Evidence — 5)

o doxorubicin** 30 mg/m² IV on days 1 and 8 + #cisplatin** 50 mg/m² IV on days 1 and 8, every 3 weeks [28];

GSI CLoE 5Grade of Recommendation – C (Level of Evidence — 5)

o #paclitaxel** 60–80 mg/m² IV weekly + #carboplatin** AUC-2 IV weekly until progression or unacceptable toxicity [28];

GSI CLoE 5Grade of Recommendation – C (Level of Evidence — 5)

o #gemcitabine** 1000 mg/m² IV on days 1 and 8 + cisplatin** 70 mg/m² IV on day 2, every 3 weeks [91].

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

o Cisplatin** 80 mg/m² IV on day 1 + #vinorelbine** 25 mg/m² IV on days 1 and 8 every 3 weeks [28, 88].

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

Comments: The cumulative dose of doxorubicin** should not exceed 450–500 mg/m², and the number of chemotherapy cycles depends on the response and tolerability of the treatment.

For recurrent unresectable or metastatic salivary gland tumors refractory to standard chemotherapy regimens, in the presence of an ERBB2 gene mutation (or positive HER2/neu status according to IHC or FISH), to increase survival, #trastuzumab** 2 mg/kg of body weight (4 mg/kg loading dose) IV drip once a week (wk) as monotherapy or 6 mg/kg (8 mg/kg loading dose) IV drip once every 3 weeks as part of medical treatment is recommended [22].

GGR CLEL 4Grading of recommendations – C (level of evidence – 4)

In the presence of androgen receptors in a patient with distant metastases and an ECOG performance status of 0–3, #bicalutamide** at a dose of 150 mg once daily enterally until progression or unacceptable toxicity is recommended as part of antiandrogen therapy [20]. To achieve the maximum antitumor effect and complete androgen blockade, the addition of #goserelin** is possible: #goserelin** 3.6 mg subcutaneously once every 28 days (or #goserelin** 10.8 mg subcutaneously once every 84 days) + #bicalutamide** 50 mg once daily enterally daily [20,84].

GGR CLEL 4Grading of recommendations – C (level of evidence – 4)

For recurrent unresectable or metastatic salivary gland tumors refractory to standard chemotherapy regimens, in the presence of a confirmed BRAF gene mutation, targeted therapy with BRAF inhibitors is recommended according to the regimen: #dabrafenib** 150 mg orally × 2 times/day + #trametinib** 2 mg orally × 1 time/day × 12 months until progression or intolerable toxicity, in order to increase survival [7, 81, 96].

GGR CLEL 4Grading of recommendations – C (level of evidence – 4)

For recurrent unresectable or metastatic salivary gland tumors refractory to standard chemotherapy regimens, comprehensive genomic profiling based on next-generation sequencing (NGS) using tumor tissue samples or liquid biopsy is recommended to identify molecular targets (mutations or gene fusions: ERBB2, NTRK, RET, BRAF, C-KIT, etc.) and subsequent benefit from specific targeted therapy [29].

GSI CLoE 5Grade of Recommendation – C (Level of Evidence — 5)

For tumors with MSI-H/dMMR or high tumor mutational burden (TMB ≥10 mut/Mb) upon progression during previous treatment (or intolerance), by decision of the medical board, #pembrolizumab** 200 mg IV once every 3 weeks may be prescribed until progression or unmanageable toxicity, but for no more than 24 months [7,82,97].

GGR CLEL 4Grading of recommendations – C (level of evidence – 4)

For recurrent unresectable or metastatic salivary gland tumors refractory to standard chemotherapy regimens in the presence of a confirmed NTRK gene fusion (1, 2, or 3), larotrectinib 100 mg orally twice daily or entrectinib 600 mg orally daily is recommended until progression or intolerable toxicity to increase survival [85,86,87].

GGR CLEL 4Grading of recommendations – C (level of evidence – 4)

For recurrent unresectable or metastatic adenoid cystic carcinoma of the salivary glands refractory to standard chemotherapy regimens, #lenvatinib** 24 mg orally daily or #sorafenib** 800 mg orally daily is recommended until progression or intolerable toxicity to increase survival [80,81].

GGR CLEL 4Grading of recommendations – C (level of evidence – 4)

Comments: Targeted therapy regimens not registered in the Russian Federation for recurrent unresectable or metastatic salivary gland tumors refractory to standard chemotherapy regimens in the presence of confirmed mutations/rearrangements of various genes may be prescribed by decision of the medical board if there are absolute contraindications to chemotherapy or its reserves are exhausted.

3.4. Principles of surgical treatment

— review the adequacy of biopsy material, staging, and tumor imaging (CT, MRI) to determine the extent of tumor spread,

— rule out the presence of a synchronous primary tumor,

— evaluate the current functional status and the feasibility of surgical treatment if primary treatment was non-surgical,

— develop a prospective patient follow-up plan that will include adequate dental, nutritional, and lifestyle assessments, as well as interventions and any other additional studies necessary for the patient's full rehabilitation.

Surgical intervention should not be modified based on the clinical response obtained before treatment during the current examination (tumor regression), except in cases of tumor progression that necessitates a more extensive operation to encompass the entire tumor during definitive resection [7,29].

GCR CGrade of recommendation – C (level of evidence – 5).

Comments:

Assessment of resectability.

Involvement of the following structures by the tumor is associated with a poor prognosis or is classified as stage T4b (e.g., unresectability associated with the technical impossibility of performing microscopically radical surgery): significant involvement of the pterygopalatine fossa, severe trismus due to tumor infiltration of the pterygoid muscles; macroscopic tumor spread to the skull base (e.g., erosion of the pterygoid plates or sphenoid bone, enlargement of the foramen ovale, etc.); possible invasion (encasement) of the wall of the common or internal carotid artery. "Encasement" is usually assessed radiologically (by CT and MRI) and in cases where the tumor surrounds ≥270° of the carotid artery circumference. Also, direct tumor extension from regional lymph nodes with skin involvement, direct extension to mediastinal structures, prevertebral fascia, or cervical vertebrae constitutes criteria for unresectability[17,29].

Removal of the primary tumor.

En-bloc resection of the primary tumor is recommended whenever possible. It is recommended to plan surgical removal based on the extent of the primary tumor determined during clinical examination and careful interpretation of relevant radiographic images. If the tumor is adjacent to a motor or sensory nerve, perineural invasion cannot be excluded. In this situation, the nerve should be dissected proximally and distally and resected until clear margins are obtained. Frozen section analysis of the proximal and distal nerve margins is proven useful for obtaining tumor-free tissue (urgent pathomorphological examination of the surgical specimen). Immediate reconstruction of the resected nerve segment is preferred [17][30].

Resection margins.

A clear margin is defined as a distance of ≥5 mm from the invasive tumor edge to the resection margin. A close margin is defined as a distance from the invasive tumor edge to the resection margin of

<5 mm. The primary tumor should be marked so that the pathologist can adequately assess specimen orientation. Neck lymphadenectomy specimens must be oriented or sectioned sequentially to determine the level of lymph nodes included in the dissection zone. Reconstruction of surgical defects should be performed using conventional techniques at the surgeon's discretion. Primary closure is recommended whenever possible, but wide resection margins should not be compromised. At the surgeon's discretion, reconstruction may be performed using local/regional flaps, free flaps, split-thickness skin grafts, or other flaps with/without facial skeleton reconstruction [17,31].

3.5 Anesthesia

Pain management protocols and recommendations for malignant neoplasms of the salivary glands correspond to the recommendations presented in the clinical guidelines "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care".

4. Medical Rehabilitation and Sanatorium-Resort Treatment

For cancer rehabilitation, the tactics of restorative treatment and the choice of its methods are not tied to the duration of hospitalization.

During the second and third stages of rehabilitation, the use of hydrotherapy and balneotherapy is not excluded. Without a level of evidence.

4.1. Prehabilitation

• All patients with malignant neoplasms of the salivary glands are recommended to undergo prerehabilitation, as it significantly accelerates functional recovery, shortens hospital stay after surgery, and reduces the rate of complications and mortality associated with cancer treatment. Prerehabilitation includes physical conditioning, psychological and nutritional support, and patient education [32].

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

• Patients with malignant neoplasms of the salivary glands, especially those with marked muscle weakness and high fatigability, are recommended to engage in therapeutic exercise. Physical prerehabilitation generally consists of moderate-intensity aerobic exercise, which improves exercise tolerance, enhances quality of life, and increases muscle tone [33].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1)

• Patients with malignant neoplasms of the salivary glands scheduled for surgical treatment are recommended to undergo therapeutic exercise in the preoperative period, as this reduces the overall number of postoperative complications and the incidence of lymphedema [34].

GRC BLEL 3Grade of Recommendation – B (Level of Evidence – 3)

• Patients with malignant neoplasms of the salivary glands scheduled for multimodal anti-tumor treatment are recommended to undergo prophylactic exercise programs and swallowing training before the initiation of treatment, as this can reduce swallowing disorders during this type of therapy [35,36]

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

• Nutritional and metabolic rehabilitation in the preoperative period is recommended in the presence of at least one of the following factors: unintentional weight loss over the past 3 months (10% or more), body mass index less than 18.5 kg/m², deterioration in oral intake over the past week, low food intake (caloric intake less than 1500 kcal/day) [37].

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

Comments: The preferred route of nutritional support is oral nutrition (sipping). If oral nutrition is impossible or inadequate, placement of a nasogastric tube or gastrostomy using video-endoscopic techniques is necessary. If feeding a severely ill patient via the mouth and/or nasogastric tube is impossible, parenteral nutrition is indicated. The caloric intake 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. Daily requirements for vitamins and micronutrients must be met. Ready-to-use formulas enriched with protein and omega-3 fatty acids are preferred. Their use significantly reduces the rate of infectious complications in the postoperative period. Prophylactic placement of a nasogastric tube or PEG is not recommended in patients with normal nutritional status, minor weight loss, absence of airway obstruction, or severe dysphagia. However, these patients require subsequent monitoring of dietary caloric intake and assessment of body weight dynamics throughout anti-tumor therapy. If necessary, a temporary PEG or nasogastric tube may be placed during anti-tumor treatment or after its completion. Indications for prophylactic nasogastric tube placement or PEG insertion are:

1) documented significant weight loss (5% of baseline body weight over the previous month or 10% of baseline body weight over the preceding 6 months); 2) existing dehydration, dysphagia, anorexia, or pain syndrome that limits the patient's ability to eat or drink adequately; 3) significant comorbid and morbid conditions that may be aggravated by dehydration, hypocaloric diet, or inability to swallow necessary medications; 4) aspiration syndrome, especially in the elderly or patients with cardiopulmonary insufficiency; 5) patients likely to have prolonged swallowing disorders, including those anticipated during radiation therapy. However, other risk factors for impaired swallowing function should also be considered. Natural nutrition is indicated to maintain swallowing function during and after anti-tumor therapy provided the swallowing act is preserved and there is no risk of aspiration. It should be noted that changes in swallowing function may appear throughout the entire course of treatment and after its completion and must be monitored over the patient's lifetime.

• If oral intake is impossible for the patient, it is recommended to provide tube feeding, parenteral nutrition, or mixed nutrition according to calculated requirements [37–39]

GRC CLOE 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: Nutritional support provided in the outpatient setting and continued throughout the evaluation period up until surgery reduces the rate of postoperative complications and length of hospital stay. If oral intake is maintained, high-protein ready-to-use formulas are preferred, with a daily dosage of at least 400 ml per day.

Adequate nutritional support for at least 7 days reduces the rate of postoperative complications and length of hospital stay [40].

4.2. Stage I rehabilitation in surgical treatment

• During surgical treatment, the patient is recommended to follow Fast track rehabilitation and Enhanced Recovery After Surgery (ERAS) protocols, which include multimodal analgesia, early initiation of oral and/or nasogastric tube feeding for severely ill patients, avoidance of routine catheters and drains, and early mobilization of patients starting from the first or second postoperative day (activation and verticalization) in order to reduce the length of hospital stay, non-surgical complications, and overall postoperative complications [41,42]

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

• Early mobilization (verticalization, performing a set of therapeutic exercises to strengthen facial and neck muscles with aerobic load, and therapeutic exercises aimed at reducing spasticity, under the supervision of an instructor) is recommended for all patients undergoing surgical treatment to improve functional capabilities [43,44]

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

• Relief of pain syndrome in the early postoperative period combined with physical therapy, facial and neck muscle strengthening exercises, positioning therapy, psychological correction methods, transcutaneous electrical nerve stimulation, and acupuncture is recommended for all patients with malignant salivary gland tumors to improve functional outcomes [44].

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

• Medical massage in the postoperative period in patients who have undergone head and neck surgery is recommended to improve quality of life [45].

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

• In the preoperative and early postoperative periods, a speech-language pathologist consultation is recommended; the specialist prescribes a set of specialized exercise therapy exercises for dysphagia to restore swallowing function and train the patient's speaking ability. There are several limitations for speech therapy rehabilitation: active functional training is not recommended in the early postoperative period, at the primary healing stage, and when fistulas occur. Violating the functional training regimen is unacceptable [46].

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

Comment: To restore swallowing function in patients with malignant neoplasms of the salivary glands, therapeutic exercises for dysphagia are used to increase the range of motion and muscle strength, and to enhance voluntary control over the timing and coordination of the swallow. Postural support is also important, i.e., finding a suitable posture during swallowing. Additionally, phonopedic techniques (e.g., falsetto glide), swallowing maneuvers (e.g., effortful swallow), and the selection of swallowing textures are used [47][48]. To improve respiratory function, especially after tracheostomy placement, it is advisable to use inhalation and exhalation coordination, taking an inhalation sufficient for speech, finding an optimal body position, pausing, and breathing exercises. Work on breathing is structured on the principle of progressing from simple to complex. First, patients are asked to blow lightweight objects off the palm and table, the sequence of inhalation and exhalation phases is practiced, the exhalation phase is built up, then phonatory exhalation is added, and diaphragmatic breathing is also practiced. During functional training, exercises are performed for all articulation organs: lips, cheeks, tongue, floor of the mouth, hard palate, soft palate muscles, pharyngeal muscles, and external neck muscles [49][50] 

4.3. Stage III rehabilitation in surgical treatment

• Performing sets of exercises to strengthen the facial and neck muscles and dysphagia exercise therapy after radical surgical treatment for head and neck cancer is recommended for all patients to facilitate rapid physical recovery and improve the patient's quality of life [51].

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

• Maintaining a stable body weight and an active lifestyle for all patients with malignant salivary gland neoplasms after surgical treatment are recommended to increase overall survival. Regimen: moderate-intensity aerobic exercise 3–5 times per week (totaling 150 min per week) combined with resistance training 2–3 times per week. Resistance exercises should involve major muscle groups (8–10 muscle groups, 8–10 repetitions, 2 sets). Each session should include a warm-up and cool-down [52].

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

4.4. Stage II rehabilitation in surgical treatment

• To overcome trismus—tonic spasm of the masticatory muscle group leading to restricted mobility of the temporomandibular joint—exercises regulating the degree of mouth opening are recommended for all patients after surgical treatment. These include static, dynamic, and resistance exercises. Movements are performed not only in the jaw opening and closing plane. Other movements are also necessary to restore function: lateral, protrusive, retrusive, and circular [53].

GCR CLEL 3Grade of Recommendation — C (Level of Evidence — 3)

• Complete decongestive therapy is recommended as the "gold standard" in the treatment of lymphedema of all localizations. It includes facial and neck muscle strengthening exercises, compression therapy, medical massage of the neck, scalp and face, and skin care [55].

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

• Medical massage of the neck, scalp, and face is recommended as the leading method in the treatment of head and neck lymphedema [56].

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

• Low-frequency magnetotherapy combined with complete decongestive therapy is recommended for the treatment of lymphedema [57].

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

• The use of low-level laser therapy (intravenous laser blood irradiation) in combination with complete decongestive therapy is recommended to accelerate the reduction of edema severity [58].

Level of Evidence CLevel of Recommendation Confidence – C (Level of Evidence Validity – 5)

4.5. Rehabilitation during chemotherapy, combined chemoradiotherapy

Anticancer treatment of head and neck cancer causes psychological distress, anxiety, and depression, which worsens patients' quality of life [59].

• Performing resistance exercises is recommended for all patients receiving postoperative chemotherapy to reduce fatigue, improve quality of life, and enhance psychological well-being. Early initiation of physical exercise during chemotherapy is recommended to prevent muscle weakness, the onset and progression of sarcopenia, and decreased exercise tolerance [60].

Level of Evidence BLevel of Evidence Validity 2Level of Recommendation Confidence – B (Level of Evidence Validity – 2).

• Conducting a set of exercise therapy exercises incorporating aerobic loads and Tai Chi elements for 4 months during chemotherapy is recommended for all patients receiving chemotherapy to increase vital capacity, blood oxygen saturation, muscle strength, range of motion in large joints, and reduce body mass index [61].

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

• To reduce fatigue and increase endurance during chemoradiotherapy, performing exercise therapy exercises aimed at reducing spasticity is recommended. Moderate-intensity aerobic exercises combined with resistance exercises provide the optimal effect [62].

Level of Evidence CLevel of Evidence Validity 2Level of Recommendation Confidence – C (Level of Evidence Validity – 2).

• Combining exercise therapy with psychological support is recommended for treating fatigue during chemotherapy [63].

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

4.6. Rehabilitation during radiotherapy

• Three days after the start of radiation therapy, it is recommended to initiate low-level laser therapy (intravenous laser blood irradiation), 3 days a week for the prevention of radiation dermatitis [69].

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

5. Prevention and Dispensary Observation

1) anamnesis collection and physical examination;

2) ultrasound of the primary tumor area and bilateral neck lymph nodes;

3) CT/MRI of the head and neck region when recurrence signs are detected via ultrasound and physical examination, as well as when the area is inaccessible to adequate physical examination;

4) chest CT every 12 months;

5) determination of thyroid-stimulating hormone levels every 6–12 months if neck irradiation was performed to assess thyroid function [70,71];

6) PET/CT execution (as clinically indicated).

Level of Evidence CLevel of Evidence Validity 5Level of Recommendation Confidence – C (Level of Evidence Validity – 5)

Comments: The goal of follow-up is early detection of disease progression to promptly initiate chemotherapy or surgical treatment of resectable metastatic lesions, recurrent tumors, as well as to detect metachronous head and neck tumors [29].

Comment: RT to the head and neck region can cause xerostomia and salivary gland dysfunction, which significantly increases the risk of dental caries and associated adverse consequences, such as dentoalveolar infection and osteoradionecrosis. RT also affects dental tissues, increasing the likelihood of demineralization against the background of xerostomia, post-RT microflora alterations, and predisposing the patient to a caries-associated diet. Furthermore, infectious processes in the oral cavity impair the efficacy of postoperative tissue repair and necessitate intensified antibacterial therapy regimens. Radiation-associated caries and other dental tissue changes may develop within the first three months after completing RT.

6. Organization of Medical Care

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

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

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

3) based on these clinical guidelines;

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

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

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

Consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

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

The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

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

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

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

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

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

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

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

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

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

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

Indications for discharging a patient from a medical organization are:

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

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

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

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

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

7. Additional Information

Factors influencing the prognosis of the disease include:

• size and extent of the primary tumor;

• tumor differentiation grade;

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

• regional lymph node status (pN) (neck lymph node metastases reduce patient survival by half);

• extranodal tumor extension;

• cellular proliferation activity (Ki-67 index);

• margin status (R0-1).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

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

2. Saprina Oksana Alexandrovna, PhD, Oncologist, Surgical Department No. 11 of Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the All-Russian Public Organization "Russian Society of Head and Neck Tumor Specialists".

3. Ignatova Anastasia Valerievna, 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 Russian Ministry of Health, Member of the All-Russian Public Organization "Russian Society of Head and Neck Tumor Specialists", Senior Lecturer at the Department of General and Clinical Dentistry named after V.S. Dmitrieva, RUDN University. ORCID: https://orcid.org/0000-0002-6796-0968

4. Tatev A. Agababyan, Head of the Department of Diagnostic Radiology, A.F. Tsyb Medical Radiological Research Center — branch of the National Medical Research Radiological Center of the Russian Ministry of Health, PhD in Medicine, Obninsk https://orcid.org/0000-0002-9971-3451

5. Sevil B. Alieva, MD, PhD, Leading Researcher, Department of Radiation Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

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

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

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

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

10. Larisa V. Bolotina, MD, PhD, Associate Professor of the Russian Academy of Sciences, Head of the Chemotherapy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health. Chair of the Head and Neck Tumors Group of Practical Guidelines of the Russian Society of Clinical Oncology, Board Member.

11. Vyacheslav V. Vinogradov, MD, PhD, Professor, Head of the Scientific and Clinical Department of Otorhinolaryngological Oncology, Scientific and Clinical Center of Otorhinolaryngology of the Federal Medical-Biological Agency of Russia.

12. Lyubov Yu. Vladimirova, 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

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

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

15. Igor A. Gulidov, Head of the Department of Radiation Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

16. Aleksandr O. Guz, PhD in Medicine, Oncologist, Head of the Department of Head and Neck Tumors, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine

17. Nikolay A. Daikhes, Corresponding Member of the Russian Academy of Sciences, MD, PhD, Professor, Director of the Scientific and Clinical Center of Otorhinolaryngology of the Federal Medical-Biological Agency of Russia.

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

19. Marina A. Engibaryan, MD, PhD, Head of the Department of Head and Neck Tumors, National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

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

21. Anna L. Korniyetskaya, PhD in Medicine, Senior Researcher, Chemotherapy Department, 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.

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

23. Larisa A. Krasilnikova, PhD in Medicine, Cytopathologist N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

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

25. Denis E. Kulbakin, MD, PhD, Senior Researcher, Oncologist at the Department of Head and Neck Tumors, Cancer Research Institute of Tomsk National Research Medical Center

26. Aleksandr V. Mordovskiy – PhD in Medicine, Researcher at the Department of Microsurgery, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center, Russian Ministry of Health

27. Ali M. Mudunov, MD, PhD, Professor of the RAS, Head of the Department of Surgical Treatment No. 10 of Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health, President of the All-Russian Public Organization "Russian Society of Head and Neck Tumors Specialists"

28. Shamil I. Musin, MD, PhD, Head of Surgical Department No. 6, Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Bashkortostan

29. Sergey O. Podvaznikov, MD, DSc, Professor, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Vice-President of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

30. Vyacheslav V. Polkin, MD, PhD, Head of the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

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

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

33. Zamira A. Radzhabova, MD, PhD, Associate Professor of the RAS, Head of the Department of Head and Neck Tumors, N.P. Napalkov National Medical Research Center of Oncology, Russian Ministry of Health, Associate Professor at the Department of Continuing Professional Education, N.P. Napalkov National Medical Research Center of Oncology https://orcid.org/0000-0002-6895-0497

34. Reshetov Igor Vladimirovich, MD, PhD, Academician of the RAS, Head of the Department of Oncology, Radiotherapy and Reconstructive Surgery, I.M. Sechenov First Moscow State Medical University, President of the All-Russian Public Organization "Federation of Specialists in the Treatment of Head and Neck Diseases"

35. Romanov Ilya Stanislavovich, MD, PhD, Senior Researcher, Department of Oncoendocrinology, N.N. Blokhin National Medical Research Center of Oncology, Associate Professor of the Department of Oncology, Faculty of Continuing Professional Education, Pirogov Russian National Research Medical University

36. Rubtsova Natalia Alevtinovna, MD, PhD, Head of the Department of Diagnostic Radiology, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health. Chief Freelance Specialist in Diagnostic and Instrumental Radiology of the Russian Ministry of Health in the Central Federal District of the Russian Federation.

37. Rudyk Andrey Nikolaevich, MD, PhD, Oncologist, Oncology Department No. 5 (Head and Neck Tumors), Professor M.Z. Sigal Republican Clinical Oncological Dispensary of the Ministry of Health of the Republic of Tatarstan, Acting Head of the Department of Maxillofacial Surgery and Surgical Dentistry, Associate Professor of the Department of Oncology, Radiology and Palliative Medicine, Kazan State Medical Academy — branch of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Associate Professor of the Department of Surgical Diseases of Postgraduate Education, Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan.

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

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

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

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

42. Falaleeva Natalia Alexandrovna, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Centre — branch of the National Medical Research Radiological Centre of the Russian Ministry of Health

43. Fedenko Alexander Alexandrovich, MD, PhD, Professor of the RAS, Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute — branch of the National Medical Research Radiological Centre of the Russian Ministry of Health

44. Evgeny V. Khmelevsky, MD, PhD, Professor, Head of the Department of Radiation Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health, radiation oncologist at the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

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

46. Tsirlina Evgenia Vladimirovna, MD, PhD, Endocrinologist, Department of Functional Diagnostics, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

47. Choinzonov Evgeny Lhamatsyrenovich, MD, DSc, Academician of the RAS, Director of the Cancer Research Institute, Tomsk National Research Medical Center; Head of the Department of Head and Neck Tumors, Cancer Research Institute, Tomsk National Research Medical Center; Head of the Department of Oncology, Siberian State Medical University of the Russian Ministry of Health; Member of the All-Russian Public Organization "Russian Society of Head and Neck Tumors Specialists"

48. Liliya P. Yakovleva, PhD in Medicine, Oncologist, Head of the Center for Diagnosis and Treatment of Head and Neck Tumors, Moscow Clinical Scientific Center named after A.S. Loginov, Healthcare Department of Moscow

    Section: Organization of Medical Care

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

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

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

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

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1) oncologists;

2) surgeons;

3) radiation oncologists;

4) geneticists;

5) medical students, residents, and postgraduate students.

Methods used for evidence collection/selection: electronic database searches; analysis of current scientific developments on the problem of RB in Russia and abroad; synthesis of the practical experience of Russian and international specialists.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Information is not available.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Recommendations for follow-up after completed treatment

Follow-up after completed treatment is essential for maintaining the patient's 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 – once every 6–12 months. After 5 years from surgery, visits are conducted annually or upon the appearance of symptoms. However, the frequency of doctor visits may be increased depending on disease characteristics and associated risks and is determined on an individual basis in each specific case. If complaints appear or previous symptoms recur before treatment, 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 smoking cessation and alcohol abstinence:

• Higher survival rates;

• greater treatment efficacy;

• fewer and less severe side effects of antitumor therapy (cardiopulmonary complications, fatigue, weight loss, mucositis, loss of taste);

• faster recovery of general condition after treatment;

• lower risk of recurrence;

• lower risk of secondary tumors;

• lower risk of infections;

• higher quality of life.

Recommendations for chemotherapy/chemoradiotherapy complications – contact your oncologist or radiologist:

1. If body temperature rises to 38 °C or higher: start taking antibiotics (as prescribed by a physician).

2. For stomatitis:

1. Diet – mechanical, thermal, and chemical sparing, as well as the use of medical nutrition (products prescribed by a physician).

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

3. Treat the oral cavity as prescribed by a physician.

3. In case of diarrhea:

1. Diet – exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meat, flour products, fermented milk products, and rice broth are permitted. Drink plenty of fluids.

2. Take medications as prescribed by a physician.

4. For nausea.

Take medications as prescribed by a physician.

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

Appendix G1. ECOG Scale (0–5 points)

Designed to assess the general condition of an oncology patient.

The left column shows scores, and the right column shows the description of the condition corresponding to the specified score.

Material adapted from Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982

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

Source (official developer website, validation publication): Lavnikova, G.A. (1979) Histological method for quantitative assessment of therapeutic tumor damage. Moscow: Methodological recommendations, 13 p.

Type: rating scale.

Purpose: assessment of therapeutic pathomorphosis of the tumor.

Content (template) and Key (interpretation).

Score

Grade I — more than 50% of the tumor parenchyma is preserved; Grade II — 20–50% of the tumor parenchyma is preserved;

Grade III — up to 20% of the tumor parenchyma is preserved in the form of separate foci; Grade IV — complete absence of tumor parenchyma

Notes: none.