Hypopharyngeal Cancer: Clinical Guidelines

List of Abbreviations

NOS – Not Otherwise Specified

IV – intravenous (route of administration)

WHO – World Health Organization

CT – computed tomography

RT – radiotherapy

LN – lymph node(s)

ICD-O – International Classification of Diseases for Oncology

MRI — magnetic resonance imaging

ChT – polychemotherapy

PEG – percutaneous endoscopic gastrostomy

PET – positron emission tomography

LoE – Level of Evidence

USDG – ultrasound Dopplerography

ultrasound – ultrasound examination

LoE – level of evidence / recommendation strength

CRT – chemoradiotherapy

AJCC – American Joint Committee on Cancer

ECOG – Eastern Cooperative Oncology Group performance status scale

ENE – extracapsular extension

ERAS – Enhanced Recovery After Surgery

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

QUANTEC – Quantitative Analyses of Normal Tissue Effects in the Clinic

R0 – tumor-free resection margin

R1 – microscopic residual tumor

TNM – (tumor, node, and metastasis) international classification of cancer staging

VMAT – volumetric modulated arc therapy

Terms and Definitions

Adjuvant chemotherapy – a type of chemotherapy administered after complete surgical removal of the primary tumor to eliminate potential metastases.

Second stage of rehabilitation – inpatient rehabilitation in medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual disease symptoms.

First stage of rehabilitation – rehabilitation during the period of specialized treatment for the primary disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the primary disease.

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

Stabilization – a decrease in the lesion size by less than 50% or an increase by less than 25% with no new lesions appearing.

Levels of Evidence – reflect the degree of certainty that the estimated effect of a medical technology is true. According to epidemiological principles, the certainty of evidence is determined by three main criteria: qualitative and quantitative characteristics, and consistency of evidence.

Grades of Recommendation – unlike levels of evidence, reflect not only the degree of certainty in the intervention's effect, but also the degree of certainty that following the recommendations will bring more benefit than harm in a specific situation.

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

3D conformal radiotherapy – precise computer-supported treatment planning based on advanced diagnostic imaging methods, enabling highly precise (conformal) delivery to the target area while minimizing exposure to healthy adjacent tissues and organs at risk.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hypopharyngeal cancer – a malignant tumor originating from the elements of the non-keratinizing epithelium of the hypopharynx [1].

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

In most cases, patient history reveals a prolonged period of smoking, alcohol consumption, employment in dusty environments (textile industry), and inhalation of harmful carcinogenic substances (petroleum, petroleum products, benzene, phenolic resins, asbestos). A high risk of malignant transformation is noted in papillomas (human papillomavirus-associated cancer), recurrent papillomatosis, pachydermia, and dyskeratosis. In addition, chronic inflammatory processes (laryngitis) are considered risk factors [2].

1.3 Epidemiology of the Disease or Condition

According to global data, the absolute number of newly diagnosed hypopharyngeal cancer cases in 2020 was 84,254, including 70,254 cases in men and 14,000 cases in women. Age-standardized incidence rates of hypopharyngeal cancer in Russia in 2020 were 0.39–0.98 per 100,000 population among men and 0.12–0.18 per 100,000 population among women [3].

1.4 Features of Coding the Disease or Condition

ICD-10 Coding

C12 Malignant neoplasm of pyriform sinus

Pyriform recess

C13 Malignant neoplasm of hypopharynx

C13.0 Malignant neoplasm of postcricoid region

C13.1 Aryepiglottic fold of hypopharynx

Aryepiglottic fold:

• NOS

• marginal zone

C13.2 Malignant neoplasm of posterior wall of hypopharynx

C13.8 Lesion of hypopharynx overlapping one or more of the above subcategories

C13.9 Hypopharynx, unspecified

International Classification of Diseases for Oncology (ICD-O, 4th Edition, 2010): Classification of hypopharyngeal tumors

Malignant epithelial tumors

1.5 Classification of the disease or condition

The extent of epithelial malignant tumors of the hypopharynx is presented in the TNM classification of malignant tumors (8th edition) by the American Joint Committee on Cancer (AJCC).

Clinical classification

The T category includes the following grades:

* The soft tissues of the central triangle of the neck include the infrahyoid muscles and subcutaneous adipose tissue.

The cN symbol indicates the presence or absence of metastases in regional lymph nodes (LNs) based on clinical and instrumental examination data

The pN symbol indicates the presence or absence of regional lymph node metastases according to routine pathological examination of the surgical specimen

The M symbol characterizes the presence or absence of distant metastases

Table 1. Hypopharyngeal cancer stage grouping

Grade

Gx – grade cannot be assessed

G1 – well differentiated

G2 – moderately differentiated

G3 – poorly differentiated

1.6 Clinical presentation of the disease or condition

In early stages, the clinical course of hypopharyngeal cancer is asymptomatic. The main complaints and primary reasons for seeking medical attention are dysphagia (local pain during swallowing, sometimes radiating to the ear on the affected side; functional disorders: choking on food, sensation of saliva "rolling" over a "ridge", food retention, etc.) and voice impairment manifested as hoarseness, rarely – cough. If the process obstructs the laryngeal lumen, breathing difficulties may develop.

When taking the medical history, attention is paid to identifying etiopathogenetic factors of the disease development. History of voice disorders (nature of voice impairment, duration, patient's vocal load requirements) is important, as well as assessment of swallowing and nutritional disorders.

In addition, symptoms such as persistent cough; sore throat unresponsive to antibacterial and anti-inflammatory treatment; painful swallowing; enlargement of cervical lymph nodes may be concerning [2].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis is established based on:

1) anamestic data, specifically the presence of a neoplasm refractory to conservative treatment for 2–3 weeks;

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

3) cytological examination of smears from tumor punctates, soft tissue tumor-like lesions, and lymph node tissue preparation

4) biopsy of the hypopharyngeal mucosa followed by pathological examination, as well as pathological examination of the lymph node biopsy (surgical) specimen;

5) instrumental examinations, including neck ultrasound (US), fibrolaryngoscopy, computed tomography (CT) / magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), as indicated

2.1 Complaints and Anamnesis

2.2 Physical Examination

Comments: Attention should be paid to changes in neck contours and enlargement of regional LNs. Mobility and changes in the laryngeal skeleton should be assessed. Indirect laryngoscopy allows visualization and suspicion of a tumor.

2.3 Laboratory Diagnostics

No specific laboratory diagnostic tests are provided. Laboratory diagnostic tests are performed at the discretion of the oncologist to the extent ensuring effective and safe patient treatment.

2.4 Instrumental Diagnostics

2.5 Other Procedures

Comments: Biopsy of the hypopharynx can be performed during fibrolaryngoscopy, indirect laryngoscopy, or direct laryngoscopy.

Comments: the report must reflect the following parameters:

1. Tumor dimensions.

2. Depth of tumor invasion.

3. Histological structure of the tumor.

4. Tumor grade of differentiation.

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

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

7. Regional lymph node status (pN) (indicating the total number of examined and involved lymph nodes, signs of extranodal tumor extension).

8. Presence of resection margin involvement (a negative result must also be stated)

9. Invasion of laryngeal cartilages.

10. Invasion of surrounding organs and tissues.

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

Treatment tactics for hypopharyngeal cancer aim not only at curing the patient but also at restoring swallowing, voice, respiratory, and protective functions of the organ and depend on the localization of the hypopharyngeal lesion, the extent of the tumor process, and the tumor's sensitivity to radiation or drug therapy.

3.1. Treatment Strategy

• For patients with stage T1-2N0M0 hypopharyngeal cancer, it is recommended to administer definitive radical radiation therapy alone or concurrent CRT (for T2N0M0) to improve survival rates [7, 8].

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

• For stage T1-2N0M0 hypopharyngeal cancer, it is recommended to perform organ-preserving surgery to improve survival and reduce treatment toxicity [9].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comment: When choosing a surgical treatment method, it is advisable to perform transoral surgery (removal of the laryngeal neoplasm by laser resection) with unilateral or bilateral neck dissection per indications (prophylactic neck dissection); partial laryngopharyngectomy (open or endoscopic) + ipsilateral or bilateral neck dissection. Following surgical treatment, further management depends on the presence/absence of adverse pathological features (APFs) according to the morphological examination of the surgical specimen. The absence of APFs and pN0 status do not require additional treatment; active surveillance is advisable. Indications for postoperative RT include the presence of only a single regional metastasis pN1 without ENE or only a single APF (perineural, perivascular, perilymphatic invasion) in the absence of other APFs.

An indication for postoperative chemoradiotherapy (CRT) is the presence of two or more adverse pathological factors (APFs): pT3–4, perineural, perivascular, or perilymphatic invasion. If the only APF is microscopic residual tumor (R1), reresection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of ENE+ either alone or in combination with other APFs is an indication for concurrent CRT [10].

Prognostically unfavorable characteristics (factors): extranodal extension, positive resection margins, tumor growth close to the resection margin, pT3 or pT4, pN2 or pN3, perineural invasion, vascular invasion, lymphatic invasion [10].

T1N+, T2–3 (resectable), any N (if pharyngeal resection with partial or total laryngectomy is required) - the following treatment methods are recommended:

• For hypopharyngeal cancer stages T1N+, T2–3, any N M0, induction chemotherapy followed by concurrent CRT is recommended to improve survival and reduce the risk of distant metastasis [11].

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

In case of complete regression of the primary tumor (according to WHO criteria) after induction chemotherapy (based on neck computed tomography with intravenous bolus contrast enhancement or neck magnetic resonance imaging with intravenous contrast enhancement, fibrolaryngoscopy, ultrasound of neck lymph nodes), standalone RT or CRT is performed. In case of partial regression of the primary tumor, CRT or surgical treatment is performed. If tumor regression is less than 50%, surgical treatment is advisable, followed by deciding on indications for RT/CRT. In the presence of residual tumor and/or metastatic LNs after completion of RT/CRT, surgical treatment is advisable. In case of complete regression after conservative treatment methods, follow-up monitoring is indicated.

Comment: evaluation of conservative therapy efficacy should be performed 2–3 months after completion of the treatment course.

• For hypopharyngeal cancer stages T1N+, T2–3, any N M0, partial or total laryngopharyngectomy (any modification - laryngopharyngectomy with pedicled flap reconstruction, laryngopharyngectomy with bioengineered reconstruction, laryngopharyngectomy with microvascular reconstruction, laryngopharyngectomy with microvascular reconstruction using video-endoscopic technologies) + unilateral or bilateral (as indicated) neck dissection is recommended to improve patient survival [4].

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

Comments: Following surgical treatment, further management is discussed depending on the presence/absence of APFs according to the morphological examination of the surgical specimen.

An indication for postoperative RT is the presence of only a single regional metastasis pN1 without ENE or only a single APF (perineural, perivascular, perilymphatic invasion) in the absence of other APFs.

An indication for postoperative CRT is the presence of two or more APFs: pT3–4, perineural, perivascular, perilymphatic invasion. If the only APF is microscopic residual tumor (R1), reresection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of ENE+ either alone or in combination with other APFs is an indication for concurrent CRT.

• For hypopharyngeal cancer stage T4aNAnyM0, laryngopharyngectomy with unilateral or bilateral (as indicated) neck lymph node dissection (including level VI) + hemi- or thyroidectomy followed by RT or chemoradiotherapy is recommended to improve patient survival [4].

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

Comments: Following surgical treatment, further management is discussed depending on the presence/absence of APFs according to the morphological examination of the surgical specimen. The absence of APFs and pN0 status do not require additional treatment; follow-up monitoring is advisable. An indication for postoperative RT/CRT is the presence of at least one of the APFs: pT3–4; perineural, perivascular, perilymphatic invasion; pN+. If the only APF is R1, reresection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of ENE+ either alone or in combination with other APFs is an indication for concurrent CRT.

• For hypopharyngeal cancer stage T4aNAnyM0, induction chemotherapy is recommended to increase patient survival rates [11].

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

In case of complete/partial regression of the primary tumor (according to WHO criteria) after induction chemotherapy (based on neck computed tomography with intravenous bolus contrast enhancement or neck magnetic resonance imaging with intravenous contrast enhancement, fibrolaryngoscopy, ultrasound of neck lymph nodes), concurrent CRT is performed. If tumor regression is less than 50%, surgical treatment is performed, followed by deciding on indications for CRT. Following surgical treatment, further management is discussed depending on the presence/absence of APFs according to the morphological examination of the surgical specimen. An indication for postoperative CRT is the presence of at least one of the APFs: pT3; perineural, perivascular, perilymphatic invasion; pN+. If the only APF is R1, reresection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of pT4, ENE+ either alone or in combination with other APFs is an indication for concurrent CRT. In the presence of residual tumor and/or metastatic LNs after completion of RT/CRT, surgical treatment is performed. In case of complete regression after conservative treatment methods, follow-up monitoring is indicated [4].

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

Comment: evaluation of conservative therapy efficacy should be performed 2-3 months after completion of the treatment course.

• For hypopharyngeal cancer stage T4aNAnyM0, concurrent chemoradiotherapy is recommended [12].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

In the presence of residual tumor and/or metastatic LNs after completion of CRT, surgical treatment is performed. In case of complete regression after conservative treatment methods, follow-up monitoring is indicated [4].

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

Comment: evaluation of conservative therapy efficacy should be performed 2-3 months after completion of the treatment course.

• For patients with local recurrence without prior radiation therapy, surgical intervention (for resectable cases) is recommended to improve survival [4].

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

Comments: the absence of APFs and pN0 status do not require additional treatment; follow-up monitoring is performed. An indication for postoperative RT/CRT is the presence of at least one of the APFs: pT3–4, perineural, perivascular, perilymphatic invasion, pN+. If the only APF is R1, reresection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of pT4, ENE+ either alone or in combination with other APFs is an indication for concurrent CRT.

or

• In case of local recurrence without prior radiation therapy, concurrent chemoradiotherapy is recommended to improve survival [4].

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

• In case of local recurrence or residual tumor without prior radiation therapy, induction chemotherapy followed by concurrent chemoradiotherapy (if ECOG performance status is 0–1 according to the Eastern Cooperative Oncology Group scale) is recommended to improve survival [4].

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

• In case of local recurrence or residual tumor without prior radiation therapy, palliative RT or systemic drug therapy (using a single agent) (for unresectable cases and ECOG 2; see Appendix G) is recommended to improve survival [4].

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

Local recurrence or residual tumor after radiation therapy.

• In case of local recurrence or residual tumor after radiation therapy when the tumor is resectable, surgical intervention with discussion of re-irradiation or concurrent chemoradiotherapy is recommended to improve patient survival [4].

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

• In case of local recurrence or residual tumor after radiation therapy when the tumor is unresectable, drug therapy, discussion of re-irradiation/concurrent chemoradiotherapy, or symptomatic treatment is recommended to improve survival [4].

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

• In case of local recurrence or residual tumor with distant metastases with an ECOG performance status of 0–1 (see Appendix G), drug therapy is recommended to improve survival [4].

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

Comments: In selected cases with solitary metastases, surgical treatment or CRT may be considered.

• In case of local recurrence or residual tumor with distant metastases with an ECOG performance status of 2, drug therapy is recommended to increase survival or symptomatic treatment to relieve patient discomfort [4].

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

• In case of a local recurrence or residual tumor with distant metastases, with an ECOG performance status of 3 (see Appendix G), recommended is symptomatic treatment aimed at alleviating the patient's condition [4].

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

3.2 Surgical Treatment

Introduction: Surgical treatment involves procedures of varying extent aimed at removing the primary tumor focus, including organ-preserving techniques (endolaryngeal laser resection, endoscopic resection), open resection of affected hypopharyngeal sites (pyriform sinus, posterior hypopharyngeal wall), combined horizontal resection of the larynx with resection of the posterior cricoid/arytenoid region of the hypopharynx, and laryngectomy, as well as restoring the integrity of the upper gastrointestinal tract using various reconstructive and plastic surgery techniques (voice prosthetics may be performed).

• For hypopharyngeal cancer with no clinical signs of cervical lymph node involvement, prophylactic unilateral/bilateral neck dissection (levels 2–4) is recommended for all patients to reduce the risk of locoregional recurrence and improve survival [4].

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

Comments: Hypopharyngeal cancer is characterized by a high risk of regional metastasis even in T1–2 (50% of cases).

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

- palpable metastasis in level IV or V;

- regional metastasis greater than 6 cm in diameter;

- large multiple metastases (greater than 3 cm);

- pronounced extracapsular tumor spread with involvement of major anatomical structures (sternocleidomastoid muscle, internal jugular vein, common carotid artery);

- regional recurrence.

Removal of level VI lymph nodes is advisable in case of T3–4a tumor extent or suspected metastasis in level VI [13].

3.3 Conservative Management

Prior to treatment, all patients should be evaluated by a radiation oncologist, preferably one specializing in head and neck tumors, who should take the following steps: review the adequacy of the biopsy material, staging, and imaging of the tumor process (CT, MRI) to determine the extent of tumor spread, rule out synchronous primary tumors, assess current functional status and eligibility for radiation/chemoradiation therapy, and develop a prospective follow-up plan that includes oropharyngeal sanitation, including dental examination, provision of adequate nutrition, analgesia, wound healing, and other measures necessary for maximum patient rehabilitation. For patients undergoing radiation/chemoradiation therapy, a plan for implementing antitumor therapy in full and within optimal timeframes must be developed. The radiation dose to radical doses should not be modified based on the clinical response achieved prior to radiation therapy (after induction polychemotherapy), except in cases of tumor progression. It is permissible to discuss reducing the volume by excluding vital structures free of tumor involvement at the time of radiotherapy planning, provided the dose limits for these structures are exceeded according to QUANTEC criteria (quantitative analyses of normal tissue effects in the clinic).

Comment:Preference is given to 3D conformal external beam radiation therapy (3D-CRT), as well as external beam radiation therapy using complex dose delivery techniques: IMRT (Intensity-Modulated Radiation Therapy), VMAT (volumetric-modulated arc therapy (volumetric modulated arc therapy)) [4].

• For patients with hypopharyngeal cancer scheduled for radiotherapy or chemoradiotherapy, proton beam conformal external beam radiation therapy is recommended as an alternative radiation therapy method to reduce the frequency and severity of radiation reactions and thus improve treatment tolerability [14].

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

RT Regimens

• Exclusive RT is recommended for the primary tumor and clinically detectable regional metastases at 66–70 Gy (2.0–2.2 Gy/fraction) daily Monday through Friday for 6–7 weeks; for the locoregional region, including regional lymph nodes, from 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction), taking into account the risk of subclinical involvement, to improve survival rates [4].

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

• Concurrent chemoradiotherapy (CRT) as a standalone option is recommended for the primary tumor and clinically detectable regional metastases at 70 Gy (2.0 Gy/fraction) daily Monday through Friday for 7 weeks; for the locoregional region, including regional lymph nodes, from 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction), taking into account the risk of subclinical involvement [4].

GCP CLEL 5Grade of Recommendation – 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 RT (the target cumulative dose during RT is 300 mg/m²) [15, 16]. Following induction polychemotherapy (PCT), carboplatin** (AUC 1.5–2 weekly) or cetuximab** is indicated as an alternative to cisplatin**, taking into account the tolerability of CRT and the patient's performance status. Cetuximab** is administered IV at a loading dose of 400 mg/m² one week before the start of RT, followed by a maintenance dose of 250 mg/m² weekly during RT. Omission of platinum-based chemoradiotherapy regimens in favor of cetuximab** is advisable in case of a high risk of failure/incomplete implementation of the standalone chemoradiotherapy plan and a high risk of platinum drug side effects (glomerular filtration rate less than 50–60 ml/min, patient age over 65 years, severe concomitant renal, cardiovascular, neurological, hepatic pathology, and/or debilitated patient status – ECOG >1). [17] (see Appendix G).

The following regimen may be used in the CRT protocol: ^#Carboplatin** 70 mg/m² IV drip on days 1 to 4 + ^#fluorouracil** (600 mg/m⁴) IV drip on days 1 to 4, once every 21 days [46, 48].

• Postoperative RT is recommended for stages pT3 and N0, as well as selected patients with stages pT1–2, N1 (in the presence of adverse features) [4]. The interval between resection and postoperative RT should not exceed 6 weeks. Postoperative RT to the tumor bed: 60–66 Gy (2.0 Gy/fraction); daily Monday through Friday for 6–6.5 weeks. To the locoregional region, including regional lymph nodes: from 44–50 Gy (2.0 Gy/fraction) or up to 54–63 Gy (1.6–1.8 Gy/fraction).

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

• Postoperative RT is recommended in cases of – pT3, the presence of only a single regional metastasis pN1 without ENE, or only a single adverse pathological feature (perineural, perivascular, or perilymphatic invasion) provided no other adverse features are present [4, 10].

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

• Postoperative CRT is recommended in the presence of two or more adverse pathological features: pT3, perineural, perivascular, or perilymphatic invasion. In the presence of only one adverse pathological feature – microscopic residual tumor (R1) – reresection is indicated (if feasible); if not feasible, concurrent CRT is indicated. The presence of pT4, ENE+ isolated or in combination with other adverse pathological features is an indication for concurrent CRT [4, 10].

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

Comment: prognostically unfavorable characteristics (factors): extranodal extension, positive resection margins, tumor growth close to the resection margin, pT3 or pT4, pN2 or pN3, perineural invasion, vascular invasion, lymphatic invasion.

• Postoperative concurrent CRT is recommended when the tumor invades the lymph node capsule or in case of a positive resection margin (if reoperation is declined), and is also discussed in the presence of two or more unfavorable factors combined (pT3 or pT4; N2 or N3, presence of perineural invasion and/or tumor emboli in lymphatic vessels) [4].

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

3.4. Principles of Medical Chemotherapy

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

• When choosing induction CT as the primary treatment method for all patients with hypopharyngeal cancer with the aim of improving survival, it is recommended to use the following PCT regimen: docetaxel** 75 mg/m² on day 1 + cisplatin** 75 mg/m² on day 1 + fluorouracil** 1000 mg/m²/day on days 1–4, for a total of 2–3 cycles of CT with a 3-week interval [47].

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

• As concurrent CRT following induction for all patients with hypopharyngeal cancer with the aim of improving survival, it is recommended to administer CT including cisplatin** 100 mg/m² once every 3 weeks [19].

Level of Recommendations C Level of Evidence 5Level of Recommendation – C (Level of Evidence – 5)

Comment: considering the high toxicity of the specified concurrent therapy regimen, weekly administration of carboplatin **AUC 1.5–2 or cetuximab **400 mg/m² one week before radiotherapy or 250 mg/m² weekly during radiotherapy is possible. If there are comorbid conditions precluding concurrent chemoradiotherapy containing platinum coordination compounds (chronic renal failure, severe heart disease, etc.), replacing platinum coordination compounds with cetuximab ** during radiotherapy is preferred [18].

• For patients with a local unresectable recurrence or residual tumor who have undergone radiotherapy, as well as in the presence of distant metastases, mono- or polychemotherapy is recommended to increase survival [4].

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

Comment: depending on the patient's general condition and/or treatment goals, the following drugs or their combinations may be prescribed as the 1st line (the number of cycles is determined by treatment tolerance and efficacy):

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

1. For patients with an ECOG performance status of 2 points.

2. Suboptimal treatment regimens; applicable 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 the level of PD-L1 expression.

4. As the 1st line in the presence of PD-L1 expression CPS >20. Upon progression during or after chemotherapy including platinum-based drugs, with a TPS level ≥ 50%. The recommended duration of use corresponds to the design of registration clinical trials.

5. As the 1st line with PD-L1 expression ≥ 1%.

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

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

• When choosing induction chemotherapy as the primary treatment method for all patients with hypopharyngeal cancer, in order to improve survival, it is recommended to use the following polychemotherapy regimen: docetaxel** 75 mg/m2 on day 1 + cisplatin** 75 mg/m2 on day 1 + fluorouracil** 1000 mg/m2/day on days 1–4, for a total of 2–3 chemotherapy courses with an interval of 3 weeks [18].

Paclitaxel **/cisplatin **/fluorouracil ** - another recommended regimen

LoE CGoE 5Level of Evidence – C (Grade of Recommendation – 5).

Simultaneous chemotherapy based on platinum coordination compounds is advisable, preferably with cisplatin **at a dose of 100 mg/m² every 3 weeks, or a combination of #docetaxel **15 mg\m² + #cetuximab ** at a loading dose of 400 mg/m² one week before the start of radiotherapy, followed by a maintenance dose of 250 mg/m² weekly during radiotherapy [18, 50].

LoE CGoE 5Level of Evidence – C (Grade of Recommendation – 5)

3.5 Other treatments

The procedure and recommendations for pain management in malignant neoplasms of the hypopharynx correspond to the guidelines presented in the clinical guidelines "Chronic pain syndrome (CPS) in adult patients requiring palliative medical care".

3.6. Dietary therapy

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Nutritional support during the planning of surgical treatment is provided if at least one of the following factors is present: unintentional weight loss over the past 6 months (10% or more loss), body mass index <20 kg/m², hypoproteinemia <60 g/l or hypoalbuminemia <30 g/l, or deteriorated food intake over the past week. In the case of chemotherapy, indications include: body mass index <20 kg/m2; weight loss of more than 5% over 6 months; hypoproteinemia <60 g/l or hypoalbuminemia <30 g/l; inability to maintain adequate oral intake; moderate to severe enteropathy.

• For patients with malignant neoplasms of the hypopharynx receiving chemotherapy, it is recommended to start physical therapy early to prevent the onset and progression of sarcopenia, reduce fatigue, improve the quality of life and psychological state of patients receiving adjuvant chemotherapy, and increase exercise tolerance [33].

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

Comments: Performing a set of physical exercises including aerobic loads and Tai Chi elements for 4 months during chemotherapy leads to an increase in vital capacity of the lungs, blood oxygen saturation, muscle strength, range of motion in large joints, and a decrease in body mass index [34].

• To reduce fatigue and increase endurance in patients with malignant neoplasms of the hypopharynx during chemoradiotherapy, it is recommended to perform physical therapy in the form of moderate-intensity aerobic exercises combined with resistance training [35].

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

Comment: Combining physical therapy with psychotherapy is used as part of comprehensive management of chemotherapy-induced fatigue [36]. In addition, a 6-week course of medical massage is advisable to reduce fatigue during combined treatment [37].

• Balance therapy is recommended for patients with oral cavity malignancies to correct polyneuropathy [38].

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

• Low-level laser therapy is recommended to prevent hair loss and accelerate hair growth after chemotherapy [41].

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

Comments: From the onset of manifestations until the complete disappearance of radiation mucositis, the use of agents with emollient and protective action — tissue repair stimulators (gels, urea solution, etc.) is indicated. Regular irrigation of the oral cavity with an isotonic solution (sodium chloride** 0.9%) removes food debris and accumulated secretions. Oils are used for oral applications or nose drops. In the presence of pain, local anesthetics and systemic analgesics are used [43]. Opioids are most commonly required, and attention should be paid to their transdermal application forms [44].

From the onset of radiation dermatitis and until reactions subside completely, the use of agents with emollient and protective properties (gels, dioxomethyltetrahydropyrimidine, riboflavin), as well as sunscreens, is indicated. The skin must be protected from friction and irritation. To combat xerosis, a cream with urea and an oil solution of vitamin A (retinol) are used.

In the post-radiation period, normal irradiated tissues are very vulnerable and must therefore be handled with care. Invasive diagnostic procedures and biopsies are not indicated in the early stages unless absolutely necessary. Selection of a diet is indicated, if necessary in combination with medications for the treatment of peptic ulcer disease and gastroesophageal reflux disease [45]. Trauma, alcohol, smoking, and irritating foods easily cause mucosal ulceration, which is often accompanied by exposure of the mandible bone followed by the development of osteomyelitis. A frequent cause of radiation osteomyelitis is tooth extraction in the previously irradiated area, and therefore conservative methods should be used whenever possible, and tooth extraction should only be performed when necessary, accompanied by antibiotic therapy.

5. Prevention and Dispensary Observation

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

Primary symptoms:

In the early stages of the disease, it is asymptomatic. Patients complain of paresthesia, dryness, a foreign body sensation in the throat, discomfort when swallowing; later these symptoms are joined by pain when swallowing radiating to the ear on the affected side, and difficulty swallowing. When breakdown phenomena occur, a foul breath odor and hemoptysis appear. Sometimes patients independently notice the presence of neck masses.

Carcinogenic factors:

Smoking (including passive smoking), alcohol consumption, contact with asbestos, wood dust, petroleum products, and exposure to ionizing radiation.

Precancerous conditions.

Chronic inflammatory diseases, leukoplakia of the hypopharyngeal mucosa, papillomas.

Dispenser observation (Follow-up):

In the 1st year, physical examination and history taking are recommended every 1–3 months, in the 2nd year every 2–6 months, and at 3–5 years every 4–8 months. After 5 years from the completion of specialized treatment, visits are conducted annually or upon the appearance of complaints. In high-risk patients, the interval between examinations may be shortened [4].

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

Comments: The scope of examination includes:

1) History and physical examination

2) Ultrasound of bilateral neck lymph nodes, abdominal organs (comprehensive), and pelvic organs (comprehensive);

3) CT/MRI (computed tomography of the upper respiratory tract and neck, spiral computed tomography of the neck, computed tomography of the brain, computed tomography of the soft tissues of the head with contrast, magnetic resonance imaging of the brain, magnetic resonance imaging of the brain with contrast, magnetic resonance imaging of the neck) as indicated, as well as when the area is inaccessible to adequate physical examination.

4) Fibrolaryngoscopy

5) Targeted chest X-ray or chest CT every 12 months.

6) Ultrasound, CT/MRI of abdominal organs (comprehensive) as indicated

7) Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals / Positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast as indicated

8) Determination of blood thyroid-stimulating hormone (TSH) levels every 6–12 months if neck irradiation was performed, to assess thyroid function.

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

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals 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 body;

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 body.

Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological care center or in a primary oncological office, primary oncological department, or outpatient department of an oncological dispensary.

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general family practitioners, specialist physicians, and mid-level medical personnel shall, in the established manner, refer the patient for a consultation to an outpatient oncological care center, a primary oncological office, or a primary oncological department of a medical organization to receive primary specialized health care. The consultation at an outpatient oncological care center, primary oncological office, or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (or the oncologist of the primary oncological office or primary oncological department, if an outpatient oncological care center is absent) shall organize the collection of biopsy (surgical) material, as well as the performance of other diagnostic examinations necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease. If it is impossible to collect biopsy (surgical) material or perform other diagnostic examinations at the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary 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 of the hypopharynx must not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathological anatomy bureau (department).

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.

The oncologist of the outpatient oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (if the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department is unable to establish the diagnosis, including the extent of the oncological process and the stage of the disease) and to receive specialized, including high-tech, medical care.

The timeframe for initiating specialized, excluding high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to patients with oncological diseases must not exceed 14 calendar days from the date of histological verification of the malignant neoplasm of the hypopharynx or 14 calendar days from the date of establishing a preliminary diagnosis of a malignant neoplasm (in the absence of medical indications for outpatient pathological examinations).

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or in medical organizations providing medical care to patients with oncological diseases that hold a license, have the necessary material and technical base and certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, and treatment of oncological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with oncological diseases, the tactics of medical examination and treatment are established by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the medical concilium, and entered into the patient's medical documentation.

Indications for admission to an inpatient or day care unit of a medical organization providing specialized, including high-tech, medical care in the field of oncology are determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary.

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

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

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

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

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

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

Indications for discharging a patient from a medical organization are:

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

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

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

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

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

7. Additional Information

Factors influencing the prognosis of the disease include:

- size and extent of the primary tumor;

- tumor grade;

- presence/absence of perivascular, perilymphatic, perineural invasion;

- regional lymph node status (pN) (neck lymph node metastases double patient mortality);

- extranodal tumor extension;

- resection margin status (R0-1)

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Anatoly M. Avanesov, MD, PhD, Professor, Head of the Department of General and Clinical Dentistry, Peoples' Friendship University of Russia, Senior Researcher at the Department of Surgery and Surgical Treatment Methods in Oncology, Russian Scientific Center of Roentgenoradiology of the Russian Ministry of Health

2. Aliyeva Sevil Bagaturovna, MD, DSc, Leading Researcher at the 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".

3. Alymov Yuri Vladimirovich, MD, PhD, Oncologist, Postgraduate Student at the Department of Oncology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Executive Director of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

4. 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

5. Mikhail V. Bolotin, PhD, Researcher at the Department of Surgical Oncology No. 11 of Upper Aerodigestive Tract Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

6. Larisa V. Bolotina, MD, PhD, 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, member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

7. Aleksey V. Butenko, MD, PhD, Professor, Chief Physician of the Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

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

9. Lyubov Yu. Vladimirova, MD, PhD, Professor, Head of the Department of Drug Treatment of Tumors, National Medical Research Center of Oncology of the Russian Ministry of Health (Rostov-on-Don, Russia).

10. Nadezhda N. Volchenko, MD, PhD, Professor, Head of the Department of Oncomorphology, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

11. Vitaly I. Voshedsky, PhD, Radiation Oncologist at the Department of Radiotherapy No. 2, National Medical Research Center of Oncology of the Russian Ministry of Health (Rostov-on-Don, Russia).

12. Artyom R. Gevorkov, PhD, Senior Researcher, Radiation Oncologist at 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, member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists».

13. Tigran G. Gevorkyan, Deputy Director of the Research Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Chief Oncologist Specialist of the Moscow Region.

14. Aleksandr O. Guz, Head of the Head and Neck Tumors Department, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine, member of the All-Russian Public Organization «Russian Society of Head and Neck Oncology Specialists» (Chelyabinsk, Russia).

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

16. Nikolay A. Daikhes, Corresponding Member of the Russian Academy of Sciences, MD, PhD, Professor, Director of the National Medical Research Center for Otorhinolaryngology of the Federal Medical-Biological Agency of Russia.

17. Dronova Ekaterina Leonidovna, Radiologist at 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".

18. Marina A. Engibaryan, MD, PhD, Head of the Head and Neck Tumors Department, 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» (Rostov-on-Don, Russia).

19. Zharov Andrey Alexandrovich, Pathologist at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

20. Mikhail S. Zinkovich, PhD, Radiation Oncologist at the Department of Radiotherapy No. 2, National Medical Research Center of Oncology of the Russian Ministry of Health (Rostov-on-Don, Russia).

21. 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

22. Anastasia V. Ignatova, PhD, Assistant at the Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Assistant at the Department of General and Clinical Dentistry, Peoples' Friendship University of Russia.

23. Pavel A. Isaev, MD, DSc, Leading Researcher, Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health.

24. Anna L. Korniyetskaya, MD, PhD, Senior Researcher, Department of Chemotherapy, Division of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health.

25. Mikhail A. Kropotov, MD, DSc, Head of the Head and Neck Tumors Department, National Medical Research Center of Oncology, Russian Ministry of Health.

26. Denis E. Kulbakin, MD, DSc, Senior Researcher, Highest Qualification Category Oncologist, Head and Neck Tumors Department, Oncology Research Institute, Tomsk National Research Medical Center.

27. Svetlana I. Kutukova, MD, PhD, Associate Professor, Department of Dentistry and Maxillofacial Surgery, Academician I.P. Pavlov First Saint Petersburg State Medical University, Russian Ministry of Health; Oncologist, Chemotherapy Department No. 11, City Clinical Oncology Dispensary of Saint Petersburg; Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

28. Aza A. Lyanova, MD, PhD, Chemotherapy Physician, Department of Antitumor Drug Therapy, National Medical Research Center of Oncology, Russian Ministry of Health (Rostov-on-Don, Russia).

29. Olga A. Malikhova, MD, DSc, Professor, Head of the Endoscopy Department, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health.

30. Ali M. Mudunov, MD, DSc, Professor, Head of Surgical Treatment Department No. 10 (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 Oncology Specialists".

31. Shamil I. Musin, MD, PhD, Head of the Head and Neck Tumors Department, Republican Clinical Oncological Dispensary, Ministry of Health of the Republic of Bashkortostan.

32. Mekhti N. Narimanov, MD, DSc, Chemotherapy Physician, Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

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

34. Alexey V. Novik, MD, PhD, Senior Researcher, Research Department of Oncoimmunology, N.P. Napalkov National Medical Research Center of Oncology, Russian Ministry of Health; Physician at the Chemotherapy and Innovative Technologies Department, N.P. Napalkov National Medical Research Center of Oncology, Russian Ministry of Health; Associate Professor, Department of Oncology, Pediatric Oncology and Radiation Therapy, Saint Petersburg State Pediatric Medical University, Russian Ministry of Health.

35. Olga A. Obukhova, MD, PhD, Senior Researcher, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health; Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

36. Akgul A. Odzharova, MD, PhD, Leading Researcher, Positron Emission Tomography Department, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health; Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

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

38. 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, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health.

39. Andrey P. Polyakov, MD, DSc, Head of the Microsurgery Department, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health; Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

40. Zamira A. Radzhabova, MD, PhD, Head of the Surgical Department of Head and Neck Tumors, N.P. Napalkov National Medical Research Center of Oncology, Russian Ministry of Health; Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

41. Igor V. Reshetov, MD, DSc, Academician of the Russian Academy of Sciences, Head of the Department of Oncology, Radiotherapy and Plastic Surgery, Sechenov First Moscow State Medical University; President of the All-Russian Public Organization "Federation of Specialists in the Treatment of Head and Neck Diseases".

42. Sergey S. Reshulsky, MD, DSc, Head of the Head and Neck Tumors Department, National Medical Research Center for Otorhinolaryngology, Federal Medical-Biological Agency of Russia.

43. Ilya S. Romanov, MD, DSc, Senior Researcher, Head and Neck Tumors Department, Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health.

44. Natalya A. Rubtsova, MD, DSc, Head of the Diagnostic Radiology Department, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center of Radiology, 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.

45. Andrey N. Rudyk, MD, PhD, Assistant Professor, Department of Oncology, Radiology and Palliative Medicine, Kazan State Medical Academy; Oncologist, Head and Neck Tumors Department, Prof. M.Z. Sigal Republican Clinical Oncological Dispensary of the Republic of Tatarstan.

46. Olga D. Ryzhova, Radiologist, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health.

47. Tatyana Yu. Semiglazova, MD, DSc, Associate Professor, Head of the Research Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.P. Napalkov National Medical Research Center of Oncology.

48. Anton V. Snegovoy, MD, DSc, Head of the Outpatient Chemotherapy Department (Day Hospital), N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health; Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

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

50. Vera A. Titova, MD, DSc, Professor, Russian Scientific Center of Roentgenoradiology, Russian Ministry of Health.

51. Yulia V. Ulyanova, MD, PhD, Surgical Oncologist, Head and Neck Tumors Department, National Medical Research Center of Oncology, Russian Ministry of Health (Rostov-on-Don, Russia).

52. Natalia A. Falaleeva, MD, DSc, Professor, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health.

53. Alexander A. Fedenko, MD, DSc, Professor of the Russian Academy of Sciences, Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health.

54. Elena V. Filonenko, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health.

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

56. Evgeny V. Khmelevsky, MD, DSc, Professor, Head of the Radiation Therapy Department, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health; Radiation Oncologist, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center of Radiology, Russian Ministry of Health.

57. Natalia A. Chertova, MD, PhD, Surgical Oncologist, Head and Neck Tumors Department, National Medical Research Center of Oncology, Russian Ministry of Health (Rostov-on-Don, Russia).

58. Evgeny L. Choynzonov, MD, DSc, Academician of the Russian Academy of Sciences, Director and Head of the Head and Neck Tumors Department, Oncology Research Institute, Tomsk National Research Medical Center; Head of the Department of Oncology, Siberian State Medical University, Russian Ministry of Health; Member of the All-Russian Public Organization "Russian Society of Head and Neck Oncology Specialists".

59. Lilia P. Yakovleva, MD, PhD, Head of the Head and Neck Tumors Department, A.S. Loginov Moscow Clinical Scientific Center.

Conflict of interest:

All members of the Working Group have confirmed that they have no conflicts of interest to disclose.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines: specialists with higher medical education in the following specialties:

1. Oncologists.

2. Surgeons.

3. Radiologists.

4. Medical students, residents, and postgraduate students.

In these clinical guidelines, all information is ranked by the level of reliability (evidence) depending on the quantity and quality of studies on the issue.

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

Table 2. Scale for assessing levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Russian Ministry of Health No. 422an dated July 7, 2015, "On Approval of Criteria for Assessing the Quality of Medical Care".

2. Order of the Russian Ministry of Health No. 915n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncology".

3. Current package inserts for medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Flowchart for the diagnosis and treatment of a patient with hypopharyngeal cancer

Appendix C. Patient Information

Guidelines for post-treatment follow-up

Follow-up after completed treatment is essential for maintaining the patient's health. Typically, during the first 1–2 years, follow-up visits with an oncologist are recommended every 1–3 months, in the 2nd year every 2–6 months, and at 3–5 years every 4–8 months. After 5 years from the surgery, visits are conducted annually or upon the appearance of symptoms. Nevertheless, the frequency of doctor visits may be increased depending on the disease characteristics and associated risks, and is determined individually in each specific case. If any complaints arise or if symptoms present before treatment recur, it is necessary to consult a doctor immediately without waiting for the scheduled visit date.

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

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

Benefits of quitting smoking and alcohol consumption

• Higher survival rates

• Higher treatment efficacy

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

• Accelerated recovery of general condition after treatment

• Lower risk of recurrence

• Lower risk of second primary tumors

• Lower risk of infections

• Higher quality of life

Recommendations for complications of chemotherapy/chemoradiotherapy – contact your oncologist (chemotherapist, radiation oncologist)!

1) If body temperature rises to 38 °C or higher:

• Start taking antibiotics as prescribed by your doctor.

2) For stomatitis:

• Diet – mechanical and thermal sparing;

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

• Treat the oral cavity as prescribed by the doctor.

3) For diarrhea:

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

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

• Take medications as prescribed by a physician.

4) For nausea:

• Take medications as prescribed by a physician.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO Patient 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 activities, and physical abilities (walking, work, etc.).

Contents:

Key (interpretation): provided within the scale itself

Appendix G2. Questionnaire for initial patient presentation to a primary care physician within the framework of cancer awareness

Russian title: Questionnaire for the initial patient visit to a primary care physician within the framework of oncological alertness

Original title (if applicable): none

Source (official developer website, publication with

validation): https://oncology-association.ru/

Type (underline): questionnaire

Purpose: assessment of the probability 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. Up to 1 year

2. Up to 3 years

3. From 3 to 5 years

4. 6–10 years

5. More than 10 years

6. More than 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

2. Yes

3. More than 20 cigarettes a day

4. Smoking history less than 10 years

5. Smoking history 10–15 years

6. Smoking history more than 20 years

5. Have you noticed any weight loss recently?

1. No

2. I don't know

3. Yes, by more than 5 kg

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

2. Yes

3. With sputum

4. Blood-tinged

13. Are you bothered by hoarseness?

1. No

2. Periodically

3. Constantly over the last month

4. Yes, not evaluated and not treated

5. Yes, treatment received was ineffective

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

1. No

2. Sometimes

3. Frequently

4. Difficulty breathing is present at rest

5. With minor physical exertion

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

2. Yes, only liquids

3. Yes, only solid food

4. Swallowing is painful

5. Choking and coughing occur while eating

6. Within the last month

7. More than 3 months

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

1. No

2. Rarely

3. Frequently (constantly)

4. Nasal breathing difficulty on both sides

5. Nasal breathing difficulty on the right/left

6. Nasal breathing absent on both sides

7. Nasal breathing absent on the right/left

19. Rate your sense of smell:

1. Normal

2. Decreased

3. Absent

4. Bilaterally

5. Right/left

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

1. No

2. Rarely

3. Frequently (constantly)

4. Mucous or clear

5. Purulent with an unpleasant odor

6. Blood-tinged

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

2. Yes

3. Painless

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 possible tumor disease; in such cases, a detailed examination by relevant specialists is required.