Malignant neoplasms of the lip: clinical guidelines

List of Abbreviations

DOI - depth of invasion

Gy – Gray

EBRT - External beam radiation therapy

CT — computed tomography

ICT - induction chemotherapy

RT - Radiation therapy

LN — lymph nodes

PT – physical therapy

MRI — magnetic resonance imaging

wk – week

PEG - percutaneous endoscopic gastrostomy

Ultrasound — ultrasound examination

CRT - chemoradiotherapy

FU - fluorouracil**

CPS - chronic pain syndrome

LoE – level of evidence

LER — level of evidence and recommendation

GTV (Gross Tumor Volume) - gross tumor volume - represents the tumor volume that is palpable or visualized instrumentally

CTV (Clinical Target Volume) - clinical target volume - includes the gross tumor volume and tissues with a probability of microscopic tumor invasion, in most cases within 0.5 to 1.0 cm

ECOG - Eastern Cooperative Oncology Group performance status scale

ENE – extranodal extension of tumor in lymph nodes

ERAS – Enhanced Recovery After Surgery

NaF – sodium fluoride

PTV – Planning Target Volume

R0 – tumor-free resection margin

R1 – microscopic residual tumor

TNM – international classification of cancer stages (abbreviation for tumor, nodus, and metastasis)

Terms and Definitions

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

Stage I rehabilitation — rehabilitation during the period of specialized treatment of the underlying disease (including surgical treatment/chemotherapy/radiotherapy) in departments of medical organizations specialized in the underlying disease.

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

Stage III rehabilitation – rehabilitation in the early and late rehabilitation periods, and the period of residual effects of the disease course in departments (rooms) of rehabilitation, physiotherapy, exercise therapy, reflexology, manual therapy, psychotherapy, medical psychology, and speech therapy (defectology) providing medical care in outpatient settings, day hospitals, as well as by mobile outreach teams at home (including in sanatorium-resort organizations).

1. Brief information on the disease or condition

Lip cancer – a malignant tumor arising from the stratified squamous epithelium of the red vermilion border of the lower or upper lip. Involvement of the skin and mucous membrane is due to the further spread of the tumor process.

1.1 Definition of the disease or condition

Among the etiological factors for the development of lip cancer, the following should be highlighted:

• adverse meteorological factors (prolonged solar insolation, sharp temperature fluctuations);

• bad habits: smoking, especially in combination with strong alcohol consumption, chewing various mixtures (naswar, betel nut, etc.);

• background conditions: flat leukoplakia, erythroplakia, chronic ulcers and fissures of the lips, cheilitis [1, 2].

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

Men develop lip cancer more often than women; the ratio is 3:1. Thus, in 2021, the prevalence was 22.5 per 100,000 population. In 2021, the absolute number of newly diagnosed cases was 1,881. In 83.5% of cases, the disease is detected at early (I–II) stages. The maximum number of cases occurs in the 55–75 years and older age group [3].

1.3 Epidemiology of the Disease or Condition

ICD-10 coding

Malignant neoplasm of lip (C00):

C00.0 Malignant neoplasm of external upper lip

C00.1 Malignant neoplasm of external lower lip

C00.2 Malignant neoplasm of external lip, unspecified

C00.3 Malignant neoplasm of inner upper lip

C00.4 Malignant neoplasm of inner lower lip

C00.5 Malignant neoplasm of inner lip, unspecified

C00.6 Malignant neoplasm of commissure of lip

C00.8 Overlapping lesion of lip

C00.9 Malignant neoplasm of lip, unspecified

ICD-O coding, 4th edition, 2010: lip tumors

Malignant epithelial tumors

8070/3 Squamous cell carcinoma, NOS

8051/3 Verrucous carcinoma, NOS

8083/3 Basaloid squamous cell carcinoma

8052/3 Papillary squamous cell carcinoma

8074/3 Spindle cell squamous cell carcinoma

8075/3 Adenoid squamous cell carcinoma

8560/3 Adenosquamous carcinoma

8082/3 Lymphoepithelial carcinoma

1.4 Features of Coding the Disease or Condition

ICD-10 coding

Malignant neoplasm of lip (C00):

C00.0 Malignant neoplasm of external upper lip

C00.1 Malignant neoplasm of external lower lip

C00.2 Malignant neoplasm of external lip, unspecified

C00.3 Malignant neoplasm of inner upper lip

C00.4 Malignant neoplasm of inner lower lip

C00.5 Malignant neoplasm of inner lip, unspecified

C00.6 Malignant neoplasm of commissure of lip

C00.8 Overlapping lesion of lip

C00.9 Malignant neoplasm of lip, unspecified

ICD-O coding, 4th edition, 2010: lip tumors

Malignant epithelial tumors

8070/3 Squamous cell carcinoma, NOS

8051/3 Verrucous carcinoma, NOS

8083/3 Basaloid squamous cell carcinoma

8052/3 Papillary squamous cell carcinoma

8074/3 Spindle cell squamous cell carcinoma

8075/3 Adenoid squamous cell carcinoma

8560/3 Adenosquamous carcinoma

8082/3 Lymphoepithelial carcinoma

1.5 Classification of the disease or condition

The degree of spread of epithelial malignant tumors of the oral cavity is presented in the TNM classification (international classification of cancer stages), 8th edition, edited by the American Joint Committee on Cancer.

Clinical classification

The T category includes the following grades:

• Depth of invasion is not tumor thickness.

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 metastases in regional LNs based on routine pathological examination of surgical material

The M symbol characterizes the presence or absence of distant metastases

M0 – no distant metastases.

M1 – presence of distant metastases.

Table 1 – Stage grouping

1.6 Clinical presentation of the disease or condition

Malignant tumor of the lip is usually localized somewhat away from the midline; it occurs extremely rarely at the corners of the mouth. In 85–90% of cases, the lower lip is affected [4]. Exophytic forms (papillary, verrucous) develop against the background of productive dyskeratosis. The process lasts a long time, infiltration of the underlying tissues increases gradually, and the tumor resembles a papilloma, multiple small growths, or cauliflower.

Endophytic forms develop against the background of destructive dyskeratosis, presenting as induration, a fissure, erosion, or an ulcer. In the early stages, a small roller-like rim appears along the edges of the induration or erosion, indicating malignant transformation. Gradually, infiltration spreads to surrounding tissues, and processes of breakdown and secondary infection occur [2].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the disease or condition

The diagnosis is established based on complaints, anamnesis, physical and instrumental examination, while morphological verification is a mandatory reliable criterion for establishing the diagnosis.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

2.4 Instrumental Diagnostics

• For patients with malignant neoplasms of the lip, it is recommended to perform a biopsy of the oral mucosa, puncture of oral cavity tissues, collection of scrapings from erosive and ulcerative elements of the skin and mucous membranes, followed by cytological examination of scrapings from erosions, ulcers, wounds, and fistulas, and cytological examination of fine-needle aspiration biopsy micropreparations for morphological verification of the tumor process [1, 5, 6].

FoR ALoE 1Level of recommendation evidence - A (level of data reliability - 1).

• If the cytological examination is inconclusive, patients with malignant neoplasms of the lip are recommended to undergo pathological examination of biopsy (surgical) material from oral cavity tissues, pathological examination of biopsy (surgical) material from oral cavity tissues using histobacterioscopic methods, or pathological examination of biopsy (surgical) material from oral cavity tissues using immunohistochemical methods for morphological verification of the tumor process [1, 5, 6].

FoR ALoE 1Level of recommendation evidence - A (level of data reliability - 1).

Comments: The depth of invasion by ultrasound is determined subject to the technical capabilities of the ultrasound transducer and the presence of an ultrasound image

Comment: if chest CT cannot be performed, chest radiography is recommended.

2.5 Other Procedures

1. size and extent of the primary tumor;

2. depth of invasion of the primary tumor;

3. histological structure of the tumor;

4. tumor differentiation grade;

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

6. regional lymph node status (pN) indicating the total number of examined and affected lymph nodes, signs of extranodal tumor extension (ENE+/-);

7. microscopic assessment of the resection margins indicating the distance to the closest resection margin in mm [4,5].

8. In unresectable processes and when planning palliative treatment, determination of PDL1 protein expression by immunohistochemistry.

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

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

3.1. General principles of treatment depending on the stage

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

Comments: For Tis, mucosectomy using physical methods (laser, radiofrequency ablation, electrochemical lysis, plasma coagulation, photodynamic therapy) can be performed [2, 5].

• For T1–T2, N0 with a tumor invasion depth of ˂2 mm, it is recommended to perform surgery only on the primary focus; neck dissection is not recommended [5; 13].

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

• For T1-T2, N0 with a tumor invasion depth of >4 mm, it is recommended to perform surgery on the primary focus and selective lymph node dissection (minimally levels 1–3) [5; 13].

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

Comments: With a tumor invasion depth of 2–4 mm, the decision to perform selective neck dissection is made individually (depending on the presence of enlarged lymph nodes in the neck, extent of the tumor process). Lymph node dissection (extirpation of lymph nodes) can be replaced by sentinel lymph node biopsy, which is an adequate method for controlling regional metastasis zones and detecting occult metastases [5; 13].

External beam radiation therapy for lip tumors according to a radical program is also a radical method of treatment if the patient refuses surgery or if there are contraindications to surgical treatment [5].

An alternative method of radical treatment for lip cancer can be interstitial radiation therapy of the lip tumor as a standalone option or in combination with external beam radiation therapy (EBRT) of the lip tumor if the patient refuses surgery or if there are contraindications to surgical treatment [14].

If the patient refuses surgical treatment or if there are contraindications to it, photodynamic therapy as a standalone option may be recommended [15].

If routine pathomorphological examination of the surgical material reveals unfavorable histological signs of perineural/perivascular/lymphatic invasion, adjuvant radiation therapy (RT) of the lip tumor is indicated. If a positive resection margin is determined, re-operation (in case of positive resection margins) or RT is recommended [1, 16].

• For T3,T4_a, N0, any T1-4a N1-3, it is recommended to perform surgery on the primary focus with neck lymphadenectomy [5, 17].

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

Comments: In N0 status, selective neck lymphadenectomy is performed on the affected side (levels 1–3). The minimum number of removed lymph nodes must be at least 18.

If the tumor process is located medially or crosses the midline, bilateral selective neck lymphadenectomy is performed (levels 1–3).

For N1, N2a-b, N3, radical neck lymphadenectomy is performed on the affected side (levels 1–5).

If the tumor is located medially or crosses the midline, radical neck lymphadenectomy is performed on the affected side (levels 1–5) and selective neck lymphadenectomy on the contralateral side (levels 1–3).

For N2c, bilateral radical neck lymphadenectomy is performed (levels 1–5).

• If surgery is impossible (patient refusal and/or presence of absolute contraindications), it is recommended to perform external beam radiation therapy of the lip tumor / chemoradiotherapy (CRT) [14].

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

• If surgery is impossible (patient refusal and/or presence of absolute contraindications), it is recommended to perform interstitial radiation therapy of the tumor at the primary site in combination with EBRT/CRT [14].

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

• If surgery is impossible (patient refusal and/or presence of absolute contraindications) in small tumor processes (T1–T3), it is recommended to perform photodynamic therapy on the primary lesion as a standalone option or in combination with EBRT/CRT [15].

LoR CLoE 4Level of Recommendations — C (Level of Evidence — 4).

• Patients with malignant neoplasms of the lip are recommended to undergo surgical treatment in the absence of absolute contraindications at stage I [1, 5, 10, 18, 19, 20, 21, 22].

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

Comment: the scope of surgery is determined by the localization and local spread of the tumor. Simultaneously with the surgery on the primary focus, surgery on the cervical lymphatic collector is performed in the volume of neck lymphadenectomy on the affected side or bilaterally in case of central localization of the tumor or the presence of bilateral metastases.

• Patients with malignant neoplasms of the lip are recommended to undergo postoperative concurrent CRT if routine pathomorphological examination of the surgical material reveals unfavorable histological signs such as positive resection margins or extracapsular spread of metastasis/metastases [1, 5, 10, 18, 19, 20, 21, 22].

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

• Patients with malignant neoplasms of the lip are recommended as an alternative to undergo re-operation if routine pathomorphological examination of the surgical material reveals a positive resection margin [1, 5, 10, 18, 19, 20, 21, 22].

GCP CLeveled 5Level of Evidence Assurance - C (level of evidentiary validity - 5).

• Patients with malignant neoplasms of the lip are recommended to undergo postoperative RT or concurrent CRT if unfavorable histological signs such as perineural/perivascular/lymphatic invasion, pT3/pT4, multiple regional metastases are detected [1, 5, 10, 18, 19, 20, 21, 22].

GCP CLeveled 5Level of Evidence Assurance - C (level of evidentiary validity - 5).

• Patients with malignant neoplasms of the lip are recommended to undergo concurrent CRT/RT if surgery is impossible [1, 5, 10, 18, 19, 20, 21, 22].

GCP CLeveled 5Level of Evidence Assurance - C (level of evidentiary validity - 5).

• For T4bN0–3 or unresectable regional metastases, or other stages with absolute contraindications for surgical treatment, it is recommended to select the treatment method depending on the general condition according to the Eastern Cooperative Oncology Group (ECOG) performance status scale [1, 5]:

ECOG 0–1 Administration of CRT or induction chemotherapy followed by EBRT/CRT.

ECOG 2 Administration of EBRT ± concurrent chemotherapy (depending on general condition)

ECOG 3 Palliative EBRT or monochemotherapy or immunotherapy or best supportive care.

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

• In case of local recurrence or residual tumor after surgical treatment without prior external beam radiation therapy, it is recommended to perform surgery achieving tumor-free resection margins (R0) or concurrent CRT, or polychemotherapy followed by EBRT/CRT [1, 5, 10, 18].

GOM CLoE 4Grade of Recommendation — C (Level of Evidence — 4).

Comment: if routine pathomorphological examination of the surgical material after surgery reveals unfavorable histological signs such as positive resection margins or extracapsular spread of metastasis/metastases, postoperative concurrent CRT is indicated. In case of a positive resection margin, re-operation may be recommended as an alternative. If unfavorable histological signs such as perineural/perivascular/lymphatic invasion, pT3/pT4, multiple regional metastases are detected, postoperative RT or concurrent CRT is indicated [1, 5, 10, 18].

• For patients with malignant neoplasms of the lip, surgery is recommended with a discussion of re-irradiation or concurrent chemoradiotherapy if the tumor is resectable in cases of local recurrence or residual tumor after external beam radiotherapy [1, 5].

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

• For patients with malignant neoplasms of the lip, re-irradiation / concurrent chemoradiotherapy, systemic therapy, or palliative care is recommended if the tumor is unresectable in cases of local recurrence or residual tumor after external beam radiotherapy [1, 5].

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

Distant metastases

The treatment strategy for lip cancer in the presence of distant metastases is chosen depending on the patient's performance status (ECOG) [1, 5].

• For ECOG 0–1, patients with lip cancer are recommended a combination of polychemotherapy or monotherapy. Surgical treatment (if all distant metastases are resectable and the primary tumor is resectable with R0 margins) or radiotherapy/chemoradiotherapy targeting the distant metastasis site in the absence of recurrence/residual tumor in the primary site and regional nodal basins is an option. If not feasible, best supportive care [5].

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

• For ECOG 2, patients with lip cancer are recommended monotherapy, immunotherapy, or best supportive care [5].

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

• For ECOG 3, patients with lip cancer are recommended best supportive care [5].

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

3.2. Principles of radiotherapy

Standalone radiotherapy

• For curative purposes in patients with lip cancer, standalone interstitial radiotherapy for lip tumors is recommended for T1-2 [5, 14].

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

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

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

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

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

Comment: Cf-252, Ir-192, and Co-60 sources can be used for interstitial radiotherapy of lip tumors

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

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

When performing standalone Cf-252 brachytherapy for primary tumors, the total cumulative dose is 7–9 Gy in terms of the neutron component. The neutron dose rate ranges from 0.04 to 0.27 Gy/hour. Dosimetric planning for Cf-252 interstitial neutron therapy includes two main elements: selecting the source placement scheme based on target dimensions and calculating the dose distribution generated by the combination of these sources. Various standard or custom immobilization devices can be used for optimal implementation of Cf-252 brachytherapy dosimetric planning [14, 15, 16].

When performing Ir-192 brachytherapy, a remote afterloader for contact radiotherapy is used, allowing high-dose-rate (HDR) irradiation and pulsed dose rate (PDR) irradiation, where Ir-192 is used as the radioactive agent.

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

Adjuvant high-dose-rate Ir-192 brachytherapy is performed 1–2 months after surgery. Postoperative standalone brachytherapy delivers 45–60 Gy, while combined modality therapy delivers a total dose of 22–29 Gy via Ir-192 along with external beam radiotherapy delivering a total dose of 47–60 Gy. [15]

• Postoperative external beam radiotherapy is recommended for pT3–4 and N2–3 stages, as well as for selected patients with pT1–2 and N0–1 stages (in the presence of adverse features, positive or close resection margins) [1, 5].

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

Comment: the preferred interval after surgery is ≤6 weeks and should not exceed 3 months.

For R0, a dose of 60 Gy (1.8–2.0 Gy/fraction) is delivered to the resected primary tumor bed and regional metastases.

For R+, the total radiation dose is 66 Gy (1.8–2.0 Gy/fraction).

To the locoregional area, including uninvolved regional lymph nodes, the total dose is 44–50 Gy (2.0 Gy/fraction); to lymph nodes involved by metastases, it is 54–63 Gy (1.8–2.0 Gy/fraction)

Postoperative concurrent chemoradiotherapy

• As postoperative treatment for patients with lip cancer presenting with tumor growth through the lymph node capsule and/or positive resection margins and/or adverse risk factors (primary stage pT3 or pT4; N2 or N3, presence of perineural invasion and/or lymphovascular emboli), as well as combinations of two or more adverse factors (primary stage pT3 or pT4; N2 or N3, presence of perineural invasion and/or lymphovascular emboli), concurrent platinum-based chemoradiotherapy is recommended: cisplatin** at 100 mg/m² every 3 weeks combined with radiotherapy [1, 5].

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

Comment: For R0, a dose of 60 Gy (1.8–2.0 Gy/fraction) is delivered to the resected primary tumor bed and regional metastases.

For microscopic residual tumor (R1), the recommended total radiation dose is 66 Gy (1.8–2.0 Gy/fraction).

To the locoregional area, including uninvolved regional lymph nodes, the total dose is 44–50 Gy (2.0 Gy/fraction); to lymph nodes involved by metastases, it is 54–63 Gy (1.8–2.0 Gy/fraction).

3.3. Principles of systemic chemotherapy

• For patients with malignant neoplasms of the lip (for the treatment of recurrent, primarily unresectable tumors, or metastatic disease when chemoradiotherapy is not feasible), poly- or monotherapy is recommended to improve patient survival (Table 1) [5, 23, 27, 29, 31, 34, 36, 38, 39, 116–123].

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

Comment: an individualized choice of chemotherapy (Table 1) is advisable based on patient characteristics (general condition, treatment goals) taking into account general principles of chemotherapy for squamous cell carcinoma of the head and neck [5].

Table 1. Regimens for squamous cell carcinoma of the head and neck.

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 CPS > 20. In case of progression during or after platinum-based chemotherapy, with a TPS level ≥ 50%. The recommended duration of use corresponds to the design of registration trials.

⁵As first-line therapy with CPS expression ≥ 1 %.

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

• In case of disease progression during platinum-based chemotherapy (Table No. 1) or after its completion, it is recommended to use nivolumab** 3 mg/kg IV once every 2 weeks (30- or 60-minute infusion) until progression or unacceptable toxicity [36]

GOM CLoE 2Grade of Recommendation — C (Level of Evidence — 2).

• In case of disease progression during platinum-based chemotherapy (Table No. 1) or after its completion, it is recommended to use #pembrolizumab** 200 mg IV once every 3 weeks (30-minute infusion) until progression or unacceptable toxicity [37, 38; 39]

GCR CLOE 2Grade of Recommendation — C (Level of Evidence — 2).

• In case of progression following platinum-based therapy, it is recommended to use #afatinib** 40 mg daily (efficacy in squamous cell carcinoma of the head and neck has been evaluated only in foreign studies) [40]

GCR CLOE 2Grade of Recommendation — C (Level of Evidence — 2).

Concurrent chemoradiotherapy for unresectable tumors is recommended to be administered using the cisplatin** + RT regimen.

External beam radiation therapy to the primary tumor and clinically detectable regional metastases — 70 Gy (2.0 Gy/fraction) daily from Monday to Friday for 7 weeks, to clinically uninvolved lymph nodes — 46–50 Gy (2.0 Gy/fraction), cisplatin** at a dose of 100 mg/m² with hyperhydration on days 1, 22, and 43 of RT (cumulative dose during RT — 300 mg/m²) [41].

GCR CLOE 2Grade of Recommendation — C (Level of Evidence — 2).

Comment: It is possible to use cetuximab** or carboplatin** taking into account the patient's tolerance and performance status. In the presence of comorbid conditions that preclude concurrent chemoradiotherapy containing platinum agents (chronic kidney disease, severe heart disease, etc.), substituting platinum agents with cetuximab** alongside RT is preferred

3.4. Principles of surgical treatment

• Evaluation. It is recommended that all patients be evaluated prior to treatment by a surgical oncologist 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 a synchronous primary tumor, assess current functional status and the feasibility of potential surgical treatment; if primary treatment was non-surgical, develop a prospective follow-up plan that includes adequate dental, nutritional, and lifestyle assessments, as well as interventions and any other supplemental investigations necessary for complete rehabilitation [1, 5].

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

Comment: For patients undergoing planned surgeries, the surgical intervention, margins, and plan for defect reconstruction following the resection of the clinically apparent tumor with tumor-free surgical margins must be carefully planned. Surgical intervention should not be modified based on the pre-treatment clinical response observed at the current examination (tumor regression), except in cases of tumor progression that necessitates a more extensive operation to encompass the entire tumor during definitive resection

• Assessment of resectability. It is recommended to evaluate for tumor involvement of structures associated with a poor prognosis or classified as stage T4b (e.g., unresectability associated with the technical inability to obtain clear margins): significant involvement of the pterygopalatine fossa, severe trismus due to tumor infiltration of the pterygoid muscles; macroscopic tumor extension to the skull base (e.g., erosion of the pterygoid plates or sphenoid bone, widening of the foramen ovale, etc.); potential invasion (encasement) of the common or internal carotid artery wall [1, 5].

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

Comment: Encasement is usually assessed radiologically (via contrast-enhanced CT and MRI) and is diagnosed if the tumor surrounds ≥270° of the carotid artery circumference; direct tumor extension from regional lymph nodes with skin involvement, direct extension into mediastinal structures, prevertebral fascia, or cervical vertebrae

• Removal of the primary lesion. Whenever possible, it is recommended to perform en bloc resection of the primary tumor [1, 5].

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

Comment: Surgical removal must be planned based on the extent of the primary tumor established during clinical examination and careful interpretation of relevant radiographic imaging. If the tumor abuts a motor or sensory nerve, perineural invasion cannot be ruled out. In this situation, the nerve should be dissected proximally and distally and resected to obtain a clear margin. Adequate intervention may require marginal, partial, or sagittal mandibulectomy for tumors involving or abutting the periosteum. Segmental resection is indicated for massive tumor infiltration of the mandibular periosteum (determined by tumor fixation to it) or when signs of direct bone invasion by the tumor are detected intraoperatively or during complete preoperative evaluation. The extent of mandibular resection will depend on the extent of involvement assessed clinically and intraoperatively.

• Resection margins. It is recommended to achieve R0 status during surgical treatment [1, 5, 42].

GOM CLoE 4Grade of Recommendation — C (Level of Evidence — 4).

Comment: Adequate excision is defined as a distance of ≥1.5 cm from the resection margin to the macroscopically visible tumor or a negative frozen section margin. In general, frozen section analysis is usually performed intraoperatively if the macroscopically tumor-free zone at the resection margin is <1.5 cm, if the resection line cannot be determined due to unclear tumor margins, or if residual tumor is suspected. A detailed description of the resection margin must be included in the operative report. Margins can be assessed from the resected specimen or, alternatively, from the tumor bed with proper orientation. A clear margin is defined as an invasive tumor edge located ≥5 mm from the resection margin. A close margin is defined as an invasive tumor edge located <5 mm from the resection margin. The primary tumor should be marked so that the pathologist can adequately assess specimen orientation. Neck dissection must be oriented or sectioned sequentially to determine the level of lymph nodes included in the dissection zone. Primary closure is recommended whenever possible, but wide tumor-free resection margins should not be compromised. Plastic closure using local/regional flaps, free flaps, split-thickness skin grafts, or other flaps with/without mandibular reconstruction is performed at the surgeon's discretion.

Comment: the incidence of lymph node metastasis, especially in early-stage lip cancer, is low, averaging <10%. The risk of tumor involvement in lymph nodes depends on the location, size, and grade of differentiation of the primary tumor. In patients with early-stage disease and no clinical signs of regional metastases, elective neck dissection or neck irradiation can be avoided.

The indication for prophylactic neck lymphadenectomy in T1–2 tumors is the depth of tumor invasion (according to ultrasound/CT ≥4 mm); for midline tumors or tumors crossing the midline, bilateral neck lymphadenectomy is recommended.

3.5. Other treatment modalities

Pain management protocols and recommendations for malignant lip neoplasms comply with the guidelines presented in the clinical guidelines "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Care".

• To correct xerostomia, it is recommended to use abundant fluid intake, saliva substitutes (e.g., calcium phosphate solutions, gels containing lysozyme, lactoferrin, and peroxidase), alcohol-free mouthwashes, sialagogues and taste stimulants (e.g., xylitol chewing gum, sorbitol/malic acid or xylitol lozenges) [43, 44].

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

3.6. Dietary therapy

The need for medical nutrition is determined by the patient's nutritional status, as well as the advisability of correcting comorbid conditions and preventing complications of 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, including those based on natural therapeutic factors".

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• To improve the quality of life of patients with lip cancer, it is recommended to use a multidisciplinary approach in rehabilitation [45, 124].

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

• In patients with lip cancer and a life expectancy of less than several months, it is recommended to reduce the invasiveness of nutritional interventions; when planning nutritional support, preference should be given to dietary counseling and sipping enteral nutrition [47].

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

• In patients with malignant neoplasms of the lip with an expected survival of less than several weeks, it is recommended to provide comfort-oriented care and symptomatic therapy, including relief of thirst and hunger [47].

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

• In patients with malignant neoplasms of the lip receiving antitumor treatment, it is recommended to maintain a daily caloric intake of 25–30 kcal/kg of body weight per day, and the required protein amount of 1.2–2 g of protein per 1 kg of body weight per day [47].

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

• In patients with malignant neoplasms of the lip, it is recommended to use a multimodal approach aimed at alleviating symptoms affecting food intake, ensuring adequate energy and nutrient intake, minimizing catabolic changes, supporting physical activity, and providing psychological and social support in order to correct malnutrition and improve quality of life [47].

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

• In patients with malignant neoplasms of the lip, it is recommended at the first stage to conduct dietary counseling in order to increase the intake of energy, protein, and other essential nutrients [47].

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

• Parenteral nutrition is recommended in case of complete absence of gastrointestinal function, or if it is not possible to cover the required energy and protein needs with enteral nutrition (sipping/tube feeding) [47].

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

Comments: The enteral route of nutrient delivery in patients with malignant neoplasms of the lip is preferred.

• In patients with malignant neoplasms of the lip, it is recommended to combine nutritional support with an increase in physical activity to prevent sarcopenia [47].

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

• In patients with malignant neoplasms of the lip, in order to improve appetite, it is recommended to use short courses of glucocorticoids (up to 2–3 weeks) [47].

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

Comments: With longer use of glucocorticoids, the effect on appetite regresses [47].

• In order to improve appetite and body weight in cachectic patients, it is recommended to prescribe progestins. It is necessary to consider the risk of adverse effects, including thromboembolic complications [47].

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

Comments: Such patients require nutritional support. The preferred method is oral feeding (sipping). If oral nutrition is impossible or inadequate, placement of a nasogastric tube or creation of a temporary gastrostomy using video-endoscopic technologies is required. If oral feeding is impossible, parenteral nutrition is indicated. The caloric value of the diet should be 25–30 kcal/kg of body weight per day, and the protein dose should be 1.0–1.5 g/kg of body weight per day. Replenishment of the daily requirement for vitamins and trace elements is necessary. It is preferable to use ready-to-use formulas enriched with protein and omega-3 fatty acids. Their use significantly reduces the incidence of infectious complications in the postoperative period.

Prophylactic nasogastric tube placement or video-assisted endoscopic gastrostomy is not recommended in patients with normal nutritional status, minor weight loss, absence of airway obstruction, or severe dysphagia. However, these patients require subsequent monitoring of dietary caloric intake and assessment of body weight dynamics throughout antitumor therapy. If necessary, during or after the completion of antitumor treatment, a temporary video-assisted endoscopic gastrostomy or nasogastric tube may be placed.

Indications for prophylactic nasogastric tube placement or video-assisted endoscopic gastrostomy are: 1) documented significant weight loss (5% of baseline body weight over the previous month or 10% of baseline body weight over the preceding 6 months); 2) existing dehydration, dysphagia, anorexia, pain syndrome that limits the patient's ability to eat or drink adequately; 3) significant comorbid and morbid conditions that can be exacerbated by dehydration, hypocaloric diet, or inability to swallow necessary medications; 4) aspiration syndrome, especially in elderly individuals or patients with cardiopulmonary failure; 5) patients in whom prolonged swallowing disorders are likely, including those expected during radiation therapy. However, other risk factors for impaired swallowing function should also be considered.

To maintain swallowing function during and after antitumor therapy with a preserved swallowing act and no risk of aspiration, natural nutrition is indicated. It should be taken into account that changes in swallowing function may appear throughout the entire course of treatment and after its completion, and must be monitored for the remainder of the patient's life.

• In patients with lip cancer, increasing and maintaining a sufficient level of physical activity is recommended to improve quality of life [49].

FoR ALoE 1Level of recommendation evidence - A (level of data reliability - 1).

Comments: Telerehabilitation is a set of rehabilitation and assistive measures and educational programs provided to the patient remotely via telecommunication and computer technologies. It allows patients to independently perform recovery treatment programs under the remote monitoring and guidance of a medical specialist. Phone calls or messages, email, mobile applications, web platforms, and videoconferencing can be used as remote support tools. Telerehabilitation technologies can be used at all stages of antitumor treatment: during preoperative preparation, in the delayed and late postoperative periods after discharge from the hospital, and to improve the tolerability of chemoradiotherapy, but it is especially relevant after the transition from inpatient to outpatient rehabilitation for patients. Advantages of telerehabilitation: ensuring continuity control between inpatient and outpatient treatment, including under conditions of viral load, the possibility of reducing the duration and frequency of hospitalizations, organizing control of complications and adverse events of antitumor treatment, increasing treatment accessibility for the patient by reducing transportation efforts and costs, monitoring the patient's condition in the postoperative period, and maintaining the necessary intensity of rehabilitation sessions using an economical method of organizing individual and group physical therapy (PT) classes to restore impaired functions during antitumor treatment.

4.1. Prehabilitation

• Pre-rehabilitation is recommended for all patients with malignant head and neck tumors scheduled for specialized treatment, as it significantly accelerates functional recovery, shortens hospital stay after surgery, and reduces the incidence of complications and mortality associated with cancer treatment. Pre-rehabilitation includes physical therapy (PT), psychological and nutritional support, and patient education [53].

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

• Prophylactic gymnastics programs and swallowing tactics training before the start of treatment are recommended to reduce swallowing disorders during combined antitumor therapy [54, 55].

GCR CLEL 5Level of Evidence - C (Level of Likelihood of Evidence - 5).

Comment: Such patients need nutritional support. The preferred method is oral nutrition (sipping). If oral nutrition is impossible or inadequate, placement of a nasogastric tube or temporary video-assisted endoscopic gastrostomy is necessary. If enteral nutrition cannot be used, parenteral nutrition is indicated. The caloric intake of the diet should be 25–30 kcal/kg of body weight per day, and the protein dose should be 1.0–1.5 g/kg of body weight per day. It is necessary to replenish the daily requirement for vitamins and trace elements. It is preferable to use ready-made formulas enriched with protein and omega-3 fatty acids. Their use significantly reduces the incidence of infectious complications in the postoperative period.

Prophylactic nasogastric tube placement or video-assisted endoscopic gastrostomy is not recommended in patients with normal nutritional status, minor weight loss, absence of airway obstruction, or severe dysphagia. However, these patients require subsequent monitoring of dietary caloric intake and assessment of body weight dynamics throughout antitumor therapy. If necessary, during or after the completion of antitumor treatment, a temporary video-assisted endoscopic gastrostomy or nasogastric tube may be placed.

Indications for prophylactic nasogastric tube placement or video-assisted endoscopic gastrostomy are: 1) documented significant weight loss (5% of baseline body weight over the previous month or 10% of baseline body weight over the preceding 6 months); 2) existing dehydration, dysphagia, anorexia, pain syndrome that limits the patient's ability to eat or drink adequately; 3) significant comorbid and morbid conditions that can be exacerbated by dehydration, hypocaloric diet, or inability to swallow necessary medications; 4) aspiration syndrome, especially in elderly individuals or patients with cardiopulmonary failure; 5) patients in whom prolonged swallowing disorders are likely, including those expected during radiation therapy. However, other risk factors for impaired swallowing function should also be considered.

To maintain swallowing function during and after antitumor therapy with a preserved swallowing act and no risk of aspiration, natural nutrition is indicated. It should be taken into account that changes in swallowing function may appear throughout the entire course of treatment and after its completion, and must be monitored for the remainder of the patient's life.

Nutritional and metabolic rehabilitation is indicated in the presence of at least one of the following factors: unintentional weight loss over the past 3 months (loss ≥10%), body mass index <18.5 kg/m2, impaired food intake capacity over the past week, low food volume (caloric intake <1500 kcal/day). The preferred method is oral nutrition (sipping). If oral nutrition is impossible or inadequate, placement of a nasogastric tube or creation of a temporary gastrostomy using video-endoscopic techniques is necessary. The caloric value of the diet should be 25–30 kcal/kg of body weight per day, and the protein dose should be 1.0–1.5 g/kg of body weight per day. Replenishment of the daily requirement for vitamins and trace elements is necessary. It is preferable to use ready-to-use formulas enriched with protein, omega-3 fatty acids, arginine, and ribonucleic acids. Their use significantly reduces the incidence of postoperative infectious complications [57, 58].

• For patients with head and neck malignant neoplasms and a risk of nutritional insufficiency, nutritional support is recommended, carried out at the outpatient stage and continued throughout the entire examination period up to surgical intervention, as it reduces the number of postoperative complications and the length of hospital stay. If oral food intake is maintained, ready-to-use high-protein formulas are preferred, with a daily dosage of at least 400 ml/day. If oral intake is impossible, tube feeding, parenteral nutrition, or mixed nutrition is performed according to the calculated requirement [58].

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

• In case of malnourished status or the risk of developing nutritional insufficiency, adequate nutritional support for at least 7 days is recommended at the preoperative stage for patients with head and neck malignant neoplasms, as it reduces the number of postoperative complications and the length of hospital stay [59].

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

• In patients with malignant neoplasms of the lip, pre-rehabilitation is recommended, incorporating aerobic training, breathing exercises, and strength training to improve long-term functional outcomes [60].

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

4.2. Rehabilitation Following Surgical Treatment

STAGE I REHABILITATION

Comment: breathing exercises combined with early activation, as they reduce the length of hospital stay and the number of postoperative complications [64].

Early mobilization (verticalization, performing a set of exercise therapy and aerobic load, resistance exercises under the supervision of an instructor) is safe, does not increase the number of postoperative complications, and improves the patient's functional capabilities [65].

Comments: percutaneous electrical nerve stimulation (TENS), acupuncture point stimulation with other physical factors, general medical massage, exercises to strengthen facial and neck muscles, breathing exercises aimed at coordinating phonational breathing, exercise therapy for aphasia and dysarthria, exercise therapy exercises aimed at reducing spasticity, skin care for a severely ill patient, low-level laser therapy (intravenous blood irradiation), balance therapy, local cryotherapy, general cryotherapy (cryochamber), procedures aimed at reducing spasticity, exercise therapy for dysphagia – these procedures yield good results.

• Restoration of swallowing function is possible through the recovery of motor function in preserved anatomical structures, as well as the mobility of transplanted tissues with adequately performed plastic surgery. To restore swallowing function, exercises to increase range of motion and muscle strength and to enhance voluntary control over the timing and coordination of the swallow are recommended [67, 68].

Level of Recommendation ALevel of Evidence 3Level of recommendation confidence - A (level of evidence validity - 3).

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

• In patients with malignant neoplasms of the lip, to create compensatory mechanisms for speech production, the use of dynamic and static articulation exercises with a gradual increase in load is recommended to improve functional outcomes and quality of life [69].

GOM CLoE 4Grade of Recommendation — C (Level of Evidence — 4).

Comments: start with exercises that activate lip movements, then proceed to exercises for the lower jaw and articulation gymnastics for the tongue, relying on phantom sensations of the lost organ. To eliminate resonance disorders and ensure the maximum possible velopharyngeal closure in the postoperative period, manifested by the appearance of hypernasality and nasal emission, exercises promoting the activation of the soft palate and faucial pillars, and the development of plasticity and extensibility of soft palate tissues with simultaneous contraction of the posterior pharyngeal wall muscles and soft palate muscles, are recommended. [69]

• To improve postoperative wound healing in patients with malignant neoplasms of the lip, low-level laser therapy is recommended [72]. .

LoR CLoE 4Level of Recommendations — C (Level of Evidence — 4).

Comments: Low-level laser therapy is safe and does not increase the rate of progression and local recurrence [72].

STAGE II REHABILITATION

• Maintaining a stable body weight and an active lifestyle are recommended to increase overall survival rates in patients who have undergone surgical treatment [74].

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

Comments: target indicators are moderate-intensity aerobic exercise 3–5 times a week (totaling 150 minutes per week) combined with resistance training 2–3 times a week. Resistance exercises should involve major muscle groups (8–10 muscle groups, 8–10 repetitions, 2 sets). Each session should include a warm-up and a cool-down [74].

STAGE III REHABILITATION

• Maintaining a high level of physical activity after the completion of treatment is recommended for patients with malignant neoplasms of the lip to improve functional outcomes [75].

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

• Increasing and maintaining a high level of physical activity is recommended for patients with malignant neoplasms of the lip to improve overall survival [75,76].

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

• To overcome trismus (tonic spasm of the masticatory muscle group), which leads to limited mobility of the temporomandibular joint, exercises regulating the degree of mouth opening are recommended for patients with malignant neoplasms of the lip [77].

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

Comments: static, dynamic, and resistance exercises are used to overcome trismus. Movements are performed not only in the plane of jaw lowering and elevation. Other movements are also necessary to restore function: lateral, forward, backward, and circular [77].

• In patients with malignant neoplasms of the lip, a comprehensive approach to the treatment of secondary head and neck lymphedema, including compression therapy, exercises, skin care, manual lymphatic drainage, and patient self-management training, is recommended [82].

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

• To treat head and neck lymphedema in patients with malignant neoplasms of the lip, medical massage of the neck, scalp, and face is recommended [83].

LoR CLoE 4Level of Recommendations — C (Level of Evidence — 4).

• Physiotherapy, including a specialized set of exercises and compression therapy, is also recommended for patients with malignant neoplasms of the lip to manage lymphedema [84, 85].

LoR CLoE 4Level of Recommendations — C (Level of Evidence — 4).

• Low-level laser therapy combined with complete decongestive therapy is recommended for patients with malignant neoplasms of the lip to reduce edema [86].

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

4.3. Rehabilitation during drug therapy

• Anticancer treatment for head and neck cancer causes psychological distress, anxiety, and depression, which impairs patients' quality of life. Resistance exercise is recommended to reduce fatigue and improve the quality of life and psychological status of patients receiving adjuvant chemotherapy [87].

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

Comments: early initiation of physical activity during chemotherapy helps prevent muscle weakness, the onset and progression of sarcopenia, and decreased exercise tolerance [88, 89]. A physical therapy program incorporating aerobic exercise and Tai Chi elements for 4 months during chemotherapy increases vital capacity, blood oxygen saturation, muscle strength, range of motion in large joints, and reduces body mass index [90].

• To reduce fatigue and improve endurance during chemoradiotherapy, therapeutic exercise is recommended. Moderate-intensity aerobic exercise combined with resistance training yields the optimal effect [90, 91].

AGR BLEL 2Level of Evidence - B (level of data reliability - 2).

• A combination of therapeutic exercise and psychological support is recommended for patients with malignant neoplasms of the lip to treat fatigue during chemotherapy [91].

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

• Therapeutic exercise incorporating coordination exercises is recommended for patients with malignant neoplasms of the lip to prevent toxic peripheral polyneuropathy [95].

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

4.4. Rehabilitation During Radiation Therapy

Comments: although there is insufficient evidence regarding the efficacy of measures such as mouthwashing with sodium bicarbonate** solutions, saline (sodium chloride**), and oral hygiene education, these methods may be used given their safety. Although there is insufficient evidence to support professional oral care for the prevention of oral mucositis, most experts agree that dental evaluation and treatment prior to chemoradiotherapy are desirable to reduce the risk of local and systemic infections from odontogenic sources.

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

5. Prevention and Dispensary Observation

During the first year, physical examination and history taking should be performed every 1–3 months; in the 2nd year, every 2–6 months; and at 3–5 years, once every 4–8 months. After 5 years from surgery, visits are conducted annually or upon the appearance of symptoms. In patients at high risk of recurrence, the interval between examinations may be shortened. Scope of examination:

• medical history and physical examination;

• Ultrasound of bilateral cervical lymph nodes, abdominal organs, and the pelvis;

• CT of the head and neck as clinically indicated and when the area is inaccessible to adequate physical examination;

• Chest X-ray / CT every 12 months;

• Determination of thyroid-stimulating hormone levels every 6–12 months if neck irradiation was performed, to assess thyroid function [1, 4].

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

Comment: the objective of follow-up is early detection of disease progression in order to timely initiate chemotherapy or surgical treatment of resectable metastatic lesions and recurrent tumors, as well as to detect metachronous head and neck tumors.

Comment. Head and neck radiation therapy (RT) can cause xerostomia and salivary gland dysfunction, significantly increasing the risk of dental caries and associated adverse consequences such as dentoalveolar infection and osteoradionecrosis. RT also affects dental tissues, increasing the likelihood of demineralization due to xerostomia, post-RT microflora changes, and a shift toward a caries-promoting diet. Moreover, oral infections impair post-surgical tissue repair and require intensified antibacterial regimens. Radiation-associated caries and other dental tissue changes may develop within the first 3 months following RT completion.

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 of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Public Health Protection in the Russian Federation," is organized and provided:

• in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;

• in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

• based on these clinical guidelines;

• 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 physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an outpatient cancer center, a primary oncology office, or a primary oncology department of a medical organization to receive primary specialized health care.

Consultation at an outpatient cancer center, primary oncology office, or primary oncology department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral. The oncologist at the outpatient cancer center (or the oncologist at the primary oncology office or department, if an outpatient center is absent) shall arrange for the acquisition of biopsy (surgical) material and other diagnostic tests necessary to establish a diagnosis, including the extent of the oncological process and the disease stage.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that incorporates the outpatient cancer center (primary oncology office, primary oncology department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing care to cancer patients.

The timeframe for performing pathological anatomical examinations necessary for the histological verification of a malignant neoplasm shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material at the department of pathological anatomy (pathology bureau).

If an oncological disease is suspected and/or detected during the provision of emergency medical care, such patients shall be transferred or referred to medical organizations providing care to cancer patients to determine management tactics and the need for additional specialized anticancer treatment methods.

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

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

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

In a medical organization providing care to cancer patients, the medical examination and treatment strategy is determined by a concilium of oncologists and radiotherapists, with the involvement of other specialist physicians if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the concilium, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the profile of «oncology» are determined by a concilium of oncologists and radiation therapists, with the involvement of other medical specialists if necessary.

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

• presence of oncological disease complications requiring emergency and urgent specialized medical care;

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

Indications for planned hospitalization in a medical organization are:

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

• presence of indications for specialized anticancer treatment (surgical intervention, RT including contact, external beam, and other types of RT, drug therapy, etc.) requiring monitoring in a 24-hour or day-care hospital setting.

Indications for discharging a patient from a medical organization are:

• completion of a treatment course or a stage of specialized, including high-tech, medical care in a 24-hour or day-care hospital, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

• refusal by the patient or their legal representative of specialized, including high-tech, medical care in a 24-hour or day-care hospital setting prescribed by the concilium of the cancer care organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or inpatient medical interventions;

• non-compliance by the patient with prescriptions or internal regulations of the healthcare institution, provided this does not threaten the patient's life or the health of others;

• the need to transfer the patient to another medical organization in the relevant profile of medical care.

The conclusion regarding the feasibility of transferring the patient to a specialized medical organization is made following a preliminary consultation based on provided medical documents and/or a preliminary examination of the patient by specialist physicians of the destination medical organization.

6. Organization of Medical Care

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

1. in accordance with the regulations on the organization of medical care by types of medical care, which is approved by the authorized federal executive body;

2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

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

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

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

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

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

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

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

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

For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as corresponding International Classification of Diseases for Oncology (ICD-O) 3rd edition codes 8936, 906–909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, the oncologist of an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall, in order to determine treatment tactics, 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 for the purposes of this Procedure as national medical research centers).

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 fourth-group pathologo-anatomical bureau (department) (reference center) via information interaction, including the use of teleconsultation technologies for remote interaction between medical personnel;

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 determined by a medical concilium comprising oncologists, a radiotherapist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for treating malignant neoplasms, antitumor drug therapy, and radiotherapy (hereinafter referred to as the oncology concilium), including an oncology concilium conducted using telemedical technologies, with the involvement of other specialist physicians if necessary.

Dispensary follow-up by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological diseases.

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

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.

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

Waiting times for the provision of specialized (excluding high-tech) medical care shall not exceed the timeframes established in the program of state guarantees of free medical care to citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the regulations on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations and other non-profit organizations operating in the field of health protection.

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

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

1. presence of oncological disease complications requiring emergency and urgent specialized medical care;

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

Indications for planned hospitalization in a medical organization are:

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

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

Indications for discharging a patient from a medical organization are:

1. completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

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

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

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

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

7. Additional Information

Factors influencing the disease prognosis are:

• size and extent of the primary tumor;

• depth of invasion of the primary tumor;

• tumor differentiation grade;

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

• regional lymph node status (pN) (neck lymph node metastases halve patient survival)

• extranodal tumor extension;

• surgical resection margin status (R0-1);

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. 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"

2. Kulbakin Denis Evgenyevich, MD, Head of the Head and Neck Tumors Department, Cancer Research Institute, Tomsk National Research Medical Center

3. Agababyan Tatev Artakovna, Head of the Diagnostic Radiology Department, A.F. Tsyb Medical Radiological Research Center — branch of the National Medical Research Radiological Center of the Russian Ministry of Health, PhD, Obnisk 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, PhD in Medicine, Ultrasound Diagnostics Physician, Radiologist at the Department of Diagnostic Radiology, Researcher at the Scientific Department of Diagnostic and Interventional Radiology, N.N. Petrov National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Associate Professor at the Department of Radiology and Medical Imaging, Faculty of Postgraduate Education, Saint Petersburg State Medical University; https://orcid.0000-0002-4245-687X

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

24. Mikhail A. Kropotov, 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

25. 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

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

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

31. 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

32. 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

33. Reshetov Igor Vladimirovich, MD, Professor, Academician of the Russian Academy of Sciences, Head of the Department of Oncology, Radiotherapy and Reconstructive Surgery, I.M. Sechenov First Moscow State Medical University, President of the 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. 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

38. 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

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

40. 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

41. 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

42. 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

43. 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.

44. 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.

45. 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

46. Choynzonov Evgeny Lkhamatsyrenovich, MD, Professor, Academician of the Russian Academy of Sciences, Director of the 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 Oncology Specialists»

47. 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

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

49. 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

50. 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.

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

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologists

2. Surgeons

3. Radiologists

4. Medical students, residents, and postgraduate students

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

Table 3. Scale for assessing levels of evidence (for prevention, treatment and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)).

Table 4. Scale for assessing grades of recommendation (GR) 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 3 years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of well-founded additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Information is not available.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

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 oncological specialist are recommended every 3‒6 months; at 3‒5 years, once every 6‒12 months. After 5 years from the time of surgery, visits are conducted annually or upon the appearance of complaints. Nevertheless, the frequency of doctor visits may be increased depending on the disease characteristics and associated risks and is discussed individually in each specific case. If complaints arise, as well as if symptoms observed 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 radiation therapy to the neck area, nutritional status decline, assessment of speech and swallowing function, etc.).

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

Benefits of quitting smoking and alcohol consumption

• Higher survival rates

• Higher treatment efficacy

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

• Accelerated recovery of general condition after treatment

• Lower risk of recurrence

• Lower risk of second primary tumors

• Lower risk of infections

• Higher quality of life

In case of complications from chemotherapy/chemoradiotherapy − contact your oncologist or radiation oncologist.

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

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

2. For stomatitis:

   diet – mechanical, thermal, and chemical sparing, as well as the use of medical nutrition ‒ as recommended by a physician;

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

   perform oral cavity care as recommended by a physician.

3. For diarrhea:

   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;

   take medications as prescribed by a physician.

4. For nausea:

   Take medications as prescribed by a physician.

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

Appendix G1.

ECOG SCALE

Russian name: WHO/ECOG Performance Status Scale

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

Contents:

Key (interpretation): provided within the scale itself

Appendix G2.

NUTRITIONAL RISK SCREENING

Russian title: Nutritional Risk Screening

Original name (if available): Nutritional Risk Screening 2002, NRS-2002

Source (official developer website, validation publication): Bolayir B., et al. Validation of Nutritional Risk Screening-2002 in a Hospitalized Adult Population. Nutr Clin Pract. 2019. PMID: 29603374

Type: rating scale

Purpose: screening for malnutrition in elderly and senile patients during hospitalization

Content (template):

Clinical interpretation of disease severity grades

1 point: a patient with a chronic condition is hospitalized due to an exacerbation or complications. The patient is weakened, but mobile and able to move around (not permanently bedridden). Protein requirements are increased, but can be met through regular food intake with the addition of sip feeds or specialized nutrition;

2 points: the patient is on bed rest due to illness, e.g., following abdominal surgery. Protein requirements are significantly increased, but can be met through the use of specialized nutritional products and artificial nutrition;

3 points: the patient is in the ICU on mechanical ventilation and other critical conditions. Protein requirements are maximized and cannot be met solely via clinical (artificial) nutrition. Protein breakdown and nitrogen loss are significantly increased.

Total score = score for the severity of nutritional status disorders + score for disease severity.

If aged 70 years or older, add 1 point.

Key (interpretation)

3 or more points — nutritional risk; a nutritional support plan is developed.

Less than 3 points — weekly assessment. If major surgery is planned, a preventive nutritional support plan is discussed.