Malignant neoplasm of bronchus and lung: clinical guidelines

List of Abbreviations

ALK – (anaplastic lymphoma kinase) anaplastic lymphoma kinase

AUC – (area under the curve) area under the plasma concentration–time curve (the dose of carboplatin** based on the area under the curve is calculated using the Calvert formula (Calvert, 1989): carboplatin** dose, mg = AUC × (creatinine clearance + 25))

BRAF – B-raf serine/threonine kinase

ECOG PS – (Eastern Cooperative Oncology Group Performance Status) Eastern Cooperative Oncology Group performance status scale

EGFR – (epidermal growth factor receptor) epidermal growth factor receptor

EUS/EBUS – (esophageal/endobronchial ultrasound) transesophageal/transbronchial sonography (A04.11.003 – transesophageal mediastinal endosonography) PD1/PD-L1 – (programmed cell death 1/programmed cell death 1 ligand) programmed cell death protein 1/its ligand

RUSSCO – (Russian Society of Clinical Oncology) Russian Society of Clinical Oncology

MEK – (mitogen-activated protein kinase) intracellular signaling protein kinase, also known as MAPK/ERK kinase (mitogen-activated protein kinase)

SCC – (squamous cell carcinoma antigen) squamous cell carcinoma antigen TNM – (from tumor, nodus, and metastasis) international classification of cancer staging

ALT – alanine aminotransferase

AST – aspartate aminotransferase

ATX – Anatomical Therapeutic Chemical (ATC) Classification System

aPTT – activated partial thromboplastin time

Biofeedback therapy – biofeedback therapy

IV – intravenous

WHO – World Health Organization

G-CSF – granulocyte colony-stimulating factors (ATC: Colony-stimulating factors)

GC – glucocorticoids

EBRT – external beam radiotherapy

BMI – body mass index

IT – immune therapy (immunotherapy)

CT – computed tomography

RT – radiotherapy

INR – international normalized ratio

SCLC – small cell lung cancer

MRI – magnetic resonance imaging

BW – body weight

NSCLC – non-small cell lung cancer

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

PET-CT – positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals

SFD – single focal dose

TFD – total focal dose

LCE – level of confidence of evidence

GRS – grade of recommendation strength

CT – chemotherapy

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or doses contained in the drug's instructions for use)

Terms and Definitions

EGFR (epidermal growth factor receptor) – epidermal growth factor receptor gene

BRAF (rapidly accelerated fibrosarcoma (RAF) family gene B) – gene of the kinase family identified in rapidly growing fibrosarcomas (ARAF, BRAF, CRAF)

KRAS (Kirsten rat sarcoma virus) – gene homologous to the Kirsten rat sarcoma virus gene (RAS gene family – KRAS, NRAS, HRAS)

ALK (anaplastic lymphoma kinase) – anaplastic lymphoma kinase gene

ROS1 (homolog of RNA tumor virus UR2 (University of Rochester tumor virus2)

Of avian sarcoma type 1) – gene homologous to avian sarcoma RNA virus type 1

CTLA4 – monoclonal antibody blocking cytotoxic T-lymphocyte associated protein 4, also known as CD152. Functions as a receptor with B7.1 or B7.2 molecules serving as ligands.

CYFRA 21-1 – cytokeratin 19 fragment.

PD1/PD-L1 (programmed cell death 1/programmed cell death 1 ligand) – programmed cell death protein 1 / its ligand

Computed tomography (CT) – a method of obtaining cross-sectional images by scanning an object with a fan-shaped x-ray beam.

Magnetic resonance imaging (MRI) – a method of obtaining cross-sectional images based on the use of nuclear magnetic resonance and detection of electromagnetic radiation

Positron emission tomography (PET) – a radionuclide diagnostic method based on the detection of electromagnetic waves generated during the annihilation of positrons with electrons

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

PET-CT scan – simultaneous PET and CT imaging followed by image fusion

Lung cancer is a malignant neoplasm originating from the epithelial cells of the lung.

Chest radiography (lung X-ray) is a method of obtaining a projection image of the object under study by recording X-ray radiation attenuated within the object.

Bone scintigraphy (whole-body bone scan) is a radionuclide diagnostics method based on the administration of a bone-tropic diagnostic radiopharmaceutical into the patient's body, followed by the recording of its distribution and accumulation in the skeleton using gamma radiation from the isotope included in the preparation.

Doppler ultrasound (duplex scanning of lower extremity blood vessels [arteries and veins]) is a non-invasive examination of moving objects using ultrasound waves.

Ultrasound examination is a method of imaging the structure of the object under study by registering the reflected ultrasound signal.

Stages of rehabilitation:

• Stage I – rehabilitation during the period of specialized treatment of the underlying disease (including surgical treatment / chemotherapy / radiotherapy) in departments of medical organizations corresponding to the profile of the underlying disease;

• Stage II – rehabilitation in the early recovery period of the disease, late rehabilitation period, and the period of residual manifestations of the disease in inpatient settings of medical organizations (rehabilitation centers, rehabilitation departments);

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Lung cancer (LC) is an umbrella term encompassing malignant epithelial tumors of diverse origin, histological structure, clinical course, and treatment outcomes arising from the surface epithelium of the bronchial mucosa, bronchial mucous glands of bronchioles, and pulmonary alveoli [1, 2].

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

In the vast majority of patients suffering from LC (85-90%), the development of the disease is associated with smoking, both active and passive. In addition, risk factors include radiation exposure (previous radiotherapy [RT] for other intrathoracic tumors), radon, asbestos, and arsenic exposure [3].

1.3 Epidemiology of the Disease or Condition

In terms of morbidity, LC ranks 1st among other malignant tumors in men in Russia, and in terms of mortality, it ranks 1st among both men and women in Russia and worldwide.

In Russia in 2022, there were 44,981 newly registered cases of diagnosed LC. First-year mortality is 44.8% [4]. It claims the lives of more patients annually than prostate, breast, and colorectal cancer combined [5].

1.4 Features of Coding the Disease or Condition

Malignant neoplasm of bronchus and lung (C34)

C34.0 Malignant neoplasm of main bronchus

C34.1 Malignant neoplasm of upper lobe, bronchus or lung

C34.2 Malignant neoplasm of middle lobe, bronchus or lung

C34.3 Malignant neoplasm of lower lobe, bronchus or lung

C34.8 Malignant neoplasm of bronchus or lung, overlapping lesion

C34.9 Malignant neoplasm of bronchus or lung, unspecified

1.5 Classification of the disease or condition

International Histological Classification (2021) [6]

ICD-O Code WHO Classification of Tumours of the Lung (2021)

Papillomas

8052/0 Squamous cell papilloma, NOS

8053/0 Squamous cell papilloma, inverted type

8260/0 Glandular papilloma

8560/0 Mixed squamous cell and glandular papilloma

Adenomas

8832/0 Sclerosing pneumocytoma

8251/0 Alveolar adenoma

8260/0 Papillary adenoma

8140/0 Bronchiolar adenoma / ciliated micronodular muconodular papillary tumor*

8470/0 Mucinous cystadenoma

8480/0 Mucinous gland adenoma

Preinvasive glandular processes

8250/0 Atypical adenomatous hyperplasia

8250/2 Adenocarcinoma in situ, non-mucinous

8253/2 Adenocarcinoma in situ, mucinous

Adenocarcinomas

8256/3 Minimally invasive adenocarcinoma, non-mucinous

8257/3 Minimally invasive adenocarcinoma, mucinous

8250/3 Lepidic adenocarcinoma

8551/3 Acinar adenocarcinoma

8260/3 Papillary adenocarcinoma

8265/3 Micropapillary adenocarcinoma

8230/3 Solid adenocarcinoma

8253/3 Invasive mucinous adenocarcinoma

8254/3 Mixed invasive mucinous and non-mucinous adenocarcinoma

8480/3 Colloid adenocarcinoma

8333/3 Fetal adenocarcinoma

8144/3 Enteric-type adenocarcinoma

8140/3 Adenocarcinoma, NOS

Preinvasive squamous cell processes

8070/2 Squamous cell carcinoma in situ

8077/0 Mild squamous dysplasia

8077/2 Moderate squamous dysplasia

8077/2 Severe squamous dysplasia

Squamous cell carcinomas

8070/3 Squamous cell carcinoma, NOS

8071/3 Keratinizing squamous cell carcinoma

8072/3 Non-keratinizing squamous cell carcinoma

8083/3 Basaloid squamous cell carcinoma

8082/3 Lymphoepithelial carcinoma

Neuroendocrine neoplasms Preinvasive process

8040/0 Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Neuroendocrine tumors

8240/3 Carcinoid, NOS / neuroendocrine tumor, NOS

8240/3 Typical carcinoid / neuroendocrine tumor, G1

8249/3 Atypical carcinoid / neuroendocrine tumor, G2

Neuroendocrine carcinomas

8041/3 Small cell carcinoma

8045/3 Combined small cell carcinoma

8013/3 Large cell neuroendocrine carcinoma

8013/3 Combined large cell neuroendocrine carcinoma

Other epithelial tumors

8012/3 Large cell carcinoma, NOS

8560/3 Adenosquamous carcinoma

8022/3 Pleomorphic carcinoma

8032/3 Spindle cell carcinoma

8031/3 Giant cell carcinoma

8980/3 Carcinosarcoma

8972/3 Pulmonary blastoma

8023/3 NUT carcinoma

8044/3 Thoracic SMARCA4-deficient undifferentiated tumor*

Salivary gland-type tumors

8430/3 Mucoepidermoid carcinoma

8200/3 Adenoid cystic carcinoma

8562/3 Epithelial-myoepithelial carcinoma

8940/0 Pleomorphic adenoma

8982/0 Myoepithelioma

8982/3 Myoepithelial carcinoma

8310/3 Hyalinizing clear cell carcinoma

Clinical and anatomical classification

Central lung cancer is localized in the bronchi (main, intermediate, lobar, segmental, subsegmental). According to the growth pattern, exophytic (endobronchial) cancer is distinguished, in which the tumor grows into the lumen of the bronchus; endophytic (exobronchial) cancer, in which the tumor grows predominantly into the thickness of the pulmonary parenchyma; branched cancer with sleeve-like peribronchial tumor growth around the bronchi, as well as tumors with a mixed growth pattern with a predominance of a particular component [1, 2].

Peripheral lung cancer is localized in the peripheral parts of the lung.

Nodal tumor form, pneumonia-like cancer, and Pancoast syndrome superior sulcus tumor are distinguished [1, 2].

Atypical forms of lung cancer: mediastinal form, miliary carcinomatosis [8, 9]

Staging

To determine the stage of lung cancer, the TNM Classification of Malignant Tumors TNM (Tumor, Nodus, and Metastasis) (9th edition, 2024) [6, 7] is used (Table 1).

T – Primary tumor

Tx – Primary tumor cannot be assessed, or tumor is proven by the presence of malignant cells in sputum or washings, but is not visualized by bronchoscopy.

T0 – No evidence of primary tumor.

Tis – Carcinoma in situ.

T1 – Tumor 30 mm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).

T1mi – Minimally invasive adenocarcinoma.

T1a – Tumor 10 mm or less in greatest dimension.

T1b – Tumor more than 10 mm but not more than 20 mm in greatest dimension.

T1c – Tumor more than 20 mm but not more than 30 mm in greatest dimension.

T2 – Tumor more than 30 mm but not more than 50 mm in greatest dimension; or tumor with any of the following features: involves main bronchus, regardless of distance to carina, but without involvement of the carina; invades visceral pleura; associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung.

T2a – Tumor more than 30 mm but not more than 40 mm in greatest dimension, or tumor whose size cannot be determined (e.g., if the tumor is inseparable from atelectasis).

T2b – Tumor more than 41 mm but not more than 50 mm in greatest dimension.

T3 – Tumor more than 50 mm but not more than 70 mm in greatest dimension; or tumor that directly invades any of the following: chest wall (including parietal pleura and superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe.

T4 – Tumor more than 70 mm in greatest dimension; or tumor that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, visceral pericardium; or separate tumor nodule(s) in a different ipsilateral lobe.

N – Regional lymph nodes

Nx – Regional lymph nodes cannot be assessed.

N0 – No regional lymph node metastasis.

N1 – Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension

N2 – Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s).

N2a – Involvement of a single N2 lymph node station

N2b – Multiple involvement of N2 lymph node stations

N3 – Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).

M – Distant metastasis

M0 – No distant metastasis.

M1 – Distant metastasis is present.

M1a – Tumor nodule(s) in a contralateral lobe; pleural tumor nodules or malignant pleural/pericardial effusion.

M1b – Single distant extrathoracic metastasis.

M1c – Multiple extrathoracic metastases in one or several organs.

M1c1 – Multiple metastases in a single organ or system

M1c2 – Multiple metastases in multiple organs

To specify the localization of a distant metastatic site (M), additional descriptors are used:

PUL – Lung PER – Peritoneum

MAR – Bone marrow BRA – Brain

OSS – Bone SKI – Skin

PLE – Pleura LYM – Lymph nodes

ADP – Kidney SADP – Adrenal gland

HEP – Liver OTH – Other

For clinical assessment of tumor extent, the prefix "c" is used before the TNM symbols, and for pathohistological classification, the prefix "p". Requirements for determining pT, pN, and pM categories are similar to those for cT, cN, and cM categories. The pN symbol can be assessed by examining at least 6 lymph nodes, 3 of which must be mediastinal, including at least 1 subcarinal.

Table 1. Lung cancer staging according to the TNM classification of malignant tumors (9th edition, 2024)

Abbreviations: T – primary tumor, N – regional lymph nodes, M – distant metastasis.

For small cell lung cancer (SCLC), a simplified extent-of-disease classification can be used: limited-stage and extensive-stage disease. Limited-stage disease is characterized by tumor involvement confined to one hemithorax, mediastinum, and supraclavicular lymph nodes, safely encompassed within a single radiotherapy field.

1.6 Clinical presentation of the disease or condition

Clinical symptoms of the tumor may be combined with symptoms of concomitant complications. Primary symptoms include cough, dyspnoea, chest pain, and haemoptysis; general symptoms include weakness, fatigue, and decreased appetite. Secondary symptoms arise as a result of concomitant inflammatory complications, regional or distant metastasis, or invasion of adjacent organs [9]. Clinical manifestations also include paraneoplastic syndromes. An asymptomatic course of lung cancer is also possible.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria: if the results of a comprehensive evaluation of tumor spread and morphological verification are available, the diagnosis of "lung cancer" is considered proven. If, for any reason, morphological verification of the diagnosis is not possible, treatment tactics may be determined based on the clinical and radiological picture by decision of a medical board.

Names of medical services according to the nomenclature are presented in Appendix A3 (Table A3-1. Terms describing procedures in the clinical guideline and possible (closest) terms from the current nomenclature of medical services).

2.1 Complaints and Anamnesis

The severity of clinical symptoms in lung cancer depends on the clinical and anatomical form of the neoplasm, its histological structure, localization, size and growth type of the tumor, the nature of metastasis, and concomitant inflammatory changes in the bronchi and lung tissue [1, 9].

Cough in central lung cancer is dry in most patients, sometimes hacking. With increasing bronchial obstruction, the cough may be accompanied by mucous or mucopurulent sputum.

Haemoptysis may manifest as streaks of bright red blood in the sputum or as diffusely stained sputum.

Dyspnoea is more pronounced the larger the lumen of the affected bronchus in central cancer, or its severity depends on the size of the peripheral tumor, i.e., the degree of compression of mediastinal anatomical structures, especially large venous trunks, bronchi, and trachea.

Chest pain of varying intensity on the affected side may be due to the localization of the neoplasm in the mantle zone of the lung, especially when the tumor invades the pleura and chest wall, as well as the presence of pleural effusion or atelectasis of the lung with signs of obstructive pneumonitis.

In the presence of peripheral superior sulcus (Pancoast) lung cancer, the symptom complex described by H. Pancoast in 1924 may be observed (pain in the shoulder joint and arm, forearm muscle atrophy, Horner syndrome). Radiological features of this form are considered to be the localization of the tumor node in the apex region, relatively rapid invasion of the pleura, destruction of the 1st and 2nd ribs, and sometimes the transverse processes of the vertebrae.

Superior vena cava syndrome (cyanosis, edema of the face, neck, upper extremities, prominent subcutaneous venous collaterals on the trunk) is most characteristic of the mediastinal form of lung cancer and small cell lung cancer, which is often accompanied by massive mediastinal lymph node involvement and, consequently, compression of the superior vena cava.

The listed symptoms and syndromes are not pathognomonic for lung cancer and may occur in non-neoplastic pulmonary and general somatic extrapulmonary pathologies. For instance, hemoptysis may be observed in pulmonary tuberculosis and decompensated cardiac pathology, dyspnea in chronic obstructive pulmonary disease, chest pain in inflammatory pleurisy, radiculitis, intercostal neuralgia, cough in colds, viral infections, tuberculosis, and suppurative pulmonary processes, while general intoxication symptoms are characteristic of a wide range of diseases.

Some patients present with paraneoplastic syndromes associated with hormone hypersecretion (syndromes of adrenocorticotropic, antidiuretic, parathyroid hormone, estrogen, and serotonin secretion).

Lung cancer may be accompanied by thrombophlebitis, various types of neuropathy and myopathy, distinctive dermatoses, disorders of fat and lipid metabolism, arthralgic, and rheumatoid-like conditions. It frequently manifests as hypertrophic osteoarthropathy (Pierre-Marie-Bamberger syndrome), characterized by thickening and sclerosis of the long tubular bones of the legs and forearms, the small tubular bones of the hands and feet, joint swelling (elbow, ankle), and clubbing of the terminal phalanges of the fingers (digital clubbing) [1]. In peripheral superior sulcus (Pancoast) tumors, Bernard-Horner syndrome (ptosis, miosis, enophthalmos) may develop in combination with pain in the shoulder joint and arm, progressive atrophy of the distal forearm muscles, resulting from direct tumor extension through the pleural dome to the brachial plexus, transverse processes and arches of the lower cervical vertebrae, as well as sympathetic nerves [2].

Asymptomatic development of the disease is possible, in which case it is an incidental radiological finding.

• When taking a medical history in all patients, it is recommended to pay attention to smoking history and the number of cigarettes smoked, occupational hazards (subcl. 1, Table A3-1) [1–3, 9].

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

2.2 Physical Examination

2.3 Laboratory Diagnostics

• If non-squamous (including dimorphic) non-small cell lung cancer is detected, it is recommended to perform molecular genetic and immunohistochemical (IHC) studies (on histological or cytological material) for activating mutations and PD-L1 expression, depending on the stage:

  • in stages I–III after radical surgical treatment, the "mandatory testing scope" includes determining mutations in exons 18–21 of the EGFR gene (molecular genetic testing for EGFR mutations in biopsy [surgical] material) and molecular genetic testing for ALK gene translocations (subcl. 7, Table A3-1);

  • in stage II–III, the "mandatory scope of testing" following radical surgical treatment includes the determination of PD-L1 protein expression by immunohistochemistry;

  • for unresectable stage III and stage IV – "mandatory scope of testing" [gene mutations EGFR exons 18–21 (molecular genetic testing for EGFR mutations in biopsy (surgical) material, or molecular genetic testing for EGFR mutations in cytologic specimens, or molecular genetic testing for EGFR mutations in blood by PCR), translocation ALK (molecular genetic testing for ALK gene translocations), translocation ROS1 (molecular genetic testing for ROS1 gene translocations) and mutations BRAF V600E (molecular genetic testing for BRAF gene mutations in biopsy (surgical) material); in the absence of the listed activating mutations, IHC – determination of protein expression PD-L1 by immunohistochemistry and "optional scope of testing" [translocations RET (molecular genetic testing for RET gene mutations in biopsy (surgical) material, molecular genetic testing for RET gene mutations in blood), mutations c-MET, exon 20 mutations HER2 (item 12, Table A3-1) (determination of HER2 gene amplification by fluorescence in situ hybridization (FISH)), mutations KRAS (molecular genetic testing for KRAS mutations in biopsy (surgical) material) and family gene translocations NTRK, determination of the sequence of insertions in exon 20 of the EGFR (molecular genetic testing for EGFR mutations in biopsy (surgical) material, or molecular genetic testing for EGFR mutations in cytologic specimens, or molecular genetic testing for EGFR mutations in blood by PCR)] [347].

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

Comments: several biomarkers have currently been identified that help isolate a subgroup of patients with a significant response to specific therapy. These biomarkers include: ALK, ROS1 gene translocations, EGFR (exons 18–21), BRAF V600E, determination of insertion sequences in exon 20 of the EGFR gene, and PD-L1 expression. Molecular genetic testing may also be justified in squamous cell carcinoma or when it is difficult (due to a small amount of material) to determine the histological subtype in non-smoking young patients [6,12].

Expanded molecular genetic testing may be useful not only for determining treatment tactics within the framework of standards, but also for enrolling the patient in clinical trials evaluating novel antitumor drugs, which can provide significant benefit to the patient compared to standard treatment. Molecular genetic and IHC testing may also be justified when it is difficult (due to scant material) to determine the histological subtype or in cases of squamous cell carcinoma in young non-smoking patients (<50 years). Given tumor heterogeneity and the emergence of new mutations during therapy upon progression, repeat biopsies are advisable in order to modify treatment tactics.

If necessary, NGS can be used as a method of molecular profiling for lung cancer to test for biomarkers, taking into account the current availability of targeted drugs and to individualize immunotherapy approaches.

To optimize the use of NGS, candidates for this type of testing should be considered patients with advanced non-squamous NSCLC with indications for systemic drug therapy [347].

• When non-squamous (including dimorphic) carcinoma is detected and molecular genetic testing is not feasible in biopsy (surgical) material (including cytologic material), it is recommended to test cell-free circulating tumor DNA from blood plasma to detect mutations in the EGFR gene (molecular genetic testing for EGFR mutations in blood by PCR) [11, 175].

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

Comments:testing of cell-free circulating tumor DNA from blood plasma (or "liquid biopsy") should not be performed instead of molecular genetic testing of biopsy material. Mutation testing using liquid biopsy is characterized by low sensitivity and high specificity due to the insignificant and unstable amount of circulating tumor DNA. According to studies, the probability of a false-negative result with liquid biopsy compared to traditional biopsy can be up to 30% [176,177,178,179]. Despite these limitations of liquid biopsy, molecular genetic testing for EGFR mutations in blood by PCR must be performed to detect EGFR mutations and determine the efficacy of targeted therapy in two cases: 1) in unresectable cancer when a tissue sample is unavailable for molecular genetic testing; 2) when it is impossible to perform molecular genetic testing on a tissue sample due to its low quality or quantity [176].

• When performing molecular genetic testing, it is recommended to analyze EGFR gene mutations (molecular genetic testing for EGFR gene mutations in biopsy (surgical) material, or molecular genetic testing for EGFR gene mutations in cytologic samples, or molecular genetic testing for EGFR gene mutations in blood by PCR) both for common genetic alterations (exon 19 deletions; p.L858R point mutation in exon 21) and for less common genetic alterations in exons 18–21 (in particular, exon 19 insertions, exon 20 insertions, as well as p.L861Q, p.G719X, and p.S768I point mutations) [180,181,182, 183,184].

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

Comments: genetic alterations associated with both potential efficacy of and resistance to EGFR tyrosine kinase inhibitors have been described in the EGFR gene. When using next-generation sequencing, additional EGFR gene mutations may be detected, the significance of which for prescribing targeted therapy may be uncertain. Thus, the results of molecular genetic testing for EGFR gene mutations must include information on the specific genetic alteration detected.

• Further treatment strategy should be determined at a multidisciplinary team meeting.

Comments: Tumor mutational burden is a relative indicator of the total number of mutational events that occurred in the tumor tissue and, in some cases, is regarded as correlating with the emergence of neoantigens capable of activating an antitumor immune response [229]. A high mutational burden is frequently recorded in smoking-associated NSCLC.

Preliminary data from CheckMate 227 (a phase 3 randomized study of the combination regimen of nivolumab** + #ipilimumab**) suggested that tumor mutational burden may be a valid marker of tumor sensitivity to immuno-oncology therapy [210]. However, the final analysis showed that the efficacy of this therapy does not depend on the level of mutational burden, the level of PD-L1 expression, or the combination of these markers. Overall survival resulting from the combination of nivolumab** and #ipilimumab** was improved in all patients with NSCLC [219].

The KEYNOTE-158 study (a phase 2 study on the efficacy of pembrolizumab** in second-line therapy) defined tumor mutational burden as a marker of efficacy for immuno-oncology drugs in a number of malignancies, but not in NSCLC [230]. Moreover, major obstacles to using tumor mutational burden as a valid marker include the lack of standardization of assay methods and discrepancies in the cutoff values distinguishing low and high mutational burden across various studies [231].

Thus, at present, tumor mutational burden cannot be used as a marker of sensitivity to immuno-oncology therapy in NSCLC.

2.4 Instrumental Diagnostics

2.4.1. Imaging

Comments: CT is the primary imaging modality for assessing abnormalities detected on radiography. Chest CT can reveal changes not visible on plain radiographs that are critical for determining the management strategy in patients with lung cancer. When abnormalities are localized in the mediastinum and lung roots, and when differential diagnosis of the detected changes is required, it is advisable to use contrast-enhanced chest CT with intravenous bolus injection.

In centrally located tumors, CT allows detection of bronchial changes prior to the development of pneumonia and obstructive atelectasis. Compared to bronchoscopy, the accuracy of CT is higher for peribronchially located lesions and lower for superficial endobronchial tumors.

A peripheral tumor may present as a solitary nodule of varying density, a cavity of destruction, or an area of non-rounded infiltration (pneumonia-like cancer). Less commonly, at the initial diagnosis stage, a tumor is detected that invades the chest wall (corticopleural form), mediastinum (mediastinal form), thoracic inlet (Pancoast tumor), or presents as focal dissemination in the lung.

Depending on its density, a peripheral cancer nodule can be of solid type, part-solid type, or a ground-glass opacity nodule. A solid nodule frequently has lobulated and/or spiculated margins, the walls of the draining bronchus are thickened, and the visceral pleura is retracted into the tumor and locally thickened.

Contrast enhancement within the tumor (on dynamic CT) can be useful for differential diagnosis with benign granulomas (tuberculoma).

PET as a diagnostic method for solid nodules is viewed ambiguously, especially in countries with a high tuberculosis burden. A ground-glass opacity nodule is characteristic of adenocarcinoma with lepidic growth, including adenocarcinoma in situ. Ground-glass opacity nodules grow more slowly than solid nodules. On 18F-fluorodeoxyglucose ([18F]FDG) PET/CT (positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals), such nodules are characterized by a low level of isotope uptake. A subsolid nodule has a central solid component and a peripheral ground-glass zone. The solid part of the nodule is associated with invasive growth and is important for determining prognosis and assessing the T-stage of tumor growth.

1. To assess the primary tumor in the chest cavity, contrast-enhanced chest CT with intravenous bolus injection from above the thoracic inlet to the level of the costophrenic sinuses (including the liver and adrenal glands) [197, 198, 199];

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

Comment: if chest CT cannot be performed (equipment failure, etc.) or if intravenous contrast cannot be administered (history of severe allergic reaction to iodine-containing radiopaque agents, absence of an automatic injector, etc.), chest MRI (or contrast-enhanced magnetic resonance imaging of the chest) may be performed if equipment and trained specialists are available.

2. To assess regional lymph nodes (N) and detect distant metastases (M), a whole-body combined PET/CT scan (item 17, Table A3-1) [198, 200, 201].

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

Comments:combined 18F-FDG PET/CT(positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals, including contrast-enhanced) overall is a more effective examination compared to ultrasound, CT, and MRI (comprehensive ultrasound examination of the abdominal organs, ultrasound examination of the retroperitoneal space, ultrasound examination of lymph nodes, computed tomography of the chest organs, computed tomography of the abdominal organs and retroperitoneal space with intravenous bolus contrast enhancement, magnetic resonance imaging of the abdominal organs with intravenous contrast enhancement, magnetic resonance imaging of the retroperitoneal space) in detecting the extent of the tumor process, including detecting metastases in lymph nodes, solid organs, bones and bone marrow, and serous membranes. The use of 18F-FDG PET/CT allows the stage of the tumor to be modified in 1/3 of patients process. Combined 18F-FDG PET-CT does not reliably detect metastases in the brain, which necessitates the use of MRI or CT with intravenous contrast enhancement (computed tomography of the brain with intravenous contrast enhancement, magnetic resonance imaging of the brain with contrast enhancement). If 18F-FDG PET-CT cannot be performed, this examination can be replaced by CT with intravenous contrast enhancement of the abdomen and pelvis (computed tomography of the abdomen and retroperitoneal space with intravenous bolus contrast enhancement, spiral computed tomography of the pelvic organs in women with intravenous bolus contrast enhancement, spiral computed tomography of the pelvic organs in men with intravenous bolus contrast enhancement) combined with bone scintigraphy (SPECT/CT) (whole-body bone scintigraphy, single-photon emission computed tomography combined with whole-body bone computed tomography).

3. To detect lung cancer brain metastases, brain MRI with contrast enhancement is performed [391].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: intravenous contrast enhancement reliably increases the sensitivity of the method in detecting brain metastasis lesions, especially small ones. If MRI cannot be performed, the examination can be replaced by brain CT with intravenous contrast enhancement.

Comments: a number of prospective randomized trials have demonstrated that the use of low-dose computed tomography (LDCT) in lung cancer risk groups once a year reduces mortality from this disease in the population by 20% or more [200–202]. Risk groups include patients aged 55–80 years who are current smokers (with a smoking history of at least 30 pack-years) or who have quit smoking no more than 15 years ago.

The lung cancer screening program includes three main stages: 1) organizational and methodological (informing the population, identifying risk groups, drawing up a schedule of examinations, maintaining a card index, etc.); 2) diagnostic (administering the diagnostic test in accordance with international and domestic guidelines and standards, taking into account regional features of the healthcare system); 3) oncological (the possibility of further examination or follow-up of patients with lung pathology detected by LDCT in a specialized oncological care setting).

The feasibility of implementing an LDCT lung cancer screening program is determined by the regional capabilities of the healthcare system, including technological, organizational, geographical, economic, and other factors. In the presence of limited resources, the implementation of such screening is inappropriate.

Population-based lung cancer screening using LDCT should not be used for patients without proven risk factors, in particular individuals over 80 and under 55 years of age, with lower smoking intensity, as well as with chronic lung diseases (chronic obstructive pulmonary disease, interstitial lung diseases, occupational diseases, chronic infections, in particular tuberculosis, etc.), since the efficacy of screening for these population groups has not been proven.

Chest radiography should not be performed for population-based lung cancer screening, because conducted prospective randomized trials have not revealed a significant reduction in lung cancer mortality using this method. At the same time, chest radiography remains the primary method for initial detection of lung cancer during diagnostic examinations performed for clinical indications.

Comments: bronchoscopy is considered one of the core and mandatory methods for lung cancer diagnosis. It allows not only visual examination of the larynx, trachea, and all bronchi, direct visualization of the tumor location and determination of the extent of its spread, indirect assessment of the enlargement of root and mediastinal lymph nodes, but also biopsy for histological examination (tracheal and bronchial biopsy during bronchoscopy, lung biopsy during bronchoscopy), and collection of material (brush biopsy specimens, smear-imprints, scrapings, or washings from the bronchial tree) for cytological evaluation (cytological examination of tracheal and bronchial tissue micro preparations, cytological examination of lung tissue micro preparations, cytological examination of lower respiratory tract tissue micro preparations), i.e., morphological confirmation of the diagnosis and determination of the histological structure of the tumor.

In recent years, diagnostic devices combining the capabilities of X-ray endoscopy, endosonography, and fluorescence endoscopy (ultrasonic endoscopic center, flexible videobronchoscope, flexible endoscopes for upper respiratory tract examination, etc.) have been increasingly used. Autofluorescence bronchoscopy, which is based on the autofluorescence effect and records the concentration of endogenous photosensitizers in the tumor, is considered the most promising method for detecting occult microfoci of mucosal cancer [1, 2].

• Transbronchial or transesophageal needle aspiration (EBUS/EUS) (transesophageal mediastinal endosonography), mediastinoscopy, or thoracoscopy [8, 9] are recommended for patients with suspected metastatic lesions in mediastinal lymph nodes (N2-3) to assess the extent of the disease. EBUS and EUS techniques can also be used to verify primary peripheral paramediastinal neoplasms.

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

Diagnostic video-assisted thoracoscopy (A03.10.001 – thoracoscopy) is performed:

• in the absence of results from bronchological and/or other studies to obtain morphological material from mediastinal lymph nodes or the primary tumor in inoperable patients;

• for the differential diagnosis of mediastinal lung cancer and anterior mediastinal tumors (in case of uninformative transthoracic biopsy); o for exudative pleurisy of unclear etiology;

• for lung cancer staging;

• for tumor metastases in the lung and pleura (when minimally invasive diagnostic methods are not feasible).

Comments: following intraoperative thoracoscopic revision and urgent pathomorphological examination of the biopsy (surgical) material, depending on the clinical situation, the surgery is completed by resection of an adequate volume of lung tissue, and in the case of a malignant process, it is supplemented by mediastinal lymphadenectomy.

• All patients with suspected lung cancer are recommended to undergo abdominal ultrasound (comprehensive) or abdominal CT with intravenous bolus contrast enhancement to stage the extent of the disease [8, 9].

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

• Patients with a confirmed diagnosis of stage II-III lung cancer are recommended to undergo bone scintigraphy (whole-body bone scan) to assess disease dissemination and monitor treatment efficacy, unless whole-body 18F-FDG PET-CT has been performed [11, 12].

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

2.5 Other Procedures

Comments:in approximately 70% of cases, the morphological diagnosis in patients with unresectable or metastatic lung cancer is established based on the examination of cytological or biopsy material. The main objectives of examining small diagnostic material are: a) to determine the most accurate possible nosological affiliation of the tumor in accordance with the 2021 WHO classification, and b) to preserve tissue for molecular genetic testing, especially in patients with advanced stages of the disease. In the case of poorly differentiated tumors, the volume of material may be insufficient for an accurate determination of the histological type of lung cancer even with the use of ICC/IHC. Therefore, in the absence of morphological signs of neuroendocrine differentiation, the optimal panel for ICC/IHC is a two-marker panel: TTF1 and p63 (or p40) [WHO, IASLC]. This will help minimize the number of block sectionings and preserve biomaterial for molecular genetic testing. In the presence of morphological signs of neuroendocrine differentiation when performing ICC/IHC, one may use antibodies to CD56, synaptophysin, or chromogranin A. Wider panels of antibodies should be used if the histogenesis of the tumor is unclear or a metastatic nature of the lung lesion is suspected.

Comments: when examining small diagnostic material, the probability of incorrect determination of the tumor histological type is higher than when examining surgical material. Therefore, the following diagnostic formulations are acceptable: "poorly differentiated carcinoma, likely adenocarcinoma", "poorly differentiated carcinoma, likely squamous cell carcinoma", "poorly differentiated carcinoma without reliable signs of neuroendocrine and squamous differentiation". Also, when examining a small volume of biopsy material, one should not indicate the following histological types of lung cancer under the pathomorphological diagnosis heading: adenocarcinoma in situ, minimally invasive adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, carcinosarcoma, sarcomatoid (spindle cell) carcinoma, giant cell carcinoma [WHO].

Comments: upon repeat biopsy of tumors or tumor-like soft tissue formations in the setting of progression or the appearance of new lesions, its histological structure type should be compared with the tumor in the primary biopsy material obtained for diagnosis verification. Since the priority study on repeat biopsy material is molecular genetic testing to determine resistance mechanisms to the administered therapy, ICC/IHC is performed only in the event of morphological transformation of the tumor—for example, in the case of transformation of adenocarcinoma into neuroendocrine carcinoma.

Comments: the histological type of lung cancer should be indicated in accordance with the 2021 WHO classification (see Table 1, ICD Coding). Histological grade is not validated for squamous cell carcinoma, has very limited prognostic value for adenocarcinoma, but must be indicated for neuroendocrine tumors of the lung.

For patients who received neoadjuvant chemotherapy and/or radiation therapy prior to surgical treatment, quantitative assessment of the degree of morphological tumor regression should be performed. The proportion of viable tumor cells relative to the entire tumor bed should be calculated. The threshold value for major morphological regression is <10% viable tumor cells.

If two or more primary lung cancer nodules are identified, the details of items 1–8 and 12–13 should be reported for each nodule.

Comment: various antibody clones have been developed for PD-L1 testing by IHC. Some of them are comparable in intensity and the proportion of stained cells, while others are not. However, at high levels of PD-L1 expression, test results with antibodies 22C3, SP263, and SP142 are comparable in a large percentage of cases and these tests are interchangeable. Positivity criteria depend on the antibody used and the staining platform. For tests using clones 22C3 and SP263, the percentage of positive tumor cells should be reported. For the test using clone SP142, both the percentage of positive tumor cells and the percentage of positive immune cells should be reported. The simultaneous use of multiple IHC tests is generally discouraged. The immunohistochemistry report should specify which test was performed and the criteria used to evaluate PD-L1 expression.

Currently, there is limited evidence to support determining tumor PD-L1 status by ICC.

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

3.1. Treatment of patients with non-small cell lung cancer

Surgery is one of the main treatment methods for stages I-II and partially stage III NSCLC. The scope of surgery is determined by the extent of the tumor process, the histological type of the tumor, and the patient's functional status.

Surgery is the primary treatment for carcinoid tumors. Carcinoid tumors, especially their typical forms, are characterized by less aggressive local infiltrative growth and distant metastasis compared to other (more common) forms of NSCLC – squamous cell carcinoma and adenocarcinoma. Carcinoids most frequently develop in large bronchi of the 1st, 2nd, and 3rd order and are characterized predominantly by exophytic, intraluminal growth without tumor invasion through the bronchial wall, which often makes it possible to perform an organ-sparing radical operation in the volume of lobectomy or bilobectomy using resection and reconstruction of the bronchi and trachea, or isolated radical resection of the bronchi, trachea, and its bifurcation with preservation of the function of the entire lung (A16.09.018.001. Bronchial plastics. Reconstructive operations on the trachea and bronchi). When a routine histological report of a typical neuroendocrine tumor is obtained after diagnostic wedge resection of the lung with total tumor removal and a histologically confirmed negative resection margin (R0) in patients with limited functional reserves, the volume of resection performed should be considered sufficient. Endoscopic or endobronchial removal of carcinoid tumors can be performed in patients without tumor invasion through the entire bronchial wall, in whom for various reasons radical open or thoracoscopic resection of the lung and bronchus cannot be performed. Preoperative evaluation often makes it difficult to determine the true depth of bronchial wall involvement by the tumor [14,17].

3.1.1. Principles of treatment for patients with stage 0–IIIA disease

Patients with stages 0-IIIA NSCLC and stage IIIB (T3N2) are potentially operable (if an R0 resection is feasible), taking into account functional parameters [1, 2].

• Patients with stages 0-IIIA NSCLC are recommended surgical treatment to improve survival, provided that the requirements for radical surgery (R0 resection) and functional operability are met. When planning a pneumonectomy, potential treatment options should be discussed at a multidisciplinary team meeting involving the patient, among others [7,12].

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

Comments: the standard scope of surgery includes anatomical lung resection (segmentectomy, lobectomy/bilobectomy, or pneumonectomy) with ipsilateral systematic mediastinal lymph node dissection (removal of at least 6 lymph nodes: at least 3 root or bronchopulmonary, at least 3 mediastinal from 3 different groups (including at least 1 lymph node from the subcarinal group))

Surgical treatment may be offered to patients with T3 (satellite tumor in the same lobe)

Surgical treatment may be considered as a possible option for patients with T4 (satellite tumor in a different lobe).

Thoracoscopic surgery for clinical stage I NSCLC can be considered as a standard surgical treatment option alongside conventional open procedures [15-20].

Thoracoscopic surgery for stage II disease is optimally performed only in medical centers with extensive experience in such surgical interventions.

• For high-risk patients with stage IB (visceral pleural involvement, vascular invasion, poor differentiation, wedge resection, Nx, age under 75 years), adjuvant chemotherapy (CT) is recommended to improve overall survival [20].

GOM ALOE 1Level of Evidence – A (Level of Data Reliability – 1)

• For patients with cT1-2N0 disease extent in whom surgery is contraindicated or refused by the patient, stereotactic ablative radiotherapy (SABR) (A07.30.009.001 conformal external beam radiotherapy, including IMRT, IGRT, VMAT, stereotactic) on a radical program (high-dose irradiation) using high doses per fraction (fraction dose 10-18 Gy, total dose 50-54 Gy) is recommended to improve the survival of these patients [11,24].

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

• In the absence of morphological verification, the decision to perform stereotactic radiotherapy in this category of patients can be made by an expanded medical board of the organization based on the dynamics of imaging data (CT or PET-CT). Biopsy confirmation prior to SBRT is strongly recommended, but is not mandatory if the procedure is associated with a high risk of complications.

Possible fractionation regimens:

• 7.5 Gy in 8 fractions for ultracentral tumors*

• 12 Gy in 5 fractions for central tumors

• 20 Gy in 3 fractions for peripheral tumors

* When irradiating ultracentral tumors (planned target volume abuts or overlaps the proximal bronchial tree, esophagus, or trachea), it is advisable to use a standard fractionation scheme [7, 12, 19, 32].

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

Comment: treatment is performed using respiratory gating techniques.

• Patients with stage II NSCLC are recommended adjuvant systemic antineoplastic therapy to improve survival outcomes (see Table 3). Preoperative antineoplastic therapy is not recommended for this group of patients due to the lack of evidence of its impact on survival [20–23].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: for adjuvant systemic antineoplastic therapy regimens, see Table 3.

• For patients with stage II NSCLC in whom surgery is not feasible, CT, RT, or CRT is recommended to improve survival [7, 12, 19].

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

• Neoadjuvant systemic therapy (2–4 cycles) is recommended for operable patients with stage IIIA (with N2 lymph node status) and operable stage IIIB (T3N2) confirmed by pathological examination of biopsy (surgical) material or PET/CT, as part of combined modality treatment [294].

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

Patients who are candidates for neoadjuvant systemic therapy (operable patients with stage IIIA (with N2 lymph node status) and operable stage IIIB (T3N2) confirmed by pathological examination of biopsy or surgical material, or PET-CT, with PD-L1 expression >1% at initial diagnosis) are indicated for neoadjuvant chemotherapy combined with immune checkpoint inhibitors (ICIs, L01F Monoclonal antibodies and antibody-drug conjugates): #nivolumab** 360 mg every 3 weeks [334], or #pembrolizumab** 200 mg every 3 weeks, or #durvalumab** 1500 mg every 3 weeks [347] (for patients with borderline resectable stages) + platinum-based CT regimens (for neoadjuvant systemic therapy regimens, see Table 2). Contraindications to ICIs may include active or previously documented autoimmune disorders, immunosuppressive therapy, or driver mutations associated with less benefit from immunotherapy (EGFR mutations, ALK translocations).

Table 2. Recommended combined neoadjuvant systemic therapy regimens for non-small cell lung cancer

** Vital and Essential Drugs;

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages approved in the package leaflet).

Note: the actual dose of carboplatin** is calculated individually based on the patient's blood creatinine levels measured prior to treatment.

• Adjuvant chemotherapy, in the absence of contraindications, is recommended for patients in all N+ cases to improve overall survival [2].

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

• Radiotherapy is recommended for patients with NSCLC after non-radical surgery (R+) as it reduces the risk of recurrence in these patients [7].

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

Relative indications for postoperative radiotherapy in patients with NSCLC may include:

• extracapsular extension in N2;

• involvement of the highest resected lymph node (potentially non-radical resection);

• inadequate lymphadenectomy and/or N2 with tumor extension beyond the capsule: chemoradiotherapy (sequential regimen) up to 54 Gy with standard fractionation is recommended to improve locoregional control [11].

Postoperative radiotherapy does not affect overall survival in NSCLC patients.

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

Table 3. Recommended regimens for adjuvant drug therapy, including perioperative treatment regimens

• Following the completion of 1–4 cycles of platinum-based chemotherapy, patients with positive PD-L1 expression in ≥50% of tumor cells without activating mutations in EGFR, ALK genes are recommended maintenance immunotherapy with atezolizumab** (if neoadjuvant therapy including immunotherapy was not administered) [240].

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

• In patients with stage Ib–IIIA with detected activating EGFR mutations (exon 19 deletions; p.L858R point mutation in exon 21), adjuvant targeted therapy with the 3rd-generation epidermal growth factor receptor inhibitor osimertinib** (L01E protein kinase inhibitors) for 3 years is recommended to improve disease-free and overall survival in these patients. Targeted therapy may be initiated after adjuvant chemotherapy (up to 26 weeks after surgery) or instead of adjuvant chemotherapy (up to 10 weeks after surgery) [204].

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

• In patients with stage Ib–IIIA with identified ALK translocation, adjuvant therapy with alectinib** 600 mg twice daily for 2 years improved disease-free survival rates [239]. For initially unresectable tumors in patients with a good general condition (0–1 score on the ECOG scale, Appendix G3) at stage IIIA, concurrent chemoradiotherapy is recommended as the 1st stage; in patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 2, sequential use of the 2 methods is preferable to improve survival in these patients [2]. Recommended approaches to chemoradiotherapy and patient management after completion of chemoradiotherapy are described in Section 3.1.2.

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

• In patients with stage IIIA disease following the completion of concurrent chemoradiotherapy who have no signs of disease progression (follow-up CT [computed tomography of the chest organs with intravenous bolus contrast enhancement, computed tomography of the abdominal organs and retroperitoneum with intravenous bolus contrast enhancement] should preferably be performed immediately after the end of chemoradiotherapy), without activating mutations in the EGFR/ALK genes and with a PD-L1 expression level greater than 1%, maintenance immunotherapy with durvalumab** is recommended. With the initiation of the maintenance phase no later than 60 days from the end of radiotherapy to improve progression-free survival and overall survival in these patients. The drug is prescribed at a dose of 10 mg/kg as a 60-minute intravenous infusion every 2 weeks, or at a dose of 1500 mg once every 4 weeks for at least 12 months, or until disease progression, or until the development of unacceptable toxicity [40, 42].

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

3.1.2. Principles of treatment for patients with stage IIIB–IIIC disease

• For patients with stage IIIB–IIIC NSCLC at stage 1, it is recommended to administer concurrent chemoradiotherapy to achieve remission and increase survival [23,35]. The most critical goals of modern radiotherapy are to achieve maximum tumor control and minimize treatment toxicity. The minimum technological standard is 3D-CRT.

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: Stages IIIB and IIIC are unresectable; stage IIIB (T3N2) is potentially resectable (provided an R0 resection is feasible), and concurrent (preferred) or sequential CRT is recommended as the primary treatment modality for this category of patients. The planned total radiation dose (TRD) within CRT should be 60 Gy (± 10%) over 6 weeks (treatment breaks reduce efficacy); recommended CT regimens for concurrent CRT are presented in Table 4. CT regimens include platinum compounds: cisplatin** or carboplatin** if cisplatin** is contraindicated.

Concurrent chemoradiotherapy yields superior outcomes compared to sequential therapy in patients with unresectable stage III NSCLC; however, it is more toxic and is prescribed only to patients in a satisfactory general condition (ECOG performance status 0–1). In debilitated patients (ECOG performance status 2), sequential chemotherapy and radiotherapy is advisable. The management strategy is determined individually by a multidisciplinary tumor board.

The most critical goals of modern radiotherapy are to maximize tumor control and minimize treatment toxicity. The minimum technological standard is 3D-CRT.

More advanced technologies are appropriate when necessary to safely deliver the radiation dose. These technologies include (but are not limited to) 4D-CT and/or PET-CT, IMRT, VMAT, IGRT (conformal external beam radiotherapy, including IMRT, IGRT, VMAT, stereotactic), and respiratory gating.

Randomized trials of currently used radiotherapy technologies demonstrate reduced toxicity and improved survival compared to older methods. In a prospective trial of radical chemoradiotherapy programs for patients with stage III NSCLC (RTOG 0617), IMRT was associated with an almost 60% reduction (from 7.9% to 3.5%) in the incidence of radiation pneumonitis, as well as similar improvements in survival and tumor control compared to 3D-CRT.

External beam radiotherapy of the primary tumor and affected lymph nodes: radiotherapy with IMRT, VMAT, IGRT, respiratory gating (minimum required standards: 3D conformal radiotherapy), fractional dose (FD) 2 Gy, total dose (TD) 60 Gy ± 10% (CT, PET).

Induction chemotherapy is not advisable, as this approach fails to provide efficacy advantages over standard chemoradiotherapy. Induction chemotherapy should be considered in cases of large tumor volumes and the impossibility of achieving the planned irradiation volumes. Consolidation chemotherapy after chemoradiotherapy is not indicated due to the lack of progression-free survival (PFS) benefits. The chemotherapy regimens used in combination with radiotherapy are listed in Table 4.

Table 4. Chemotherapy regimens commonly used in the treatment of stages IIIA, IIIB, and IIIC NSCLC in combination with radiotherapy

Note: the actual dose of carboplatin** is calculated individually based on the patient's blood creatinine level on the eve of treatment.

• Upon completion of concurrent or sequential chemoradiotherapy, in patients with no signs of disease progression (follow-up chest CT and abdominal ultrasound (comprehensive), with other additional tests performed as indicated immediately after completion of chemoradiotherapy) and no contraindications to immunotherapy, without activating EGFR/ALK mutations and with a PD-L1 expression level > 1%, it is recommended to administer immunotherapy with durvalumab**. The maintenance phase should be initiated no later than 60 days** regardless of the completion date of radiotherapy or the level of PD-L1 expression [42].

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

Comments: The drug is prescribed at a dose of 10 mg/kg as a 60-minute IV infusion every 2 weeks or at a dose of 1500 mg as a 60-minute IV infusion every 4 weeks for at least 12 months or until disease progression or unacceptable toxicity. Maintenance therapy with durvalumab** in patients with driver mutations in EGFR or ALK genes may be associated with lower efficacy [42].

• In patients with activating mutations in the EGFR gene (exon 19 deletion and L858R mutation), it is recommended that osimertinib** maintenance therapy (80 mg orally once daily until disease progression or unacceptable toxicity) following cCRT improves progression-free survival [241, 345].

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

Patients with unresectable locoregional recurrence after radical surgical treatment may undergo cCRT. It is possible to administer 3–4 cycles of chemotherapy prior to radiotherapy, or 2–4 cycles of chemotherapy concurrently with radiotherapy. Following the completion of radiotherapy, in the absence of signs of disease progression, consolidation immunotherapy with durvalumab** for 12 months should be considered. To achieve maximum efficacy and safety of combined treatment (cCRT + immunotherapy), multidisciplinary planning of the treatment strategy for stage III NSCLC patients, continuity of care between specialists, and minimization of the time interval between the completion of cCRT and the initiation of immunotherapy are crucial.

• If there are contraindications to cCRT, it is recommended to administer systemic drug therapy (see section 3.1.3.1), including targeted therapy and immunotherapy. If chemotherapy is contraindicated, monotherapy with radiotherapy may be considered [317].

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

3.1.3. Principles of treatment for patients with stage IV disease

• For patients with stage IV disease, it is recommended to prescribe treatment taking into account predictive and prognostic factors [43, 44].

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

Comments: first-line platinum-based combination chemotherapy regimens for stage IV non-small cell lung cancer are presented in Table 5.

• Upon detection of activating EGFR gene mutations (exons 18–21) or ALK, ROS1 translocations, or BRAF V600E mutation, targeted therapy is recommended [43–51] (see 3.1.3.4).

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

• In the absence of driver molecular-genetic alterations, chemotherapy, chemoimmunotherapy, or immunotherapy is recommended depending on a number of clinical and laboratory parameters, in some cases taking into account the level of PD-L1 expression by tumor cells (see 3.1.3.1 First-line chemotherapy) [12].

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

3.1.3.1. First-line chemotherapy

Recommendations for the use of active first-line platinum-based combination chemotherapy regimens for the treatment of patients with stage IV NSCLC (Table 5) are presented below.

Table 5. Active first-line platinum-based combination chemotherapy regimens for stage IV non-small cell lung cancer

** Vital and Essential Drugs;

# – off-label drug use (used outside the scope of indications, contraindications, routes of administration, or dosages specified in the official product labeling).

Note: the actual dose of carboplatin** is calculated individually based on the blood creatinine level measured prior to treatment.

Abbreviations: i.v. – intravenous, AUC – area under the pharmacological curve.

Comment: in a meta-analysis, the combination of cisplatin** and pemetrexed** in patients with non-squamous NSCLC showed a benefit compared to the combination with gemcitabine** [60].

• All patients with stage IV NSCLC without activating mutations and performance status of 0-2 on the ECOG scale (see Appendix G3), in the absence of contraindications, are recommended to receive combination platinum-based chemotherapy [62–64].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: regimens are presented in Table 5. 4 cycles of chemotherapy are appropriate if tumor growth is controlled (stable disease, complete, or partial response); the number of cycles may be increased to 6 in case of a growing objective response and satisfactory tolerability [65]. In non- squamous lung cancer, in the absence of signs of disease progression after 4–6 cycles of treatment, maintenance therapy with pemetrexed**, bevacizumab**, or their combination is possible if these drugs were part of the first-line treatment regimen. To monitor treatment efficacy, objective imaging examinations (CT, radiography, MRI, PET-CT, skeletal scintigraphy) should be performed before treatment, after every 2 cycles of chemotherapy at approximately 2 weeks from day 1 of even-numbered cycles, and then every 6–12 weeks as clinically indicated. It is advisable to use the same assessment method as before treatment.

• It is recommended to consider monochemotherapy (vinorelbine**, gemcitabine**, etoposide**, pemetrexed**) for patients with an ECOG performance status of 2 (see Appendix G3) as a minimum treatment option.

• etoposide** 50 mg/m² orally for 14–21 days with cycles repeated every 28 days [54; 273, 297];

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

• vinorelbine** (oral or intravenous administration), pemetrexed** (for non-squamous NSCLC), taxanes, gemcitabine** [67–69].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: for regimens see Table 6.

• monotherapy with pembrolizumab** at a PD-L1 expression level >50% [78],

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

• In case of chemotherapy intolerance and PD-L1 expression >1%, pembrolizumab** may be recommended [242].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• In case of chemotherapy intolerance and ECOG 2, regardless of the PD-L1 expression level, atezolizumab** may be recommended [242]

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Table 6. Treatment regimens for patients with an ECOG performance status of 2

Abbreviations: IV – intravenous, NSCLC – non-small cell lung cancer.

** Vital and Essential Drugs.

3.1.3.2. Immunotherapy

Immunotherapy is an effective type of systemic drug therapy for NSCLC and includes checkpoint inhibitors (L01X Other antineoplastic agents). Immune checkpoint inhibitors targeting PD-1 (nivolumab**, pembrolizumab**, proлгоliimab**), PD-L1 ligand (atezolizumab**, durvalumab**), and CTLA-4 (#ipilimumab**) are used in NSCLC.

Recommendations for the use of drug regimens prescribed as part of immunotherapy and chemotherapy for the treatment of patients with NSCLC (Table 7) are presented below.

Table 7. Immuno- and immunochemotherapy in the first-line treatment of non-small cell lung cancer.

** Vital and Essential Drugs;

# – drug used off-label, contrary to the indications, contraindications, routes of administration, and dosages contained in the medication's package leaflet.

Notes: the actual dose of carboplatin** is calculated individually based on the creatinine level in the patient's blood test performed on the eve of treatment).

Abbreviations: IV – intravenous, AUC – area under the concentration-time curve.

Immunotherapy can be used either in combination with cytostatic drugs (L01BA Folic acid analogues, L01CD Taxanes, L01XA Platinum compounds) or as monotherapy. The use of immunotherapy is advisable in patients without activating EGFR, BRAF mutations or ALK, ROS1 translocations.

Comment: the use of immunotherapy can be considered most effective only in patients with a high (≥50% of tumor cells) or ultra-high (≥90% of tumor cells) PD-L1 expression level. In other groups (1-49%, <1%), the number of responsive patients is small, and there are currently no criteria to identify such patients prior to treatment, therefore immunotherapy is advisable in combination with chemotherapy, which, however, does not lead to a critical improvement in outcomes for the group of patients with absent PD-L1 expression [246- 253].

In patients with PD-L1 expression in ≥50% of tumor cells, the addition of checkpoint inhibitor therapy (other antineoplastic agents) is highly desirable. With high (≥50%) and especially ultra-high PD-L1 expression (≥90%), a history of smoking, a low tumor burden, and the absence of prominent symptoms related to the tumor process, immunotherapy can be used without the cytostatic component – pembrolizumab** [246, 251], atezolizumab** [247, 248, 253].

In case of chemotherapy intolerance, as first-line immunotherapy for advanced NSCLC with PD-L1 expression in ≥1% of tumor cells in the absence of activating mutations in EGFR, BRAF genes and ALK/ROS1 translocations, anti-PD-1 mAb (monoclonal antibodies) therapy with pembrolizumab** 200 mg IV over 30 min every 3 weeks or 400 mg IV over 30 min every 6 weeks may be administered.

In case of chemotherapy intolerance in frail patients (ECOG 2), atezolizumab** monotherapy may also be used regardless of PD-L1 status [242].

If PD-L1 expression is >50%, with a high tumor burden and pronounced disease symptoms, it is preferable to consider chemoimmunotherapy due to a higher immediate response rate [243, 244].

Comment: pembrolizumab** is prescribed at a dose of 200 mg IV, administered over 30 min every 3 weeks or pembrolizumab** 400 mg every 6 weeks, administered intravenously as a 30-minute infusion [77, 221]; atezolizumab** is prescribed at one of the following doses [90, 215–217, 218]: 1200 mg IV every 3 weeks, 840 mg IV every 2 weeks, or 1680 mg IV every 4 weeks [219].

It is possible to use the subcutaneous formulation of atezolizumab at a dose of 1875 mg/15 ml (regardless of the patient's body weight) once every 3 weeks. The pharmacokinetic profile, clinical efficacy, and safety of subcutaneous administration of atezolizumab** at a dose of 1875 mg are equivalent to standard intravenous administration of atezolizumab** at a dose of 1200 mg [286].

None of the regimens demonstrated superiority over other options; therefore, the choice may be made taking into account organizational, financial, economic, or other factors.

In the event of a risk of rapid clinical deterioration with an insufficiently deep or rapid tumor response to treatment in patients with high PD-L1 expression levels and in patients with moderate or negative expression levels, it is advisable to use a combination of checkpoint inhibitors and platinum-based cytostatic doublets (checkpoint inhibitors: L01F monoclonal antibodies and antibody-drug conjugates, L01BA folic acid analogues, L01CD taxanes, L01XA platinum compounds). The optimal choice of combination cytostatic partners depends on the histological type of the tumor.

• It is recommended to combine IT with chemotherapy in patients with advanced nonsquamous NSCLC using one of two regimens:

  pembrolizumab** 200 mg + pemetrexed** 500 mg/m² + cisplatin** 75 mg/m² (in case of cisplatin intolerance – #pemetrexed** 500 mg/m² + carboplatin** AUC 5, the actual dose of which is calculated individually based on the creatinine level in the patient's blood test on the eve of treatment): IV infusion every 3 weeks, 4 cycles; followed by maintenance therapy with pembrolizumab** and pemetrexed** until disease progression or development of intolerable toxicity (only in nonsquamous NSCLC without activating mutations) [83, 246, 250];

  atezolizumab** 1200 mg (subcutaneous formulation of atezolizumab** at a dose of 1875 mg/15 ml [regardless of the patient's body weight] q3w may be used [286]) + #paclitaxel** 200 mg/m² (for East Asian patients – 175 mg/m²) + carboplatin** AUC 6 + bevacizumab** 15 mg/kg IV infusion on day 1 every 3 weeks, 4 cycles; followed by maintenance therapy with atezolizumab** and bevacizumab** at previous doses until disease progression or unacceptable toxicity (only in non-squamous NSCLC). Prior to initiating this combination, patients with confirmed EGFR or ALK gene mutations must have received targeted therapy [248]. PD-L1-positive patients derive greater benefit from immunotherapy, according to clinical trials.

• dual IT (#nivolumab** 3 mg/kg infusion q2w + #ipilimumab** 1 mg/kg IV infusion q6w until disease progression or unacceptable toxicity for a maximum of 2 years) and/or dual IT (nivolumab** + #ipilimumab**) combined with two cycles of CT [219, 220, 253].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comment: selection of bevacizumab-containing regimens to achieve maximum immediate efficacy or reduce tumor burden [252].

• Patients with advanced squamous LC may be recommended a combination of IT and CT in the following regimen:

  • pembrolizumab** 200 mg + #paclitaxel** 200 mg/m² on day 1 + carboplatin** AUC 6 (for exact dose calculation, see above) on day 1 every 3 weeks, 4 cycles; followed by maintenance therapy with pembrolizumab** until disease progression or unacceptable toxicity [81, 251] or dual IT (#nivolumab** 3 mg/kg infusion q2w + #ipilimumab** 1 mg/kg IV infusion q6w until disease progression or unacceptable toxicity for a maximum of 2 years) and/or dual IT (nivolumab** + #ipilimumab**) combined with two cycles of CT [219, 253].

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

Comments: re-administration of drugs of this class is possible in the 2nd and 3rd lines if the 1st line of IT was completed without signs of tumor progression and/or without unacceptable toxicity. Treatment is administered continuously until progression or unacceptable toxicity.

Currently, there are no results of direct comparisons between various immunochemotherapy options. Based on indirect comparisons, the results of using any of the regimens across PD-L1 expression levels for all histological subtypes are similar.

A slight advantage in indirect comparison regarding the proportion of progression-free patients at 3 years or more, as well as patients with a history of smoking and negative PD-L1 expression levels, is held by the combination of two immunotherapy drugs. The combination of nivolumab** and #ipilimumab** combined with two cycles of CT in clinical trials demonstrated superiority in cohorts of patients with squamous lung cancer and in the absence of PD-L1 expression.

Switching between drugs belonging to PD-L1 and PD-1 inhibitors is not accompanied by worse outcomes or increased toxicity [294].

Deviations from the instruction must be justified by the clinical situation and confirmed by a decision of the medical organization's medical board. According to available non-randomized studies, reducing the dose density of PD-1 inhibitors (L01X Other antineoplastic agents) may not be accompanied by worsening of immediate and long-term treatment outcomes (e.g., #pembrolizumab** 100 mg q3w, #pembrolizumab** 300 mg q6w, #nivolumab** 100 mg q3w) [387, 388, 390].

3.1.3.3. Second-Line Drug Therapy

The use of systemic therapy in the second line can reduce the severity of LC-related symptoms and increase the lifespan of individual patients. Second-line therapy is used strictly upon progression of the tumor process during or after first-line treatment. When choosing a treatment option, the potential impact on the patient's quality of life should be considered, taking into account comorbidities [84].

All patients who experience disease progression after first-line therapy can be divided into four groups:

1) patients who have not previously received IT;

2) patients sensitive to immunotherapy (progression 6–8 months after the end of immunotherapy, administered either as monotherapy or as maintenance after a combination with CT and completed either upon reaching the scheduled end date – e.g., 2 years for pembrolizumab** – or due to toxicity, or for other reasons);

3) patients sensitive to platinum compounds but resistant to immune checkpoint inhibitor therapy (other antineoplastic drugs) – progression during immunotherapy after 6–8 months of maintenance therapy or first-line monotherapy;

4) patients resistant to immunotherapy and platinum compound therapy.

• Following 1st-line chemotherapy in patients with squamous or non-squamous cell carcinoma with a known absence of activating EGFR/ALK mutations, immunotherapy with PD-(L)1 monoclonal antibodies is recommended if they were not administered in the 1st line: nivolumab** [83, 84], atezolizumab** [85], or pembrolizumab** [86]. The efficacy of these monoclonal antibodies increases (compared to chemotherapy) with higher expression levels [87].

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

• In the second group of patients, it is recommended to reintroduce immunotherapy with monoclonal antibodies against PD- (L)1: nivolumab** [85, 86], or atezolizumab**[87], or pembrolizumab** when PD-L1 expression is ≥1% of tumor cells [87].

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

Comments: The efficacy of these monoclonal antibodies increases (compared to chemotherapy) with increasing PD-L1 expression levels [88].

Comments: the dosing regimen and administration interval of nivolumab** can be switched from 3 mg/kg or 240 mg once every 2 weeks to 480 mg once every 4 weeks and vice versa as follows:

• If the patient received nivolumab** at a dose of 3 mg/kg or 240 mg once every 2 weeks, the first 480 mg dose should be administered after 2 weeks, and treatment should then be continued at a dose of 480 mg once every 4 weeks.

• If the patient received nivolumab** at a dose of 480 mg once every 4 weeks, the first 3 mg/kg or 240 mg dose should be administered after 4 weeks, and treatment should then be continued at a dose of 3 mg/kg or 240 mg once every 2 weeks.

• or

  pembrolizumab** at a dose of 400 mg every 6 weeks administered intravenously as a 30-minute infusion [221].

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

• Atezolizumab** is recommended for the treatment of patients with squamous and non-squamous NSCLC [86] in one of three dosing regimens:

  - 1200 mg IV every 3 weeks,

  - 840 mg IV every 2 weeks,

  - 1680 mg IV every 4 weeks [87, 92, 286].

It is possible to use the subcutaneous formulation of atezolizumab** at a dose of 1875 mg/15 ml (regardless of the patient's body weight) once every 3 weeks. The pharmacokinetic profile, clinical efficacy, and safety of subcutaneous atezolizumab** at a dose of 1875 mg are equivalent to the standard intravenous administration of atezolizumab** at a dose of 1200 mg.

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

Comment: there are no proven differences in the efficacy of different antibodies or regimens; therefore, the choice of drug and administration regimen should be made taking into account organizational factors.

• In the third group, it is recommended to prescribe platinum-based combinations for patients in a generally satisfactory condition (0–1 ECOG score, Appendix G3) when targeted treatment options for known activating mutations are exhausted, in the absence of activating mutations, and with a prolonged progression-free interval after the 1st platinum-containing line of therapy [7, 12].

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

For gemcitabine, the strength of recommendation is C (level of confidence in evidence – 4).

Comment: the choice between immunotherapy and re-introduction of a platinum doublet in patients with a prolonged progression-free interval after completion of the first platinum-containing line of therapy can be made according to the principles of first-line prescribing – taking into account the level of PD-L1 expression.

Level of evidence – B (level of confidence in evidence – 2).

Comment: it should be noted that the clinical efficacy of these drugs in this group of patients is lower than that of immunotherapy and chemotherapy.

• The prescription of the 3rd and subsequent lines of therapy is recommended for patients in a satisfactory general condition (0–1 ECOG score) if previously unused treatment options with a fundamentally different mechanism of antitumor effect are available to achieve remission and prolong life [7, 12].

Level of evidence – C (level of confidence in evidence – 5).

3.1.3.4. Molecularly targeted therapy: EGFR+, ALK/ROS1+, BRAF+

Recommendations for the use of targeted drugs for the treatment of NSCLC patients with activating mutations (Table 8) are presented below.

Table 8. Targeted drugs for the treatment of patients with non-small cell lung cancer

** Vital and Essential Drugs.

# – off-label drug use (used outside the scope of indications, contraindications, routes of administration, or dosages specified in the official product labeling).

Abbreviation: IV – intravenous.

• Molecularly targeted therapy is recommended for all patients with EGFR, BRAF mutations, or ALK, ROS1 translocations in the tumor to achieve maximum efficacy [101, 363].

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

Comment: Targeted treatment (protein kinase inhibitors) may be prescribed to patients in a weakened condition, including cases with ECOG 3–4. Given its high efficacy, good tolerability, and less pronounced negative impact on quality of life, targeted therapy should be considered the preferred treatment option compared to chemotherapy. Testing for rarer molecular alterations and the use of targeted inhibitors is advisable in patients with a satisfactory performance status and minimal smoking history after progression on first- and subsequent-line non-specific therapy [363].

• For patients with EGFR gene mutations in exon 19 or 21, EGFR tyrosine kinase inhibitors are recommended as first-line therapy: osimertinib** [108], gefitinib** or erlotinib** [106], afatinib** [107], or a combination regimen of bevacizumab**/ramucirumab** with erlotinib** or osimertinib** with chemotherapy [223, 225, 289].

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

Comments: upon detection of an EGFR mutation (exons 19 and 21), prescribing osimertinib** in the 1st line of treatment allows to increase overall survival compared to gefitinib** and erlotinib** [109]. For patients with the most frequent EGFR mutations (exon 19 deletion and L858R in exon 21) the determination of the optimal first-line drug therapy approach is made taking into account risk factors for progression on TKI monotherapy. For patients with L858R, metastatic involvement of the brain, liver, or more than three organs, and the presence of a TP53 co-mutation (if next-generation sequencing is performed), due to the high probability of insufficient efficacy of TKI monotherapy and a significant advantage in time to progression on against the background of a combination regimen, combination treatment (osimertinib** + CT, erlotinib** + bevacizumab**) is indicated [223, 225, 289]. In all other clinical situations, EGFR TKI monotherapy (gefitinib**, erlotinib**, afatinib**, osimertinib**) is an option. Considering the results of direct comparison, lower toxicity, and greater impact on overall survival, priority should be given to third-generation inhibitors (osimertinib**).

The cumulative probability of CNS progression or death in the FLAURA-2 study is 2.5 times lower in the combination regimen group compared with monotherapy.

Rare EGFR mutations, and primarily exon 20 insertions, differ significantly in their sensitivity to standard TKIs (afatinib** and osimertinib**). Thus, some alterations (e.g., L861Q, ex20ins A763_Y764, etc.) may determine sensitivity to approved EGFR TKIs (afatinib** and osimertinib**), whereas for other alterations (e.g., Asp770_Asn771ins, Val769_Asp770ins, etc.), targeted therapy with small-molecule drugs is ineffective, and platinum-based chemotherapy is indicated [364]. In these cases, a geneticist's consultation is required with the aim of determining potential sensitivity to targeted therapy.

If an EGFR gene mutation is detected after the initiation of 1st-line non-targeted antitumor therapy, such therapy must be completed and switched to EGFR tyrosine kinase inhibitors.

• In case of systemic progression of the tumor process with an EGFR gene mutation during the 1st line of targeted therapy with 1st- and 2nd-generation inhibitors, it is recommended to evaluate the feasibility of a repeat biopsy of any lesion containing tumor tissue and the determination of circulating tumor DNA in plasma to identify a potential mechanism of resistance to the ongoing therapy in order to determine further treatment tactics [110, 111].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• Upon detection of the EGFR T790M mutation, all patients are recommended to receive osimertinib** to achieve maximum efficacy and prolong survival [47, 108].

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

When disease progression according to RECIST criteria is detected during first-line therapy, it is extremely important to carefully assess the presence of disease symptoms associated with progression. If there are no symptoms or risks of clinical deterioration (expansion toward vessels, risk of compression, appearance of new asymptomatic brain metastases), continuation of targeted therapy in the previous regimen until the next evaluation may be considered [365].

In addition, the scale of progression must be assessed — in the case of an oligometastatic pattern (appearance of 1–5 lesions in a single organ), the feasibility of local treatment modalities (surgery, radiotherapy) should be evaluated to ablate newly appeared or enlarging lesions. If local treatment is administered to "progressing" lesions, continuation of the previous treatment is possible [366].

Upon disease progression on TKI monotherapy or a combination of TKIs with antiangiogenic drugs (L01FG VEGF/VEGFR inhibitors), first-line platinum-based cytotoxic chemotherapy is indicated, supplemented with bevacizumab** (in the absence of contraindications) or the four-drug regimen of atezolizumab** + paclitaxel** + carboplatin** + bevacizumab** [367, 400]. If disease progression occurs on a combination of osimertinib and chemotherapy, the time interval since the completion of the cytotoxic doublet must be evaluated. If progression occurs 6 months or more after the last administration of the platinum doublet, a re-challenge with the same doublet may be attempted while continuing the previous TKI. If progression occurs within 6 months, standard second-line therapy is indicated (docetaxel**, pemetrexed**, gemcitabine**).

As an alternative (if timely administration of osimertinib** is not feasible, and in the absence of the T790M mutation), chemotherapy including platinum-based doublets can be performed (see 1st line of chemotherapy) [82].

In patients with activating EGFR mutations, second-line administration of immune checkpoint inhibitors (monoclonal antibodies) does not improve overall survival compared with docetaxel**.

In individual cases, when it is impossible to determine activating EGFR gene mutations in the tumor or plasma in either adenocarcinoma or squamous cell lung cancer, molecularly targeted therapy with erlotinib** [98] or afatinib** [96–101] may be implemented.

In case of efficacy/stabilization, continuation of treatment until clinical progression is indicated.

If an ALK translocation is detected in the tumor, one of three drugs must be prescribed as the 1st line of NSCLC treatment: alectinib**, ceritinib**, or lorlatinib. Treatment is continued until clinical progression or the development of unacceptable toxicity [11, 49–51, 101, 112].

• alectinib** 600 mg orally twice daily,

• ceritinib** 450 mg orally,

• lorlatinib 100 mg orally once daily.

If an ALK translocation is detected after the initiation of 1st-line non-targeted antitumor therapy, such therapy should be completed (if effective, ongoing chemotherapy may be continued for up to 4 cycles) and switched to targeted therapy as soon as possible. When an ALK mutation is detected, prescribing alectinib** and lorlatinib in the 1st line of treatment increases overall survival [226, 368]. In brain metastases, alectinib** and lorlatinib demonstrate the highest intracerebral efficacy; alectinib** and lorlatinib statistically significantly increase the time to intracerebral progression of ALK-positive NSCLC.

As an alternative, if timely administration of 2nd-generation anaplastic lymphoma kinase (ALK) inhibitors is not feasible, therapy with crizotinib** or platinum-based chemotherapy with pemetrexed** and, in the absence of contraindications, bevacizumab**, or chemoimmunotherapy according to the regimen: atezolizumab** 1200 mg IV + #paclitaxel** 200 mg/m² IV (for Asian patients – 175 mg/m²) + carboplatin** AUC6 IV + bevacizumab** 15 mg/kg IV on day 1 every 3 weeks for 4 cycles, followed by maintenance therapy with atezolizumab** and bevacizumab** at previous doses until progression or unacceptable toxicity [82].

• For patients with an ALK translocation who started therapy with crizotinib** prior to the release of the current version of clinical guidelines, upon disease progression, it is recommended to administer 2nd-line targeted therapy with ceritinib** or alectinib** [11, 49, 50].

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

Comments: as an alternative, if timely administration of 2nd-generation anaplastic lymphoma kinase (ALK) inhibitors is not feasible, platinum-based chemotherapy with pemetrexed** and, in the absence of contraindications, – bevacizumab** may be administered.

Patients with ALK translocation who experience disease progression on first-line alectinib** or ceritinib** therapy are indicated for second-line targeted therapy with lorlatinib at a dose of 100 mg orally once daily until disease progression or unacceptable toxicity. If timely administration of third-generation anaplastic lymphoma kinase (ALK) inhibitors_ is not possible , platinum-based chemotherapy with pemetrexed** and, in the absence of contraindications, bevacizumab** is indicated. Chemotherapy or chemoimmunotherapy according to the regimen: atezolizumab** 1200 mg IV + #paclitaxel** 200 mg/m² IV (for patients of Asian descent – 175 mg/m²) + carboplatin** AUC6 IV + bevacizumab** 15 mg/kg IV on day 1 every 3 weeks for 4 cycles, followed by maintenance therapy with atezolizumab** and bevacizumab** at previous doses until disease progression or unacceptable toxicity [333].

For patients with an ALK translocation upon progression during therapy with crizotinib**, who started crizotinib** therapy prior to the release of the current version of clinical guidelines and received at least one more 2nd-generation anaplastic lymphoma kinase (ALK) inhibitor, administering 3rd-line targeted therapy with lorlatinib is advisable.

• Upon progression during targeted therapy with crizotinib**, it is recommended to administer platinum-based chemotherapy [7,12] or targeted therapy with other subsequent-generation protein kinase inhibitors.

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

Comments: Entrectinib exhibits higher intracranial efficacy compared to crizotinib**, exerting a protective effect against brain metastases.

• In the presence of the BRAF V600E mutation, the recommended 1st-line therapy regimen is a combination of BRAF/MEK protein kinase inhibitors: dabrafenib** 150 mg orally twice daily and trametinib** 2 mg orally once daily until clinical progression or the development of unacceptable toxicity [116].

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

• If a BRAF V600E mutation is detected after the initiation of 1st-line non-targeted antineoplastic therapy, such therapy is recommended to be continued for up to 4 cycles if effective, followed by a switch to a BRAF/MEK inhibitor combination. In case of progression, recommended targeted therapy is indicated [330, 331].

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

When using BRAF/MEK inhibitors in the 1st line of therapy, platinum-based chemotherapy with pemetrexed** and, in the absence of contraindications, bevacizumab** or immunotherapy is indicated in the 2nd line [401].

In adult patients with advanced NSCLC without activating EGFR, BRAF, ALK, or ROS1 mutations in the 1st line of therapy, standard therapy options are prescribed, as in NSCLC without activating mutations. If rare molecular alterations are detected upon the exhaustion of standard therapy options (>2 lines of systemic therapy), targeted drugs may be used. If rare molecular alterations are detected upon the exhaustion of standard therapy options (>2 lines of systemic therapy), targeted drugs may be used (Table 9).

Table 9. Molecularly targeted therapy for NSCLC with activating mutations and rearrangements.

For the treatment of adult patients with locally advanced or metastatic NSCLC with a c-MET gene mutation leading to exon 14 skipping (METex14) upon the exhaustion of standard therapy options (>2 lines of systemic therapy), capmatinib monotherapy may be used until disease progression or unacceptable toxicity [255, 369].

Comments: Capmatinib achieves an intracranial response in more than half of patients with METex14 NSCLC with brain metastases [255].

If capmatinib cannot be administered, crizotinib** therapy may be used (the objective response rate with its use reaches 32%).

For the treatment of adult patients with locally advanced or metastatic NSCLC with an NTRK gene rearrangement upon the exhaustion of standard therapy options (>2 lines of systemic therapy), entrectinib monotherapy at 600 mg once daily may be used [370] until disease progression or unacceptable toxicity.

• For the treatment of adult patients with locally advanced or metastatic NSCLC with an activating mutation in exon 20 of the HER2 (ERBB2) gene and/or HER2 overexpression (3+) upon the exhaustion of standard therapy options (>2 lines of systemic therapy), it is recommended to prescribe standard therapy options, as for NSCLC without activating mutations. Monotherapy with #trastuzumab** and afatinib** is not recommended due to the low objective response rate in this patient cohort.

  For the treatment of adult patients with locally advanced or metastatic NSCLC with a RET gene translocation upon the exhaustion of standard therapy options (>2 lines of systemic therapy), selpercatinib monotherapy may be used until disease progression or unacceptable toxicity [372].

  In adult patients with advanced NSCLC with a KRAS G12C mutation who progress after at least two prior lines of systemic therapy (including immunotherapy) and have brain metastases, sotorasib may be recommended as monotherapy orally at a dose of 960 mg once daily [257].

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

Comment: sotorasib demonstrated more than a 2-fold increase in PFS compared to docetaxel** in pretreated NSCLC patients with a KRAS G12C mutation. Long-term clinical benefit was observed across PD-L1 expression levels, including tumors with low PD-L1 expression and STK11 co-mutations.

3.1.3.5. Treatment of brain metastases

The appearance of brain metastases is a frequent manifestation of lung cancer progression, predominantly adenocarcinoma (up to 30%) [40, 65, 74, 120, 121].

Comment: adding whole-brain radiotherapy to local treatment improves intracranial control but does not affect overall survival [124].

• In case of multiple (5 or more) cerebral metastases, whole-brain radiotherapy is recommended (fraction dose 2.5 Gy (15 fractions) to a total dose of 37.5 Gy; fraction dose 3 Gy (10 fractions) to a total dose of 30 Gy) [392-394].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• In asymptomatic brain metastases in patients with high (greater than 50% tumor cells) PD-L1 expression levels without driver mutations in the 1st line of therapy, it is recommended to use the monoclonal antibody pembrolizumab** or atezolizumab** [373].

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

Comment: In other cases, in patients without driver mutations, RT (stereotactic irradiation if possible) should be considered at the onset of the disease. In such a clinical situation, it is advisable to consider bevacizumab-containing chemoimmunotherapy regimens.

• In asymptomatic brain metastases in patients with activating mutations in the EGFR gene, ALK translocations, ROS1 translocations, BRAF mutations, it is recommended to start treatment with protein kinase inhibitors to increase patient survival [7, 12]. The same approach may be considered in patients with symptomatic brain metastases; however, in this case, the decision must be carefully weighed, taking into account extracranial disease spread, general performance status, and the risk of primary resistance to protein kinase inhibitors (approximately 10-20% of patients).

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

Comment: Osimertinib** in patients with activating EGFR mutations, alectinib**, and lorlatinib in patients with activating ALK mutations, and entrectinib in patients with activating ROS1 mutations have advantages in terms of intracranial control and PFS compared to first-generation protein kinase inhibitors in the 1st line of therapy. Given the lower efficacy of first-generation EGFR, ALK, and ROS1 TKIs regarding intracranial control, if their use is considered in the 1st line of therapy, RT (stereotactic irradiation if possible) should be considered at the outset of the disease. The use of second- and third-generation TKIs allows RT to be deferred until intracranial progression. This same principle applies to patients with leptomeningeal disease.

The use of TKIs with good blood-brain barrier penetration helps to reduce the risk of intracranial progression. The 12-month cumulative incidence of CNS progression with osimertinib** is 3 times lower compared to first-generation EGFR tyrosine kinase inhibitors (8% vs. 24%). The 12-month cumulative incidence of CNS progression with alectinib** is 4 times lower compared to the first-generation ALK inhibitor crizotinib** (9.4% vs. 41.4%). The incidence of brain metastasis progression with entrectinib in patients with ROS-1 translocation without baseline metastases was 1%, and the median PFS in this subgroup was 25.2 months.

• In symptomatic brain metastases, when cerebral edema is instrumentally confirmed (computed tomography or magnetic resonance imaging of the brain), it is recommended to prescribe GCS to reduce brain tissue edema; the minimum necessary dose of GCS should be used for the shortest possible duration, attempting to taper the dose whenever possible. The starting dose of dexamethasone** is 4–8 mg/day; if glucocorticoids are ineffective at the recommended dose, a further increase in dose is not recommended; this indicates an unfavorable prognosis [300]. Patients with extensive edema with or without mass effect should be prescribed GCS at least 24 hours before starting radiation therapy.

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

Comment: Patients at high risk for gastrointestinal side effects (e.g., patients with a history of GI ulcers/bleeding, taking NSAIDs or antithrombotic agents) should receive H2-receptor antagonists or proton pump inhibitors.

Doses of dexamethasone** are tapered gradually over 2 weeks or more, taking into account individual dynamics of clinical symptoms and potential complications of steroid therapy.

Reduction/withdrawal of GCS (dexamethasone**) prior to surgical resection and/or radiation therapy is inappropriate. GCS are prescribed and administered in 1–3 oral doses (for total daily doses under 4 mg) or intramuscularly, in accordance with the circadian rhythm, with maximum doses in the morning hours and the last dose no later than 4:00–5:00 PM.

#Bevacizumab** in patients with brain metastases and neurological symptoms caused by radionecrosis and extensive cerebral edema following RT, which are resistant to standard anti-edema therapy, is prescribed to manage post-radiation changes [301, 324]. Therapy with #bevacizumab** should be considered in patients with contraindications to corticosteroids, presence of radionecrosis and local recurrence (according to positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals: tyrosine (fluoroethyl-L-tyrosine (18F)) and methionine (11C-methionine (11C-MET)) in the previously irradiated lesion in order to minimize complications after re-irradiation. The dose of #bevacizumab** is 5 mg/kg of body weight every 2 weeks or 7.5 mg/kg every 3 weeks, administered until symptom regression or improvement in the radiological picture (usually 4–6 injections).

Principles of treatment for oligometastatic NSCLC

Oligometastatic disease is defined as the detection of 1 distant metastasis of NSCLC (up to 3 in the brain) during workup for the primary tumor process (synchronous detection) or during follow-up after completion of treatment (metachronous detection).

• In synchronous detection, it is recommended to evaluate the feasibility of local intervention for the primary tumor. For primary tumor extent T1-3N0-1, local treatment methods (surgery or radiation therapy) are used for both the primary lesion and solitary metastases. If local methods are not feasible, systemic drug therapy is recommended, the principles of which are outlined above. When mediastinal lymph node metastases (N2+) are detected and morphologically confirmed by one of the methods mentioned above (via EBUS/EUS-guided biopsy, mediastinoscopy, or thoracoscopy), patients are recommended to receive systemic antineoplastic therapy regardless of the T stage (see 3.1.3. Principles of treatment for patients with stage IV disease) [7, 12].

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

• In metachronous detection of oligometastases and absence of signs of primary tumor recurrence, it is recommended that patients undergo surgical treatment or (stereotactic) radiation therapy in accordance with general principles. Resection of a solitary metastasis may be recommended if it is localized in the brain, adrenal gland, ipsilateral or contralateral lung, or chest wall. The local control stage should be supplemented with systemic therapy considering the histological subtype and molecular-biological characteristics of the tumor (see 3.1.3 Principles of treatment for patients with stage IV disease) to increase patient survival [7, 12].

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

• If local intervention is not feasible, it is recommended to administer systemic antineoplastic therapy considering the histological subtype and molecular-biological characteristics of the tumor (see 3.1.3 Principles of treatment for patients with stage IV disease) to increase patient survival [7, 12].

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

3.1.4. Aspects of surgical treatment

Radical surgical treatment for patients with lung cancer involves organ removal (pneumonectomy) or anatomical resection (lobectomy [bilobectomy] with bronchial and tracheal bifurcation resection and reconstruction; extended bilobectomy for lung neoplasms, extended lobectomy for lung neoplasms) of the disease focus along with intrapulmonary, hilar, and mediastinal lymph nodes (systematic ipsilateral mediastinal lymph node dissection). For typical central carcinoid tumors, isolated bronchial resection and reconstruction with full preservation of lung function is feasible [1, 2].

Mediastinal lymph node dissection (removal of adipose tissue with lymph nodes from regional metastasis zones) is a mandatory step of the surgery regardless of the volume of resected lung tissue [1]. The goal of mediastinal lymph node dissection is the preventive removal of mediastinal adipose tissue and lymph nodes. The surgery should be performed by sharp dissection; modern coagulation technologies may be used.

The standard volume of surgery on the mediastinal lymphatic pathways should be considered systematic ipsilateral mediastinal lymph node dissection, performed regardless of the volume of lung parenchyma resection, size, and macroscopic characteristics of the lymph nodes [1].

During surgery on the right, the right mediastinum is widely exposed, and the right and anterior surfaces of the trachea are revealed (including the tracheal bifurcation area with visualization of the left main bronchus); for this, the superior vena cava is retracted medially. The upper boundary is the exposed brachiocephalic arterial trunk of the aorta, the left boundary is the right semicircle of the ascending aorta, and the lower boundary is the tracheobronchial angle. The main trunk of the vagus nerve should be preserved whenever possible.

Surgery on the left involves the removal of paraaortic, subaortic, and left lower paratracheal lymph nodes, exposure of the upper semicircle of the aorta, and removal of adipose tissue along the initial segments of the common carotid and subclavian arteries. When indicated, ligation (transection) of the arterial ligament allows for the removal of pretracheal lymph nodes and partial exploration of the right paratracheal region. A wide incision of the mediastinal pleura and removal of anterior mediastinal adipose tissue with visualization of the left brachiocephalic vein along its entire length is possible.

Regardless of the side of surgery, bifurcation, paraesophageal, and pulmonary ligament lymph nodes of the respective sides are removed.

Super-extended mediastinal lymph node dissection (systematic), i.e., a surgery whose scope exceeds the described (standard) one, involves a transsternal approach with the removal of paratracheal adipose tissue on the right and left, including above the confluence of the right and left brachiocephalic veins, and the supraclavicular regions. Such a surgery cannot be recommended for widespread clinical practice, and its feasibility requires special discussion [1].

Based on their nature, surgeries are categorized into radical and palliative. A radical operation (R0) refers to the oncologically sound removal of the affected organ or its resection within healthy tissue boundaries along with adipose tissue and lymph nodes of regional metastasis zones, including mediastinal ones [1, 2].

The radicality of the surgical intervention is confirmed intraoperatively by the results of frozen (if necessary) and routine morphological examinations of tissues along the resection margin. In cases of limited involvement of adjacent organs detected during surgery, provided the surgical team has sufficient experience and the hospital has adequate equipment, a combined resection should be performed to increase the radicality of the surgical intervention.

The surgery is considered palliative in case of microscopic (R1) detection of tumor cells along the resection line of the bronchus, vessels, lung tissue, additionally resected structures and organs, as well as visually (R2) determined tumor in the remaining part of the lung, organs and structures of the mediastinum, pleura, with tumor pleuritis or pericarditis.

In recent years, anatomical lung resections with mediastinal lymphadenectomy using minimally invasive surgical approaches have been widely used for the stage I clinical form of the disease. The immediate results of such interventions surpass the results of thoracotomic

operations, while oncological outcomes are comparable to those of interventions using open approaches [17, 18, 127, 129].

Recommendations on determining the extent of surgical intervention are presented below.

• Segmentectomy, lobectomy, bilobectomy, or pneumonectomy (extended lobectomy for lung neoplasms, extended bilobectomy for lung neoplasms, extended pneumonectomy, anatomical segmentectomy of the lung) with ipsilateral mediastinal lymphadenectomy is recommended as the minimum oncologically justified scope of surgery in patients to increase patient survival [1, 2].

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

• For peripheral tumors up to 2 cm in size, located within the thickness of the resected segment(s), and with the technical feasibility of ensuring a radical nature of the operation, patients may undergo anatomical lung segmentectomy to increase patient survival [1, 2].

GPP CLoE 5Grade of Recommendation – C (Level of Evidence – 5).

• Atypical lung resection as a surgical treatment for primary lung cancer is not indicated for patients [130].

Comments: an exception is made for patients with typical carcinoid tumors of the lungs and bronchi. The biological features of these rare tumors, their predominantly endobronchial growth allow for organ-sparing surgeries in the volume of lobectomy or segmentectomy with resection and reconstruction of bronchi, isolated resections of bronchi or tracheal bifurcation while preserving all functioning lung tissue and with satisfactory long-term results [16].

3.1.5. Antineoplastic drug therapy

Adjuvant therapy

Adjuvant antitumor drug therapy (chemotherapy) is administered in addition to local treatment methods (surgery and radiotherapy) and helps reduce the risk of disease recurrence. When planning adjuvant therapy, it is necessary to evaluate the stage of the disease, the presence of activating mutations in non-squamous NSCLC (mutations in exons 19 or 21 of the EGFR gene and ALK translocations), PD-L1 expression level, prognosis, expected benefit, comorbidities, potential complications and their impact on quality of life, as well as patient preferences. Age per se is not a limitation in the absence of contraindications associated with comorbidities.

For small-sized tumors and the absence of regional metastases, which is prognostically favorable, adjuvant drug therapy has minimal efficacy.

When administering adjuvant drug therapy, standard regimens should be used while maintaining optimal dose intensity; whenever possible, unjustified dose reductions, increases in intervals between courses, and reductions in the number of courses should be avoided.

After completing 1–4 courses of adjuvant platinum-based chemotherapy, patients with positive PD-L1 expression in ≥50% of tumor cells and without activating mutations in EGFR and ALK genes may receive maintenance immunotherapy with atezolizumab** (if neoadjuvant therapy including immunotherapy was not performed).

• For patients with stage Ib-IIIA with identified activating mutations in the EGFR gene (exons 19 and 21), adjuvant targeted therapy with 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, osimertinib**, is recommended to improve disease-free survival in these patients. Targeted therapy can be initiated after adjuvant chemotherapy (up to 26 weeks after surgery) or instead of adjuvant chemotherapy (up to 10 weeks after surgery) [204].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

In patients with detected ALK translocation, adjuvant therapy with alectinib** 600 mg twice daily for 2 years improved disease-free survival rates [239].

• Adjuvant chemotherapy is recommended to be initiated no later than 8 weeks after surgery upon patient recovery (with a performance status of 0–1 score on the ECOG scale, Appendix G3) to increase the survival of these patients, using any platinum-based combinations. A total of 4 treatment cycles are administered to increase the survival of these patients. The most studied and frequently used combinations are vinorelbine** and cisplatin**, gemcitabine** and cisplatin** (#gemcitabine** and carboplatin**), #paclitaxel** and carboplatin** [22, 27, 34].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: for adjuvant chemotherapy regimens, see Table 3.

• In non-squamous NSCLC, the following regimen is recommended: #pemetrexed** + cisplatin** to increase the survival of these patients. If there are contraindications to prescribing cisplatin**, carboplatin** is used with #pemetrexed** [7, 12].

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

Comments: for adjuvant chemotherapy regimens, see Table 3.

• If surgical treatment and/or radiotherapy is impossible or the patient refuses it, palliative chemotherapy is recommended to be used as an independent method (see 3.1.3 Principles of treatment of patients with stage IV disease) to improve the quality of life and increase the survival of these patients [7, 12].

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

3.1.6. Palliative, including radiation, and supportive therapy

• Palliative radiotherapy is recommended for patients at any stage of the disease for local control of solitary metastases, for symptomatic treatment (relief of pain syndrome, hemoptysis, obstruction), and to improve the quality of life of patients [7, 12].

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

• In case of pleural effusion and/or pericarditis with a clinically significant deterioration of the patient's condition, thoracentesis or pericardiocentesis is recommended for symptomatic treatment and to improve the quality of life of patients [7, 12].

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

• In case of pulmonary hemorrhage, it is recommended to consider palliative surgical treatment; if it cannot be performed, conservative hemostatic therapy is recommended to correct this complication [1, 2].

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

• In case of massive tumor breakdown or secondary pneumonia, it is recommended to consider palliative surgery to correct this complication [1, 2].

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

Comment: the goal of the so-called best supportive care is the prevention of the onset, alleviation of symptoms of the disease, and maintenance of the quality of life of patients and their loved ones regardless of the stage of the disease and the need for other types of therapy.

3.2. Treatment of patients with small cell lung cancer

Surgical treatment of patients with localized SCLC can be performed at stage I (IA, IB, IIA) (T1-2N0M0) and in selected cases at stage II. The surgical phase must be supplemented with adjuvant chemotherapy according to the following scheme: etoposide** + cisplatin** (or etoposide** + carboplatin**), 4 courses with an interval of 3–4 weeks [131, 132]. In the case of N+ on histological examination, in addition to adjuvant chemotherapy, a course of external beam radiation therapy (EBRT) to the area of affected lymph nodes of the lung root and/or mediastinum is indicated [324].

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

• For patients with disease extent cT1-2N0 in the event that surgical treatment is impossible, stereotactic ablative radiotherapy (conformal external beam radiation therapy, including IMRT, IGRT, VMAT, stereotactic) according to a radical program (high-dose irradiation) followed by 4 cycles of chemotherapy (EP/EC) is recommended [395, 396].

  Possible fractionation regimens:

  • 7.5 Gy in 8 fractions – for ultracentral tumors;

  • 12 Gy in 5 fractions – for central tumors;

  • 20 Gy in 3 fractions – for peripheral tumors.

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

• For localized SCLC (not extending beyond one hemithorax), chemoradiotherapy is recommended for patients as the standard of treatment [9].

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

Comments: there are 2 options for chemoradiotherapy. The first is concurrent use of chemotherapy (ChT) and radiotherapy (RT), in which treatment begins with ChT according to the etoposide** + cisplatin**/carboplatin** regimen, and RT to the tumor area and mediastinum is added no later than the 2nd course of ChT ("early" RT) or after the 3rd ("late" RT). A non-significant advantage of "early" RT over "late" has been noted based on meta-analyses of randomized trials [264, 265,266].

Therefore, after assessing the extent of the tumor process and the patient's general condition, concurrent chemoradiotherapy should be initiated as early as possible. In the 2nd option, ChT and RT are used sequentially: 2–4 courses of ChT are administered, and upon their completion, RT is initiated. Sequential chemoradiotherapy, due to better tolerability, can be administered to debilitated patients.

RT is administered at a dose of 2 Gy 5 days a week. Before initiating treatment, it is preferable to perform PET-CT no earlier than 4 weeks prior. The irradiation volume includes the tumor, affected mediastinal lymph nodes, as well as the entire mediastinal volume up to the contralateral hilum. Supraclavicular regions are included in the irradiation field only in the presence of metastases. TDF is 60 Gy to the tumor and affected lymph nodes. Hyperfractionated RT is an option – irradiation 2 times a day with an interval of 4–6 hours between fractions at 1.5 Gy up to a TDF of 45 Gy, which slightly increased survival at the cost of a significant increase in the incidence of grade III–IV esophagitis, comparable to the standard conventional regimen in both tolerability and overall survival [134,269,270,271].

According to the results of recently published phase 2 randomized trials, increasing the total radiation dose from 45 Gy to 60–65 Gy in a hyperfractionation regimen leads to a significant increase in both progression-free survival and overall survival [269, 270].

• In extensive-stage SCLC, systemic drug therapy is recommended. As a 1st-line chemotherapy standard in patients with an ECOG performance status of 0–2 (3 due to the tumor process), the etoposide** + cisplatin** and etoposide** + carboplatin** chemotherapy regimens are used. The use of chemoimmunotherapy with etoposide** + carboplatin** + atezolizumab** or etoposide** + cisplatin**/carboplatin** + durvalumab** can increase patients' overall survival time [135, 227, 228].

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

Comments: in case of contraindications to immunotherapy, chemotherapy with etoposide** + cisplatin**, etoposide** + carboplatin** or an alternative regimen – #irinotecan** + cisplatin** and #irinotecan** + carboplatin** is administered. The etoposide** + cisplatin** and #irinotecan** + cisplatin** ChT regimens demonstrate equal immediate efficacy and similar long-term outcomes. When using the #irinotecan** + cisplatin** regimen, diarrhea (15.4% vs. 0.5%) and vomiting (10.9% vs. 4.4%) are more frequently observed, whereas neutropenia (59.6% vs. 38.1%) is more common with the etoposide** + cisplatin** regimen [374]. If contraindications exist, cisplatin** is replaced by carboplatin** [136]. The regimens are presented in Tab. 10.

Table 10. Recommended drug therapy regimens for small cell lung cancer

** Vital and Essential Drugs;

# – off-label drug use (used outside the scope of indications, contraindications, routes of administration, or dosages specified in the official product labeling).

Abbreviations: IV – intravenous, AUC – area under the curve.

If "emergency" care is required for a patient with severe superior vena cava syndrome, the CAV regimen (cyclophosphamide**, doxorubicin**, vincristine**) may be used as 1st-line treatment for SCLC.

Prophylactic cranial irradiation (PCI) may be considered due to the high risk of brain metastases (up to 70%) in patients after achieving complete or partial remission in localized disease and complete remission in extensive SCLC upon completion of primary treatment. The total dose of prophylactic cranial irradiation is 25 Gy (10 fractions of 2.5 Gy per day) [7, 12].

It should be noted that the risk of cognitive impairment after prophylactic cranial irradiation is significantly higher in patients older than 60 years and those with poor performance status [275, 276]. Therefore, prophylactic cranial irradiation is not indicated for patients with neurocognitive disorders and poor performance status.

Prophylactic cranial irradiation may be avoided if brain MRI is performed every 2 months. If regular MRI is not feasible in such a clinical situation, prophylactic cranial irradiation is permissible.

Comment: based on a meta-analysis in patients with localized SCLC participating in randomized clinical trials who achieved a complete response, prophylactic cranial irradiation increases patient survival (increased 3-year overall survival from 15.3% to 20.7%) [277].

In case of disease progression, second-line therapy is administered depending on the patient's general condition and the time to progression (early progression up to 6 months warrants second-line therapy, while progression after more than 6 months warrants re-induction with the initial regimen).

• If the 1st-line therapy is poorly tolerated, as well as in the event of early progression, recommended are 2nd- and 3rd-line, and subsequent line regimens (CAV or topotecan [136], #docetaxel [278]), as well as alternative regimens and palliative RT. Alternative 2nd- and 3rd-line regimens: #irinotecan** [137] or #paclitaxel** as monotherapy [139, 140, 141].

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

Comments: second-line and subsequent regimens are presented in Tab. 11.

Table 11. Recommended second-line and subsequent drug therapy regimens (in case of disease progression)

¹ When using #docetaxel** at a dose of 100 mg/m², prophylactic administration of G-CSF (filgrastim**) is required for the primary prevention of febrile neutropenia and the reduction of the duration of neutropenia.

As a 3rd-line therapy, immunotherapy may be used if the patient has not received it as 1st-line therapy, either nivolumab** [279] or #pembrolizumab** [280] as monotherapy (10 mg/kg every 2 weeks or 200 mg every 3 weeks).

In the presence of asymptomatic brain metastases, it is advisable to administer 4–6 cycles of chemotherapy or chemoimmunotherapy followed by brain irradiation.

In the presence of neurological symptoms, brain irradiation is performed followed by chemotherapy or chemoimmunotherapy (4–6 cycles) (in case of life-threatening symptoms, chemotherapy). When planning radiation therapy (RT), preference should be given to stereotactic RT in oligometastatic brain disease. For multiple lesions or leptomeningeal involvement, palliative whole-brain radiation therapy at a dose of 30–36 Gy in 10–12 fractions is indicated.

• In the presence of brain metastases, whole-brain RT at a total dose of 30–40 Gy is recommended for patients [314, 379].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1. Pre-rehabilitation

• Prior to surgery, physical prehabilitation is recommended for patients, which significantly improves the functional state of the respiratory muscles and respiratory biomechanics, thereby increasing lung ventilation capacity, improving bronchial patency, accelerating the functional recovery of the respiratory system, significantly shortening hospital stay after surgery, and reducing the incidence of complications and mortality during cancer treatment [145].

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

Comment: the aerobic focus of physical prehabilitation improves blood and lymph circulation, lung ventilation activity, increases exercise tolerance, and improves quality of life [146].

• Prior to surgery, it is recommended that patients perform a set of physical exercises as part of prehabilitation, which reliably increases forced vital capacity by 630 ml and forced expiratory volume by 420 ml, while also reducing the length of hospital stay by 4.83 days and the risk of postoperative complications by 45% [147].

CGR BLEL 1Level of recommendation grade – B (level of evidence – 1).

Comments: effective use of breathing exercises during prehabilitation reduces the incidence of postoperative pulmonary complications and shortens the length of hospital stay [148].

• To diagnose nutritional deficiency, it is recommended to regularly assess the quantitative and qualitative composition of the diet, body weight dynamics, and body mass index (BMI) starting from the time of diagnosis and continuing throughout anticancer treatment. When nutritional deficiency is detected, it is necessary to assess the quantitative and qualitative composition of the diet, dyspeptic problems, muscle mass, physical performance, and the degree of systemic inflammation. Energy requirements, if not measured individually, should be considered equal to 25–30 kcal/kg of body weight per day. Protein requirements should be 1.0–1.5 g/kg of body weight per day. The volume of vitamins and minerals should equal standard daily allowances. High-dose micronutrient supplementation is possible only for a proven specific nutrient deficiency.

  In order to preserve energy density and reduce glycemic load in the presence of both nutritional deficiency and insulin resistance, an increase in dietary fat intake combined with a reduction in carbohydrate intake is necessary.

  In patients with varying degrees of malnutrition or at risk of developing it who are capable of eating independently, dietary adjustment and treatment of dyspeptic disorders are recommended; if target energy and protein intake goals are not achieved, the use of specialized medical nutrition in the form of sipping is indicated. The use of any low-calorie diets is not recommended [281].

CGR CLEL 5Level of recommendation grade – C (level of evidence – 5).

4.2. First stage of rehabilitation after surgical treatment

• In the early postoperative period, it is recommended to apply fast-track rehabilitation and ERAS (early recovery after surgery) tactics, which include multimodal analgesia, early enteral nutrition, avoidance of routine placement of tubes and drains, and early patient mobilization on the 1st postoperative day [148, 149].

80

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

Comments: this tactic reduces the risk of early postoperative complications, decreases the length of hospital stay, and lowers the readmission rate [150]. Furthermore, early mobilization combined with anticoagulants (antithrombotic agents) and elastic compression of the lower extremities helps prevent postoperative thromboembolic complications [150]. Additional enteral nutrition, ensuring a total caloric intake of 25 kcal/kg of body weight per day, has a positive effect on the recovery of respiratory function in the postoperative period, helps improve overall treatment outcomes, and reduces overall mortality during the first year after surgery [284].

• Following lobectomy, it is recommended to consider kinesiology taping, which reliably reduces the intensity of postoperative pain [149].

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

• Following lobectomy, it is recommended to administer deep high-frequency oscillation and chest vibration massage in the early postoperative period, which increase forced expiratory volume in the early postoperative period and contribute to an increase in the partial pressure of oxygen in arterial blood [315, 316].

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

4.3. Second stage of rehabilitation after surgical treatment

• Patients who have undergone surgery for lung cancer are recommended adequate physical activity, alternation of aerobic and anaerobic loads, and a combination of static and dynamic breathing exercises in order to improve external respiration parameters, increase overall physical performance, expand the body's adaptive capabilities, and improve patients' quality of life [153].

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

Patients who have undergone surgery for lung cancer are recommended regular exercise therapy, which improves external respiration function, increases endurance, has a positive effect on the patient's psychological status, reduces the severity of anxiety and depression, fatigue, and pain, and improves mood [154, 155].

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

Comments: following combined treatment for malignant lung neoplasms, work with a medical psychologist, relaxation techniques, and cognitive behavioral therapy methods reduce symptoms of depression and anxiety [156–159].

4.4. Third stage of rehabilitation after surgical treatment

• Following comprehensive treatment for lung cancer, it is recommended that patients lead an active lifestyle to achieve a compensated functional state, accelerate social adaptation, and prevent the development of a chronic stress state [155], maintain an optimal body weight (BMI 18.5–25 kg/m²), and follow a diet that includes sufficient amounts of vegetables, fruits, and whole grains (400–600 g per day) with low amounts of fat, red meat, and alcohol [281].

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

Comments: Exercise therapy and increased physical activity are accompanied by decreased fatigue, improved patient mobility, reduced levels of depression, improved quality of life, and serve as a preventive measure against cardiovascular and pulmonary complications [160, 162]. The use of audiovisual relaxation techniques significantly reduces the severity of pain, fatigue, and anxiety, and improves the quality of life and social adaptation of the patient [162].

4.5. Rehabilitation during chemotherapy

• Patients receiving chemotherapy are recommended to ensure adequate nutrition and maintain physical activity. If, during chemotherapy, despite consultations with a clinical nutritionist and the prescription of sip feeding, the patient does not receive a sufficient amount of nutrients, additional enteral nutrition is recommended; if that is insufficient or impossible, parenteral nutrition is indicated [281].

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

Comments. Various chemotherapy regimens cause nutritional deficiency of varying degrees. For example, body weight loss is a frequent side effect of targeted therapy. It has been proven that body weight stabilization in patients with lung neoplasms correlates with a significant improvement in survival; however, currently there are few studies analyzing the relationship between improved nutritional status, chemotherapy efficacy, and increased survival [281].

• Patients receiving chemotherapy are recommended sessions of acupuncture, which increases IL-2, CD3+, and CD4+ levels, reduces bone marrow suppression, decreases fatigue and nausea, and improves quality of life parameters [161].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• In the event of chemotherapy-induced polyneuropathy, patients are recommended to perform physical exercises and practice terrain cure (walking therapy) in order to control the clinical manifestations of polyneuropathy [162].

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

Comment: balance training exercises are more effective for correcting polyneuropathy than a combination of endurance and strength exercises [163]; regular performance of exercise therapy complexes during chemotherapy reduces the incidence of cardiac complications [165].

• In the complex treatment of peripheral polyneuropathy associated with chemotherapy, patients are recommended to use physiotherapeutic treatment methods according to indications: low-level laser therapy, low-frequency magnetotherapy, transcutaneous electrical nerve stimulation (TENS) [163, 164, 165].

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

• To prevent oral mucositis during chemotherapy, patients are recommended to undergo low-level laser therapy [166].

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

• To prevent alopecia during chemotherapy, patients are recommended to use scalp cooling systems (e.g., chemotherapy-induced alopecia prevention devices, etc.) [167].

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

• To restore cognitive functions (working memory capacity, attention stability), reduce anxiety levels, and improve respiratory function and heart rate variability, patients are recommended biofeedback therapy (various biofeedback techniques), 20–30 sessions [168].

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

4.6. Rehabilitation during radiotherapy

• To improve external respiration function, reduce fatigue, decrease the number of complications, and improve quality of life, patients undergoing radiotherapy are recommended to engage in exercise therapy (aerobic exercise combined with strength training) [169].

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

• To prevent radiation dermatitis, patients recommended low-level laser therapy [170].

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

• To enhance patients' adaptability to a new lifestyle, reduce symptoms of anxiety and depressive disorders, and improve coping with stressful situations outside of and after therapeutic sessions, recommended conducting short-term psychotherapeutic sessions within cognitive behavioral therapy (CBT) lasting 45–60 min for 2 months [171].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• To ensure adequate nutrient intake, stabilize nutritional status, and avoid interruptions in radiation therapy, it is recommended to consult a nutritionist (initial and follow-up consultations/examinations by a nutritionist) and/or prescribe sip feeding. In severe radiation mucositis, enteral nutrition via a nasogastric tube or percutaneous endoscopic gastrostomy is recommended. Parenteral nutrition is indicated if adequate oral or enteral nutrition is impossible [281].

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

5. Prevention and Dispensary Observation

• Patients are recommended to quit smoking, both active and passive, in order to prevent the occurrence of lung cancer. There is a direct proportionality between the number of cigarettes smoked per day and the risk of developing lung cancer. Passive smoking increases the risk of developing lung cancer by 20–30% [7, 12].

GRL CGrade of Recommendations — C (Level of Evidence — 5).

Comment: Smoking is associated with poorer overall and cancer-specific survival. Continued tobacco smoking by patients after a lung cancer diagnosis negatively affects their overall survival and adversely impacts the outcomes of antineoplastic therapy. Tobacco smoking significantly increases the rate of postoperative complications and mortality in such patients. Tobacco smoking increases the risk of complications associated with radiation therapy and significantly decreases the response to ongoing therapy. Tobacco smoking likely alters the metabolism and efficacy of chemotherapy and targeted therapy [290].

• For patients with small cell lung cancer who have not undergone prophylactic cranial irradiation, it is recommended to perform brain MRI every 3–4 months for the first 2 years [12].

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

Comment: the objective of follow-up is the early detection of disease progression for the purpose of prompt initiation of chemotherapy or surgical removal of resectable metastatic lesions and recurrent tumors.

5.1 Prevention and treatment of complications of malignant tumors and antineoplastic drug therapy

• When administering antineoplastic drug therapy with emetogenic side effects, it is recommended that patients receive prevention and treatment for nausea and vomiting [1, 2].

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

Comments: The principles of diagnosis, prevention, and treatment of nausea and vomiting during antineoplastic drug therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vladimirova L.Yu. et al. Nausea and Vomiting [3]. https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting

• In patients with bone metastases, it is recommended to provide prevention and treatment for skeletal-related events [4].

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

Comments:The principles of diagnosis, prevention, and treatment of skeletal-related events are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Bagrova S.G. et al. Bone Pathology [5]. https://rosoncoweb.ru/standarts/?chapter=bone_pathology

• For patients with risk factors for thromboembolic events, it is recommended to provide prevention and treatment for venous thromboembolic events [6-8].

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

Comments: The principles of diagnosis, prevention, and treatment of venous thromboembolic complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Somonova O.V. et al. Thromboembolic complications [9]. https://rosoncoweb.ru/standarts/?chapter=thromboembolism

• During antineoplastic drug therapy, patients are recommended to receive prophylaxis and treatment for febrile neutropenia and infectious complications [10-12].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, as well as the principles of antibacterial therapy, are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sakaeva D.D. et al. Practical Guidelines for the Diagnosis and Treatment of Febrile Neutropenia [13]. https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia

• During antineoplastic drug therapy, patients are recommended management of hepatotoxicity [14, 15].

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

Comments: The principles of diagnosis, prevention, and treatment of hepatotoxicity are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Tkachenko P.E. et al. Hepatotoxicity [16]. https://rosoncoweb.ru/standarts/?chapter=hepatotoxicity

• During antineoplastic drug therapy, patients are recommended to receive prophylaxis and treatment for cardiovascular complications [8, 9].

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

Comments: The principles of diagnosis, prevention, and treatment of cardiovascular complications during antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vitsenya M.V. et al. Cardiovascular Toxicity [21]. https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity

• During antineoplastic drug therapy, patients are recommended to receive prophylaxis and treatment for dermatological reactions [8, 9].

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

Comments: The principles of diagnosis, prevention, and treatment of skin complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Koroleva I.A. et al. Dermatological Reactions [23]. https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions

• To maintain the metabolic reserves of a cancer patient's body and increase their resistance to treatment (surgical, medical, radiation), nutritional support is recommended. The choice of nutritional support method is determined by the various types of nutritional disorders in the patient. Placement of a nasogastric, nasointestinal, percutaneous, endoscopic, laparoscopic, or laparotomic stoma, endoscopic stenting for tumor stenosis, or palliative radiotherapy may be recommended [8, 9].

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

Comments: The principles of nutritional support are presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A.V. et al. Nutritional Support [26]. https://rosoncoweb.ru/standarts/?chapter=nutritional_support

• During antineoplastic drug therapy, patients are recommended to receive prophylaxis and treatment for nephrotoxicity [8, 9].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of nephrotoxicity is presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antitumor drug therapy: Gromova E.G. et al. Nephrotoxicity [30]. https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity

• During antitumor drug therapy, patients are recommended prevention and treatment of immune-related adverse events [8, 9].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of immune-related adverse events is provided in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antitumor drug therapy: Novik A.V., Protsenko S.A. et al. Immune-related adverse events [35]. https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events

• During antitumor drug therapy, patients are recommended prevention and treatment of mucositis [8, 9].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of mucositis is provided in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antitumor drug therapy: Semiglazova T.Yu. et al. Mucositis [38]. https://rosoncoweb.ru/standarts/?chapter=mucositis

• Patients are recommended treatment for anemia, which occurs as a symptom of a malignant neoplasm and as an adverse event during antitumor drug therapy [8, 9].

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

Comments: The procedure and principles of anemia prevention and treatment comply with the principles set forth in the clinical guidelines "Anemia in Malignant Neoplasms" (ID: KR624, approval year 2024, www.cr.rosminzdrav.ru) and in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antitumor drug therapy: Orlova R.V. et al. Anemia [41]. https://rosoncoweb.ru/standarts/?chapter=anemia

• During treatment, patients are recommended treatment for anorexia-cachexia syndrome [8, 9].

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

Comments: A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is provided in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant neoplasms and antitumor drug therapy: Sytov A.V. et al. Practical guidelines for the treatment of anorexia-cachexia syndrome in cancer patients [43]. https://rosoncoweb.ru/standarts/?chapter=anorexia-cachexia

• When administering cyclic antitumor drug therapy involving continuous prolonged (over 6 hours) infusions of antineoplastic agents (doxorubicin**, etc.) or in case of poor peripheral venous access, patients are recommended to use central venous access and infusion pumps [8, 9].

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

Comments: The choice of central access option is determined by the planned duration of the entire treatment course, patient preferences, and anatomical features. For prolonged (over 3 months) courses of therapy, implantation of a subcutaneous venous port system is most convenient. For shorter periods, a peripherally inserted central venous catheter can serve as an alternative. The principles of using central venous access are set forth in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antitumor drug therapy: Isyangulova A.Z. et al. Central venous access [45].https://rosoncoweb.ru/standarts/?chapter=central_venous_access

• During antitumor drug therapy, patients are recommended the prevention and treatment of extravasation of antineoplastic agents. When planning antitumor drug therapy, the choice of vascular access is important for preventing the extravasation of antineoplastic drugs [8, 9].

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

Comments: Algorithms for selecting vascular access, as well as for the prevention, diagnosis, and treatment of extravasation, are set forth in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antitumor drug therapy: Buydenok Yu.V. et al. Extravasation of antineoplastic drugs [47]. https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs

• During antitumor treatment, patients are recommended treatment for chronic pain syndrome [8, 9].

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

Comments: Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antitumor drug therapy: Kogonia L.M. et al. Chronic pain syndrome [49]. https://rosoncoweb.ru/standarts/?chapter=chronic_pain_syndrome

• During antitumor drug therapy, patients are recommended prevention and treatment of infusion reactions [8, 9].

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

Comments: Algorithms for the prevention, diagnosis, and treatment of infusion reactions are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Orlova R.V. et al. Infusion reactions [51]. https://rosoncoweb.ru/standarts/?chapter=infusion_reactions

• During therapy, patients are recommended monitoring and treatment of reactivation/exacerbation of chronic viral hepatitis [8, 9].

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

Comments: Principles of monitoring and management tactics in cancer patients with chronic viral hepatitis are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Feoktistova P.S. et al. Chronic viral hepatitis [53]. https://rosoncoweb.ru/standarts/?chapter=chronic_viral_hepatitis

During antitumor drug therapy, patients are recommended prevention and treatment of neurological complications [8, 9].

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

Comments:

Principles of diagnosis, prevention, and treatment of neurological complications of antitumor therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Latipova D.Kh. et al. Neurological complications [55]. https://rosoncoweb.ru/standarts/?chapter=neurological_complication

• During antitumor hormone therapy, patients are recommended prevention and treatment of hormone-mediated adverse events [8, 9].

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

Comments: Principles of diagnosis, prevention, and treatment of hormone-mediated adverse events are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Stenina M.B. et al. Hormone-mediated adverse events [57]. https://rosoncoweb.ru/standarts/?chapter=hormone-mediated_side_events

• During therapy, patients are recommended prevention and treatment of thrombocytopenia induced by antitumor drug therapy [8, 9].

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

Comments: a detailed algorithm for the diagnosis and treatment of thrombocytopenia is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Rykov I.V. et al. Thrombocytopenia. https://rosoncoweb.ru/standarts/?chapter=thrombocytopenia

6. Organization of Medical Care

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

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

2) in accordance with the procedures for the provision of medical care approved by the authorized federal executive authority and mandatory for implementation across the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

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

Primary specialized health care is provided by an oncologist and other medical specialists at an ambulatory cancer care center, or, in its absence, at a primary oncology office or the outpatient department of an oncological dispensary (cancer hospital).

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, family physicians,

medical specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an ambulatory cancer care center, or, in its absence, at a primary oncology office or the outpatient department of an oncological dispensary (cancer hospital) to receive primary specialized health care.

Consultation at an ambulatory cancer care center or at a primary oncology office or outpatient department of an oncological dispensary (cancer hospital) shall not exceed the timeframe established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation. The oncologist of the ambulatory cancer care center (in the absence of an ambulatory cancer care center, the oncologist of the primary oncology office or outpatient department of the oncological dispensary (cancer hospital)) arranges for the acquisition of biopsy (surgical) material, as well as the performance of other diagnostic tests necessary to establish a diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic tests within the medical organization that includes the ambulatory cancer care center (primary oncology office), the patient is referred by the oncologist to an oncological dispensary (cancer hospital) or to a medical organization providing medical care to patients with oncological diseases.

The turnaround time for pathomorphological examinations necessary for the histological verification of malignant neoplasms shall not exceed the timeframe established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

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 a medical specialist based on the results of diagnostic tests, including cytological and/or histological verification of the diagnosis, except for cases where obtaining biopsy and/or puncture material is not feasible.

The oncologist of the ambulatory cancer care center (primary oncology office) refers the patient to an oncological dispensary (cancer hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive authority (hereinafter referred to as a federal medical organization), to clarify the diagnosis (in case of the impossibility of establishing a diagnosis, including the extent of the oncological process and the stage of the disease), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

In complex clinical cases, to clarify the diagnosis (in case of the impossibility of establishing a 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 arranges for the referral of:

digital images obtained from pathomorphological examinations to the pathomorphological bureau (department) of the fourth group (reference center) via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

digital images obtained from diagnostic imaging methods to the remote consultative center for diagnostic imaging 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 multidisciplinary team of physicians, including oncologists, a radiation therapist, a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological multidisciplinary team), including an oncological multidisciplinary team conducted using telemedicine technologies, involving other specialist physicians if necessary.

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

For accounting purposes, information about a newly diagnosed case of an oncological disease is sent within 3 working days by the oncologist of the medical organization where the corresponding diagnosis was established to the cancer dispensary or an organization of a constituent entity of the Russian Federation that performs the function of registering patients with newly diagnosed malignant neoplasms, including through the use of the Unified State Health Information System. If the presence of an oncological disease is confirmed in a patient, information about the refined diagnosis is sent from the cancer dispensary or the organization of the constituent entity of the Russian Federation that performs the function of registering patients with newly diagnosed malignant neoplasms to the medical organization providing follow-up care to the patient.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization of specialized, including high-tech, medical care.

Specialized medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided on the basis of medical indications stipulated by the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities to provide specialized (excluding high-tech) medical care, as stipulated in the appendix to the regulations on the organization of specialized, including high-tech, medical care. If several federal medical organizations providing specialized medical care for diseases, conditions (group of diseases, conditions) corresponding to the diseases, conditions (group of diseases, conditions) of the patient participate in the implementation of the Program, the attending physician is obliged to inform the patient (the patient's legal representative) about the possibility of choosing a federal medical organization, including the potential waiting times for specialized medical care, which may exceed the waiting times established by the program of state guarantees of free medical care for citizens.

Waiting times for the provision of specialized (excluding high-tech) medical care must not exceed the timeframes established in the program of state guarantees of free medical care for 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 the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations and public associations, and other non-profit organizations operating in the field of health protection.

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

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

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

2) the presence of complications of oncological treatment (surgical intervention, RT, drug therapy, etc.) requiring the provision of specialized medical care in an emergency and urgent form.

Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures, as well as endoscopic studies when it is impossible to perform them on an outpatient basis, requiring subsequent monitoring in an inpatient or day hospital setting;

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

Indications for discharging a patient from a medical organization are:

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

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

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

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

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

7. Additional Information

In addition to the extent of the tumor process, morphological and molecular genetic characteristics of the tumor, concomitant pathologies, adequacy of supportive therapy, social adaptation of the patient, and the presence or absence of daily physical activity have a significant impact on the course of the disease and the effectiveness of its treatment. Daily 30-minute moderate-intensity physical activity is recommended. Smoking cessation improves the prognosis of the disease [7, 12].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Artamonova Elena Vladimirovna, MD, PhD, Head of the Department of Drug Treatment No. 1 of Department 3 of Drug Treatment at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

2. Barmin Vitaly Valerievich, MD, PhD, Associate Professor, Thoracic Surgeon, Head of the Center for Mediastinal and Myasthenia Pathology, Head of the Myasthenia Group at the Thoracoabdominal Oncosurgery Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Bychkov Yury Markovich, MD, PhD, Oncologist, Head of the Day Hospital at the Radiotherapy Clinic (Center for Radiation Therapy and Combined Treatment Methods) of the Russian Scientific Center of Roentgenology and Radiology (RNCRR) of the Russian Ministry of Health.

4. Vladimirova Lyubov Yuryevna, MD, DSc, Professor, Head of the Department of Antitumor Drug Therapy, National Medical Research Center of Oncology of the Russian Ministry of Health.

5. Zhabina Albina Sergeyevna, PhD, Oncologist, Oncological Chemotherapy (Antitumor Drug Therapy) Department of Biotherapy, Saint Petersburg Clinical Scientific and Practical Center for Specialized Medical Care (Oncology).

6. Kozlov Nikolay Alexandrovich, PhD, Pathologist, Department of Pathology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

7. Kononets Pavel Vyacheslavovich, MD, DSc, Director of the N.N. Trapeznikov Institute of Clinical Oncology, Head of the Department of Thoracic Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

8. Kuzminov Alexander Evgenyevich, PhD, Researcher, Department of Antitumor Drug Therapy No. 3, Department of Drug Treatment Methods, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

9. Levchenko Evgeny Vladimirovich, MD, DSc, Head of the Research Department, Leading Researcher, Research Department of Thoracic Oncology, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

10. Miller Sergey Viktorovich, MD, DSc, Leading Researcher, Department of Thoracic Oncology, Research Institute of Oncology, Tomsk National Research Medical Center of the Russian Academy of Sciences (Tomsk NMRC RAS).

11. Moiseenko Fedor Vladimirovich, MD, DSc, Head of the Oncological Chemotherapy Department of Biotherapy, Saint Petersburg Clinical Scientific and Practical Center for Specialized Medical Care named after N.P. Napalkov, Professor of the Department of Oncology, North-Western State Medical University named after I.I. Mechnikov.

12. Novikov Sergey Nikolaevich, MD, DSc, Head of the Radiotherapy Department, Head of the Research Department of Radiation Oncology and Nuclear Medicine, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

13. Pikin Oleg Valentinovich, MD, DSc, Professor, Head of the Department of Thoracic Surgery, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

14. Reutova Elena Valeryevna, PhD, Senior Researcher, Department of Antitumor Drug Therapy No. 3, Department of Drug Treatment Methods, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

15. Savelov Nikita Alexandrovich, Chief freelance specialist in pathological anatomy in oncology, Head of the Department of Pathology, Moscow City Oncology Hospital No. 62 of the Moscow Healthcare Department.

16. Sakaeva Dina Damirovna, MD, DSc, Professor, Deputy Chief Medical Officer for Oncology, Mother and Child Clinic Group, Oncologist, Department of Antitumor Drug Therapy 1, Clinic of the Bashkir State Medical University.

17. Sarantseva Ksenia Andreevna, PhD, Oncologist, Researcher, Department of Antitumor Drug Therapy No. 3, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

18. Semenova Anna Igorevna, PhD, Senior Researcher, Research Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, Oncologist, Department of Chemotherapy and Innovative Technologies, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

19. Chernykh Marina Vasilyevna, PhD, Deputy Director for Medical Work, Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor, Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University.

20. Filonenko Elena Vyacheslavovna, MD, DSc, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

21. Gulidov Igor Alexandrovich, MD, DSc, Professor, Honored Scientist of the Russian Federation, 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.

22. Falaleeva Natalya Alexandrovna, MD, DSc, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

23. Belokhvostova Anna Sergeevna, PhD, Head of the Department of Antitumor Drug Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Associate Professor, Department of Radionuclide Medicine, Institute of Atomic Energy, National Research Nuclear University MEPhI.

Medical Care Organization Section

1. Ivanov Sergey Anatolyevich, MD, DSc, Professor, Corresponding Member of the RAS, Honored Doctor of the Russian Federation, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Chief Freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

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

3. Gevorkyan Tigran Gagikovich, Deputy Director for Federal Project Implementation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

4. Komarov Yury Igorevich, PhD, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health.

5. Fomenko Yury Alexandrovich, PhD, Deputy General Director for Clinical and Expert Work, National Medical Research Center of Oncology of the Russian Ministry of Health.

Medical Rehabilitation Section

1. Konchugova Tatyana Venediktovna, MD, DSc, Professor, Head of the Department of Preformed Physical Factors, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health, Physiotherapist.

2. Obukhova Olga Arkadyevna, PhD, Physical and Rehabilitation Medicine Physician, Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the European Society for Clinical Nutrition and Metabolism (ESPEN), Russian Association for Parenteral and Enteral Nutrition (RESPEN).

3. Semiglazova Tatyana Yuryevna, MD, DSc, Professor, Head of Department, Leading Researcher, Research Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor, Department of Oncology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health.

4. Stepanova Alexandra Mikhailovna, PhD, Deputy General Director for Science and Education, Federal Research and Clinical Center of Medical Rehabilitation and Balneology of the Federal Medical-Biological Agency, Physical and Rehabilitation Medicine Physician, Oncologist, Member of the Union of Rehabilitologists of Russia, Russian Society of Oncologists, International K-Taping Academy.

Supportive Care Section

1. Gladkov Oleg Alexandrovich, Professor, MD, DSc, Director of EVIMED Medical Center LLC.

2. Karaseva Vera Vitalievna, MD, DSc, Associate Professor, Professor, Department of Oncology, Institute of Continuing Professional Education, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1) oncologists,

2) surgeons,

3) radiologists,

4) radiation therapists,

5) medical geneticists.

Methods used for evidence collection/selection: search in electronic databases; analysis of current scientific developments on the problem in the Russian Federation and abroad; synthesis of practical experience of Russian and foreign specialists.

Method used to formulate recommendations is expert consensus.

Economic analysis. Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Methods of recommendation validation:

• external expert review,

• internal expert review.

Description of the recommendation validation method. The preliminary version of these guidelines was reviewed by independent experts, who were asked to comment primarily on how accessible and understandable the interpretation of the evidence underlying the recommendations is. Comments were received from primary care oncologists regarding the clarity of the presentation of the guidelines and their evaluation of the importance of the recommendations as a working tool for daily practice. Expert comments were carefully systematized and discussed with the chair and members of the working group. Each item was discussed, and the resulting changes were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and expert review. The draft guidelines were also reviewed by independent experts, who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Table A1. Scale for assessing levels of evidence (LoE) for diagnostic methods (diagnostic interventions)

Table A2. Scale for grading levels of evidence (LoE) for preventive, therapeutic, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table A3. Scale for grading grades of recommendation (GoR) for preventive, diagnostic, therapeutic, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision

– at least once every three years, as well as upon the emergence of new evidence from an evidence-based medicine perspective regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the availability of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Current package inserts for medicinal products mentioned in these clinical guidelines can be found in the State Register of Medicinal Products hosted on the website of the Russian Ministry of Health: http://grls.rosminzdrav.ru.

Table A3-1. Terms describing procedures in the clinical guideline and potential (closest) terms from the current nomenclature of medical services.

Appendix B. Physician Action Algorithms

* For patients with stage I NSCLC with compromised functional status, high risk of surgical complications, or patient refusal of surgical treatment, radical radiotherapy is recommended. For stage II disease when surgical treatment is not feasible, chemotherapy, chemoradiotherapy, or radiotherapy is recommended. For T1-2N0 stage disease when surgical treatment is not feasible, stereotactic ablative fractionated radiotherapy using high doses per fraction (fraction dose 12 Gy, total dose 48–56 Gy) may be performed

Abbreviations: LNs – lymph nodes, NSCLC – non-small cell lung cancer,

BSG – bone scintigraphy,

PET and CT – positron emission tomography and computed tomography,

FB – fiberoptic bronchoscopy,

EBUS – endobronchial ultrasound.

platinum compounds.

Note: medicinal products used off-label regarding their indications, contraindications, routes of administration, and dosages contained in the instructions for use – #Pembrolizumab**, #Paclitaxel**, #Pemetrexed**; medicinal products included in the VLEL list – #Pembrolizumab**, Denosumab**, Atezolizumab**, Bevacizumab**, #Paclitaxel**, #Pemetrexed**, Cisplatin**, Carboplatin**; platinum preparations / platinum derivatives – ATC platinum compounds.

Appendix C. Patient Information

Recommendations for chemotherapy complications by an oncologist (chemotherapy specialist).

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

   • start taking systemic antibacterial drugs as prescribed by a physician;

   • complete blood count (CBC).

2. For stomatitis:

   • mechanically and thermally sparing diet;

   • frequent (hourly) mouth rinsing with an infusion of chamomile flowers / sage leaves, oak bark decoction, smearing the mouth with sea buckthorn (peach) oil;

   • oral cavity care as recommended by a physician.

3. For diarrhea:

   • exclude fatty, spicy, smoked, sweet, dairy foods, and fiber. Lean meat, flour products, fermented dairy products, rice water, and abundant fluids are permitted;

   • 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. Karnofsky Performance Scale

Russian title: Karnofsky Performance Scale [172].

Original title: Karnofsky Performance Status. Source (official developer website, validation publication): Karnofsky D.A., Burchenal J.H: The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of chemotherapeutic agents. Edn. Edited by MacLeod C. New York: Columbia University Press, 1949.

191–205 p.

Type: rating scale.

Purpose: describing the patient's functional level in terms of their ability to care for themselves, daily activities, and physical capabilities (walking, working, etc.).

Content (template):

Scoring key (interpretation): provided within the scale itself.

Appendix G2. Visual Analogue Scale for pain assessment

Russian title: Visual Analog Scale for Pain Assessment Original title: The Numeric Pain Rating Scale Instructions

Source (official developer website, validation publication): https://www.sralab.org/rehabilitation-measures/numeric-pain-rating-scale; McCaffery, M., Beebe, A., et al. (1989). Pain: Clinical manual for nursing practice, Mosby St. Louis, MO

Type: rating scale

Purpose: to describe the level of pain syndrome in a patient.

Instructions: The patient is asked to mark the intensity of pain on a 10 cm line on a scale from 0 to 10.

Key: 1–3 points – mild pain; 4–7 points – moderate pain; ≥8 points – severe pain.

Appendix G3. WHO/ECOG performance status scale [158]

Russian title: 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

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.