Gastric cancer: clinical guidelines

List of Abbreviations

AJCC – American Joint Committee
on Cancer

APACHE II – Acute Physiology and Chronic Health Evaluation

CIS – carcinoma in situ

CPS – combined positive score

CTCAE – Common Terminology Criteria for Adverse Events

D0–3 – extent of lymphadenectomy

EBER – Epstein-Barr virus-encoded early transcripts

ECL – enterochromaffin-like

ECOG – Eastern Cooperative
Oncology Group

EMR – endoscopic mucosal resection

en bloc – removal of tumor elements as a single block

ESD – endoscopic submucosal dissection

HIPEC – Hyperthermic
Intraperitoneal Chemotherapy

MSI – microsatellite instability

per os – orally (route of drug administration)

PIPAC – Pressurized Intraperitoneal Aerosol Chemotherapy

RECIST – Response Evaluation
Criteria In Solid Tumors

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

UICC – Union for International Cancer Control

VEGFR – vascular endothelial growth factor receptor

IV – intravenous (route of drug administration)

WHO – World Health Organization

Du – duodenum

GE - gastrectomy

Malignant neoplasm – malignant neoplasm

CT – computed tomography

LN – lymph node(s)

PT – physical therapy

PFS – progression-free survival

mAbs – monoclonal antibodies (ATC code: L01XC)

ICD-10 – International Classification of Diseases 10th Revision

OS – overall survival

MRI – magnetic resonance imaging

disorders (Acute Physiology and Chronic Health Evaluation)

NS – nutritional support

OS – overall survival

BSC – best supportive care

OR – objective response

GEJ – gastroesophageal junction

PET – positron emission tomography

PET/CT – positron emission tomography combined with computed
tomography

GC – gastric cancer

RF – Russian Federation

CDU – color duplex ultrasonography

US – ultrasound examination

CRT – chemoradiotherapy

CT – chemotherapy

EGD – esophagogastroduodenoscopy

ECG – electrocardiography

** – vital and essential drugs

**** – drugs used for parenteral nutrition

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified
in the product information/instructions for use
)

Terms and Definitions

Relapse-free survival (RFS) – the time interval from the start of treatment to disease progression, development of a second malignancy, or patient death from any cause. Used in radical treatment of localized disease.

Time to progression (TTP) – the time interval from the start of treatment (or the date of randomization in clinical trials) to the date of disease progression, excluding patient deaths from causes unrelated to disease progression.

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

Progression-free survival (PFS) – the time interval from the start of treatment (or randomization date in clinical trials) to the date of disease progression or patient death from any cause.

Gastrectomy – removal of the stomach along with surrounding adipose tissue and lymph nodes.

Chemotherapy cycle is the time period calculated from the first to the last day of cytostatic administration.

Overall survival (OS) – the time interval from the start of treatment to patient death from any cause.

R1 resection – removal of the affected organ within healthy tissues along with regional lymph node basins, with microscopically detected residual tumor (at the resection margins).

R2 resection – removal of the affected organ along with regional lymph node basins, leaving macroscopic (visible) tumor residue.

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

Complete response (CR) – disappearance of all target lesions for at least 4 weeks.

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

Progressive disease (PD) – an increase of at least 20% in the sum of diameters of target lesions, taking as reference the smallest sum recorded since the treatment started and/or during follow-up, or the appearance of one or more new lesions.

Radical surgery (R0) – removal of the affected organ within healthy tissue boundaries along with regional metastasis zones, with no residual macroscopic evidence of the tumor process.

Symptomatic treatment – a set of therapeutic measures aimed at relieving the most distressing symptoms of the tumor process, treating complications, or managing the side effects of anticancer therapy.

Stable disease (SD) – neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study, and no new lesions or clear progression of non-target lesions.

Third stage of rehabilitation – rehabilitation during the early and late recovery periods and the period of residual disease effects, carried out in outpatient departments, day care units, or via mobile teams at home (including sanatorium-resort settings), utilizing physical therapy, exercise therapy, reflexology, manual therapy, psychotherapy, medical psychology, and speech therapy.

Chemotherapy cycle – the time period calculated from the first day of cytostatic administration to the planned first day of the next cycle, including the days of drug administration and the scheduled break between cycles. An example of a 21-day cycle is the XELOX regimen: 14 days of treatment followed by a 7-day break; examples of 14-day cycles include FOLFOX or FLOT regimens, where the next administration is scheduled for day 15, counting from day 1 of the previous cycle.

Partial response (PR) – at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, sustained for at least 4 weeks, with no clear progression of non-target lesions.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition (group of diseases or conditions)

Gastric cancer (GC) – a heterogeneous group of malignant epithelial tumors originating from the cells of the gastric mucosa.

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

GC is a multifactorial disease; the main risk factors include the following:

1. family history. The following hereditary cancers and hereditary syndromes with an increased risk of gastric cancer are distinguished:
   1. Hereditary diffuse gastric cancer. An autosomal dominant syndrome caused by mutations in the CDH1 gene, which encodes E-cadherin, a cell-cell adhesion molecule. It leads to signet-ring cell carcinoma, which accounts for 30–50% of cases. The cumulative risk of developing GC by age 80 reaches 67% for men and 83% for women, with the average age at diagnosis being 37 years;
   2. Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC). The risk of developing GC ranges from 1 to 13%;
   3. Juvenile polyposis syndrome. The risk of developing GC reaches 21%;
   4. Peutz-Jeghers syndrome. The risk of developing GC reaches 29%;
   5. Familial adenomatous polyposis. The risk of developing GC is 1–2%;
2. infection with Helicobacter pylori;
3. Lifestyle habits – smoking;
4. Dietary factors – alcohol consumption, excessive intake of salted, fried, canned, pickled, and highly spiced foods; consumption of mycotoxin-contaminated foods; micronutrient and vitamin deficiencies.

Background conditions: chronic atrophic hyperplastic gastritis, adenomatous polyps, pernicious anemia, post-gastrectomy status, Ménétrier disease (hypertrophic gastropathy, hyperplastic giant fold gastritis) [1–6].

1.3. Epidemiology of the disease or condition (group of diseases or conditions)

Gastric cancer is one of the most common human malignancies, ranking 5th in incidence and 3rd in cancer mortality in the Russian Federation. There is geographical heterogeneity in incidence, with the highest rates in Japan, Russia, Chile, Korea, and China, and the lowest in the USA, Australia, and New Zealand. Men are affected 1.3 times more often than women, with the peak incidence occurring at age 65 [6, 7].

1.4. Coding of the disease or condition (group of diseases or conditions) according to the International Statistical Classification of Diseases and Related Health Problems

Malignant neoplasm of stomach (C16):

C16.1 – Malignant neoplasm of cardia

C16.2 – Malignant neoplasm of body of stomach

C16.3 – Malignant neoplasm of pyloric antrum

C16.4 – Malignant neoplasm of pylorus

C16.5 – Malignant neoplasm of lesser curvature of stomach, unspecified

C16.6 – Malignant neoplasm of greater curvature of stomach, unspecified

C16.8 – Malignant neoplasm of overlapping sites of stomach

C16.9 – Malignant neoplasm of stomach, unspecified

1.5. Classification of the disease or condition (group of diseases or conditions)

1.5.1. WHO Classification of Tumours: Digestive System Tumours (5th ed., 2019) with ICD-O codes [8]

Benign epithelial tumors and pre-invasive lesions

8148/0 Low-grade glandular intraepithelial neoplasia

8148/2 High-grade glandular intraepithelial neoplasia

8213/0 Low-grade serrated dysplasia*

8213/2 High-grade serrated dysplasia*

Intestinal-type dysplasia

Foveolar-type dysplasia (gastric-type)

Gastric crypt dysplasia

8144/0 Low-grade intestinal-type adenoma*

8144/2 High-grade intestinal-type adenoma*

Sporadic intestinal-type gastric adenoma

Syndromic intestinal-type gastric adenoma

8210/0 Adenomatous polyp with low-grade dysplasia*

8210/2 Adenomatous polyp with high-grade dysplasia*

Malignant epithelial tumors

8140/3 Adenocarcinoma, NOS

8211/3 Tubular adenocarcinoma

8214/3 Parietal cell carcinoma

8255/3 Mixed adenocarcinoma

8260/3 Papillary adenocarcinoma, NOS

8265/3 Micropapillary carcinoma, NOS

8430/3 Mucoepidermoid carcinoma

8480/3 Mucinous adenocarcinoma

8490/3 Squamous cell carcinoma

8490/3 Diffuse gastric cancer (poorly cohesive carcinoma)

8512/3 Medullary carcinoma with lymphoid stroma

8576/3 Hepatoid adenocarcinoma

Paneth cell carcinoma

8070/3 Squamous cell carcinoma, NOS

8560/3 Adenosquamous carcinoma

8020/3 Undifferentiated carcinoma, NOS

8014/3 Large cell carcinoma with rhabdoid phenotype

8022/3 Pleomorphic carcinoma

8033/3 Sarcomatoid carcinoma

8035/3 Carcinoma with osteoclast-like giant cells

8976/1 Gastroblastoma*

8240/3 Neuroendocrine tumor, NOS

8240/3 Neuroendocrine tumor, G1

8249/3 Neuroendocrine tumor, G2

8249/3 Neuroendocrine tumor, G3

8153/3 Gastrinoma, NOS

8156/3 Somatostatinoma, NOS

8241/3 Enterochromaffin cell carcinoid

8242/3 ECL cell carcinoid

8246/3 Neuroendocrine carcinoma, NOS

8013/3 Large cell neuroendocrine carcinoma

8041/3 Small cell neuroendocrine carcinoma

8154/3 Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)

*Nosological entities first included in the current WHO Classification (2019) [8].

1.5.2. Histological classification of invasive GC according to Laurén (P. Laurén) (1965)

1. Intestinal type: adenocarcinoma is characterized by papillary and/or glandular structures of varying sizes, as well as solid areas; the degree of mucin production is not significant (prototypes: intestinal-type adenocarcinoma).
2. Diffuse type: adenocarcinoma is composed of diffusely growing cells with a variable content of intracellular and extracellular mucin, without the formation of glandular, papillary, or solid architectural patterns; tumor cells may exhibit either signet-ring cell or non-signet-ring cell morphology (prototypes: signet-ring cell carcinoma).
3. Mixed type: adenocarcinoma is represented by various combinations of intestinal and diffuse type areas.
4. Unclassified type: this type includes all gastric carcinomas that lack the morphological characteristics of any of the types described above [3].

The use of other morphological classification schemes for gastric cancer (Goseki, Ming, etc.) is permissible, but is not a mandatory component of the histological report.

1.5.3. Macroscopic classification of gastric cancer

1. "Early" gastric cancer (T1N0–3M0):

• Type 0 – superficial flat tumors:
• Type 0-I – elevated (tumor height is 2 or more times the thickness of the mucosa);
• Type 0-II – superficial:
• 0-IIa – elevated type;
• 0-IIb – flat type;
• 0-IIc – depressed type.
• Type 0-III – ulcerated (ulcerative mucosal defect).

2. Advanced gastric cancer:

• Type I – fungating or polypoid;
• Type II – ulcerated with well-defined margins (bavarian/discs-shaped / saucer-like);
• Type III – ulcerated-infiltrative;
• Type IV – diffusely infiltrative (linitis plastica);
• Type V – unclassified tumors.

1.5.4. Japanese classification of regional lymph nodes of the stomach.

Standard anatomical nomenclature of the lymphatic system of the stomach is rarely used in the treatment of gastric cancer patients because it does not reflect the sequence of lymph drainage and the prognostic role of metastatic involvement of a particular lymph node group depending on the tumor location in the stomach. In addition, there is a need to systematize the extent of surgical interventions on the lymphatic system. The classification by the Japanese Gastric Cancer Association (1998) is the most successful from a practical point of view (Table 1) [9].

Currently, the numbering system for lymph node groups is adopted by the majority of surgical oncologists and recommended by the international community for classifying the extent of lymph node dissection in gastric cancer. The assignment of a particular lymph node group to the 1st, 2nd, or 3rd tier of lymph drainage may vary depending on the tumor location in the stomach.

Table 1. Assignment of regional gastric lymph nodes to the 1st, 2nd, or 3rd tier of lymph drainage depending on tumor location

In accordance with the classification described above, the scope of lymph node dissection in gastric cancer is determined as follows:

• D0 – absence of lymph node dissection or incomplete removal of 1st-tier lymph nodes;
• D1 (standard lymph node dissection) – removal of 1st-tier lymph nodes (groups 1–6);
• D2 (extended lymph node dissection) – removal of 1st- and 2nd-tier lymph nodes (perigastric lymph nodes, lymph nodes along the branches of the celiac trunk and the hepatoduodenal ligament, groups 1–11, 12a, 14v)*;
• D3 (para-aortic lymph node dissection) – removal of 1st-, 2nd-, and 3rd-tier lymph nodes.

Notes:

• * – the extent of D2 lymph node dissection varies depending on the tumor location in the stomach and the type of surgical intervention (distal or proximal subtotal resection, gastrectomy);
• for "early" gastric cancer, incomplete removal of 2nd-tier lymph nodes is permitted, the so-called D1+ lymph node dissection (see "Surgical treatment of early gastric cancer");
• ** – removal of lymph node (LN) groups 13, 14a, and 15 is not included in the scope of D3 lymph node dissection due to the extremely unfavorable prognosis in case of their metastatic involvement;
• according to the TNM classification (international tumor staging system), UICC, involvement of 3rd-tier lymph nodes is classified as M1.

1.5.5. TNM Staging of Gastric Cancer (8th ed.)

Gastric cancer staging is based on clinical examination results (cTNM) [3]; in the absence of distant metastases, the definitive stage is established postoperatively based on the histological examination of the surgical specimen (pTNM), which must evaluate the following parameters:

1. depth of tumor invasion into the gastric wall and extension beyond its boundaries ("T" category);
2. number of removed lymph nodes and number of lymph nodes affected by metastases ("N" category); to determine the "N" category, at least 16 removed lymph nodes must be examined.

In cases where the tumor is evaluated during or immediately following combined-modality or multimodal treatment, the cTNM or pTNM categories are preceded by the prefix "y". The ycTNM or ypTNM values characterize the extent of the tumor at the time of examination.

When the esophagogastric junction is involved by a tumor, an adenocarcinoma whose center is located 2–5 cm below the anatomical esophagogastric junction (Siewert type III) is classified and treated as gastric cancer. If the center of the adenocarcinoma involving the esophagogastric junction is located at the level of the squamocolumnar junction, i.e., within 2 cm below and 1 cm above the anatomical esophagogastric junction (Siewert type II), or in the lower third of the esophagus above the anatomical esophagogastric junction within 1–5 cm (Siewert type I), the process is classified and treated as esophageal cancer.

The treatment tactics for localized forms of Siewert type I and II esophagogastric junction adenocarcinoma are similar to those for esophageal cancer, whereas the treatment for disseminated and metastatic forms is similar to that of disseminated gastric cancer [3].

The TNM classification of gastric cancer and stage grouping according to the 8th edition of the American Joint Committee on Cancer (AJCC) are presented in Tables 2 and 3.

Table 2. AJCC TNM Classification (8th ed., 2017)

Table 3. Gastric cancer: stage grouping (prognostic groups)

1.6. Clinical presentation of the disease or condition (groups of diseases or conditions)

Clinical symptoms of GC can be divided into general symptoms (general weakness, progressive weight loss, loss of appetite, nausea, anemia, epigastric pain) and symptoms caused by the tumor location, growth pattern, and metastasis. When the tumor is located in the gastroesophageal junction, dysphagia occurs; in gastric antral cancer with pyloric stenosis, nausea and vomiting of ingested food are observed. Ulcerated cancer is more often complicated by bleeding and perforation, while diffuse-infiltrative cancer, leading to a decrease in stomach capacity, is accompanied by a feeling of fullness after eating a small amount of food [11–13].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1. anamnestic data;
2. physical examination and instrumental test data;
3. pathological anatomy examination data.

2.1. Complaints and anamnesis

2.2. Physical examination

2.3. Laboratory diagnostic tests

Comments: detailed clinical and general biochemical blood tests, blood clotting system assessment, and urinalysis are performed prior to planning any treatment method. In patients receiving chemotherapy, clinical and biochemical blood tests are performed before each cycle, while other tests are performed according to clinical indications.

2.4. Instrumental diagnostic tests

Comments: endoscopic examination is the most informative diagnostic method for GC, allowing direct visualization of the tumor, determination of its size, location, and macroscopic type, assessment of the risk of complications (bleeding, perforation), as well as obtaining material for morphological examination. To obtain a sufficient amount of material, 6–8 biopsies using standard endoscopic forceps must be performed. In case of submucosal infiltrative tumor growth, a false-negative biopsy result is possible, which requires repeated deep biopsy. The efficacy of the method increases when modern endoscopic imaging technologies are used (magnifying endoscopy, narrow-band imaging, chromoendoscopy, fluorescence diagnostics). In patients receiving palliative systemic therapy, esophagogastroduodenoscopy (EGD) to assess treatment efficacy is performed according to clinical indications.

• Patients with "early" GC (T1N0–3M0) are recommended to undergo gastric endosonography when endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is planned [4, 5, 14–17].

GCP BLOE 1Level of Evidence – B (Grade of Recommendation – 1).

Comments: endoscopic ultrasonography (endosonography) performed prior to treatment allows determination of the depth of tumor invasion (T stage) and the presence of pathologically altered or enlarged involved lymph nodes (N stage), as well as tumor invasion into adjacent structures. This method is of particular importance in "early" gastric cancer (cTcis–T1aN0M0), where precise determination of the depth of invasion and the extent of the process enables the planning of organ-sparing treatment (endoscopic resection).

Comments: multi-position radiocontrast examination allows determining the location and extent of the tumor lesion, detecting spread to the esophagus and duodenum, and assessing the severity and extent of stenosis. Radiological examination has high efficacy in diffuse-infiltrative gastric cancer, when biopsy results may be negative due to submucosal growth. Performing radiography in early gastric cancer is impractical due to low information value.

• All patients diagnosed with gastric cancer are recommended to undergo ultrasound examination (ultrasound) of the supraclavicular areas and, if timely CT/MRI is not feasible, of the abdominal cavity, retroperitoneal space, and lesser pelvis for initial assessment of tumor spread [4–5, 18].

GGR CLeveled Evidence 5Level of evidence and recommendation grade – C (level of confidence of data – 5).

Comments: transabdominal ultrasound allows detecting metastatic liver lesions, enlargement of perigastric and retroperitoneal lymph nodes, ovarian involvement, ascites, as well as tumor invasion beyond the organ wall and involvement of adjacent structures. The advantages of the method are its non-invasive nature, simplicity, and availability, while the main disadvantages are the influence of subjective and objective factors on the accuracy of the obtained information (patient's body habitus, preparation for the study, technical characteristics of the equipment, and the physician's experience).

• All patients diagnosed with gastric cancer are recommended to undergo computed tomography (CT) of the chest, abdomen, and pelvis with intravenous and oral contrast enhancement to assess the extent of the tumor process and plan treatment [4, 5, 19–21].

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

Comments: CT of the chest, abdomen, and pelvis with intravenous and oral contrast enhancement is the standard of staging diagnostics for gastric cancer in most developed countries. In practice, if timely CT/MRI is not feasible, these studies can be partially replaced by abdominal and pelvic ultrasound and chest radiography in two projections for patients in situations where the detection of metastases is of no clinical significance (e.g., patients with distant metastases receiving palliative chemotherapy to assess disease dynamics [22, 23]).

• Patients diagnosed with stage IB–III gastric cancer are recommended to undergo diagnostic laparoscopy with peritoneal washings for cytological examination (determination) of free tumor cells in the lavage and tissue sampling of identified lesions for pathological examination to detect peritoneal dissemination and free tumor cells in peritoneal washings [5, 24–28].

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

Comments: Diagnostic laparoscopy is the most accurate method for preoperative staging of peritoneal dissemination and also allows for the assessment of the location and extent of the primary tumor's involvement of the serosa. Diagnostic laparoscopy must include obtaining tissue samples of the identified lesions for pathological examination and collecting peritoneal washings for cytological examination to detect free tumor cells in the lavage fluid. Cytological examination of peritoneal washings is a mandatory component of tumor staging. The detection of tumor cells in peritoneal washings is classified as M1 and requires appropriate treatment [4, 5, 26–27]. Diagnostic laparoscopy is the most informative method for assessing the efficacy of chemotherapy in peritoneal tumor dissemination. The procedure is mandatory for total and subtotal gastric lesions.

• To assess the extent of the tumor process when planning specific antineoplastic treatment, all patients diagnosed with gastric cancer are recommended to undergo cervical lymph node ultrasonography [29].

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

2.5. Other diagnostic tests

2.5.1. Pathological anatomical examination

• In all patients diagnosed with gastric cancer after surgical treatment, it is recommended to perform a pathological examination of the surgical specimen, and the report should include the following characteristics to determine the stage of the disease and prognosis [7, 8]:
• Tumor histological type: WHO classification nomenclature (2019) [8].
• Presence of signet-ring cells in the tumor: not detected / proportion of signet-ring cells <50% (adenocarcinoma with signet-ring cell component) / signet-ring cell carcinoma.
• Grade (if applicable): indicate only a single grade—the highest grade (the proportion of the most aggressive component must be at least 15% of the invasive tumor volume).
• Tumor invasion into: lamina propria of the mucosa / muscularis mucosae / submucosa / muscularis propria / subserosa / serosa.
• Invasion into adjacent structures: not detected / spleen / transverse colon / liver / diaphragm / pancreas / abdominal wall / adrenal gland / kidney / small intestine / retroperitoneal adipose tissue / other (specify).
• Invasion into omenta: not detected / greater omentum without peritoneal invasion (including the omental peritoneum) / lesser omentum without peritoneal invasion (including the omental peritoneum).
• Spread of tumor to the duodenal wall: not detected / invasion into mucosa / submucosa / muscularis propria / serosa.
• Spread to the esophageal wall: not detected / invasion into mucosa / submucosa / muscularis propria / adventitia.
• Lauren type – intestinal / diffuse / mixed / unclassified.
• Proximal resection margin – R0 / R1 / R2.
• Distal resection margin – R0 / R1 / R2.
• Circumferential resection margin (for cardial tumors only) – (distance in mm).
• Gastric mucosa away from the tumor.
• Lymphovascular invasion.
• Perineural invasion.
• Tumor regression grade / therapeutic pathomorphism (Becker K. et al., Mandard A.M. et al. [32, 33]).
• Number of lymph nodes examined (at least 16 lymph nodes must be examined).
• Number of affected lymph nodes.
• Number of lymph nodes with micrometastases or isolated tumor cells.
• Lymph nodes by groups (if labeled by groups by the clinician) [3, 4, 5, 8, 9, 34, 35].

GGR CLeveled Evidence 5Level of evidence and recommendation grade – C (level of confidence of data – 5).

Comments: taking into account the requirements of the latest WHO classification (2019), the histological grading of gastric adenocarcinoma is preferably performed in a binary manner, dividing tumors into low grade or high grade malignancy, replacing the previously used four-tier grading scheme. For the continuity of grading schemes, Appendix G3 provides the histological grading of gastric adenocarcinomas.

It should be noted that certain types of gastric carcinomas either always have a single (fixed) grade of malignancy or, due to their extreme rarity, have no grade assigned at all. Given these features, indicating the grade of malignancy in the histological report is optional for the following neoplasms: micropapillary carcinoma, signet-ring cell carcinoma (G3), medullary carcinoma with lymphoid stroma (G3), hepatoid adenocarcinoma, undifferentiated carcinoma (G4), pleomorphic carcinoma (G4), sarcomatoid carcinoma, carcinoma with osteoclast-like giant cells, large cell carcinoma with rhabdoid phenotype, gastroblastoma, large cell neuroendocrine carcinoma (G3), small cell carcinoma (G3).

In neoplasms with a mixed structure (e.g., MiNEN), the grade of malignancy must be specified for each component separately. The prognosis of the disease is evaluated taking into account the most malignant component of the mixed tumor.

Clinical and morphological features of malignant epithelial neoplasms of the stomach

Tubular adenocarcinoma is the most frequent type of gastric adenocarcinoma (45–64% of cases), the prognosis of which is directly associated with the histological grade of the tumor.

Diffuse carcinoma (including signet-ring cell carcinoma) is the second most frequent histological type of gastric adenocarcinoma (20–54% of cases), which is always poorly differentiated and has a high grade of malignancy.

Mucinous adenocarcinoma accounts for 2.1–8.1% of cases; genetically, this type of cancer differs from intestinal- or diffuse-type adenocarcinomas (according to Lauren).

Papillary adenocarcinoma accounts for no more than 10% of gastric cancer cases; despite being well-differentiated, the tumor is characterized by a high frequency of liver metastases and an unfavorable prognosis.

Mixed adenocarcinoma occurs in 6–22% of cases and consists of at least two distinct histological variants of adenocarcinoma. The prognosis of mixed adenocarcinomas is less favorable compared to single-component counterparts.

Medullary carcinoma with lymphoid stroma is an adenocarcinoma whose carcinogenesis is associated with the Epstein-Barr virus; the frequency of medullary carcinoma is 1–7%; despite poor differentiation, the tumor is characterized by a favorable prognosis; in doubtful cases, fluorescence in situ hybridization (EBER) is recommended to verify the diagnosis.

Micropapillary carcinoma as an independent tumor (rather than a minor component of more common adenocarcinomas) is relatively rare and is characterized by a high frequency of lymph node metastases.

Squamous cell carcinoma and adenosquamous carcinoma are rare histological variants of gastric cancer that may exhibit a more aggressive clinical course compared to typical adenocarcinoma of a similar stage.

Mucoepidermoid carcinoma, paneth cell carcinoma, parietal cell carcinoma, hepatoid adenocarcinoma, carcinoma with osteoclast-like giant cells, large cell carcinoma with rhabdoid phenotype, pleomorphic carcinoma, and sarcomatoid (spindle cell) carcinoma are extremely rare variants of gastric cancer; in some cases, additional morphological diagnostic methods are mandatory for verification.

Undifferentiated (anaplastic) carcinoma is always a diagnosis of exclusion and can only be made when adenogenic, squamous, neuroendocrine, or other specialized differentiation of the tumor has been completely ruled out using additional morphological research methods; the tumor is characterized by a more aggressive clinical course compared to typical adenocarcinoma of a similar stage.

Gastroblastoma is an extremely rare biphasic tumor associated with MALAT-GLI1 translocation, predominantly affecting males at a young age (median – 27 years); diagnosis requires detection of the MALAT-GLI1 translocation; due to its rarity, the prognosis currently cannot be determined [3,4,5,8,9,34,35].

2.5.2. Evaluation of therapeutic pathomorphosis

• In all patients diagnosed with gastric cancer who received preoperative chemotherapy or radiation therapy, it is recommended to assess the therapeutic response (pathomorphosis) in the surgical specimen in accordance with the classification by Becker K. [32] or Mandard A.M. [33] (see Appendix G.4).

GCR BLEL 4Grade of recommendation – B (level of evidence – 4).

Comments: currently, there is no universally accepted scheme in global practice for assessing therapeutic pathomorphosis (Tumor Regression Grade, TRG) in gastric carcinomas. Nevertheless, the WHO expert panel suggests using well-established schemes proposed byBecker Ket al. orMandar d A.Met al. The use of therapeutic response assessment schemes according to E.F. Lushnikov or G.A. Lavnikova is not recommended. Assessment of the therapeutic effect can be performed only upon examination of the surgical specimen and strictly in the invasive component of the residual tumor (total examination of the residual carcinoma bed is required).

2.5.3. Additional immunohistochemical and molecular genetic studies

• To determine indications for targeted therapy in cases of locally advanced unresectable or disseminated adenocarcinoma when examining surgical or biopsy material, it is recommended:

1. pathological examination of the HER2/neu receptor protein using immunohistochemical methods or determination of HER2 gene amplification by fluorescence in situ hybridization (FISH) to determine indications for trastuzumab therapy** [36];
2. determination of DNA microsatellite repeats in biopsy (surgical) material by PCR or DNA mismatch repair deficiency to determine indications for immunotherapy [37];
3. determination of PD-L1 protein expression by immunohistochemistry in tumor blocks to determine indications for monoclonal antibodies (PD-1 receptor inhibitors). The result is considered positive if the combined positive score (CPS) is ≥1. CPS is the ratio of PD-L1-stained cells (including tumor cells, lymphocytes, and macrophages) to the total number of tumor cells, multiplied by 100 [4-5,38].

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

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

3.1. Surgical treatment

3.1.1. Endoscopic treatment of "early" gastric cancer (cTis–T1aN0M0)

Comments: an important clinical feature of "early" gastric cancer is the low incidence of lymphogenic metastasis. The overall rate of regional lymph node involvement in T₁ category tumors does not exceed 10–15%. For invasion confined to the mucosal layer, this figure is about 3%, and with submucosal involvement, it reaches 20%. When features such as mucosal confinement, tumor size up to 2 cm, type I, IIa–b growth pattern, and high or moderate differentiation grade are combined, lymph node metastases are virtually absent [39,40].

Patient selection criteria for EMR or ESD [39,40]:

• invasion confined to the mucosa (including carcinoma in situ; T1a);
• high or moderately differentiated adenocarcinoma;
• type I, IIa–b tumor up to 2 cm in size without ulceration;
• absence of clinically detectable (endosonography, CT) metastases in regional lymph nodes.

Indications for endoscopic treatment may be expanded in patients at high risk for surgery. When planning endoscopic treatment, all patients undergo a comprehensive endoscopic examination using modern techniques (computed tomography, magnifying endoscopy, NBI, chromoendoscopy, endosonography) to assess the depth of invasion and determine the true margins of the lesion, including foci of severe dysplasia [39,40].

Options for endoscopic treatment:

Comments: the most frequent complications of endoscopic treatment are bleeding and perforation, therefore the patient must be prepared for endoscopic mucosal resection as for open surgery. In most cases, bleeding can be stopped using endoscopic hemostasis methods. After surgery, proton pump inhibitors are prescribed until complete healing of the resulting mucosal defect.

3.1.2. Surgical treatment for "early" gastric cancer

Comments: surgical intervention is indicated for "early" gastric cancer in patients who do not meet the criteria for endoscopic treatment.

The standard scope of surgery for "early" cancer is similar to that for advanced cancer and includes subtotal gastrectomy or total gastrectomy with lymphadenectomy. Given the low rate of secondary lymph node involvement, according to the Japanese Gastric Cancer Association guidelines, adequate and sufficient lymphadenectomy for T1 tumors is the removal of perigastric lymph nodes, as well as lymph nodes No. 7, 8a, 9 (D1+ lymphadenectomy) [40].

Laparoscopic distal subtotal resection for "early" gastric cancer does not increase postoperative morbidity and mortality and does not worsen prognosis. Laparoscopic distal subtotal gastrectomy for "early" gastric cancer can be recommended as a standard surgical option alongside conventional open procedures [44,45].

3.1.3. Surgical treatment of gastric cancer patients at stage ≥сT1b

Comments: oncological contraindications to surgery in gastric cancer are the presence of distant metastases. In these cases, surgery is performed for vital indications in patients with complicated tumor courses (perforation, bleeding, stenosis) within resection limits; lymph node dissection is not indicated.

Local treatment (surgery, radiofrequency ablation, stereotactic body radiotherapy) for oligometastatic disease may be considered in carefully selected patients with a good response to medical therapy and the possibility of achieving an R0 status following surgery. In cases of disease progression presenting as an isolated ovarian metastasis, patients may undergo surgical removal; however, this strategy must be discussed by a multidisciplinary team [5].

When the tumor directly invades adjacent organs and anatomical structures (liver, pancreas, colon, diaphragm), combined resections are performed [ 40, 46-48].

The planning and execution of surgical treatment for gastric cancer involve several stages: choice of surgical access, determination of the extent of resection on the organ, lymph node dissection (lymphadenectomy), and selection of the reconstruction method.

3.1.3.1. Choice of surgical access

• In patients with early gastric cancer who are not candidates for EMR/ESD, it is recommended to perform surgery via an open or laparoscopic approach [ 46-48].

GCR BLEL 2Grade of recommendation – B (level of evidence – 2).

Comments: one of the surgical approaches is laparoscopic. Resection via a laparoscopic approach for early gastric cancer can be considered a standard procedure alongside open surgery for early distal gastric cancer [44,45]. The role of the laparoscopic approach in operations for locally advanced gastric cancer is currently under investigation [49 - 53]. Performing laparoscopic surgery for advanced gastric cancer, as well as in cases requiring gastrectomy, should only be recommended in medical institutions with adequate equipment and trained specialists.

• In patients diagnosed with gastric cancer undergoing open resection, it is recommended to use a laparotomy or combined thoraco-laparotomic approach, depending on the level of esophageal involvement [4,5,46-48].

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

Comments: the choice of surgical access in open surgery depends on the level of tumor extension to the esophagus and the patient's functional status.

For limited tumors involving the cardia and extending to the distal esophagus, a left thoraco-laparotomic approach or a wide phrenotomy via a laparotomic approach may be used.

• In gastric cancer with total gastric involvement extending to the esophagus, or cancer of the body extending to the proximal stomach and esophagus, a combined abdominothoracic approach does not improve long-term outcomes due to early peritoneal dissemination. In these cases, an abdominomediastinal approach is recommended (in some cases, with high esophageal transection, a left-sided thoracotomy through the 6th intercostal space may be used to safely construct the esophago-jejunal anastomosis) [4,5,46-48]. In gastric cancer without involvement of the gastroesophageal junction and esophagus, it is advisable to perform the operation through a midline laparotomy access.

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

3.1.3.2. Choice of the extent of gastric resection

Comments: distal subtotal gastrectomy is acceptable in patients with low functional reserves when the tumor extends to the lower third of the gastric body, provided it has an exophytic or mixed growth pattern (Borrmann types I–II). Lymph nodes not removed during this procedure (left paracardial nodes, nodes at the splenic hilum) are extremely rarely involved in cancer of the lower third of the stomach [48].

• For resectable gastric cancer of the linitis plastica type, undifferentiated carcinomas, and hereditary diffuse gastric cancer syndrome, it is recommended to perform total gastrectomy only [4, 5, 40].

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

• For resectable gastric cancer of the linitis plastica type, undifferentiated carcinomas, and hereditary diffuse gastric cancer syndrome, it is recommended to perform total gastrectomy only [4,5,40].

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

Comments: The scope of radical surgery for gastric cancer must include:

• en bloc resection of the affected stomach (or the relevant part of it) along with both omenta, surrounding adipose tissue, and regional lymph nodes;
• transection of the organ at a distance of at least 5 cm from the macroscopically visible tumor margin for localized (Borrmann types I–II) growth types, and at least 6–7 cm for ulcerating-infiltrative and diffuse (Borrmann types III–IV) types. To confirm the radicality of the surgery, frozen section analysis of the resection margins is performed [4, 5].

3.1.3.3. Lymphadenectomy

Comments: Regional lymph node metastasis in gastric cancer is one of the leading prognostic factors. The overall incidence of lymphogenic metastasis in gastric cancer directly depends on the depth of invasion. For T1 tumors, the rate of lymph node involvement does not exceed 10–15%, whereas for T4b tumors it reaches 90%. First- and second-tier lymph nodes (nos. 1–11) are most frequently involved in gastric cancer, accounting for 15.7% and 20.3%, respectively.

For T1 gastric tumors, an adequate and sufficient extent of lymphadenectomy is the removal of perigastric lymph nodes, as well as lymph node stations 7, 8a, and 9 (D1+ lymphadenectomy) [40].

The standard scope of lymphatic system intervention in gastric cancer is currently considered to be the removal of first- and second-tier lymph nodes – D2 lymphadenectomy. Para-aortic lymphadenectomy (D3) is impractical, as it does not improve patient survival and is associated with a higher rate of postoperative complications [55].

Currently, the set of lymph node groups removed during lymphadenectomy is related not to the location of the primary tumor in a specific part of the stomach, but to the type of surgery.

Types of lymphadenectomy in GE [40]:

• D1 lymphadenectomy – removal of lymph node stations 1–7;
• D1+ lymphadenectomy – removal of lymph node stations 1–7, 8a, 9, 11p (plus station 110 if the tumor extends to the esophagus);
• D2 lymphadenectomy – removal of lymph node stations 1–7, 8a, 9, 10, 11p, 11d, and 12a (plus stations 19, 20, 110, and 111 if the tumor extends to the esophagus).

Types of lymphadenectomy in distal gastrectomy:

• D1 lymphadenectomy – removal of lymph node stations 1, 3, 4sb, 5, 6, and 7;
• D1+ lymphadenectomy – removal of lymph node stations 1, 3, 4sb, 5, 6, 7, 8a, and 9;
• D2 lymphadenectomy – removal of lymph node stations 1, 3, 4sb, 5, 6, 7, 8a, 9, 11p, and 12a.

Types of lymphadenectomy in proximal gastrectomy:

• D1 lymphadenectomy – removal of lymph node stations 1, 2, 3a, 4sb, 4sa, and 7;
• D1+ lymphadenectomy – removal of lymph node stations 1, 2, 3a, 4sb, 4sa, and 7, as well as stations 8a, 9, and 11p (plus station 110 if the tumor extends to the esophagus);
• D2 lymphadenectomy – not applicable

Routine splenectomy in gastric cancer is currently considered inappropriate, as it does not affect prognosis, while increasing complication rates and mortality [56,57].

3.2. Combined modality treatment of gastric cancer in the absence of distant metastases

1) for cT≥2NanyM0 – perioperative chemotherapy [5, 58-62];

2) if treatment is initiated with R0 surgery and pTanyN1–3M0, pT4N0M0, or pT3N0M0 in the presence of one or more negative prognostic factors (poorly differentiated tumor, lymphovascular or perineural invasion, age <50 years, lymph node dissection <D2, fewer than 15 lymph nodes examined) – adjuvant chemotherapy (CT) is recommended [5,63,64];

3) following surgical intervention in the volume of R1/2 as the first stage of treatment – adjuvant chemoradiotherapy [65,66] or CT [63,64].

GCR BLEL 2Grade of recommendation – B (level of evidence – 2).

3.2.1. Perioperative chemotherapy

Comments: FLOT regimen: Docetaxel** 50 mg/m² IV infusion on day 1 + #Oxaliplatin** 85 mg/m2 on day 1 + #Calcium folinate** 200 mg/m2 2-hour IV infusion on day 1 + fluorouracil** 2600 mg/m2 continuous IV infusion over 24 hours (infusion of the same total dose of fluorouracil** over 48 hours is acceptable) on day 1.

Repeat every 2 weeks

Two randomized trials have demonstrated that administering CT (CF or ECF regimens) for 8–9 weeks before and after surgery leads to a reliable and significant increase in R0 resection rates, DFS, and OS compared to surgery alone. The absolute gain in 5-year OS was 13–14% [58, 59]. In the German AIO trial [60], administering 4 cycles of FLOT chemotherapy before surgery and 4 identical cycles after surgery resulted in a significant increase in OS compared to perioperative ECF chemotherapy.

Comments:

mFOLFOX6 regimen - #Oxaliplatin** 85 mg/m² on day 1 + #Calcium folinate** 400 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 400 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2400 mg/m² over a duration of at least 46 hours. Repeat every 2 weeks [61].

XELOX (CAPOX)

Capecitabine** 1000 mg/m² twice daily orally from days 1 to 14 of the cycle or from the evening of day 1 to the morning of day 15 of the cycle + #Oxaliplatin** 130 mg/m² (dose reduction to 100 mg/m² without loss of efficacy is permissible in disseminated disease) IV infusion on day 1. Repeat every 3 weeks [62].

3.2.2. Adjuvant chemotherapy

Randomized clinical trials have shown that supplementing surgical treatment with adjuvant chemotherapy improves outcomes: administration of the oral pyrimidine analogue Tegafur+[Gimeracil+Oteracil] (S-1) for 12 months [63] after surgical treatment with D2 lymph node dissection in stage II–III gastric cancer led to a significant improvement in 5-year OS from 69% to 78%; administration of the XELOX regimen for 6 months after surgery led to an increase in 5-year DFS from 53% to 68% across all stages: II, IIIA, IIIB [64].

Comments: XELOX (CAPOX) regimen - capecitabine** 1000 mg/m² twice daily orally from days 1 to 14 of the cycle or from the evening of day 1 to the morning of day 15 of the cycle + #Oxaliplatin** 130 mg/m² (dose reduction to 100 mg/m² without loss of efficacy is permissible in disseminated disease) IV infusion on day 1. Repeat every 3 weeks.

According to the results of a retrospective analysis of MAGIC and CLASSIC trial data, the advisability of prescribing adjuvant CT is questionable in the presence of high microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR) in the tumor. However, due to the insufficient number of patients with MSI-H in these studies, it is premature to draw definitive conclusions [67, 68].

3.2.3. Postoperative chemoradiotherapy

Comments: postoperative chemoradiotherapy has long been the standard of care in the USA based on a study comparing adjuvant chemoradiotherapy with surgery alone followed by observation [69, 70]. However, the negative results of the CRITICS trial, which showed no improvement in OS from the addition of radiotherapy to perioperative CT, and the positive results of trials on perioperative CT [71] have led to a loss of interest in the use of adjuvant chemoradiotherapy.

3.3. Drug Treatment

3.3.1. Pharmacotherapy of Locally Advanced Unresectable and Disseminated Gastric and Gastroesophageal Junction Adenocarcinoma

Comments: drug therapy is the primary treatment method for disseminated gastric cancer.

3.3.2. First-line Drug Therapy

Principles of first-line systemic drug therapy:

• the standard first-line CT regimen for disseminated gastric cancer is a combination of platinum derivatives with pyrimidine analogues, i.e., XELOX, CF, CX, FOLFOX regimens; an alternative combination is #irinotecan** with pyrimidine analogues: IF, #FOLFIRI. These regimens are equally effective, differing only in their toxicity profile [72-77];
• when selecting a drug therapy regimen, it is necessary to consider the patient's general condition, the number and severity of comorbidities, the toxicity profile of the regimens, and the HER2 status of the tumor;
• the advisability of using anthracyclines in first-line therapy is questionable: according to a large randomized phase III clinical trial, the efficacy of the #FOLFIRI regimen is equal to that of the ECX regimen in first-line therapy, while exhibiting lower toxicity and better tolerability [74];
• infusional administration of fluorouracil** is more effective than bolus administration; in combinations based on the infusional administration of this drug, replacing the infusion with a bolus injection is unacceptable [72];
• capecitabine**[77] is the equivalent of infusional fluorouracil**;
• #cisplatin** and #oxaliplatin** are interchangeable drugs, with the choice of drug determined by the toxicity profile [4, 5, 72];
• Evaluation of drug therapy efficacy is performed every 6–8 weeks ± 1 week.

• For patients with an ECOG performance status of 2 and/or moderate comorbidities, it is recommended to initiate treatment with double combinations at reduced doses (XELOX, FOLFOX) or with monotherapy, followed by the use of combination regimens after the patient's general condition improves [4, 5, 72].

Level of evidence – CGrade of recommendation – 5Level of recommendation – C (level of evidence – 5)

Comments:

First-line monotherapy regimens:

• fluorouracil** 800 mg/m²/day over 24 hours on days 1–5 every 4 weeks [5];
• #Calcium folinate** 400 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 400 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2400 mg/m² for at least 46 hours, every 2 weeks [5]
• Capecitabine**: 2000 mg/m²/day orally (in 2 doses) from days 1 to 14, every 3 weeks [5]
• Docetaxel** 75–100 mg/m² once every 3 weeks [5]
• #Paclitaxel** 80 mg/m² on days 1, 8, 15 every 4 weeks [5]
• #Paclitaxel** 135–175 mg/m² once every 3 weeks [5]

First-line combination chemotherapy regimens:

• mFOLFOX6 regimen - #Oxaliplatin** 85 mg/m² on day 1 + #Calcium folinate** 400 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 400 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2400 mg/m² over at least 46 hours. Repeated every 2 weeks [75].
• XELOX (CAPOX): Capecitabine** 1000 mg/m² twice daily orally from day 1 to 14 of the cycle or from the evening of day 1 to the morning of day 15 of the cycle + #Oxaliplatin** 130 mg/m² (in disseminated disease, dose reduction to 100 mg/m² is permissible without loss of efficacy) IV drip on day 1. Repeated every 3 weeks [5].
• #CF, PF: #Cisplatin** 100 mg/m² IV drip on day 1 with hyperhydration and antiemetics + fluorouracil** 1000 mg/m²/day 24-hour IV infusion on days 1, 2, 3, 4, 5. Repeated every 4 weeks [76] .
• Modification of the #CF, PF regimen: #Cisplatin** 80 mg/m² IV drip on day 1 with hyperhydration and antiemetics + fluorouracil** 800 mg/m²/day 24-hour IV infusion on days 1, 2, 3, 4, 5. Repeated every 3 weeks [77].
• #Cisplatin** 75 mg/m2 IV drip on day 1 with hyperhydration and antiemetics + fluorouracil** 750 mg/m2/day 24-hour IV infusion on days 1, 2, 3, 4. Repeated every 4 weeks [5]
• #FOLFIRI: #Irinotecan** 180 mg/m² on day 1 + #Calcium folinate** 400 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 400 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2400 mg/m² over at least 46 hours. Repeated every 2 weeks [ 74].
• XP: Capecitabine** 1000 mg/m² twice daily orally from day 1 to 14 of the cycle or from the evening of day 1 to the morning of day 15 of the cycle + #Cisplatin** 80 mg/m² IV drip with hyperhydration and antiemetics on day 1. Repeated every 3 weeks [77].

• The administration of triplet chemotherapy regimens (DCF, mDCF, FLOT, FOLFOXINORX/FOLFIRINOX, EOX) is recommended for patients in generally satisfactory condition (ECOG 0–1), free of comorbidities and visceral organ dysfunction; a mandatory condition is the possibility of weekly monitoring of side effects and timely administration of supportive therapy [72, 76, 78-85].

GPR BLOE 2Level of Recommendation – B (Level of Evidence – 2).

Comments:

Triplet regimens:

• FLOT: Docetaxel** 50 mg/m² IV drip on day 1 + #Oxaliplatin** 85 mg/m² on day 1 + #Calcium folinate** 200 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 2600 mg/m² 24-hour IV infusion (infusion of the same total dose of fluorouracil** over 48 hours is permitted) on day 1. Repeated every 2 weeks [60].
• EOX: Epirubicin** 50 mg/m² IV bolus on day 1 + #oxaliplatin** 130 mg/m² IV drip on day 1 + capecitabine** 625 mg/m² twice daily orally from day 1 to 21. Repeated every 3 weeks[84, 85].
• DCF: Docetaxel** 75 mg/m² IV drip on day 1 + #Cisplatin** 75 mg/m² IV drip with hyperhydration and antiemetics on day 1 + fluorouracil** 750 mg/m² per day 24-hour infusion on days 1, 2, 3, 4, 5. Repeated every 3 weeks [76,78].
• mDCF: Docetaxel** 40 mg/m² IV drip on day 1 + #Cisplatin** 40 mg/m² on day 3 + fluorouracil** 2000 mg/m² on day 1 as a continuous IV infusion for 48 hours. Repeated every 2 weeks [79].
• #FOLFIRINOX: #Irinotecan** 180 mg/m² on day 1 + #Oxaliplatin** 85 mg/m² on day 1 + #Calcium folinate** 400 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 400 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2400 mg/m² over at least 46 hours. Repeated every 2 weeks [80,81, 83].
• Modified #FOLFIRINOX: #Irinotecan** 180 mg/m² on day 1 + #Oxaliplatin** 85 mg/m² on day 1 + #Calcium folinate** 200 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 250 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2200 mg/m² over 48 hours. Repeated every 2 weeks [82].

• For an ECOG performance status of 3 or the presence of severe comorbidities, symptomatic therapy is recommended [4, 5].

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

3.3.2.1. Duration of Chemotherapy

Comments: in case of disease progression during adjuvant chemotherapy or within the first 6 months after its completion, adjuvant chemotherapy should be considered as the 1st line of treatment, which requires a change in the regimen of subsequent 2nd-line drug therapy. If disease progression is recorded 6 months or more after the completion of adjuvant chemotherapy, resuming treatment with the same regimen is possible [86].

3.3.3. Treatment of disseminated HER2+ gastric cancer (IHC HER2/neu 3+ or HER2/neu 2+/FISH+

Comments: Trastuzumab dosing regimens**:

• 6 mg/kg (initial loading dose = 8 mg/kg) every 3 weeks as part of three-week treatment cycles (XELOX, XP) followed by trastuzumab maintenance therapy in the same regimen [87-89];
• 4 mg/kg (initial dose = 6 mg/kg) every 2 weeks as part of two-week treatment cycles (mFOLFOX6, FOLFIRI) [90, 91] followed by trastuzumab maintenance therapy in the same regimen or 6 mg/kg every 3 weeks.

Trastuzumab** in combination with 6–8 courses of chemotherapy followed by maintenance monotherapy with trastuzumab** until disease progression significantly increases OS.

Chemotherapy regimens with trastuzumab:

• #T-XP (only in the presence of HER-2 overexpression/amplification in the tumor): Trastuzumab** 6 mg/kg on day 1 (initial loading dose = 8 mg/kg on day 1 of the first cycle, then every 21 days) + Capecitabine** 1000 mg/m² twice daily orally from day 1 to 14 of the cycle, or from the evening of day 1 to the morning of day 15 of the cycle + #Cisplatin** 80 mg/m² IV drip on day 1 with hyperhydration and antiemetics. Repeated every 3 weeks.[87,88].
• #T-XELOX (only in the presence of HER-2 overexpression/amplification in the tumor): Trastuzumab** 6 mg/kg on day 1 (initial loading dose = 8 mg/kg on day 1 of the first cycle, then every 21 days) + Capecitabine** 1000 mg/m² twice daily orally from day 1 to 14 of the cycle, or from the evening of day 1 to the morning of day 15 of the cycle + #Oxaliplatin** 130 mg/m² IV drip on day 1. Repeated every 3 weeks [89].
• #T-mFOLFOX6(only in the presence of overexpression/amplificationHER-2 in the tumor): #Trastuzumab** 4 mg/kg on day 1 (first, loading dose = 6 mg/kg on day 1 of the first cycle) + #Oxaliplatin** 85 mg/m² on day 1 + #Calcium folinate** 400 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 400 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2400 mg/m² over at least 46 hours. Repeated every 2 weeks [90].
• #T-FOLFIRI(only in the presence of overexpression/amplificationHER-2 in the tumor): #Trastuzumab**4 mg/kg on day 1 (first, loading dose = 6 mg/kg on day 1 of the first cycle) +#Irinotecan** 180 mg/m² on day 1 + #Calcium folinate** 400 mg/m² 2-hour IV infusion on day 1 + fluorouracil** 400 mg/m² IV bolus on day 1 followed by continuous IV infusion of fluorouracil** at a dose of 2400 mg/m² over at least 46 hours. Repeated every 2 weeks [91].

3.3.4. Second- and subsequent-line drug therapy

• In case of disease progression during or within 3 months after completion of 1st-line chemotherapy and a satisfactory general condition, patients are recommended 2nd-line therapy with drugs not included in the 1st line of treatment; if the observation interval (i.e., from the end of the last chemotherapy course to the documentation of disease progression) is greater than 3 months, reinduction of the 1st-line regimen is possible in the 2nd line of treatment [86].

GPR CLOE 4Level of Recommendation – C (Level of Evidence – 4).

Comments: A comparison of docetaxel** and #irinotecan** in the 2nd line of treatment showed equal efficacy [95]. Weekly #paclitaxel** has efficacy comparable to #irinotecan**, but a better safety profile [96]. The addition of ramucirumab** (an anti-VEGFR-2 antibody) to weekly #paclitaxel** significantly improves the objective response rate, PFS, and OS compared to #paclitaxel** alone [101]. Ramucirumab** monotherapy has also demonstrated a significant improvement in OS compared to best supportive care [102], but its administration in combination with #paclitaxel** is preferred; if the patient has previously experienced disease progression on taxanes, it should be combined with #irinotecan** or the #FOLFIRI regimen [103, 104, 105].

The duration of 2nd and subsequent lines of therapy is determined by the efficacy and tolerability of the treatment, and may be continued until disease progression or the development of unacceptable toxicity.

Monotherapy regimens:

• #Irinotecan** at 150 mg/m² once every 2 weeks [92, 94, 96].
• #Irinotecan** 250 mg/m² every 3 weeks for the first cycle, with a possible gradual increase in the single dose up to 350 mg/m² once every 3 weeks depending on toxicity [95].
• Docetaxel** at 60 or 75 mg/m² once every 3 weeks [93, 95].
• #Paclitaxel** at 80 mg/m² on days 1, 8, and 15 every 4 weeks [96, 101].
• Ramucirumab** 8 mg/kg once every 2 weeks [102].

Combination therapy regimens:

• #Paclitaxel** 80 mg/m² on days 1, 8, and 15 + ramucirumab** 8 mg/kg on days 1 and 15. Repeat every 4 weeks [101].

#Irinotecan** 150 mg/m² on days 1 and 15 + ramucirumab** 8 mg/kg on days 1 and 15 every 4 weeks (this regimen is used in case of #paclitaxel** intolerance or docetaxel** refractoriness) [103, 106].

• #FOLFIRI: #Irinotecan** 180 mg/m² on day 1 (with a possible reduction of the single dose to 150 mg/m²) + #Calcium folinate** 400 mg/m² as a 2-hour IV infusion on day 1 + #fluorouracil** 400 mg/m² IV bolus on day 1, followed by continuous IV infusion of #fluorouracil** at a dose of 2400 mg/m² for at least 46 hours. Repeat every 2 weeks [97, 107, 108].
• #FOLFIRI + ramucirumab**: #Irinotecan** 180 mg/m² on days 1 and 15 + #Calcium folinate** 400 mg/m² as a 2-hour IV infusion on days 1 and 15 + #fluorouracil** 400 mg/m² IV bolus on days 1 and 15, followed by continuous IV infusion of #fluorouracil** at a dose of 2400 mg/m² for at least 46 hours + ramucirumab** 8 mg/kg on days 1 and 15. Repeat every 4 weeks (this regimen is used in case of paclitaxel** intolerance or docetaxel refractoriness) [104, 105].
• #XELIRI: #Irinotecan** 200 mg/m² on day 1 + #capecitabine** 1000 mg/m² twice daily orally from days 1 to 14 of the cycle or from the evening of day 1 to the morning of day 15 of the cycle + ramucirumab** 8 mg/kg on days 1 and 8. Repeat every 3 weeks [104].
• #XELIRI: #Irinotecan** 250¹ (180-200) mg/m² on day 1 + #capecitabine** 1000 mg/m² twice daily orally from days 1 to 14 of the cycle or from the evening of day 1 to the morning of day 15 of the cycle. Repeat every 3 weeks [109, 110].

¹ Note. Due to reports in the literature indicating high toxicity of a single irinotecan dose of 250 mg/m² in the first-line XELIRI regimen for colorectal cancer [111, 112], it is advisable to use reduced doses of irinotecan (180–200 mg/m2) as part of this regimen in the second-line treatment of patients with metastatic gastric cancer.

• In the 3rd and subsequent lines of treatment, for patients in satisfactory general condition (ECOG 0–2) and with PD‑L1 CPS≥1 expression, the use of pembrolizumab** is recommended [113]; for tumors with a high level of microsatellite instability, it is recommended starting from the 2nd line.

GCR BLEL 3Level of recommendation consensus – B (level of evidence – 3).

Comments: Dosing regimen – Pembrolizumab** 200 mg every 3 weeks.

The issue of administering and selecting the 3rd and subsequent lines of medical therapy is decided individually at the physician's discretion, taking into account the patient's performance status, the efficacy and toxicity of prior lines of medical therapy, drug availability, and the patient's preferences. The 3rd and subsequent lines are recommended for patients in satisfactory general condition (ECOG 0–2) in the absence of severe impairment of internal organ function.

The greatest benefit from pembrolizumab** is observed in patients with a high level of microsatellite instability (MSI‑H) in the tumor and a CPS ≥10.

Comments: According to a randomized trial, immunotherapy with #nivolumab** (3 mg/kg once every 2 weeks) in 3rd and subsequent lines of treatment significantly increases OS compared to optimal symptomatic therapy regardless of PD-L1 expression: median OS from 4.14 to 5.26 months [HR 0.62 (0.51–0.76), p<0.0001], 1-year survival from 11.6 to 27.3%, 2-year survival from 3.2 to 1.6% [114]. Similar data were obtained in the CheckMate 032 study in the European patient population [115].

In accordance with the product monograph, nivolumab monotherapy is recommended in the following dosing regimens: 3 mg/kg once every 2 weeks, or 240 mg once every 2 weeks, or 480 mg once every 4 weeks [116]

3.4. Other Treatment

3.4.1. Optimal supportive care and supportive therapy

• Best supportive care (BSC) aimed at relieving disease symptoms (see Section 1.6 Clinical Presentation) is recommended for all patients with symptomatic gastric cancer [4, 5].

URC CLEL 5Level of recommendation validity – C (level of evidence reliability – 5).

Comments: The goal of BSC is the prevention and alleviation of disease symptoms, and the maintenance of the quality of life for patients and their families, regardless of the disease stage or the need for other types of therapy. In gastric cancer, measures aimed at alleviating core symptoms help increase life expectancy [5].

• As an alternative method for controlling recurrent tumor bleeding in a disseminated process, palliative radiotherapy (fraction dose 3 Gy, total dose 30 Gy) is recommended [119].

GCR CLEL 4Level of recommendation consensus – C (level of evidence – 4).

Comments: The need to relieve malignant stenosis may arise at all stages of treatment and is achieved through various approaches: endoscopic procedures (balloon dilation, electro-, argon plasma, or laser destruction, placement of intraluminal self-expanding stents). Endoscopic recanalization provides a rapid but short-lived effect and is suitable in cases where effective treatment (chemotherapy, surgery) will be initiated in the near future.

3.4.2. Analgesic therapy

The procedure and principles for the optimal choice of analgesic therapy in patients with gastric cancer experiencing chronic pain syndrome correspond to the principles outlined in the clinical guidelines "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care" (ID: CR400, approval year 2018, www.cr.rosminzdrav.ru).

3.4.3. Special clinical situations

Surgical treatment [4]

1) life-threatening complications of the tumor process not manageable by conservative treatment (gastric perforation, recurrent bleeding, tumor stenosis, etc.);

2) conversion of an initially disseminated or initially unresectable locally advanced process into an resectable state as a result of drug therapy if R0 resection is feasible;

3) oligometastatic disease if R0 resection is feasible. Isolated cases of long-term patient survival have been described following the removal of single metastases in the liver, retroperitoneal lymph nodes, lungs, and Krukenberg tumors [4,5].

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

• Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) outside of clinical trials are not recommended [4,5].

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

• Signet-ring cell gastric cancer has an extremely unfavorable prognosis, is characterized by lower sensitivity to chemotherapy and chemoradiotherapy; treatment is recommended in accordance with standard guidelines for gastric cancer treatment, and no other treatment methods have been developed to date [4,5].

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

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1. Prehabilitation

Comments: Prehabilitation includes physical training (exercise therapy), psychological support, correction of nutritional status, and patient education. Cardiorespiratory training and physical conditioning accelerate functional recovery, reduce hospital stay, and lower the rate of complications and mortality during oncological treatment [125].

Comments: it is advisable to assess nutritional status and decide on the prescription of nutritional support. According to the NRS-2002 scale (Appendix G2) nutritional support (NS) is prescribed for a score of 3 or more, which includes major abdominal surgery (2 points), and an additional 1 point is added for age over 70 years, weight loss of 5% over 3 months (3.5 kg with an initial body weight of 70 kg), or meeting normal nutritional needs by 70% or less. Nutritional support is prescribed at a protein intake of 1 g/kg/day and energy of 20–30 kcal/kg/day. Special nutritional formulas may be used: Impact, Clinutren, Nutridrink Compact Protein****, Nutricomp Drink Plus, Supportan Drink, Forticare, Nutrien standard formulas and targeted formulas – 400-600 ml per day via sipping.

It is necessary to identify patients with severe malnutrition for an earlier consultation with a clinical nutritionist, intensive care physician, or clinical dietitian (nutritionist) and to address the issue of a more intensive nutritional correction program, including the use of parenteral nutrition. This group includes patients with a BMI <18.5; weight loss of more than 5% in a month or more than 15% in 3 months; consumption of less than 25% of the required nutritional needs. This group should also include patients with dysphagia of grade III and above. This category of patients may require intensive infusion therapy to correct water and electrolyte balance) [127-128].

4.2. Surgical treatment

4.2.1. First stage of rehabilitation (postoperative rehabilitation)

Comments: these protocols are safe, reduce hospital stay, decrease the rate of non-surgical complications, and do not increase the total number of postoperative complications.

Comments: the choice between oral or nasojejunal nutrition is not yet obvious. In a limited number of studies, early oral nutrition did not lead to an increase in complications or hospital stay, so its use can be considered [136-138]. If oral nutrition is impossible, enteral nutrition can be arranged via a tube or microjejunostomy placed intraoperatively. Enteral nutrition by any access route has advantages over parenteral nutrition in terms of accelerating gastrointestinal motility recovery and preventing complications [135-138].

Comments: a combination of analgesic pharmacotherapy, physiotherapy, exercise therapy, positioning, psychological counseling, transcutaneous electrical nerve stimulation, and acupuncture can yield good results [126].

4.2.2. Second stage of rehabilitation

4.2.3. Third stage of rehabilitation

• In patients in remission, it is recommended to use a comprehensive program including stable weight maintenance, nutritional support, psychological counseling, an active lifestyle, and regular exercise therapy (low-intensity aerobic exercise with a gradual increase to moderate-intensity aerobic exercise) to improve cardiorespiratory endurance and quality of life. There is evidence that this may contribute to increased overall survival [141,142].

LE RLoE 5Level of Evidence – C (Level of Evidence – 5).

4.2.4. Chemotherapy

• Patients receiving adjuvant chemotherapy are recommended to receive nutritional support (see section 4.1), perform home-based resistance exercise training targeting major muscle groups, and engage in moderate-intensity aerobic exercise for up to 150 minutes per week combined with psychological counseling to prevent treatment-related fatigue [143-145].

GCR BLEL 1Grade of Recommendation – B (Level of Evidence – 1).

Comments: Early initiation of physical exercise combined with psychological support during chemotherapy helps prevent muscle weakness, the onset and progression of sarcopenia, and decreased exercise tolerance, improves quality of life and the psychological state of patients, and reduces symptoms of polyneuropathy.

• For patients with symptoms of chemotherapy-induced peripheral polyneuropathy, balance training exercises and low-level laser therapy are recommended [146-148].

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

Comment: Balance training exercises are more effective for correcting polyneuropathy than a combination of endurance and strength exercises [144].

5. Prevention and Dispensary Observation

• To prevent gastric cancer, it is recommended to follow a diet avoiding thermal and mechanical trauma to the gastric mucosa, quit smoking and alcohol, and timely treat background and precancerous conditions, including via luminal endoscopic interventions [152].

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

• In hereditary diffuse gastric cancer with a CDH1 gene mutation, active surveillance with evaluations every 6–12 months is recommended [148, 149].

GRC CLoE 5Grade of Recommendation C (Level of Evidence 5)

Comments: In hereditary gastric cancer associated with a CDH1 gene mutation, some authors recommend prophylactic gastrectomy without D2 lymph node dissection at 18–40 years of age. Women with a mutated CDH1 gene have an increased risk of breast cancer [153,154].

• following radical surgery – for the first 1–2 years, physical examination and symptom assessment are performed every 3–6 months; at 3–5 years, every 6–12 months. After 5 years from surgery, visits are conducted annually or upon the appearance of symptoms. For patients at high risk of recurrence, the interval between examinations may be shortened [4, 5];
• following endoscopic mucosal resection or submucosal dissection – EGD is performed every 3 months in the first year, every 6 months in the second and third years, and annually thereafter [4, 5].

SoR CLoE 5Strength of recommendation – C (level of evidence – 5).

Comments: scope of examination during visits:

1. Anamnesis collection and physical examination.
2. Complete blood count (CBC) with differential and general biochemical blood test (as clinically indicated).
3. EGD (according to the schedule – see above).
4. Abdominal ultrasound or CT (as clinically indicated).
5. Chest X-ray (as clinically indicated).
6. Assessment of nutritional status, recommendations for the management of nutritional deficiency.

Organization of medical care

Medical care, excluding medical care within clinical trials, is organized and provided in accordance with Federal Law No. 323-FZ of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation":

1. in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;
2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of the Russian Federation by all medical organizations;
3. based on these clinical guidelines;
4. taking into account the standards of medical care approved by the authorized federal executive body.

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

When a gastric oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), medical specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an outpatient oncology center, a primary oncology office, or a primary oncology department of a medical organization to receive primary specialized health care.

Consultation at an outpatient oncological care center or at a primary oncological office or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or primary oncological department) shall organize the collection of biopsy (surgical) material, as well as organize other diagnostic studies necessary to establish the 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 houses the outpatient oncology center (primary oncology office, primary oncology department), the attending physician shall refer the patient to an oncology dispensary or a medical organization providing care to patients with gastric oncological diseases.

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

If a gastric oncological disease is suspected and/or detected during the provision of emergency medical care, such patients shall be transferred or referred to medical organizations providing care to patients with gastric oncological diseases to determine management tactics and the need for additional specialized anti-tumor treatment modalities.

The oncologist at the outpatient oncology center (primary oncology office, primary oncology department) shall refer the patient to an oncology dispensary or medical organizations providing care to patients with gastric oncological diseases for diagnosis clarification (if the diagnosis, including the extent of the oncological process and disease stage, cannot be established by the oncologist at the outpatient oncology center, primary oncology office, or primary oncology department) and for the provision of specialized, including high-tech, medical care.

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

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

In a medical organization providing care to patients with gastric oncological diseases, the medical examination and treatment tactics shall be determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium shall be drawn up in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.

Indications for hospitalization in a round-the-clock or day hospital of a medical organization providing specialized, including high-tech, medical care in the field of oncology are determined by a multidisciplinary team of oncologists and radiotherapists, with the involvement of other specialist physicians as necessary.

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

1. presence of gastric cancer complications requiring specialized medical care in an emergency and urgent form;
2. presence of complications related to treatment (surgery, radiation therapy, drug therapy, etc.) of gastric cancer.

Indications for elective hospitalization in a medical organization are:

1. the need to perform complex interventional diagnostic medical interventions requiring subsequent monitoring in an inpatient or day-inpatient setting;
2. presence of indications for specialized anti-tumor treatment (surgery, drug therapy, radiation therapy, including contact, external beam, and other types of radiation therapy, etc.) requiring monitoring in a 24-hour inpatient or day-care setting.

Indications for discharging a patient from a medical organization are:

1. completion of a course of treatment, or one of the stages of specialized, including high-tech, medical care in a 24-hour inpatient or day-care setting in the absence of treatment complications requiring drug correction and/or medical interventions in an inpatient setting;
2. refusal by the patient or their legal representative of specialized, including high-tech, medical care in an inpatient or day-inpatient setting, as established by a concilium of a medical organization providing oncological care, provided there are no complications of the underlying disease and/or treatment that require drug correction and/or inpatient medical interventions;
3. need to transfer the patient to another medical organization in the relevant medical specialty.

The conclusion regarding the feasibility of transferring a patient to a specialized medical organization is made after a preliminary consultation based on submitted medical documents and/or a preliminary examination of the patient by medical specialists of the target organization.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Besova Nataliya Sergeevna, Candidate of Medical Sciences, Senior Researcher at the Oncological Department of Drug Therapy (Chemotherapeutic) No. 1, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
2. Kalinin Aleksey Evgenievich, Candidate of Medical Sciences, Senior Researcher at the Surgical Department No. 6 of the Thoracoabdominal Division, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
3. Nered Sergey Nikolaevich, Doctor of Medical Sciences, Leading Researcher at the Surgical Department No. 6 of the Thoracoabdominal Division, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
4. Tryakin Aleksey Alexandrovich, Doctor of Medical Sciences, Chief Researcher at the Oncological Department of Drug Therapy (Chemotherapeutic) No. 2, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
5. Gamayunov Sergey Viktorovich, Candidate of Medical Sciences, Head of the Department of Radiation and Surgical Treatment of Thoracic Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
6. Kozlov Nikolay Alexandrovich, Candidate of Medical Sciences, physician at the Pathological Anatomy Department of Morphological and Molecular Genetic Tumor Diagnostics, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
7. Stylidi Ivan Sokratovich, Doctor of Medical Sciences, Corresponding Member of the RAS, Director of N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health
8. Karachun Alexey Mikhailovich, Doctor of Medical Sciences, Professor, Head of the Surgical Department of Abdominal Oncology, N.P. Napalkov National Medical Research Center of Oncology of the Russian Ministry of Health.
9. Kononets Pavel Vyacheslavovich, Candidate of Medical Sciences, Zaputy Director for Research and Clinical Work, Director of the Research Institute of Clinical Oncology named after Acad. of RAS and RAMS N.N. Trapeznikov.
10. Malikhova Olga Alexandrovna, Doctor of Medical Sciences, Head of the Endoscopy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.
11. Ryabov Andrey Borisovich, Doctor of Medical Sciences, Head of the Thoracoabdominal Oncosurgery Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
12. Khomyakov Vladimir Mikhailovich, Candidate of Medical Sciences, Head of the Thoracoabdominal Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.
13. Fedenko Alexander Alexandrovich, Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health
14. Bolotina Larisa Vladimirovna, Head of the Chemotherapy Department, Division of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health
15. Falaleeva Natalia Alexandrovna, Head of the Division 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

Healthcare Organization Section:

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

2. Ivanov Sergey Anatolyevich, Doctor of Medical Sciences, Professor of the RAS, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Khaylova Zhanna Vladimirovna, Candidate of Medical Sciences, 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.

4. Tigran G. Gevorkyan, Deputy Director of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology, Chief Specialist Oncologist of the Moscow Region.

Medical Rehabilitation and Supportive Care Section:

1. Aleksey V. Butenko, MD, PhD, Professor, Chief Physician of the Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, Chairman of the Scientific Board of the Association of Specialists in Oncological Rehabilitation.

2. Ilmira R. Gilmutdinova, PhD, Transfusiologist, Dermatovenerologist, Head of the Department of Biomedical Technologies and Cell Technology Laboratory, Cell Technologies Specialist, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of Russia.

3. Mikhail A. Eremushkin, MD, PhD, Professor, Head of the Department of Exercise Therapy and Clinical Biomechanics, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of Russia.

4. Galina E. Ivanova, MD, PhD, Chief Specialist in Medical Rehabilitation of the Russian Ministry of Health, Head of the Department of Medical and Social Rehabilitation of Stroke, Research Institute of Cerebrovascular Pathology and Stroke, Pirogov Russian National Research Medical University of the Ministry of Health of Russia.

5. Kristina O. Kondratyeva, Medical Psychologist, N.P. Napalkov National Medical Research Center of Oncology of the Ministry of Health of Russia.

6. Tatiana V. Konchugova, MD, PhD, Professor, Physiotherapist, Head of the Department of Preformed Physical Factors, National Medical Research Center for Rehabilitation and Balneology of the Ministry of Health of Russia.

7. Anton A. Krutov, Oncologist at the Clinical and Diagnostic Department, N.P. Napalkov National Medical Research Center of Oncology of the Ministry of Health of Russia (Saint Petersburg, Russia).

8. Olga A. Obukhova, PhD, Physiotherapist, Head of the Department of Medical Rehabilitation, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia, Member of the European Society for Clinical Nutrition and Metabolism (ESPEN), Member of the Russian Society for Clinical Nutrition and Metabolism (RESPEN).

9. Tatiana Yu. Semiglazova, MD, PhD, Head of the Department and Leading Research Fellow, Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.P. Napalkov National Medical Research Center of Oncology of the Ministry of Health of Russia, Associate Professor at the Department of Oncology, North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of Russia (Saint Petersburg, Russia).

10. Elena V. Filonenko, MD, PhD, Oncologist, Professor, 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 Ministry of Health of Russia.

11. Marina M. Khulamkhanova, Physiotherapist, Oncologist at the Department of Medical Rehabilitation, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia.

12. Aleksandr I. Romanov, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Chief Physician of the Rehabilitation Center of the Presidential Administration of the Russian Federation.

Conflict of interest: none declared by any members of the working group.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologists.
2. Surgeons.
3. Radiologists.
4. Radiation oncologists.
5. Pathologists.
6. Gastroenterologists.
7. Clinical pharmacologists.
8. General practitioners.
9. Endoscopists.
10. Surgeons (thoracic, abdominal).
11. Gynecologists.
12. Medical geneticists.
13. Medical students, residents, and postgraduate students.

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

Methods used for evidence collection/selection:

- literature search in electronic databases;

- analysis of modern scientific developments regarding esophageal cancer in Russia and abroad;

- generalization of the practical experience of Russian and foreign specialists.

Table II1. Levels of evidence according to the methodological recommendations for the development and updating of clinical guidelines (Order of the Russian Ministry of Health No. 103n dated February 28, 2019)

A) Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

B) Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table App2. Grades of recommendation according to the methodological recommendations for the development and updating of clinical guidelines (Order of the Russian Ministry of Health No. 103n dated February 28, 2019)

Methods used for formulating recommendations: expert consensus.

Economic analysis: cost analysis was not performed, and pharmacoeconomic publications were not reviewed.

Method of recommendation validation:

• External peer review
• Internal expert review

Description of the recommendation validation method. The preliminary version of these guidelines was peer-reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the guidelines is easily understandable.

Comments were received from primary care pediatric oncologists regarding the clarity of the guidelines and their perceived importance as a working tool in daily practice.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and the resulting changes to the recommendations 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 guidelines.

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.

Procedure for updating clinical guidelines. The mechanism for updating clinical guidelines provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to verify its reliability. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Appendix A3. Related documents

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

1. Order of the Ministry of Health of Russia No. 203n dated May 10, 2017 "On approval of criteria for assessing the quality of medical care" (Registered with the Ministry of Justice of Russia on May 17, 2017, No. 46740).

2. Order of the Ministry of Health of Russia No. 915n dated November 15, 2012 "On approval of the procedure for providing medical care to the adult population in the profile 'oncology'."

Current instructions for medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru.

Appendix B. Patient management algorithms

Diagram 1. Algorithm for primary diagnosis of gastric cancer

Diagram 2. Examination in gastric cancer

Diagram 3. Prognostic groups in gastric cancer

Diagram 4. Outcomes of surgical interventions in gastric cancer

Gastric cancer

Appendix C. Information for patients

The patient is informed about the clinical presentation of gastric cancer, introduced to various treatment methods, their potential outcomes and complications.

The patient should be informed about the nature of follow-up care after gastric cancer treatment and the importance of regular examinations.

Patients with metastatic gastric cancer should be informed about clinical trials currently conducted in the Russian Federation for patients with this stage of the disease.

Independent self-monitoring of the disease course by the patient is not possible; the frequency of physician visits is determined individually in each specific case.

Recommendations for chemotherapy complications – contact your oncologist (chemotherapist)!

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

• Start taking antibiotics as prescribed by the oncologist (chemotherapist).

2) For stomatitis:

• Diet – mechanical and thermal sparing;
• Frequent mouth rinsing (every hour) – chamomile, oak bark, sage, lubricating the mouth with sea buckthorn (peach) oil;
• Treat the oral cavity as recommended by the oncologist (chemotherapist).

3) For diarrhea:

• Diet – exclude fatty, spicy, smoked, sweet, dairy products, and fiber.
  Lean meat, flour products, fermented milk products, and rice broth are permitted. Drink plenty of fluids;
• Take medications as prescribed by the oncologist (chemotherapist)

4) For nausea:

• Take medications as prescribed by the oncologist (chemotherapist).

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

Appendix D1. ECOG/WHO performance status scale and Karnofsky scale for assessing general patient condition

Russian name: WHO performance status scale / ECOG

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

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

Oken M.M., Creech R.H., Tormey D.C. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. AmJClinOncol 1982;5(6):649–55 [123]

Type: rating scale

Purpose: Assessment of the patient's general condition.

Russian title: Karnofsky Performance Scale

Original name: Karnofsky Performance Status

Source (official developer website, validation publication):

Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [124]

Type: rating scale

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

Content (template):

Key (interpretation): provided within the scale itself

Notes: none.

Appendix D2. Nutritional status assessment scale NRS-2002

Russian title: NRS-2002 scale for nutritional risk screening

Original title: NRS-2002

Source (official developer website, validation publication):

Kondrup J., Allison S.P., Elia M. et al. Educational and Clinical Practice Committee, European Society of Parenteral and Enteral Nutrition (ESPEN). ESPENGuidelinesforNutritionScreening 2002.ClinNutr 2003;22(4):415–21 [125]

Type: rating scale

Purpose: The European Society for Clinical Nutrition and Metabolism (ESPEN) recommends using the two-step NRS-2002 scale for nutritional risk screening.

Content (template): Tables 1 and 2.

Key (interpretation):

NRS-2002

Block 1. Primary Screening

Conclusion

Block 2. Final Screening

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

Less than 3 points – repeat screening every week. If surgical treatment is planned, a preoperative preparation program is required.

Notes: none.

This document is the property of the Moscow Healthcare Department, and may not be reproduced or distributed without appropriate permission.

Appendix D3. Histological grading of gastric adenocarcinomas

Russian title: WHO Histological Grading System for Gastric Adenocarcinoma (2019)

Original title: WHO Gastric Cancer Pathological Grading System (2019)

Source (official developer website, validation publication): http://whobluebooks.iarc.fr/;

Fukayama M., Rugge M., Washington M.K. Tumours of the stomach. In: WHO Classification of Tumours Editorial Board. Digestive Tumours. Lyon (France): IARC 2019;59–109.

Type: rating scale

Purpose: Assessment of the histological grade/malignancy of gastric adenocarcinoma

Content (template):

Histological grading of gastric adenocarcinomas

Appendix D4. Mandard scale for assessing the degree of therapeutic pathomorphosis in gastric cancer

Russian title: Mandard Tumor Regression Grading System for Gastric Cancer

Original title: Mandard Tumor Regression Grading System

Source (official developer website, validation publication): https://journals.lww.com/journalppo/pages/default.aspx;

Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73:2680–6.

Type: rating scale

Purpose: Assessment of the degree of tumor regression in gastric and colorectal adenocarcinoma.

Content (template):

Assessment of the degree of tumor regression in gastric cancer according to Mandard (Mandard A.M. et al.)

Appendix D5. Becker scale for assessing the degree of therapeutic pathomorphosis in gastric cancer

Russian title: Becker Tumor Regression Grading System for Gastric Cancer

Original title: Becker Tumor Regression Grading System

Source (official developer website, validation publication): https://journals.lww.com/journalppo/pages/default.aspx;

Becker K, Mueller JD, Schulmacher C, Ott K, Fink U, Busch R, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer (2003) 98(7):1521–3010.

Type: rating scale

Purpose: Assessment of the degree of tumor regression in gastric and colorectal adenocarcinoma.

Content (template):

Assessment of the degree of tumor regression in gastric cancer according to Becker (Becker K. et al.)