Laryngeal cancer: clinical guidelines

List of Abbreviations

AJCC – American Joint Committee on Cancer

AUC (area under ROC curve) – area under the ROC curve

ECOG – Eastern Cooperative Oncology Group performance status scale

ENE – extracapsular nodal extension

ERAS – Enhanced recovery after surgery

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

QUANTEC – quantitative analyses of normal tissue effects in the clinic

VMAT – volumetric modulated arc therapy

R0 – tumor-free resection margin

R1 – microscopic residual tumor

TNM (abbreviation for tumor, nodus, and metastasis) – international staging system for malignant tumors

IV – intravenous

HPV – human papillomavirus; CT – computed tomography

RT – radiotherapy

LU – lymph node

PT – physical therapy

MRI – magnetic resonance imaging

NPF – adverse prognostic factors

PCT – polychemotherapy

PEG – percutaneous endoscopic gastrostomy

PET/CT – positron emission tomography combined with computed tomography

LoD – level of reliability of evidence

LoR – level of conviction of recommendation

CCF – chronic cancer pain syndrome

US – ultrasound examination

5-FU – fluorouracil**

CRT – chemoradiotherapy

CT – chemotherapy

** – vital and essential drugs

Terms and Definitions

Supraglottic larynx: laryngeal surface of the epiglottis (including the apex), aryepiglottic folds, arytenoid cartilages and interarytenoid area, portion of the epiglottis below the hyoid bone (fixed portion), vestibular folds (false vocal cords), laryngeal ventricles.

Glottic larynx: vocal cords, anterior commissure, posterior commissure.

Subglottic larynx – from the lower surface of the vocal cords to the level of the first tracheal ring.

Voice prosthesis – a special valved device designed to restore vocal function, implanted via tracheoesophageal puncture.

Electrolarynx – a vibrating electronic device applied to the chin that converts muscle vibrations of the floor of the mouth into speech. The disadvantage of this method is a metallic voice lacking timbre and emotional expression.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Laryngeal cancer – a malignant tumor developing from elements of the non-keratinizing laryngeal epithelium [1].

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

In most cases, patients have a history of prolonged smoking, alcohol consumption, occupational exposure to high dust levels (textile industry), and inhalation of harmful carcinogens (petroleum, its refined products, benzene, phenolic resins, asbestos). A high risk of malignant transformation is observed in papillomas (human papillomavirus (HPV)-associated cancer), recurrent papillomatosis, pachydermia, and dyskeratosis. In addition, chronic inflammatory processes (laryngitis) are considered risk factors [1].

1.3 Epidemiology of the Disease or Condition

The standardized incidence rate of laryngeal cancer in Russia in 2019 was 31.1 cases per 100,000 population, and the mortality rate was 7.2% [Kaprin, A.D. State of oncological care for the population of Russia in 2019 / A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. – Moscow: P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health, 2020. – 239 p. – ISBN 978-5-85502-255-1].

1.4 Features of Coding the Disease or Condition

ICD-10 Coding

Malignant neoplasm of larynx - C32

C32.0 Malignant neoplasm of glottis

C32.1 Malignant neoplasm of supraglottis

C32.2 Malignant neoplasm of subglottis

C32.3 Malignant neoplasm of laryngeal cartilage

C32.8 Malignant neoplasm overlapping lesion of larynx

C32.9 Malignant neoplasm of larynx, unspecified

Neoplasm of uncertain or unknown behavior of middle ear and respiratory and intrathoracic organs - D38

D38.0 - larynx

1.5 Classification of the disease or condition

The extent of epithelial malignant tumors of the larynx is presented in the TNM classification (international staging system for malignant tumors), 8th edition, as revised by the AJCC (American Joint Committee on Cancer).

Clinical classification TNM

The T category includes the following grades:

– Tx Primary tumor cannot be assessed;

– T0 No evidence of primary tumor;

– Tis Carcinoma in situ.

Supraglottis:

– T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility;

– T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx;

– T3 Tumor limited to larynx with vocal cord fixation and/or invasion of postcricoid area, pre-epiglottic tissues; minimal thyroid cartilage erosion;

– T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep/extrinsic muscle of tongue, strap muscles, thyroid gland, esophagus);

– T4b Tumor invades prevertebral space, mediastinal structures, or encases carotid artery.

Glottis:

– T1 Tumor limited to vocal cord(s) (may involve anterior or posterior commissure) with normal mobility;

– T1a Tumor limited to one vocal cord;

– T1b Tumor involves both vocal cords;

– T2 Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility;

– T3 Tumor limited to larynx with vocal cord fixation and/or invasion of parapharyngeal space, and/or minor thyroid cartilage erosion;

– T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep/extrinsic muscle of tongue, strap muscles, thyroid gland, esophagus);

– T4b Tumor invades prevertebral space, mediastinal structures, or encases carotid artery.

Subglottis:

– T1 Tumor limited to subglottis;

– T2 Tumor extends to vocal cord(s) with normal or impaired mobility;

– T3 Tumor limited to larynx with vocal cord fixation and/or minor thyroid cartilage erosion;

– T4a Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep/extrinsic muscle of tongue, strap muscles, thyroid gland, esophagus);

– T4b Tumor invades prevertebral space, mediastinal structures, or encases carotid artery.

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

– Nx Regional LNs cannot be assessed;

– N0 No regional LN metastasis;

– N1 Metastasis in a single ipsilateral LN ≤3 cm in greatest dimension and extranodal extension (ENE) negative;

– N2 Metastasis in a single ipsilateral LN ≤3 cm and ENE+, >3 cm but not more than 6 cm in greatest dimension and ENE–; or metastases in multiple ipsilateral LNs, none more than 6 cm in greatest dimension and ENE–; or metastases in bilateral or contralateral LNs, none more than 6 cm in greatest dimension and ENE–;

– N2a Metastasis in a single ipsilateral LN ≤3 cm and ENE+; or >3 cm but not more than 6 cm in greatest dimension and ENE–;

– N2b Metastases in multiple ipsilateral LNs, none more than 6 cm in greatest dimension and ENE–;

– N2c Metastases in bilateral or contralateral LNs, none more than 6 cm in greatest dimension and ENE–;

– N3 Metastasis in an LN >6 cm in greatest dimension and ENE–; or metastasis in a single ipsilateral LN >3 cm and ENE+; or multiple ipsilateral, contralateral, or bilateral metastases with ENE+; or a single contralateral metastasis of any size with ENE+;

– N3a Metastasis in an LN >6 cm in greatest dimension and ENE–;

– N3b Metastasis in a single ipsilateral LN >3 cm and ENE+; or multiple ipsilateral, contralateral, or bilateral metastases with ENE+; or a single contralateral metastasis of any size and ENE+;

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

– Mx Distant metastasis cannot be assessed;

– M0 No distant metastasis;

– M1 Distant metastasis is present.

Table 1. Stage grouping

Histological grade:

– G_x Cannot be assessed;

– G₁ Well differentiated;

– G₂ Moderately differentiated;

– G₃ Poorly differentiated.

1.6 Clinical presentation of the disease or condition

The most common clinical symptoms of laryngeal cancer include voice changes, hoarseness, and choking [1].

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 mass, adjacent tissues, and regional LNs;

3. cytological examination of scrapings, smears, and aspirates from the primary tumor, as well as aspirates from enlarged or suspicious LNs;

4. pathological examination of biopsy (surgical) specimens;

5. instrumental examination, including fibrolaryngoscopy, aspiration biopsy of soft tissue nodules in the neck under ultrasound guidance (ultrasound of soft tissues and neck LNs), computed tomography (CT)/magnetic resonance imaging (MRI), and positron emission tomography combined with CT (PET/CT) [3].

2.1 Complaints and Anamnesis

persistent voice impairment manifesting as hoarseness, rarely cough. If the lesion obstructs the laryngeal lumen, breathing difficulties may develop; persistent cough, sore throat unresponsive to antibacterial and anti-inflammatory treatment;

enlarged cervical lymph nodes [1].

Presence of neck masses.

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

2.2 Physical Examination

1. altered neck contours;

2. enlarged regional LNs;

3. changes in the mobility and width of the laryngeal skeleton [1].

URR CLevel of Recommendations Consensus – C (Level of Evidence

2.3 Laboratory Diagnostics

No specific laboratory diagnostic tests are mandated. Laboratory tests are performed at the discretion of the oncologist to the extent necessary to ensure effective and safe patient care. For patients with advanced stages where treatment is not limited to local therapy alone, PD-L1 expression testing in tumor cells (TPS; %) and immune cells with combined positive score (CPS) calculation is indicated.

2.4 Instrumental Diagnostics

Comments: In the absence of contraindications and when extension to the hypopharynx/esophagus is suspected, contrast-enhanced neck MRI is advisable when planning RT/CRT [3, 8].

2.5 Other Procedures

Comments: the report must reflect the following parameters:

1. tumor size;

2. depth of tumor invasion;

3. histological structure of the tumor;

4. tumor differentiation grade;

5. presence of lymphovascular or perineural invasion (negative findings must also be explicitly stated);

6. pT;

7. pN (indicating the total number of examined and involved LNs, and features of extranodal tumor extension);

8. status of resection margins (negative findings must also be explicitly stated).

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

3.1. Glottic region of the larynx

Carcinoma in situ

• All patients with carcinoma in situ are recommended to undergo endolaryngeal resection (removal of the laryngeal neoplasm using a CO2 laser, preferably) or RT to improve survival and preserve voice function [9].

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

T1, T2, N0

Comment: in the presence of adverse prognostic factors (APFs)—microscopic residual tumor at the resection margin (R1)—re-resection is indicated (if feasible), or adjuvant RT if not feasible. Postoperative RT is also indicated in the presence of the following APFs: perineural, perivascular, or perilymphatic invasion, and pN2–3. Postoperative concurrent CRT is indicated in the presence of ENE+ alone or combined with other APFs [3].

T1–2, N+

• In laryngeal cancer stage T1–2, N+ it is recommended to perform concurrent CRT or laryngeal resection (endoscopic surgery: removal of the laryngeal tumor using a CO2 laser, or open surgery) with unilateral or bilateral neck lymph node dissection to improve survival rates and preserve voice function [9].

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

Comment: following surgical treatment, further management is determined based on the presence or absence of adverse pathological factors (APFs) according to routine pathomorphological examination of the surgical specimen. The absence of APFs and pN0 status do not require additional treatment; active surveillance is recommended. Indications for postoperative radiotherapy/chemoradiotherapy include the following APFs: perineural, perivascular, or perilymphatic invasion, and pN+. If the only APF is R1, reresection is indicated (if feasible); if infeasible, concurrent chemoradiotherapy is indicated. The presence of ENE+, either alone or in combination with other APFs, is an indication for concurrent chemoradiotherapy [3].

In case of complete/partial regression of the primary tumor after induction chemotherapy (according to CT or MRI with IV contrast of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive radiotherapy or chemoradiotherapy is recommended. If tumor regression is within the range of stable disease or less, surgical treatment is indicated, followed by evaluation of indications for chemoradiotherapy [9].

If residual tumor and/or metastatic lymph nodes persist after completion of radiotherapy/chemoradiotherapy, surgical treatment is indicated. In case of complete regression following conservative treatment modalities, active surveillance is indicated [3].

T3, N0

• For T3N0 laryngeal cancer, patients are recommended concurrent chemoradiotherapy to improve survival and preserve voice function [11].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: In case of complete/partial regression (according to WHO criteria) of the primary tumor after induction chemotherapy (according to CT or MRI with IV contrast of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive radiotherapy or chemoradiotherapy is recommended. If tumor regression is within the range of stable disease or less than 50%, surgical treatment is indicated, followed by evaluation of indications for chemoradiotherapy. If residual tumor and/or metastatic lymph nodes persist after completion of radiotherapy/chemoradiotherapy, surgical treatment is indicated. In case of complete regression following conservative treatment modalities, active surveillance is indicated [3].

• For T3N0 laryngeal cancer, patients are recommended induction chemotherapy for organ preservation and survival improvement [12]

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: In case of complete/partial regression (according to WHO criteria) of the primary tumor after induction chemotherapy (according to CT or MRI with IV contrast of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive radiotherapy or chemoradiotherapy is recommended. If tumor regression is within the range of stable disease or less than 50%, surgical treatment is indicated, followed by evaluation of indications for chemoradiotherapy. If residual tumor and/or metastatic lymph nodes persist after completion of radiotherapy/chemoradiotherapy, surgical treatment is indicated. In case of complete regression following conservative treatment modalities, active surveillance is indicated [3].

• For T3N0 laryngeal cancer, surgical treatment in the volume of laryngectomy with resection of the thyroid gland on the affected side, pre- and ipsilateral paratracheal lymph node dissection is recommended to improve survival [9].

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

Comment: in selected cases reviewed on an individual basis, organ-preserving transoral laser resection or open resection is possible in the absence of thyroid cartilage erosion.

Following surgical treatment, further management is determined based on the presence or absence of APFs according to pathomorphological examination. The absence of APFs and pN0 status do not require additional treatment; active surveillance is recommended. Indications for postoperative chemoradiotherapy include the following APFs: perineural, perivascular, or perilymphatic invasion, and pN+. If the only APF is R1, reresection is indicated (if feasible); if infeasible, concurrent chemoradiotherapy is indicated. The presence of ENE+, either alone or in combination with other APFs, is an indication for concurrent chemoradiotherapy. If 2 or more APFs are present, chemoradiotherapy is indicated. If 1 APF is present, radiotherapy is indicated. If pN2 is present, chemoradiotherapy is indicated [3].

T3, N+

• For T3N+ laryngeal cancer, patients are recommended concurrent chemoradiotherapy to improve survival and preserve voice function [11].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: In case of complete/partial regression (according to WHO criteria) of the primary tumor after induction chemotherapy (according to CT or MRI with IV contrast of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive radiotherapy or chemoradiotherapy is recommended. If tumor regression is within the range of stable disease or less than 50%, surgical treatment is indicated, followed by evaluation of indications for chemoradiotherapy. If residual tumor and/or metastatic lymph nodes persist after completion of radiotherapy/chemoradiotherapy, surgical treatment is indicated. In case of complete regression following conservative treatment modalities, active surveillance is indicated [3].

• For T3N+ laryngeal cancer, patients are recommended induction chemotherapy followed by chemoradiotherapy for organ preservation [12]

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: in case of complete/partial regression (according to WHO criteria) of the primary tumor after induction chemotherapy (according to CT or MRI with IV contrast of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive radiotherapy or chemoradiotherapy is recommended. If tumor regression is within the range of stable disease or less than 50%, surgical treatment is indicated, followed by evaluation of indications for chemoradiotherapy. If residual tumor and/or metastatic lymph nodes persist after completion of radiotherapy/chemoradiotherapy, surgical treatment is indicated. In case of complete regression following conservative treatment modalities, active surveillance is indicated [3].

• For T3N+ laryngeal cancer, patients are recommended surgical treatment in the volume of laryngectomy with hemithyroidectomy/thyroidectomy on the affected side, pre- and ipsilateral paratracheal lymph node dissection, as well as ipsilateral neck lymphadenectomy to improve survival [9].

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

Comment: in selected cases reviewed on an individual basis, in the absence of thyroid cartilage erosion, organ-preserving transoral laser resection or open partial laryngectomy may be performed.

Following surgical treatment, further management is determined based on the presence or absence of APFs according to pathomorphological examination. The absence of APFs and pN0 status do not require additional treatment; active surveillance is recommended. Indications for postoperative chemoradiotherapy include the following APFs: perineural, perivascular, or perilymphatic invasion, and pN+. If the only APF is R1, reresection is indicated (if feasible); if infeasible, concurrent chemoradiotherapy is indicated. The presence of ENE+, either alone or in combination with other APFs, is an indication for concurrent chemoradiotherapy. If 2 or more APFs are present, chemoradiotherapy is indicated. If 1 APF is present, radiotherapy is indicated. If pN2 is present, chemoradiotherapy is indicated [3].

T4a, any N

• For T4a any N laryngeal cancer, recommended is surgical treatment in the volume of laryngectomy with thyroidectomy, pre- and ipsilateral paratracheal lymph node dissection, and unilateral or bilateral neck lymph node dissection to improve survival [13].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comment: Following surgical treatment, further management is determined based on the presence or absence of APFs according to pathomorphological examination. The absence of APFs and pN0 status do not require additional treatment; active surveillance is recommended. Indications for postoperative chemoradiotherapy include the following APFs: perineural, perivascular, or perilymphatic invasion, and pN+. If the only APF is R1, reresection is indicated (if feasible); if infeasible, concurrent chemoradiotherapy is indicated. The presence of ENE+, either alone or in combination with other APFs, is an indication for concurrent chemoradiotherapy. If 2 or more APFs are present, chemoradiotherapy is indicated. If 1 APF is present, radiotherapy is indicated. If pN2 is present, chemoradiotherapy is indicated [3].

Selected patients with stage T4a who refuse surgery

• For T4a laryngeal cancer, recommended are concurrent chemoradiotherapy or induction polychemotherapy followed by chemoradiotherapy, with subsequent response evaluation to improve patient survival [3].

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

Comment: in case of complete/partial regression (according to WHO) of the primary tumor after induction chemotherapy (according to CT or MRI with IV contrast of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive chemoradiotherapy is recommended. If tumor regression is within the range of stable disease or less than 50%, surgical treatment is indicated, followed by evaluation of indications for chemoradiotherapy.

In the presence of a residual tumor and/or metastatic LNs after completion of CRT, surgical treatment is appropriate. In case of complete regression after conservative treatment modalities, active surveillance is indicated [3].

T4b, any N, unresectable regional metastases, M1, or patients unsuitable for surgical treatment

• In patients with malignant laryngeal tumors stage T4b any N, or with unresectable regional metastases, distant metastases M1, or in patients unsuitable for surgical treatment, with an Eastern Cooperative Oncology Group performance status score (ECOG) (see Appendix D) of 0–1, it is recommended to consider drug therapy (in selected cases, CRT may be considered) to improve survival, or symptomatic treatment to relieve symptoms of the disease [3].

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

• In patients with malignant laryngeal tumors stage T4b any N, or with unresectable regional metastases, distant metastases M1, or in patients unsuitable for surgical treatment, with an ECOG performance status score of 2 (see Appendix D), drug therapy is recommended [3].

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

• In patients with malignant tumors stage T4b any N, or with unresectable regional metastases, distant metastases M1, or in patients unsuitable for surgical treatment, with an ECOG performance status score of 3 (see Appendix D), symptomatic treatment is recommended [3].

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

Comment: Following definitive CRT, assessment of treatment response should be performed no earlier than 2–3 months post-treatment.

3.2. Supraglottic larynx

T1, T2, N0-1

• In patients with T1-2N0-1 laryngeal cancer, laryngeal resection (endoscopic or open) is recommended to improve survival and reduce treatment toxicity [14].

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

• In patients with T1-2N0 laryngeal cancer, definitive RT is recommended to improve survival [3].

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

Comment: Due to the high risk of regional metastasis, surgery of the primary site should be supplemented with unilateral or bilateral neck dissection. In the presence of adverse prognostic factors (APF) such as R1, re-resection is indicated (if feasible); if impossible, adjuvant CRT is indicated. The presence of the following APFs is also an indication for postoperative RT: perineural, perivascular, or perilymphatic invasion. An indication for postoperative concurrent CRT is the presence of ENE+ alone or in combination with other APFs [3].

T1, T2, N2-3

• In patients with T1-2N2-3 laryngeal cancer, concurrent CRT, or induction CT followed by CRT, or laryngeal resection (endoscopic or open) with unilateral or bilateral neck dissection is recommended to improve survival [15]

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

Comment: Following surgical treatment, further management is guided by the presence/absence of APFs according to final histopathology. Absence of APFs and pN0 status do not require additional treatment; active surveillance is appropriate. Indications for postoperative CRT include the following APFs: perineural, perivascular, perilymphatic invasion, and pN+. In the presence of R1 margin status alone, re-resection is indicated (if feasible); if impossible, concurrent CRT is indicated. The presence of ENE+ alone or in combination with other APFs is an indication for concurrent CRT.

In case of complete/partial regression (according to WHO criteria) of the primary site following induction CT (based on contrast-enhanced CT or MRI of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive RT or CRT is appropriate. In case of tumor regression within stable disease or less than 50%, surgical treatment is appropriate, followed by consideration of indications for RT/CRT.

In the presence of a residual tumor and/or metastatic LNs after completion of RT/CRT, surgical treatment is appropriate. In case of complete regression after conservative treatment modalities, active surveillance is indicated [3].

T3N0–3

• In patients with T3N0–3 laryngeal cancer, concurrent CRT or induction CT followed by CRT is recommended for organ preservation [16].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: In the presence of a residual tumor and/or metastatic LNs after completion of RT/CRT, it is appropriate, based on follow-up imaging performed no earlier than 2–3 months after completion of conservative treatment, to consider surgical treatment. In case of complete regression after conservative treatment modalities, active surveillance is indicated [3].

• In patients with T3N0–3 laryngeal cancer, surgical treatment in the extent of total laryngectomy with thyroidectomy, pre- and ipsilateral paratracheal lymph node dissection, and unilateral or bilateral neck dissection is recommended [15].

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

Comment: In selected cases evaluated on an individual basis, organ-preserving resection (open or endoscopic laser) may be performed in the absence of thyroid cartilage erosion; neck dissection is mandatory regardless of regional LN status. Following surgical treatment, further management is guided by the presence/absence of APFs according to final histopathology. Absence of APFs and pN0 status do not require additional treatment; active surveillance is appropriate. Indications for postoperative CRT include the following APFs: perineural, perivascular, perilymphatic invasion, and pN+. In the presence of R1 margin status alone, re-resection is indicated (if feasible); if impossible, concurrent CRT is indicated. The presence of ENE+ alone or in combination with other APFs is an indication for concurrent CRT.

• In patients with T3N0–3 laryngeal cancer, induction CT followed by CRT is recommended, with subsequent response evaluation, for organ preservation [16].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: In case of complete/partial regression (according to WHO criteria) of the primary site following induction CT (based on contrast-enhanced CT or MRI of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive RT or CRT is appropriate. In case of tumor regression within stable disease or less than 50%, surgical treatment is appropriate, followed by consideration of indications for RT/CRT.

In the presence of a residual tumor and/or metastatic LNs after completion of RT/CRT (based on evaluation performed no earlier than 2–3 months after completion of conservative treatment), surgical treatment is appropriate. In case of complete regression after conservative treatment modalities, active surveillance is indicated [3].

T4a, N0–N3

• In patients with stage T4a, N0–N3 supraglottic laryngeal cancer, surgical treatment consisting of laryngectomy with thyroidectomy, unilateral or bilateral neck dissection, followed by postoperative concurrent CRT is recommended to improve patient survival [15].

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

Comment: Following surgical treatment, further management is guided by the presence/absence of APFs according to final histopathology. Absence of APFs and pN0 status do not require additional treatment; active surveillance is appropriate. Indications for postoperative CRT include the following APFs: perineural, perivascular, perilymphatic invasion, and pN+. In the presence of R1 margin status alone, re-resection is indicated (if feasible); if impossible, concurrent CRT is indicated. The presence of ENE+ alone or in combination with other APFs is an indication for concurrent CRT [3].

Selected patients with stage T4a who refuse surgery

• In T4a supraglottic laryngeal cancer, if the patient declines surgery, concurrent CRT or induction PCT followed by CRT is recommended, followed by response evaluation, to improve overall survival [15].

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

Comment: In case of complete/partial regression of the primary site following induction CT (based on contrast-enhanced CT or MRI of the primary tumor and neck, fibrolaryngoscopy, neck ultrasound), definitive RT or CRT is appropriate. In case of tumor regression within stable disease or less than 50%, surgical treatment is appropriate, followed by consideration of indications for RT/CRT.

In the presence of a residual tumor and/or metastatic LNs after completion of RT/CRT (based on evaluation performed no earlier than 2–3 months after completion of conservative treatment), surgical treatment is appropriate. In case of complete regression after conservative treatment modalities, active surveillance is indicated [3].

T4b, any N, unresectable regional metastases, M1, or patients unsuitable for surgical treatment

• For supraglottic laryngeal cancer of stage T4b with any N, in the presence of unresectable regional metastases or distant metastases, as well as in patients with an ECOG performance status of 0–1 (see Appendix G), it is recommended to consider drug therapy (in individual cases, concurrent chemoradiotherapy may be considered) to increase survival, or palliative treatment to improve the patient's condition [3].

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

• For supraglottic laryngeal cancer of stage T4b with any N, in the presence of unresectable regional metastases or distant metastases, as well as in patients with an ECOG performance status of 2 (see Appendix G), drug therapy is recommended to increase survival, or palliative treatment to improve the patient's condition [3].

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

• For supraglottic laryngeal cancer of stage T4b with any N, in the presence of unresectable regional metastases or distant metastases, as well as in patients with an ECOG performance status of 3 (see Appendix G), palliative treatment is recommended to improve the patient's condition [3].

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

Local recurrence without prior radiotherapy

• For patients with local recurrence of supraglottic laryngeal cancer without prior radiotherapy, surgical intervention (for resectable tumors) is recommended to increase patient survival [3].

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

Comment: the absence of adverse prognostic factors and pN0 status do not require additional treatment; active surveillance is appropriate. Indications for postoperative radiotherapy/chemoradiotherapy include the following adverse prognostic factors: perineural, perivascular, or perilymphatic invasion, and pN+. If only an R1 margin is present, re-resection is indicated (if feasible); if unfeasible, concurrent chemoradiotherapy is indicated. The presence of ENE+ (isolated or combined with other adverse prognostic factors) is an indication for concurrent chemoradiotherapy.

• For patients with local recurrence of supraglottic laryngeal cancer without prior radiotherapy and an ECOG performance status of 0–1 (see Appendix G), concurrent chemoradiotherapy, induction chemotherapy followed by radiotherapy, or concurrent chemoradiotherapy is recommended to improve survival [3].

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

• For patients with unresectable local recurrence of supraglottic laryngeal cancer without prior radiotherapy and an ECOG performance status of 2 (see Appendix G), palliative radiotherapy or drug therapy is recommended to relieve the patient's condition [3].

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

Local recurrence or residual tumor after radiotherapy

• For patients with local recurrence of supraglottic laryngeal cancer after radiotherapy with a resectable tumor, surgical intervention is recommended with consideration of re-irradiation or concurrent chemoradiotherapy [3].

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

Comments: If the tumor is unresectable, re-irradiation/concurrent chemoradiotherapy, drug therapy (see Table 1), or palliative care is advisable.

Local recurrence or distant metastasis

• For patients with local recurrence of supraglottic laryngeal cancer and distant metastases, with an ECOG performance status of 0–1 (see Appendix G), it is recommended to consider drug therapy to increase survival [3].

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

Comments: in individual cases with solitary metastases, surgical treatment or chemoradiotherapy may be considered

• For patients with local recurrence of supraglottic laryngeal cancer and distant metastases, with an ECOG performance status of 2 (see Appendix G), drug therapy is recommended [3].

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

• For patients with local recurrence of supraglottic laryngeal cancer and distant metastases, with an ECOG performance status of 3 (see Appendix G), palliative treatment is recommended to improve the patient's condition [3].

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

3.3. Principles of radiation therapy / chemoradiotherapy

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 the biopsy material, staging, and tumor imaging (CT, MRI) to determine the extent of the tumor; rule out the presence of a synchronous primary tumor; assess the current functional status and feasibility of radiotherapy/chemoradiotherapy; develop a prospective follow-up plan that includes oropharyngeal sanitation (including dental examination), provision of adequate nutrition, pain management, and wound healing, as well as other measures necessary for maximum patient rehabilitation. For patients undergoing radiotherapy/chemoradiotherapy, a plan must be developed to implement the anticancer therapy in full and within optimal timeframes. The target volume for radical doses should not be modified based on the clinical response achieved prior to radiotherapy (after induction polychemotherapy), except in cases of tumor progression. It is permissible to discuss reducing the target volume by excluding vital structures free of tumor involvement at the time of radiotherapy planning, provided that the dose constraints on these structures according to QUANTEC criteria (Quantitative Analyses of Normal Tissue Effects in the Clinic) would otherwise be exceeded.

Conformal external beam radiotherapy is preferred, including high-precision techniques such as IMRT (intensity-modulated radiotherapy), IGRT, and VMAT (volumetric modulated arc therapy) [17].

For radiation therapy of glottic laryngeal cancer T1N0M0, hypofractionation regimens of 50–55 Gy (2.75–3.5 Gy/fraction) may be used (24, 25, 26).

• For patients with laryngeal cancer, definitive radiotherapy to the primary tumor and clinically apparent regional metastases is recommended at a dose of 66–70 Gy (2.0–2.2 Gy/fraction) daily from Monday to Friday for 6–7 weeks; to the locoregional area, including regional lymph nodes, the dose is 44–63 Gy (1.8–2.0 Gy/fraction) to improve survival outcomes [3].

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

• For patients with malignant laryngeal tumor when concurrent chemoradiotherapy is chosen as the primary definitive option, radiotherapy to the primary tumor and clinically apparent regional metastases is recommended at a dose of 70 Gy (2.0 Gy/fraction) daily from Monday to Friday for 7 weeks; to the locoregional area, including regional lymph nodes, the dose is 44–63 Gy (1.8–2.0 Gy/fraction) taking risks into account [3]. Oxford Centre for Evidence-Based Medicine Level of Evidence – C (Level of Evidence – 5).

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

Comment: the standard is the use of cisplatin** at a dose of 100 mg/m² with hyperhydration on days 1, 22, and 43 of radiotherapy (total cumulative dose during radiotherapy of 300 mg/m²). Following induction polychemotherapy, as an alternative to cisplatin**, it is advisable to use carboplatin** or cetuximab** taking into account the tolerability of chemoradiotherapy and the patient's somatic status (in squamous cell carcinoma). Carboplatin** is administered at an AUC (area under the curve) of 1.5–2.0 weekly starting from day 1 of radiotherapy. Cetuximab** is administered at a loading dose of 400 mg/m² one week prior to the start of radiotherapy, followed by a maintenance dose of 250 mg/m² weekly during radiotherapy.

Omitting platinum-based chemoradiotherapy regimens in favor of cetuximab** is also advisable when there is a high risk of failure/incomplete implementation of the definitive chemoradiotherapy plan and a high risk of adverse effects from platinum compounds (glomerular filtration rate <50–60 ml/min, patient age >65 years, severe concomitant renal, cardiovascular, neurological, or hepatic pathology, and/or a weakened patient status – ECOG >1 (see Appendix G)) [18].

• For patients with malignant laryngeal tumor, postoperative radiotherapy is recommended for stages pT3–4 and N0–1, as well as for selected patients with stages pT1–2 and N0–1 (in the presence of adverse features) [3].

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

Comments: The preferred interval after surgery is ≤6 weeks and should not exceed 3 months. When resection margins are clear (R0), a dose of 60 Gy (2.0 Gy/fraction) is delivered to the bed of the resected primary tumor and regional metastases. In the case of R+, the total radiation dose is 66 Gy (2.0 Gy/fraction). To the locoregional area, including uninvolved regional lymph nodes, the total dose is 44–63 Gy (1.8–2.0 Gy/fraction) [3].

• Postoperative concurrent chemoradiotherapy is recommended for patients with malignant laryngeal tumor in cases of tumor extension through the lymph node capsule or positive resection margins (if re-operation is declined), and is also discussed when 2 or more adverse factors are present (pT3 or pT4; N2 or N3, presence of perineural invasion and/or lymphovascular emboli) [3].

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

Comments: Following an R0 resection according to histological findings, a dose of up to 60 Gy (2.0 Gy/fraction) is delivered to the area of the excised primary tumor and regional metastases. In cases of R+ resection, the total radiation dose is 66 Gy (2.0 Gy/fraction). For the locoregional area, including unaffected regional lymph nodes, the total radiation dose is 44–63 Gy (1.8–2.0 Gy/fraction). Concomitant chemotherapy with cisplatin at a dose of 100 mg/m2 every 3 weeks is advisable, or the combination of docetaxel 15 mg/m2 + cetuximab at a loading dose of 400 mg/m2 one week prior to the start of radiotherapy, followed by a maintenance dose of 250 mg/m2 weekly during radiotherapy [3].

Comments: For patients with malignant laryngeal tumors scheduled for radiotherapy or chemoradiotherapy, conformal external beam radiotherapy with neutron, proton, and heavy ion beams is recommended as an alternative radiotherapy method to reduce the frequency and severity of radiation-induced reactions and thereby improve treatment tolerability [19].

3.4. Principles of systemic drug therapy

The choice of drug therapy should be individualized based on patient characteristics (general condition, treatment goals). The presented drug regimens are indicated for squamous cell carcinoma. Drug therapy regimens for other histological tumor types (e.g., sarcomas) can be found in the relevant clinical guidelines.

Table 1. Drug therapy regimens for head and neck squamous cell carcinoma

[18], [23]. [27]. [28].

¹ For patients with an ECOG performance status of 2.

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

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

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

⁵ As first-line therapy when CPS ≥ 1

Comments: For patients with disease progression after the use of antineoplastic agents (cytostatics), cetuximab**, and immunotherapy, #afatinib** 40 mg/day orally may be prescribed until disease progression or unacceptable toxicity (efficacy in head and neck squamous cell carcinoma has been evaluated only in foreign studies) to improve progression-free survival [55].

3.5. Principles of surgical treatment

Surgical treatment involves operations of various volumes aimed at removing the primary tumor focus, including organ-preserving techniques (endolaryngeal laser resection, endoscopic resection), open resections of affected parts, and restoration of the upper gastrointestinal tract integrity using various reconstructive and plastic surgery techniques.

• For cancer of the supraglottic larynx in the absence of clinical signs of cervical lymph node involvement, prophylactic unilateral/bilateral neck lymph node dissection (levels 2–4) is recommended for all patients to reduce the risk of locoregional recurrence and improve survival [32].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments:

1. Removal of level II–V lymph nodes is advisable in the presence of one of the following factors:

2. metastases in level IV or V lymph nodes;

3. regional metastasis greater than 6 cm in diameter;

4. multiple metastases greater than 3 cm in diameter;

5. extracapsular tumor extension;

6. regional recurrence.

• 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 and evaluate the risks of bleeding, tumor size, and tumor extension to adjacent structures in the case of tumor ulceration, an existing cavity in the tumor area or tumor recurrence, proximity to branches of the carotid artery, the presence of a non-healing wound, or a past tumor hemorrhage [49-54].

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

• If a risk of bleeding from tumor nodes is established, it is recommended to perform angiography and, in the absence of contraindications, perform superselective intra-arterial embolization of tumor vessels to reduce the risk of bleeding and fatal complications [49-54].

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

3.6. Pain management

The procedure and recommendations for pain management in malignant neoplasms of the oral cavity correspond to the recommendations presented in the clinical guidelines

"Chronic pain syndrome (CPS) in adult patients requiring palliative medical care"

3.7. Supportive care

The principles of prevention and treatment of anemia in patients with laryngeal cancer correspond to the principles outlined in the clinical guidelines "Anemia in malignant neoplasms", available in the register of clinical guidelines of the Russian Ministry of Health https://cr.minzdrav.gov.ru.

The principles of treatment and prevention of nausea and vomiting in patients with laryngeal cancer correspond to the principles outlined in the guidelines "Practical guidelines for the prevention and treatment of nausea and vomiting in cancer patients" (authors: Vladimirova L.Yu., Gladkov O.A., Koroleva I.A., Rumyantsev A.A., Semiglazova T.Yu., Tryakin A.A., Kutukova S.I., Ovchinnikova E.G., Novikova O.Yu., Kornitskaya A.L. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 29–44, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-38.pdf).

The principles of treatment and prevention of mucositis in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the treatment and prevention of mucositis" (authors: Semiglazova T.Yu., Belyak N.P., Vladimirova L.Yu., Kornitskaya A.L., Koroleva I.A., Nechaeva M.N., Radzhabova Z.A., Teletaeva G.M., Tkachenko E.V. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 250–259, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-52.pdf).

The principles of treatment and prevention of bone complications in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Prevention and treatment of bone pathology in malignant neoplasms" (authors: Bagrova S.G., Basin E.M., Borzov K.A., Bychkova N.M., Dengina N.V., Kopp M.V., Krylov V.V., Kochetova T.Yu., Semiglazova T.Yu. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 45–58, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-39.pdf).

The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the diagnosis and treatment of febrile neutropenia" (authors: Sakaeva D.D., Borisov K.E., Bulavina I.S., Kogonia L.M., Kurmukov I.A., Orlova R.V., Shabaeva M.M. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 62–71, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-40.pdf).

The principles of prevention and treatment of hepatotoxicity in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the management of antineoplastic therapy-induced hepatotoxicity" (authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 69–82, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-41.pdf).

The principles of prevention and treatment of cardiovascular complications in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the management of cardiovascular toxicity of anticancer drug therapy" (authors: Vitsenya M.V., Ageev F.T., Orlova R.V., Poltavskaya M.G., Potievskaya V.I. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 86–111, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-42.pdf).

The principles of prevention and treatment of dermatological complications in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the drug treatment of dermatological reactions in patients receiving anticancer drug therapy" (authors: Koroleva I.A., Bolotina L.V., Gladkov O.A., Gorbunova V.A., Kogonia L.M., Kruglova L.S., Orlova E.V., Orlova R.V. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 108–131, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-43.pdf).

The principles of prevention and treatment of nephrotoxicity in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the management of nephrotoxicity of antineoplastic drugs" (authors: Gromova E.G., Biryukova L.S., Dzhumabaeva B.T., Kurmukov I.A. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 153–166, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-47.pdf).

The principles of prevention and treatment of thromboembolic complications in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the prevention and treatment of thromboembolic complications in cancer patients" (authors: Somonova O.V., Antukh E.A., Vardanyan A.V., Gromova E.G., Dolgushin B.I., Elizarova A.L., Sakaeva D.D., Selchuk V.Yu., Tryakin A.A., Cherkasov V.A. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 170–183, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-48.pdf).

The principles of prevention and treatment of the consequences of drug extravasation in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "A. Guidelines for the prevention and treatment of the consequences of anticancer drug extravasation" (author: Buydenok Yu.V., Obukhova O.A. Malignant Tumors: RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 179–189, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-49.pdf).

The principles of prevention and treatment of immune-mediated adverse events in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for the management of immune-mediated adverse events" (authors: Protsenko S.A., Ballyuzek M.F., Vasiliev D.A., Zhukova N.V., Novik A.V., Nosov D.A., Petenko N.N., Semenova A.I., Kharkevich G.Yu., Yudin D.I. RUSSCO Practical Guidelines, Part 2. Malignant Tumors, 2023 (vol. 13), #3s2, pp. 213–252, https://rosoncoweb.ru/standarts/RUSSCO/2023/2023-51.pdf).

3.8. Nutritional therapy

The need to prescribe medical nutrition is determined by the patient's nutritional status, as well as the advisability of correcting comorbid conditions and preventing complications of the ongoing treatment; therefore, the principles of medical nutrition and indications are presented in the section "Medical rehabilitation, indications and contraindications for the use of rehabilitation methods".

The principles of nutritional support in patients with laryngeal cancer correspond to the principles outlined in the methodical recommendations "Practical guidelines for nutritional support in cancer patients" (authors: Sytov A.V., Leiderman I.N., Lomidze S.V., Nekhaev I.V., Khoteev A.Zh. DOI: 10.18027/2224-5057-2018-8-3s2-575-583, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-41.pdf).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• In the preoperative period and in the early postoperative period, all patients with malignant laryngeal tumor are recommended a medical speech therapy procedure for dysphagia and to train the patient's ability to speak. [33].

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

Comments: To restore speech function, methods of esophageal speech, tracheoesophageal puncture, and the use of electronic speech-generating devices are used. There are a number of limitations for speech therapy rehabilitation: active functional training should not be carried out in the early postoperative period, at the primary healing stage, and when fistulas occur. Violation of the functional training regimen is unacceptable.

• Nutritional-metabolic rehabilitation (diet therapy) for at least 7 days is recommended for all patients with malignant neoplasms of the larynx in order to reduce the frequency of postoperative complications and the length of hospital stay for a patient with malignant laryngeal neoplasm [35].

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

Comments: Nutritional support during the planning of 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/m2, hypoproteinemia <60 g/L or hypoalbuminemia <30 g/L, deterioration of food intake ability over the past week. In the case of chemotherapy, the 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 adequate oral nutrition; moderate and severe enteropathy

• For patients with malignant neoplasms of the larynx receiving medical treatment, it is recommended to prescribe an early set of exercises (physical therapy) 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 [36].

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

Comments: Performing physical therapy exercises incorporating aerobic loads 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 [37].

• To reduce fatigue and increase endurance in all patients with laryngeal malignant neoplasms during chemoradiotherapy, it is recommended to perform physical therapy in the form of moderate-intensity aerobic exercise combined with resistance training [38].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: The combination of physical therapy and psychological support is used as a comprehensive treatment for chemotherapy-induced fatigue [39]. In addition, a 6-week course of medical massage is advisable to reduce fatigue associated with combination treatment [40].

• Balance training exercises are recommended for all patients with laryngeal malignant neoplasms receiving chemotherapy for the correction of polyneuropathy [41].

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

Comments: From the onset and until the complete resolution of radiation mucositis, the use of dermatoprotectors—tissue repair stimulators (gels, urea solution, etc.)—is indicated. Regular oral irrigation with an isotonic solution removes food debris and accumulated secretions. Oils (olive, peach, sea buckthorn, or rosehip) are used for oral applications or nasal instillation. In the presence of pain syndrome, local anesthetics and systemic analgesics are used [46]. Opioids are most often required, and attention should be paid to transdermal forms of administration [47].

From the onset of radiation dermatitis and until the complete subsidence of reactions, the use of tissue repair stimulators (gels, dioxomethyltetrahydropyrimidine, riboflavin), as well as sunscreens, is indicated. The skin must be protected from friction and irritation. To combat xerosis, urea cream and an oil solution of vitamin A are used. For bioradiation dermatitis, a cream with vitamin K is advisable.

In the post-radiation period, irradiated normal tissues are very vulnerable and therefore require careful handling. In the early stages, invasive diagnostic procedures and biopsies should be avoided unless absolutely necessary. Diet selection is indicated, if necessary in combination with antireflux drugs [48]. Trauma, alcohol, smoking, and irritating foods easily cause mucosal ulceration, which is often accompanied by exposure of the mandible bone with the subsequent development of osteomyelitis. A common cause of radiation osteomyelitis is tooth extraction in the prior irradiation zone; therefore, one should limit oneself to conservative methods whenever possible and perform tooth extractions against the background of antibiotic therapy only when necessary.

Rehabilitation during radiotherapy

The success of antitumor treatment and rehabilitation depends on the patient's baseline condition. Thus, risk factors for the early onset and development of severe side effects include cachexia and a severe psychological state of the patient, older age, comorbidities, trauma to the oral and pharyngeal mucosa, carious teeth, pronounced pain syndrome, smoking, and alcohol consumption. Treatment preparation and adequate patient management are tasks of such importance that the involvement of relevant allied specialists as part of a multidisciplinary team (algologist, nutritionist, dentist, etc.), as well as the scope of supportive care, are specified in international guidelines as a prerequisite for the successful treatment of head and neck cancer patients.

The management of patients with head and neck malignant tumors receiving/who have received radiation therapy requires an integrated approach comprising at least three basic components of supportive care: wound healing, pain management, and nutritional support, combined with maintaining patient contact and treatment adherence at all stages. It should be noted that supportive care and rehabilitation techniques are much more diverse and also imply detoxification therapy, correction of hematological toxicity, antiulcer, antiemetic, and antibiotic therapy, etc. Thorough post-treatment monitoring of patients and correction of potential delayed side effects of radiation therapy (xerosis, bone and/or soft tissue necrosis, etc.) are also mandatory.

Adequate nutrition and maintenance of water balance are vital. Combating "iatrogenic" nutritional deficiency resulting from radiation therapy (RT) and chemoradiotherapy (CRT) is a crucial task for the successful treatment of patients with head and neck tumors. A special role is played by a balanced food intake, which is reflected in the maintenance of stable body weight. It should be noted that nutritional support is carried out for therapeutic purposes, since the period of RT is characterized by an increased body demand for energy and plastic substrates. In patients without severe dysphagia receiving RT and CRT, the method of choice is oral enteral nutrition. Nutritional therapy should be initiated immediately upon detection of nutritional deficiency or in the absence of adequate oral intake for 7 days. It is recommended to consider prophylactic nutritional support for patients scheduled for antitumor treatment with a high risk of nutritional impairment (such as CRT in patients with locally advanced pharyngeal cancer, etc.) [56]. Enteral medical nutrition is initiated when oral dietary intake is inadequate (i.e., less than 60% of total energy requirements for 10 days). A loss of more than 10% of the baseline body weight is an indication for prescribing enteral nutrition. The optimal option for nutritional support is sipping using high-protein formulas (taking into account comorbid conditions, including renal pathology). If adequate oral nutrition is impossible, it should be provided via nasogastric tube placement (for an estimated placement duration of up to 3–4 weeks) or via gastrostomy. Parenteral nutrition may also be initiated if necessary. The calculation of the patient's basic requirements focuses on the total amount of energy consumed and the quantitative ratio of various substrates. The required number of calories is most often calculated based on energy expenditure with the goal of preventing an increasing energy deficit [57]. The main goal of nutritional support is to replenish losses based on at least the following calculation: protein / amino acids: at least 1.2 g/kg/day and up to 2 g/kg/day; energy: 25–30 kcal/kg/day [58]. For patients receiving RT and CRT, the optimal approach is the use of formulas enriched with omega-3 fatty acids and dietary fiber, as well as combining nutritional support with physical activity.

From the onset and until the complete resolution of radiation mucositis, the use of local wound-healing agents (gels, urea solution, etc.) is indicated. Regular oral irrigation with an isotonic solution removes food debris and accumulated secretions. Oils (olive, peach, sea buckthorn, or rosehip) are recommended for oral applications or nasal instillation. In the presence of pain syndrome, local and systemic analgesics are used [59]. Pain management should be prescribed in accordance with the WHO ladder. Opiates are most often required, and attention should be paid to transdermal forms of administration [Supportive Care in Oncology: A Practical Guide. Edited by S.Yu. Moorcraft, D.L.Y. Lee, D. Cunningham. Translated from English. Edited by A.D. Kaprin. Moscow: Geotar, 2016. 432 p.].

From the onset of radiation dermatitis and until the complete subsidence of reactions, the use of local wound-healing agents (gels, methyluracil ointment, riboflavin), as well as sunscreens, is indicated. The skin must be protected from friction and irritation. To combat xerosis, urea cream and an oil solution of vitamin A are used. For bioradiation dermatitis, a cream with vitamin K is advisable.

In the post-radiation period, irradiated normal tissues are highly vulnerable and must be handled with care. Invasive diagnostic procedures and biopsies are not recommended in the early period unless strictly necessary. A specialized diet is indicated, combined with anti-reflux medications if necessary [60]. Trauma, alcohol, smoking, and irritating foods easily cause mucosal ulceration, which is frequently accompanied by exposure of the mandible bone and subsequent development of osteomyelitis. A common cause of radiation osteomyelitis is tooth extraction in the prior irradiation field; therefore, conservative methods should be used whenever possible, and tooth extractions, if necessary, must be performed under antibiotic coverage.

• All patients scheduled for RT/CRT are recommended to undergo a dental consultation and examination, followed by supportive care at all stages of treatment and rehabilitation [62].

umption CLevel 2Level of evidence – C (Level of reliability of evidence – 2-5).

• All patients receiving or having received RT/CRT who present with pain syndrome are recommended to consult a pain specialist (algesiologist) to ensure treatment tolerance, adequate rehabilitation, and improved quality of life [63.].

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

• Patients with head and neck malignant neoplasms receiving chemoradiotherapy are recommended to start physical activity early to improve quality of life and treatment tolerance [51].

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

5. Prevention and Dispensary Observation

For the purpose of prevention and early diagnosis, attention should be paid to the following aspects:

Primary symptoms

Tumors of the laryngeal vestibule may be asymptomatic in the early stages of the disease. Patients complain of paresthesia, dryness, a foreign body sensation in the throat, discomfort during swallowing; later, these symptoms are joined by odynophagia radiating to the ear on the affected side, dysphagia, and in case of tumor breakdown, halitosis and hemoptysis. When the tumor is localized in the vocal fold region, symptoms appear quite early in the form of voice changes (hoarseness), cough, and less frequently, hemoptysis. As the disease progresses, stenosis develops, along with pain radiating to the ear on the affected side and halitosis. The clinical course of subglottic malignant neoplasms of the larynx is characterized by the early development of breathing difficulty. The presence of neck masses.

Carcinogenic factors: smoking (including secondhand smoking), alcohol consumption, exposure to asbestos, wood dust, petroleum products, ionizing radiation, HPV.

Precancerous conditions: chronic hypertrophic laryngitis, laryngeal mucosal pachydermia, laryngeal mucosal leukoplakia, mucosal dysplasia, mucosal hyperkeratosis, vocal fold polyps, and laryngeal papillomatosis.

A questionnaire may be used to assess the risk of malignant neoplasms (see Appendix D).

Dispensary follow-up (Active surveillance)

Scope of examination:

1. history and physical examination;

2. ultrasonography of bilateral cervical lymph nodes, abdominal organs, and pelvic organs;

3. CT/MRI of the neck and brain as indicated, and when the area is inaccessible to adequate physical examination;

4. fibrolaryngoscopy;

5. targeted chest X-ray every 12 months;

6. chest CT, abdominal CT/MRI as indicated

7. Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement (PET/CT) A07.30.043.001 to evaluate the response to induction chemotherapy — no earlier than 2–3 months later; in other cases — as indicated;

8. thyroid-stimulating hormone level measurement every 6–12 months to assess thyroid function.

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.

If it is not possible for the medical organization housing the outpatient cancer care center (primary oncology office) to obtain biopsy (surgical) material or perform other diagnostic examinations, the attending physician shall refer the patient to an oncological dispensary (oncology hospital) or 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:

1. size and extent of the primary tumor;

2. tumor differentiation grade;

3. presence/absence of perivascular, perilymphatic, and perineural invasion;

4. regional lymph node status (pN) (metastases in neck lymph nodes reduce patient survival by half);

5. extranodal tumor extension;

6. cellular proliferation activity (Ki-67 labeling index);

7. resection 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. 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

3. 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

4. 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".

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

6. 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

7. 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.

8. 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".

9. 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.

10. 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.

11. 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

12. 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"

13. 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

14. 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

15. 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

16. 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.

17. 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".

18. 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".

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

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, Cand. of Sci. (Med.), Ultrasound Diagnostics Physician, Radiologist at the Department of Diagnostic 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 Biomedical Imaging, Faculty of Postgraduate and Continuing Professional Education, Saint Petersburg State Pediatric Medical University (SPbGPMU); Associate Professor at the Department of Radiology, Surgery, and Oncology, Academician A.M. Granov Russian Scientific Center of Radiology and Surgical Technologies of the Russian Ministry of Health; https://orcid.org/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. Podvyaznikov, D. of Sci. (Med.), Professor, Russian Medical Academy of Continuing Professional Education of the Russian Ministry of Health, Vice President of the All-Russian Public Organization «Russian Society of Head and Neck Tumors».

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. 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"

34. 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

35. 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.

36. 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.

37. Oksana A. Saprina, Cand. of Sci. (Med.), Oncologist, Surgical Department No. 11 for Head and Neck Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the All-Russian Public Organization «Russian Society of Head and Neck Tumors».

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.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. oncologists;

2. surgeons;

3. radiologists;

4. medical students, residents, and graduate students.

Table 2. Scale of levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

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

Table 4. Scale of recommendation persuasiveness levels (RPL) for prevention, diagnostic, 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 data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved Clinical Practice Guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Absent

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Guidelines for post-treatment follow-up

Follow-up after completed treatment is crucial for maintaining the patient's health. Typically, in the first 1–2 years, follow-up visits with an oncologist 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. Nevertheless, the frequency of doctor visits may be increased depending on disease characteristics and associated risks, and is determined individually in each specific case. If symptoms appear or previous symptoms 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;

– greater treatment efficacy;

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

– accelerated recovery of general condition after treatment;

– lower risk of recurrence;

– lower risk of second cancers;

– lower risk of infections;

– higher quality of life.

1. When body temperature rises to 38 °C and above:

1. start taking antibiotics (J01: Antibacterials for systemic use) as prescribed by a physician.

2. In case of stomatitis:

1. diet with mechanical and thermal sparing of the mucosa;

2. frequent mouth rinsing (every hour) using chamomile flowers, oak bark, sage leaves; 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 water are permitted. Drink plenty of fluids;

2. take medications as prescribed by a physician.

4. In case of nausea:

1. take medications as prescribed by a physician.

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

Appendix G1. Template for including clinical rating scales, questionnaires, and other patient status assessment tools

Russian title: Questionnaire for initial patient presentation to primary care physicians within the framework of oncological alertness

Original title (if any): none

Source (official developer website, validation publication): https://oncology-association.ru/

Type (underline): questionnaire

Purpose: assessment of the likelihood of malignant neoplasms in a patient

Assessment tool, content:

Questionnaire for initial patient presentation to primary care physicians within the framework of oncological alertness (select correct answers, underline as appropriate, fill in if necessary)

Date of completion:

Full name:

1. Do you have occupational hazards at work?

1. No

2. Present

2. How many years do you work / have you worked with occupational hazards?

1. Under 1 year 4. 6–10 years

2. Under 3 years 5. Over 10 years

3. 3 to 5 years 6. Over 15 years

3. Have any of your close relatives had or do they have cancer of the ENT organs?

1. No

2. Had or has

3. I don't know

4. Do you smoke (or have you smoked)?

1. No 4. Smoking history less than 10 years

2. Yes 5. Smoking history 10–15 years

3. More than 20 cigarettes per day 6. Smoking history over 20 years

5. Have you noticed any weight loss recently?

1. No 3. Yes, by more than 5 kg

2. I don't know 4. Yes, I was on a diet

6. Are you troubled by increased weakness and fatigue, disproportionate to exertion?

1. No

2. More than 1 month

3. More than 6 months

7. Are you troubled by excessive generalized sweating, possibly worsening at night?

1. No

2. Yes, appeared within the last 6–12 months

3. Have always been troubled

8. Do you have pallor or skin discoloration?

1. No

2. Yes

3. I don't know

9. Have you recently noticed enlarged lymph nodes or other lumps in your neck?

1. No

2. Yes, painless

3. Yes, painful

10. Do you have any skin growths or long-standing non-healing ulcers on your face, scalp, or neck?

1. No

2. Yes

3. If yes, what specifically? (write in your options)

11. Have you recently noticed facial deformity due to newly appeared masses or swelling (changes in the shape of the nose, eyes, etc.)?

1. No

2. Yes

3. If yes, what specifically? (write in your options)

12. Are you bothered by a persistent cough or throat clearing?

1. No 3. With sputum

2. Yes 4. With blood streaks

13. Are you bothered by hoarseness?

1. No 3. Constant over the last month

2. Periodically 4. Yes, have not been evaluated or treated

5. Yes, treatment received was ineffective

14. Are you troubled by difficulty breathing through the natural airways?

1. No 4. Shortness of breath is present at rest

2. Sometimes 5. With minor physical exertion

3. Frequently 6. With significant physical exertion

15. Are you troubled by a "lump or foreign body sensation" in your throat?

1. No

2. Sometimes

3. Frequently or constantly

16. Are you troubled by an unpleasant taste in your mouth and/or bad breath?

1. No

2. Sometimes

3. Frequently or constantly

17. Are you troubled by difficulty swallowing food?

1. No 4. The act of swallowing is painful

2. Yes, only liquid food 5. Choking and coughing occur during meals

3. Yes, only solid food 6. Within the last month

7. More than 3 months

18. Are you troubled by difficulty breathing through your nose?

1. No 4. Nasal breathing difficulty on both sides

2. Rarely 5. Nasal breathing difficulty on the right/left

3. Often (constantly) 6. Nasal breathing absent on both sides

7. Nasal breathing absent on the right/left

19. Rate your sense of smell:

1. Normal 4. Bilateral

2. Decreased 5. Right/left

3. Absent

20. Do you experience nasal discharge and/or post-nasal drip?

1. No 4. Mucous or clear

2. Rarely 5. Purulent with an unpleasant odor

3. Often (constantly) 6. Bloody

21. Do you feel any discomfort or pain in the facial area corresponding to the paranasal sinuses?

1. No

2. Rarely

3. Frequently (constantly)

22. Has any new growth appeared recently in the nasal cavity or throat?

1. No 3. Painless

2. Yes 4. Painful

5. Bleeding

Key (interpretation): Affirmative answers to questions 1 through 8, in the presence of symptoms described in questions 9 through 23, suggest a neoplastic disease; a detailed examination by specialized professionals is required in this case.

Appendix G2. ECOG scale (0–4 points)

Russian title: WHO Performance Status Scale / ECOG

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

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

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

Type: rating scale

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

Content:

Key (interpretation): provided within the scale itself

Appendix G3. NRS 2002 SCALE

Russian title: Patient Nutritional Status Assessment Scale

Original title: Nutrition Risk Screening 2002 (NRS-2002)

Source: https://www.mdcalc.com/calc/4012/nutrition-risk-screening-2002-nrs-2002

Type: rating scale

Purpose: assessment of the nutritional status of an inpatient

Contents:

Primary screening

Final screening

Key:

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

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

3. Less than 3 points — rescreening every week. If surgical treatment is planned, a preoperative preparation program is required.

Appendix G4. MUST scale

Russian title: Malnutrition Universal Screening Tool

Original title: Malnutrition Universal Screening Tool

Source: https://www.bapen.org.uk/must-and-self-screening/must-calculator/

Type: assessment scale

Purpose: assessment of nutritional status in an outpatient setting

Contents:

Total score: _____________/30

Key: Interpretation of results (full scale from A to T):

>23.5 points — normal nutritional status

17–23.5 points — risk of malnutrition

<17 points — malnutrition.