Esophageal and cardia cancer: clinical guidelines

List of Abbreviations

AJCC – American Joint Committee on Cancer

AUC – area under the curve, a pharmacokinetic parameter representing the total concentration of a drug in blood plasma over the entire observation period.

CTCAE – Common Terminology Criteria for Adverse Events

ECOG – Eastern Cooperative Oncology Group

NET – Neuroendocrine tumor

RECIST – Response Evaluation Criteria in Solid Tumors

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

UICC – Union for International Cancer Control

IV – intravenous

WHO – World Health Organization

GERD – Gastroesophageal reflux disease

GI – gastrointestinal tract

CT – computed tomography

PT – physical therapy

mAb – monoclonal antibodies (ATC code: L01XC)

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

PCR – polymerase chain reaction

PET – positron emission tomography

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

CDU – color duplex ultrasonography

US – ultrasound examination

CRT – chemoradiotherapy

EGD – esophagogastroduodenoscopy

** – vital and essential drugs

# – off-label drug

Terms and Definitions

Barrett's esophagus – an optional precancerous condition of the lower third of the esophagus, characterized by intestinal metaplasia and varying degrees of dysplasia of the mucosal lining of the terminal esophagus against the background of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) – a chronic relapsing condition caused by spontaneous, regularly recurring reflux of gastric contents into the esophagus, leading to damage to the lower esophagus.

Odynophagia – painful swallowing.

Prehabilitation is rehabilitation from the moment of diagnosis until the start of treatment (surgery/chemotherapy/radiation therapy).

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.

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.

Third stage of rehabilitation – rehabilitation during the early and late rehabilitation periods and the period of residual disease symptoms in departments (offices) of rehabilitation, physical therapy, therapeutic exercise, reflexology, manual therapy, psychotherapy, and medical psychology providing outpatient care, in day hospitals, as well as by mobile home-visiting teams (including in sanatorium-resort settings), and speech therapy (defectology) rooms.

Sipping – consuming the required amount of nutritional formula in small sips throughout the day.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Esophageal cancer – a malignant tumor originating from the esophageal mucosa.

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

In the etiology of the disease, significance is attributed to constant chemical, mechanical, or thermal irritation of the esophageal mucosa, leading to the development of intraepithelial neoplasia (epithelial dysplasia).

Direct risk factors include the regular consumption of excessively hot food and beverages. Tobacco smoking and alcohol consumption are independent risk factors, but in combination with others, they increase the risk of developing the disease [1, 2].

In patients with an autosomal dominant condition characterized by palmoplantar keratoderma, the risk of developing esophageal cancer is 37%. Barrett's esophagus is singled out as a condition where metaplastic intestinal epithelium appears in the distal esophagus. The risk of esophageal cancer in such patients is approximately 30 times higher than in the general population [3, 4, 5]. The development of Barrett's esophagus is associated with gastroesophageal reflux disease and is a complication thereof [6, 7].

1.3 Epidemiology of the Disease or Condition

Esophageal cancer is one of the most aggressive malignant tumors, ranking eighth in global mortality structure. According to the International Agency for Research on Cancer (IARC) for 2014, the incidence rate was 50.1 cases per 100,000 population per year, and mortality was 34.3. In Russia in 2022, 7,139 new cases were diagnosed, of which stages III and IV accounted for 28.1% and 32.2%, respectively, and the 1-year mortality rate was 59% [8, 9].

1.4 Features of Coding the Disease or Condition

C15 Malignant neoplasm of esophagus:

C15.0 – cervical esophagus;

C15.1 – thoracic esophagus;

C15.2 – abdominal esophagus:

C15.3 – upper third of esophagus (proximal third of esophagus),

C15.4 – middle third of esophagus,

C15.5 – lower third of esophagus (distal third of esophagus);

C15.8 – lesion of esophagus overlapping one or more of the above subcategories;

C15.9 – esophagus, unspecified.

C16 Malignant neoplasm of stomach:

C16.0 Cardia (gastroesophageal junction)

1.5 Classification of the disease or condition

1.5.1. International Histological Classification of Esophageal Malignant Tumors (2019)

The histological variant of the tumor is indicated in accordance with the international classification (Table 1).

Table 1. International Histological Classification (2019)

Currently, developed countries show a decrease in the incidence of esophageal squamous cell carcinoma and an increase in the incidence of adenocarcinoma. According to the American Cancer Registry, from 1980 to 1990 the incidence of esophageal adenocarcinoma doubled. The most common morphological form in Russia is squamous cell carcinoma, with adenocarcinoma being less common (mainly in the distal esophagus and esophagogastric junction). Carcinosarcoma, small cell carcinoma, and melanoma are extremely rare.

Endoscopic boundaries are conventional and may vary depending on the patient's constitutional features. When planning surgical treatment, one should be guided by anatomical boundaries relative to the structures indicated in Table 2.

Tumor localization is established relative to the center of growth; however, when planning treatment, the upper and lower boundaries of tumor involvement must be taken into account.

Esophagogastric junction tumors (C16.0) with the epicenter of growth above the Z-line, at the level of the Z-line, and up to 2.0 cm below the Z-line are classified and staged as esophageal cancer (Siewert I-II). Esophagogastric junction tumors (C16.0) with the epicenter of growth distal to 2 cm from the Z-line (Siewert III) are classified and staged as gastric cancer regardless of involvement of the esophagogastric junction itself in the tumor process.

Table 2. Topographic classification according to International Classification of Diseases (ICD) codes

1.5.2. TNM classification by the American Joint Committee on Cancer (AJCC) 8th Ed – 2017 [10]

This staging applies to epithelial tumors of the esophagus, including squamous cell carcinoma, glandular carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, neuroendocrine carcinoma, and tumors with neuroendocrine differentiation.

Sarcomas and non-epithelial tumors are staged as soft tissue sarcomas.

Gastrointestinal stromal tumors are staged independently.

Stage grouping is based on the analysis of survival data from 22,654 patients from 33 centers across 6 continents (Tables 3–6).

• For early-stage tumors (T1-2), the grade of differentiation (G) has a significant impact on survival rates.

• Patients with esophageal adenocarcinoma have a better prognosis than patients with squamous cell carcinoma; therefore, stage groupings differ for various morphological types.

• Analysis of new survival data depending on the efficacy of neoadjuvant treatment has led to different stage groupings for clinical stage (cTNM), pathomorphological stage (pTNM), and post-neoadjuvant morphological stage (ypTNM).

Table 3. Key differences between TNM 8th Ed. and TNM 7th Ed. Squamous cell carcinoma

Regional lymph nodes:

• Cervical paratracheal (level VI) – from the hyoid bone to the jugular notch, between the common carotid arteries.

• Cervical paratracheal (level VII) – from the jugular notch to the brachiocephalic vein, between the trachea and the sternal manubrium.

• Right and left lower cervical paratracheal nodes (1L&1R) – from the supraclavicular region to the apex of the lung (recurrent laryngeal nerve lymph nodes).

• Right and left upper paratracheal (2L&2R) – paratracheally from the lung apex to the intersection of the brachiocephalic trunk (right) or aortic arch (left) with the trachea.

• Right and left lower paratracheal (tracheobronchial) (4L&4R) – between the brachiocephalic trunk and the azygos vein on the right, and between the aortic arch and the carina on the left.

• Subcarinal (7) – below the tracheal bifurcation.

• Paraesophageal: upper, middle, and lower (8U, 8M, 8Lo) – paraesophageally, corresponding to the division of the esophagus into thirds.

• Right and left pulmonary ligament lymph nodes (9L&9R).

• Diaphragmatic (15) – nodes above the diaphragm and near the diaphragmatic crura.

• Paracardial (16) – lymph nodes in the immediate vicinity of the esophagogastric junction.

• Left gastric artery nodes (17).

• Common hepatic artery nodes (18).

• Splenic artery nodes (19).

• Celiac trunk nodes (20).

Metastases to supraclavicular lymph nodes (Vb), lymph nodes along the cervical vascular bundle (III, IV), splenic hilar nodes, and hepatoduodenal ligament nodes should be regarded as non-regional lymph node metastases M1(Lymph).

Table 4. T-stage criteria. American Joint Committee on Cancer (AJCC) 8th Ed – 2017

Table 5. N-stage criteria. American Joint Committee on Cancer (AJCC) 8th Ed – 2017

Table 6. M-stage criteria. American Joint Committee on Cancer (AJCC) 8th Ed – 2017

Stage distribution differs for clinical and pathological staging. The stage distribution for squamous cell carcinoma is presented below (Tables 7, 8).

Table 7. Clinical stage grouping (squamous cell carcinoma)

Table 8. Pathological stage grouping (squamous cell carcinoma)

In multifocal esophageal lesions and after exclusion of submucosal metastasis, each tumor is staged separately.

Table 10. Pathological prognostic stage groups (esophageal adenocarcinoma)

1.6 Clinical presentation of the disease or condition

In the early stages, this disease is practically asymptomatic and has no specific symptoms. However, patients are quite frequently prescribed drug therapy for dyspepsia, gastroesophageal reflux, or neurocirculatory dystonia without proper examination. Frequently, due to the anatomical features of the organ and its distensibility, the first symptom of the disease is dysphagia, which naturally indicates significant local spread of the process. In addition, a significant proportion of patients suffer from alcoholism and pay no attention to minor changes in general well-being, so the "small signs" syndrome goes unnoticed by the patient. On average, the duration of history from the appearance of the first symptoms to seeking medical care ranges from 2 to 4 months. When analyzing history data, special attention should be paid to the following symptoms: weight loss, chest pain, regurgitation, heartburn (reflux), and initial manifestations of dysphagia. The history of concomitant cardiovascular and pulmonary pathology is also of great importance. Quite often, the first symptoms of the disease are a feeling of discomfort and burning behind the sternum, progressing as the volume of the neoplasm increases and the lumen of the organ gradually narrows. Dysphagia indicates that 50% to 75% of the esophageal lumen is occupied by a tumor involving up to 2/3 of the circumference. Initially, dysphagia occurs only when swallowing solid food, and patients constantly have to wash down swallowed pieces. In more advanced stages of the process, when the esophageal lumen is completely obstructed, patients are unable to swallow even their own saliva. Dysphagia classification proposed by Professor A.I. Savitsky: Stage I – difficulty swallowing solid food, Stage II – difficulty swallowing mushy food, Stage III – difficulty swallowing liquids, Stage IV – complete obstruction. Weight loss is most likely due to the need to change the usual diet as the disease progresses, followed by the development of malnutrition syndrome. Regurgitation and hypersalivation appear when the organ lumen is completely obstructed. Ulceration of the carcinoma may cause odynophagia, i.e., painful swallowing. As a rule, this symptom becomes constant, agonizing, and is accompanied by radiation to the back. Chest pain unrelated to swallowing indicates the spread of the tumor process to the mediastinum and diaphragm. Atypical symptoms include anorexia, early satiety, nausea, and vomiting. The latter manifest when the tumor spreads to the stomach. Various pulmonary complaints, such as chronic productive cough, pneumonia, and dyspnea, can be caused by both regurgitation and aspiration, as well as the formation of esophagotracheal fistulas. Hoarseness is a later symptom and is associated with involvement of the recurrent laryngeal nerve. Chronic bleeding from a disintegrating tumor can lead to hypochromic anemia. Profuse bleeding occurs when major vessels are involved and leads to patient death in almost all cases [11].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1) anamnesis data;

2) physical examination and instrumental diagnostic findings;

3) pathomorphological examination data of biopsy (surgical) material of the esophagus.

2.1 Complaints and Anamnesis

Comments: 50% of patients with esophageal cancer complain of pain during swallowing, difficulty passing food, weight loss, as well as general symptoms (fatigue, malaise).

2.2 Physical Examination

2.3 Laboratory Diagnostics

Comments: complete blood count with differential and biochemical blood tests, coagulopathy screening (coagulation profile), and urinalysis are performed prior to planning any treatment method. In patients receiving chemotherapy, a complete blood count with differential and a routine biochemical blood test are performed before each cycle, while other tests are performed as clinically indicated.

1) distance to the proximal and distal resection margins;

2) tumor dimensions;

3) histological type of the tumor;

4) tumor differentiation grade;

5) pT;

6) pN (indicating the total number of examined and affected lymph nodes);

7) presence of involvement of the proximal resection margin (a negative result must also be stated);

8) presence of involvement of the distal resection margin (a negative result must also be stated);

9) presence of lymphovascular or perineural invasion (a negative result must also be stated);

10) degree of tumor morphological regression after neoadjuvant therapy, indicating the grading system used for measurement (if prior combined treatment was administered) [29];

11) in pathological examination of biopsy (surgical) material—in localized esophageal adenocarcinoma when preoperative chemotherapy is planned, a pathological examination of the HER2/neu receptor protein using immunohistochemical methods, determination of DNA microsatellite repeats in the biopsy (surgical) material by PCR, or determination of mutations in the MLH1, MSH2, MSH6, PMS2 genes by immunohistochemical method is recommended;

- when planning postoperative immunotherapy with nivolumab** for stage II–III (squamous cell carcinoma and adenocarcinoma) after preoperative chemoradiotherapy, determination of PD-L1 protein expression in the tumor by immunohistochemical method (CPS) is recommended;

12) when planning palliative chemotherapy for squamous cell carcinoma, determination of PD-L1 protein expression by immunohistochemical method (TPS and CPS) is recommended; for adenocarcinoma, determination of DNA microsatellite repeats in the biopsy (surgical) material by PCR, or determination of mutations in the MLH1, MSH2, MSH6, PMS2 genes by immunohistochemical method, PD-L1 protein expression by immunohistochemical method (CPS), and pathological examination of HER2 receptor protein using immunohistochemical methods are recommended. In cases of HER2 2+, to confirm gene amplification, determination of HER2 gene amplification by fluorescence in situ hybridization (FISH) or CISH is recommended. As additional molecular genetic testing, IHC determination of NTRK may be performed, followed by confirmation of positive results with FISH or CISH.

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

2.4 Instrumental Diagnostics

Comments: EGD is the most informative diagnostic method for esophageal cancer, allowing direct visualization of the tumor, determination of its size, location, and macroscopic type, assessment of complication risks (bleeding, perforation), and acquisition of material for pathological examination. To obtain a sufficient amount of material, several (3–5) biopsies should be taken using standard endoscopic biopsy forceps. The treatment plan should not be formulated before biopsy results are obtained. In case of submucosal infiltrative tumor growth, a false-negative result is possible, which necessitates a repeat step-biopsy. It is mandatory to determine the boundaries of the tumor lesion, the distance from the esophagogastric junction, the esophageal orifice, and the level of the esophageal hiatus of the diaphragm. For esophageal adenocarcinoma in the setting of Barrett's esophagus, it is recommended to determine the boundaries of the metaplastic epithelium in the esophagus and evaluate the metaplasia segment in accordance with the Prague criteria.

The sensitivity and specificity of the method increase when using modern advanced endoscopic imaging technologies (narrow-band imaging, magnifying endoscopy, autofluorescence imaging, and intelligent color enhancement (FICE) gastrointestinal endoscopy).

Comments: Esophageal endosonography is the most informative method for assessing the depth of tumor invasion into the esophageal wall (T category) and also allows for high accuracy (sensitivity 0.8 and specificity 0.7) in assessing the status of regional lymph node stations (N category). For more precise preoperative staging and determination of treatment tactics, fine-needle aspiration biopsy of mediastinal lymph nodes under the guidance of esophageal endosonography may be performed.

Comments: Contrast-enhanced CT of the abdomen and chest with intravenous bolus injection is the standard for staging diagnostics in esophageal cancer in most developed countries. An alternative to abdominal CT can be contrast-enhanced MRI of the abdomen. In practice, these studies can be partially replaced by abdominal ultrasound (comprehensive) and chest radiography in two projections for patients in situations where the detection of metastases has no clinical significance (e.g., patients with distant metastases receiving palliative chemotherapy).

2.5 Other Procedures

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

• For patients with esophageal cancer and carcinoma of the cardia, it is recommended to administer systemic antineoplastic therapy in accordance with the general principles outlined in the "Practical Guidelines for General Principles of Systemic Antineoplastic Therapy" by the Russian Society of Clinical Oncology (RUSCO) [99].

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

• Patients diagnosed with Tis and cT1aN0M0 esophageal cancer are recommended to undergo endoscopic mucosal resection with endoscopic submucosal dissection to increase patient survival rates [30–32].

LoR AGoE 3Level of Recommendations – A (Grade of Evidence – 3).

Comments: when the tumor is confined to the mucosa (T1a), endoscopic mucosal resection or endoscopic submucosal dissection may be performed. Endoscopic mucosal resection is the method of choice for carcinoma in situ and high-grade epithelial dysplasia. In addition, this method is successfully used for esophageal tumors confined to the mucosa in patients with a significant risk of surgical complications. In such cases, the 5-year survival rate reaches 85–100% [30].

When determining the treatment strategy, prognostic factors must be taken into account. Preference should be given to the endoscopic submucosal dissection technique.

Negative prognostic factors:

• differentiation grade ≥G3;

• presence of tumor cells at the resection margins;

• lymphovascular, vascular, or perineural invasion;

• depth of invasion (involvement of the submucosal layer of the esophageal wall), >pT1sm1.

When performing endoscopic treatment, a total pathological examination of the esophageal specimen is required, including a description of the lateral and vertical resection margins and an indication of the maximum depth of tumor invasion.

If radical endoscopic treatment is not feasible, alternative treatment options for Tis and T1a include surgery, chemoradiotherapy, brachytherapy, and for high-grade dysplasia and Tis — photodynamic therapy. If the depth of invasion is pT1b-2 following endoscopic mucosal resection with submucosal dissection, esophagectomy or definitive chemoradiotherapy is recommended.

• For stage cIB–IIA esophageal cancer (low-risk cT₁N₀M_{0 and} cT₂N₀M₀ — absence of lymphovascular invasion, tumor size less than 3–5 cm, histological grade 1–2), surgical treatment is recommended; additional chemotherapy and radiotherapy are not recommended [12, 27].

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

Comments: surgery is the primary treatment method. Definitive chemoradiotherapy (see below) is recommended only when surgery is not feasible (tumor localization in the cervical esophagus, functional contraindications). In selected preserved patients with cervical esophageal cancer who have residual tumor after chemoradiotherapy, surgical treatment may be performed, up to a maximum extent of laryngopharyngoesophagectomy with various methods of esophageal reconstruction and voice prosthesis placement.

The main type of surgery for esophageal cancer is subtotal esophagectomy with simultaneous intrapleural gastric tube or colon segment interposition combined with bilateral two-field mediastinal lymph node dissection via combined laparotomy and right thoracotomy approaches (Lewis procedure) with anastomosis formation in the right pleural cavity apex above the azygos vein level. When the tumor is located above the level of the tracheal bifurcation, esophageal extirpation with cervical anastomosis formation is recommended.

In centers with adequate equipment and trained specialists, minimally invasive surgical interventions (thoracoscopy and/or laparoscopy) may be performed, provided that the extent of surgical resection is not compromised. Minimally invasive techniques help reduce the frequency and severity of postoperative complications.

The choice of surgical treatment method for esophagogastric junction tumors is determined by their anatomical location:

For Siewert type I, the Lewis procedure is performed (via open or minimally invasive approaches). In exceptional cases, transhiatal esophagectomy may be performed in patients who cannot tolerate a thoracotomy. For Siewert type I, a mandatory condition for a radical operation is D2 upper abdominal lymph node dissection and 2F bilateral mediastinal lymph node dissection.

For Siewert type II with tumor extension into the esophagus up to 3 cm, transhiatal proximal gastrectomy is performed with wide diaphragmatotomy, lower mediastinal lymph node dissection up to the level of the tracheal bifurcation, and a high mediastinal anastomosis. Alternatively, thoracotomy approaches may be used, although such operations are technically more complex and associated with an increased risk of postoperative complications. To date, there is no clear evidence base that performing thoracotomies and expanding lymph node dissection above the level of the bifurcation improves long-term treatment outcomes. For Siewert type II with tumor extension into the esophagus greater than 3.0 cm, the surgical strategy is identical to that for Siewert type I tumors.

• For stage IIB–III esophageal cancer (high-risk cT₂N₀M₀ — presence of lymphovascular invasion, tumor size over 3–5 cm, histological grade 3; cT_3–4N₀–₃M_0; cT_1–2N_1–3M₀), a combination of surgery with systemic and/or chemoradiotherapy is recommended: preoperative chemoradiotherapy or preoperative chemotherapy (for squamous cell carcinoma), perioperative chemotherapy (for adenocarcinoma), or definitive chemoradiotherapy (if there are contraindications to surgery or for cervical esophageal tumors) to improve treatment outcomes and patient survival [33].

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

Preoperative (perioperative) chemotherapy

Comments: A randomized trial conducted in Japan demonstrated that in patients with locally advanced squamous cell carcinoma of the esophagus, 3 cycles of DCF chemotherapy (docetaxel**, cisplatin**, fluorouracil**, every 3 weeks) were no less effective than preoperative chemoradiotherapy. However, a subgroup analysis suggested a potential benefit of chemoradiotherapy for tumors located in the upper third of the esophagus. The DCF regimen was associated with high toxicity and higher mortality, and therefore in frail patients it can be replaced by the mDCF combination (4–6 cycles every 2 weeks). The recommended duration of preoperative chemotherapy for squamous cell carcinoma of the esophagus is 8–12 weeks, and preoperative chemotherapy preceding chemoradiotherapy is 6–9 weeks.

For adenocarcinoma of the lower thoracic esophagus or cardia, the optimal approach is 8 cycles (16 weeks) of perioperative FLOT chemotherapy (#docetaxel**, #calcium folinate**, #oxaliplatin**, fluorouracil**), in which 4 cycles of chemotherapy are administered before surgery and 4 cycles after surgery. In selected patients (marked positive response, good tolerability, concomitant targeted therapy or immunotherapy in the presence of HER2 or MSI in the tumor), a complete neoadjuvant course (up to 16 weeks of therapy) may be administered. In patients unable to tolerate the FLOT regimen, #oxaliplatin**-, fluorouracil**-, and capecitabine-based**regregimens may be used: FOLFOX regimens (#oxaliplatin**, #calcium folinate**, fluorouracil**), XELOX (#oxaliplatin**, capecitabine**)**) or upfront surgery followed by adjuvant chemotherapy with the aforementioned regimens (there is no compelling evidence of the superiority of a perioperative approach over postoperative therapy) (Table 11).

If MSI is detected in the tumor, preoperative chemoimmunotherapy may be used (up to 16–18 weeks with FLOT, FOLFOX, or XELOX regimens combined with nivolumab** or pembrolizumab** added to any of these regimens), ipilimumab plus nivolumab combination, or, in case of contraindications to chemotherapy, nivolumab** or pembrolizumab** monotherapy. If HER2neu overexpression is detected in the tumor, the addition of trastuzumab** to FLOT (preferred), FOLFOX, or XELox chemotherapy regimens is recommended. Available data on the integration of trastuzumab and immunotherapy into preoperative chemotherapy indicate a significant increase in the rate of complete pathological responses; their impact on survival remains unknown.

Preoperative chemoradiotherapy

Comment: For squamous cell carcinoma of the esophagus, preoperative chemoradiotherapy and preoperative chemotherapy are equivalent treatment options; the former may have certain advantages when the tumor is located in the upper third of the esophagus. For esophageal adenocarcinoma, preoperative chemoradiotherapy is inferior in efficacy to FLOT perioperative chemotherapy and should therefore be used only when perioperative chemotherapy is not feasible.

Prior to chemoradiotherapy, 6–8 weeks of chemotherapy (regregimens outlined above in the preoperative/perioperative chemotherapy section) may be administered, which helps reduce dysphagia in the majority of patients and allows for advance planning of radiation therapy; however, there is no evidence that this approach improves long-term outcomes. 3D-conformal external beam radiation therapy using linear accelerators with 6–18 MeV energy, a fractional dose (FD) of 1.8–2 Gy, and a cumulative dose (CD) of up to 41.4–50 Gy is optimal [35]. Concurrent chemotherapy with platinum-based regimens, #paclitaxel** or fluorouracil** (weekly regimen of #paclitaxel** + #carboplatin**), FOLFOX, or cisplatin** + fluorouracil** is administered alongside irradiation. According to the CROSS study, the preferred preoperative regimen is weekly intravenous #paclitaxel** 50 mg/m² and intravenous #carboplatin** at AUC2 during 5 weeks of radiation therapy (CD 41 Gy, FD 1.8 Gy per fraction) [35] (Table 11).

In cases of severe dysphagia prior to irradiation, endoscopic esophageal bougienage, endoscopic argon plasma coagulation for esophageal neoplasms, endoscopic Nd:YAG laser coagulation for esophageal neoplasms, or video-assisted endoscopic gastrostomy are performed. An alternative to the above methods for severe dysphagia is administering 6–8 weeks of chemotherapy, which typically leads to its reduction. Placement of an esophageal self-expanding metal stent is not recommended to relieve dysphagia prior to chemoradiotherapy, as this increases the risk of tumor perforation during radiation. Chemoradiotherapy is frequently complicated by radiation esophagitis and worsening dysphagia, which exacerbates the patient's nutritional deficit and impairs treatment tolerance. In such situations, partial or total parenteral nutrition or video-assisted endoscopic gastrostomy may be utilized. To prevent the deterioration of nutritional status and associated complications, nutritional support should be initiated concurrently with chemoradiotherapy.

Surgery is typically performed 6 weeks after the completion of chemoradiotherapy. In patients with squamous cell carcinoma who achieve a complete clinical response after chemoradiotherapy, either surgical resection or active surveillance is an option.

Comments: in patients with gastroesophageal junction and cardia adenocarcinoma staged as pT_anyN_1-3M₀ or pT_3-4N₀M₀ who have not received preoperative treatment, adjuvant chemotherapy following the principles of gastric cancer treatment may be considered (6 months of adjuvant chemotherapy with XELOX, FOLFOX regimens or, in case of platinum doublet intolerance, fluoropyrimidine monotherapy). In patients with esophageal adenocarcinoma or squamous cell carcinoma who have received preoperative chemoradiotherapy, have not achieved a complete pathological response, and have PD-L1 overexpression with CPS ≥5, adjuvant therapy with nivolumab** for 1 year postoperatively is recommended (this approach doubles the median progression-free survival).

• Postoperative chemoradiotherapy for esophageal cancer is recommended in patients in satisfactory general condition with residual tumor to improve patient survival. Regimens and doses are similar to definitive chemoradiotherapy (see below) [36].

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

Comments: In patients with squamous cell carcinoma of the esophagus, postoperative chemoradiotherapy may be administered after R1 or R2 resections, provided the patient has recovered from surgery. In patients with adenocarcinoma, the role of postoperative chemoradiotherapy after R1 or R2 resections is not clearly defined and may be considered as an addition to postoperative chemotherapy.

• Definitive radiation therapy (without chemotherapy) administered neoadjuvantly, adjuvantly, or as a standalone treatment is not recommended for patients diagnosed with esophageal cancer N1–3 Tany M0 due to low efficacy [37].

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

Comments: radiation therapy (external beam, brachytherapy) as a standalone modality may be used for palliative care.

• In cases of local recurrence of esophageal cancer, repeat surgery and/or chemoradiotherapy (if not previously administered) is recommended to improve treatment outcomes [12, 36, 38].

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

• If repeat surgery and chemoradiotherapy are not feasible for patients diagnosed with esophageal cancer, systemic antitumor drug therapy is recommended to improve treatment outcomes [12, 36, 38].

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

• For unresectable locally advanced esophageal cancer, tumors located in the cervical esophagus, as well as in patients with stage IV disease due to supraclavicular lymph node metastases, definitive chemoradiotherapy (fractional dose 1.8–2.0 Gy to a cumulative dose of 50 Gy concurrently with chemotherapy [Table 11]) is recommended to improve treatment outcomes [37, 39].

GPR ALEL 1Level of Recommendation – A (Level of Evidence – 1).

Comments: in patients with unresectable esophageal tumors (due to disease extent, age, or comorbidities), chemoradiotherapy without surgery is the mainstay of treatment. The decision regarding the presence of contraindications to surgery due to comorbidities can only be made by a multidisciplinary tumor board including a surgeon, radiation oncologist, medical oncologist, internist, and anesthesiologist-resuscitator. Chemoradiotherapy is the treatment of choice for patients with localized squamous cell carcinoma of the cervical esophagus.

In a direct comparative trial of efficacy and toxicity between cisplatin**- and fluorouracil** infusion-based chemoradiotherapy versus surgery (without chemoradiotherapy) used as standalone modalities, no differences in long-term outcomes were observed, but toxicity and mortality following conservative treatment were significantly lower. Except for cervical tumors, where the cumulative dose may reach 52–56 Gy, increasing the cumulative dose above 56 Gy does not improve outcomes and only increases mortality. In individual cases, the cumulative dose may be increased to 60 Gy when utilizing modern radiation therapy techniques (IMRT, VMAT).

As a standalone treatment, radiotherapy for locally advanced esophageal cancer has low efficacy and can be used for palliative purposes only.

For metastases in supraclavicular lymph nodes, standalone chemoradiotherapy is also the therapy of choice. In selected patients with isolated supraclavicular lymph node involvement, surgical treatment after preoperative chemoradiotherapy may be considered. Celiac lymph node involvement is also not a contraindication to chemoradiotherapy followed by a decision on surgical treatment.

In malignant esophageal fistulas (esophagomediastinal, esophagotracheal, and esophagobronchial fistulas), which are a contraindication to chemoradiotherapy, combined surgery may be performed [40].

• In stage IV esophageal cancer (except for metastases to supraclavicular lymph nodes), it is recommended to administer palliative chemoimmunotherapy, chemotherapy, or symptomatic therapy to improve quality of life by relieving tumor-growth-related symptoms and extending life expectancy [41].

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

Comments: the main objectives of treating patients with metastatic esophageal cancer are to improve quality of life by relieving tumor-growth-related symptoms and to extend life expectancy. Evaluating the efficacy of various chemotherapy regimens in this category of patients is difficult due to the lack of randomized trials, especially in squamous cell carcinoma. Chemotherapy is administered to patients in a satisfactory general condition (ECOG 0–2 score) in the absence of severe (grade III-IV) dysphagia that impedes adequate patient nutrition. In the latter case, restoration of esophageal patency (stenting, recanalization) is indicated as a first step. In grade I-II dysphagia, chemotherapy allows for a reduction in its severity in a number of patients by the end of the first cycle.

The most effective drugs for both histological variants are cisplatin**, fluorouracil**, and taxanes. For adenocarcinomas, #oxaliplatin** (more effective and less toxic than cisplatin), #irinotecan**, and trastuzumab** (in case of HER2 overexpression) are also effective (Appendix A3, Table 11).

For squamous cell carcinomas of the esophagus, the standard chemotherapy regimen remains a combination of cisplatin** with an infusion of fluorouracil** or #capecitabine**, or a combination of #paclitaxel** with platinum compounds (L01XA Platinum compounds) (cisplatin** being preferred, #carboplatin** in case of contraindications to cisplatin**) (regimes are specified in Appendix A3, Table 11). The objective response rate with such regimens is about 35%, and life expectancy does not exceed 6–8 months. #Carboplatin** is inferior to cisplatin** in immediate efficacy, which limits its use outside of chemoradiotherapy programs. The doses of #calcium folinate** in regimens with infusional fluorouracil are poorly scientifically substantiated; available limited data suggest the possibility of using lower fixed doses (e.g., 100 mg) in case of drug shortages and deficits.

The use of taxanes is possible as part of two-drug regimens with cisplatin** or three-drug combinations (with cisplatin** and fluorouracil**) (regimes are specified in Appendix A3). In the latter case, at the cost of higher toxicity, the objective response rate can be increased to 48%, although this does not appear to lead to an extension of life expectancy.

The optimal duration of first-line chemotherapy is unknown. In squamous cell carcinoma with disease stabilization during chemotherapy, 4 cycles are usually administered, while if an objective response is achieved, 6 cycles are given. In adenocarcinoma of the esophagus and gastric cardia, in addition to the commonly used approach regarding the duration of first-line therapy, selected patients may be offered the option of switching to second-line treatment (e.g., paclitaxel, FOLFIRI, irinotecan with possible addition of targeted therapy) after 12–16 weeks of first-line induction therapy (in the ARMANI trial, this approach led to a significant increase in progression-free survival and overall survival).

Chemoimmunotherapy.

Randomized trials have demonstrated a significant improvement in progression-free survival and overall survival from the addition of pembrolizumab** and nivolumab** to the combination of cisplatin** and fluorouracil** in the first-line setting in patients with esophageal squamous cell carcinoma with PD-L1 expression TPS ≥1 or CPS ≥1. An alternative to cisplatin** with fluorouracil** in combination with PD-1/PD-L1 inhibitors can be the #paclitaxel** + cisplatin** + PD-1/PD-L1 inhibitors regimen (Appendix A3, Table 11). In frail patients who are not candidates for cisplatin, replacing cisplatin with carboplatin in this combination is permissible, although the evidence base for this approach in esophageal cancer is limited.

In patients with metastatic adenocarcinoma of the esophagus and cardia with PD-L1 expression CPS ≥5, the addition of nivolumab** to FOLFOX or XELOX combinations in the first-line setting leads to a significant improvement in progression-free survival and overall survival. In patients with metastatic adenocarcinoma of the esophagus and cardia with PD-L1 expression CPS ≥10, the addition of pembrolizumab** to the XELOX combination in the first-line setting leads to a significant improvement in progression-free survival and overall survival.

Considering the pharmacokinetics of monoclonal antibodies, if production necessity dictates, administration of monoclonal antibodies is permitted not simultaneously with the start of the chemotherapy cycle (an interval of up to 5 days before or after is allowed).

HER2neu-positive adenocarcinoma of the esophagus and cardia.

In patients with HER2neu overexpression (3+ by immunohistochemistry or 2+ with confirmed gene amplification), the addition of trastuzumab** to chemotherapy regimens is recommended, which increases life expectancy. When HER2neu and PD-L1 overexpression are combined (CPS ≥1), the combination of XELOX + #pembrolizumab** + trastuzumab** can be used, which increases patient life expectancy compared to the XELOX + trastuzumab** combination (the FOLFOX combination can be used as an alternative to the XELOX regimen) (Appendix A3, Table 11). Otherwise, first-line therapy for metastatic adenocarcinomas of the esophagus and gastric cardia is carried out according to the principles of gastric cancer treatment (see relevant clinical guidelines).

Second and subsequent lines of therapy

There is no standard second-line chemotherapy for squamous cell carcinoma of the esophagus. Its administration is possible only in selected patients in generally satisfactory condition who responded to prior chemotherapy. In patients with esophageal squamous cell carcinoma with PD-L1 expression (TPS ≥1% or CPS ≥10), the use of pembrolizumab** and nivolumab** significantly improved life expectancy compared to investigator's choice therapy [42, 92]. Other second-line options include taxane monotherapy, the combination of FOLFIRI or XELIRI (especially in patients who have not previously received fluorouracil** or capecitabine**), and irinotecan monotherapy (Appendix A3, Table 11). Recommended palliative chemotherapy regimens are presented in Appendix A3. Treatment of esophageal and cardia adenocarcinoma in the second and subsequent lines is carried out in accordance with current clinical guidelines of the Russian Ministry of Health for the diagnosis and treatment of gastric cancer.

3.1. Symptomatic and supportive care

Comment: To correct dysphagia in patients who are candidates for chemoradiotherapy, it is advisable to consider forming a feeding enterostomy or jejunostomy, as stent placement is associated with an increased risk of complications [52]. Relief of dysphagia can occur at all stages of treatment and is achieved through various approaches: endoscopic procedures (balloon dilation, electro-, endoscopic argon plasma coagulation for esophageal neoplasms or endoscopic Nd:YAG laser coagulation for esophageal neoplasms, esophageal nitinol covered stent-endoprosthesis placement), radiotherapy (external beam or brachytherapy). Endoscopic recanalizations provide a rapid but short-term effect and are suitable in cases where effective treatment (surgery, chemotherapy, radiotherapy) will be initiated in the near future.

Comments: in cases where radical surgical treatment or standalone chemoradiotherapy (CRT) is not planned, the most optimal options for correcting dysphagia are esophageal stenting or brachytherapy. According to a direct comparative study of brachytherapy and stenting, the latter option achieves the desired effects faster, but at a longer follow-up period, the complication rate (stent migration, pain, perforation, gastroesophageal reflux) turned out to be higher, and the rate of absence of dysphagia – slightly lower [53]. In the event of tracheoesophageal/bronchoesophageal or mediastinal fistulas, placement of covered nitinol stent-grafts allows for the management of these complications in 70–100% of patients.

• When administering antineoplastic drug therapy with emetogenic side effects, patients are recommended to receive prophylaxis and treatment for nausea and vomiting [140, 141].

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

Comments: The principles of diagnosis, prevention, and treatment of nausea and vomiting during antineoplastic drug therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vladimirova L. Yu. et al. Nausea and Vomiting [142]. https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting

• In patients with metastatic bone lesions, prophylaxis and treatment of bone complications are recommended [143].

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

Comments: The principles of diagnosis, prevention, and treatment of bone complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Bagrova S. G. et al. Bone Pathology [144]. https://rosoncoweb.ru/standarts/?chapter=bone_pathology

• Patients are recommended prophylaxis and treatment of venous thromboembolic complications [145-147].

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

Comments: The principles of diagnosis, prevention, and treatment of venous thromboembolic complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Somonova O. V. et al. Thromboembolic Complications [148]. https://rosoncoweb.ru/standarts/?chapter=thromboembolism

• During antineoplastic drug therapy, patients are recommended prophylaxis and treatment of febrile neutropenia and infectious complications [149-151].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, along with the principles of antibacterial therapy, is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sakaeva D. D. et al. Practical Guidelines for the Diagnosis and Treatment of Febrile Neutropenia [152]. https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia

• During antineoplastic drug therapy, patients are recommended management of hepatotoxicity [153, 154].

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

Comments: The principles of diagnosis, prevention, and treatment of hepatotoxicity are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Tkachenko P. E. et al. Hepatotoxicity [155]. https://rosoncoweb.ru/standarts/?chapter=hepatotoxicity

• When patients undergo antineoplastic drug therapy, prophylaxis and treatment of cardiovascular complications are recommended [156-159].

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

Comments: The principles of diagnosis, prevention, and treatment of cardiovascular complications during antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society for Prevention and Treatment of Tumors and Antineoplastic Drug Therapy Complications: Vitsenya M. V. et al. Cardiovascular toxicity [160]. https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity

• During antineoplastic drug therapy, patients are recommended prevention and treatment of dermatological reactions [161].

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

Comments: The principles of diagnosis, prevention, and treatment of skin complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Tumors and Antineoplastic Drug Therapy Complications: Koroleva I. A. et al. Dermatological reactions [162]. https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions

• Nutritional support is recommended to maintain the body's metabolic reserves in cancer patients and increase their resistance to treatment (surgical, medical, radiation). The choice of nutritional support method is determined by the patient's various types of nutritional disorders. Placement of a nasogastric, nasointestinal, percutaneous, endoscopic, laparoscopic, or laparotomy stoma, endoscopic stenting for tumor stenosis, or palliative radiation therapy may be recommended [163, 164].

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

Comments: The principles of nutritional support are presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Tumors and Antineoplastic Drug Therapy Complications: Sytov A. V. et al. Nutritional support [165]. https://rosoncoweb.ru/standarts/?chapter=nutritional_support

• During antineoplastic drug therapy, patients are recommended prevention and treatment of nephrotoxicity [166-168].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of nephrotoxicity is presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Tumors and Antineoplastic Drug Therapy Complications: Gromova E. G. et al. Nephrotoxicity [169]. https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity

• During antineoplastic drug therapy, patients are recommended prevention and treatment of immune-mediated adverse events [170-173].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of immune-mediated adverse events is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Tumors and Antineoplastic Drug Therapy Complications: Protsenko S. A. et al. Immune-mediated adverse events [174]. https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events

• During antineoplastic drug therapy, patients are recommended prevention and treatment of mucositis [175, 176].

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

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of mucositis is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Tumors and Antineoplastic Drug Therapy Complications: Semiglazova T. Yu. et al. Mucositis [177] https://rosoncoweb.ru/standarts/?chapter=mucositis

• Patients are recommended treatment for anemia, which occurs as a symptom of a malignant neoplasm and as an adverse event during antineoplastic drug therapy [178,179].

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

Comments: The procedure and principles for the prevention and treatment of anemia comply with the principles outlined in the clinical guidelines "Anemia in Malignant Neoplasms" (ID: KR624, approval year 2020, www.cr.rosminzdrav.ru) and in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Tumors and Antineoplastic Drug Therapy Complications: Orlova R.V. et al. Anemia [180].

• During treatment, patients are recommended treatment for anorexia-cachexia syndrome [181].

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

Comments: A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Sytov A. V. et al. Practical guidelines for the treatment of anorexia-cachexia syndrome in cancer patients [182] https://rosoncoweb.ru/standarts/?chapter=anorexia-cachexia

• When administering cyclic antitumor drug therapy to patients that includes continuous prolonged (exceeding 6 hours) infusions of antitumor drugs (fluorouracil**, doxorubicin**, etc.) or in case of poor peripheral venous condition, the use of central venous access and infusion pumps is recommended [183].

ROB BLOE 1Recommendation grade – B (evidence level – 1).

Comments: The choice of central access option is determined by the planned duration of the entire course of treatment, patient preferences, and anatomical features. For prolonged (exceeding 3 months) courses of therapy, the implantation of a subcutaneous venous port system is the most convenient. For shorter periods, a peripherally inserted central venous catheter can serve as an alternative. The principles of using central venous access are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Isyangulova A. Z. et al. Central venous access [184]. https://rosoncoweb.ru/standarts/?chapter=central_venous_access

• During antitumor drug therapy, the prevention and treatment of antitumor drug extravasation are recommended for patients. When planning antitumor drug therapy, the selection of vascular access is important for preventing the extravasation of antitumor drugs [185].

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

Comments: Algorithms for vascular access selection, prevention, diagnosis, and treatment of extravasation are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Buydenok Yu.V. et al. Extravasation of antitumor drugs [186] https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs

• During antitumor treatment, the management of chronic pain syndrome is recommended for patients [187].

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

Comments: Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Kogonia L.M. et al. Chronic pain syndrome [188]. https://rosoncoweb.ru/standarts/?chapter=chronic_pain_syndrome

• During antitumor drug therapy, the prevention and treatment of infusion reactions are recommended for patients [189].

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

Comments: Algorithms for the prevention, diagnosis, and treatment of infusion reactions are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Orlova R.V. et al. Infusion reactions [190]. https://rosoncoweb.ru/standarts/?chapter=infusion_reactions

• During therapy, the monitoring and treatment of reactivation/exacerbation of chronic viral hepatitis are recommended for patients [191].

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

Comments: The principles of monitoring and management tactics in cancer patients with chronic viral hepatitis are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Feoktistova P.S. et al. Chronic viral hepatitis [192]. https://rosoncoweb.ru/standarts/?chapter=chronic_viral_hepatitis

• During antitumor drug therapy, the prevention and treatment of neurological complications are recommended for patients [193].

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

Comments: The principles of diagnosis, prevention, and treatment of neurological complications of antitumor therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Latipova D.Kh. et al. Neurological complications [194]. https://rosoncoweb.ru/standarts/?chapter=neurological_complication

3.2. Diet therapy

Comments: it is advisable to assess nutritional status and decide on the initiation of nutritional support (NS). According to the NRS-2002 scale, NS is prescribed for a total score of ≥3. Major abdominal surgery accounts for 2 points. An additional 1 point is added for age over 70 years, or weight loss of 5% over 3 months (3.5 kg with an initial body weight of 70 kg), or meeting normal dietary requirements by 70% or less. Nutritional support is prescribed on the basis of a protein intake of 1 g/kg/day and energy of 20-30 kcal/kg/day. Special medical nutrition products can be used: high-protein and high-energy enteral nutrition formulas – 2-3 servings per day via sipping. It is necessary to identify patients with severe malnutrition for earlier specialist consultation: initial consultation (examination) by a dietitian, initial examination (consultation) by an anesthesiologist-intensivist or a nutritionist to decide on a more intensive nutritional status correction program, including the use of parenteral nutrition. This group includes patients with a body mass index (BMI) <18.5; weight loss of more than 5% within a month or more than 15% within 3 months; intake of less than 25% of the required nutritional needs. Patients with dysphagia ≥grade III should also be included in this group. This category of patients may require intensive infusion therapy to correct water and electrolyte balance [54, 55].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1. General issues

Medical rehabilitation is a complex of medical and psychological measures aimed at the full or partial restoration of impaired and/or compensation of lost functions of a affected organ or body system, maintaining body functions during the resolution of an acutely developing pathological process or exacerbation of a chronic pathological process in the body, as well as the prevention, early diagnosis, and correction of potential dysfunctions of damaged organs or body systems, prevention and reduction of the degree of potential disability, improvement of the quality of life, preservation of the patient's work capacity, and their social integration into society.

• To determine individual patient routing during the implementation of medical rehabilitation measures, including the stage of medical rehabilitation and the group of the medical organization, the use of the Rehabilitation Routing Scale (RRS) is recommended [100] (Table 1).

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

Comments: according to the RRS, patients with malignant neoplasms belong to the "somatic diseases" section.

• The first stage of medical rehabilitation for cancer patients is recommended to be carried out in structural units of a medical organization providing specialized, including high-tech, medical care in inpatient settings in the profiles: "anesthesiology and intensive care", "oncology" [100]

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

• The second stage of medical rehabilitation for cancer patients is recommended to be carried out during the provision of specialized, including high-tech, medical care in inpatient settings in the department of medical rehabilitation of patients with somatic diseases established in medical organizations, including medical rehabilitation centers and sanatorium-resort organizations [100].

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

• The third stage of medical rehabilitation is recommended to be carried out during the provision of primary health care in outpatient settings and/or in day hospital settings (outpatient medical rehabilitation department, day hospital medical rehabilitation department), including in medical rehabilitation centers and sanatorium-resort organizations [100].

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

Comments: Telerehabilitation is a branch of telemedicine that involves the delivery of rehabilitation services using information and communication technologies. Today, it is widely implemented into clinical practice, which is justified by the need for continuity and consistency of restorative treatment.

Telerehabilitation has clear benefits for gastric cancer patients, including a reduced risk of infectious diseases, coverage of remote population groups, and the psychological aspects of undergoing restorative treatment at home while maintaining contact with the attending physician. It can also be used to dynamically assess the patient's condition, provide education and adjustments to recommended rehabilitation programs, and monitor the effectiveness of home exercises. Telerehabilitation can be used during pre-treatment preparation, in the delayed and late postoperative periods, at all stages of adjuvant treatment, and, of course, at the outpatient stage after completion of therapy. Feedback technologies allow patients to independently perform recommended programs under the remote guidance and supervision of their attending physician

4.2. Prerehabilitation stage

Prehabilitation is defined as rehabilitation starting from the moment of diagnosis until the initiation of treatment, whether systemic or local. The primary goal of prehabilitation is to prevent or reduce the severity of anticipated treatment-related physical impairments and psychological disorders that could potentially lead to significant disability.

• Physical prehabilitation including aerobic training, breathing exercises, and resistance training is recommended for gastric cancer patients to improve long-term functional outcomes [107].

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

Comments: The approach to selecting exercise intensity is always individualized. It takes into account gender, age, constitutional features, the level of the patient's physical development, the duration of forced hypokinesia, general condition, the course of the underlying disease, and the nature of the main clinical manifestations. The recommended volume of physical activity should correspond to the body's functional reserves and prior physical training. Functional tests, such as the squat test, cycle ergometry, etc., are also taken into account. Individually tailored complex training in the preoperative period promotes the development of adaptation mechanisms and non-specific resistance of the entire body.

• Physical prehabilitation is recommended for gastric cancer patients to improve functional outcomes and exercise tolerance, and to reduce the number of postoperative complications [108, 109].

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

• Given the increased risk of malnutrition in gastric cancer patients, prophylactic nutritional support is recommended in the preoperative period [102].

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

• In case of a weight loss of >10% over the last six months, BMI <18.5 kg/m², and albumin level <30 g/L, or an NRS 2002 score of >5, it is recommended to postpone surgery by 7-14 days for nutritional preparation [111].

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

Comments: Preoperative parenteral nutrition is administered only in cases of severe malnutrition when enteral nutrition is ineffective or impossible. The benefits of preoperative parenteral nutrition for 7-14 days have been proven only in patients with severe malnutrition (weight loss of more than 15%) undergoing preparation for gastrointestinal surgery [113].

4.3. Stage one of rehabilitation

4.3.1. Rehabilitation after surgical treatment

• If energy and nutrient requirements cannot be met solely by oral and enteral intake (<50% of calorie requirements) for more than seven days, a combination of enteral and parenteral nutrition is recommended [112].

Level of Recommendations CLevel of Evidence 5Level of Recommendations – C (Level of Evidence – 5).

Comments: Physical therapy exercises (PT) begin on the first day after surgery, including in intensive care units, provided the patient is in a stable condition and under the supervision of blood pressure, heart rate, and oxygen saturation. Exercises for small and medium muscle groups with partial unloading and a small number of repetitions are used, combined with breathing exercises focusing on diaphragmatic breathing and relaxation exercises. At the same time, the patient should be trained in abdominal breathing with a small amplitude of abdominal wall movement, as it causes mild changes in intra-abdominal pressure, which helps improve blood circulation, reduce spastic phenomena, and stimulate and subsequently improve bowel peristalsis. In addition, early initiation of breathing exercises improves pulmonary ventilation, activates blood circulation and gas exchange, and reduces congestion in the lungs. An incentive spirometer can be used, which, combined with early mobilization, reduces the incidence of cardiopulmonary complications, hospital stay duration, and pulmonary complications.

• Following gastrointestinal surgeries in gastric cancer patients, reflexology may be prescribed for diseases of the esophagus, stomach, and duodenum to manage postoperative pain [119].

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

Comment: despite the fact that according to Order No. 266 of the Ministry of Health and Social Development of the Russian Federation dated April 13, 2007, "On Approval of Recommended Lists of Medical Indications and Contraindications for the Use of Reflexology in Clinical Practice," malignant neoplasms are a contraindication for acupuncture, the safety and efficacy of this technique in cancer patients have been proven to date [120].

• Acupuncture may be used (stimulation of acupuncture points by other physical factors, electropuncture and electropuncture in reflexology, extremely high frequency therapy (EHF puncture), over-frequency current physio-puncture, ultrasonic puncture, laser puncture) to accelerate the recovery of gastrointestinal motility [121].

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

• Following surgery on the digestive tract, esophageal cancer patients may undergo psychological rehabilitation due to the high incidence of development and progression of postoperative distress [122].

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

4.4. Stages two and three of rehabilitation

4.4.1. Rehabilitation during systemic therapy.

Management of fatigue

• Conducting physical rehabilitation during systemic therapy for esophageal cancer helps prevent weakness and fatigue: moderate-intensity physical exercises combining aerobic load and resistance training, as well as graded walking, are recommended [125].

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

Management of peripheral polyneuropathy

4.4.2. Rehabilitation during radiation/chemoradiotherapy

• In patients with obstructive malignant neoplasms of the esophagus and severe radiation mucositis, it is recommended to deliver enteral nutrition via a nasogastric tube or PEG (percutaneous endoscopic gastrostomy) [127].

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

• During radiation therapy, parenteral nutrition is not recommended except for cases where adequate oral nutrition or enteral nutrition is impossible, for example, in severe radiation enteritis or severe malabsorption [127].

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

4.4.3. Rehabilitation after completion of therapy.

5. Prevention and Dispensary Observation

• To prevent the development of esophageal cancer, it is recommended to follow a diet that avoids thermal and mechanical trauma to the esophageal mucosa, quit smoking and alcohol, and timely treat background and precancerous conditions (Barrett's esophagus, GERD, achalasia cardia, esophageal strictures), including the use of intraluminal endoscopic interventions [1, 2, 6].

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

• Patients with Barrett's esophagus are recommended continuous therapy with proton pump inhibitors (#esomeprazole**) at a dosage of 80 mg/day. If low-grade dysplasia of the Barrett's epithelium is detected, a repeat endoscopic examination is recommended after 0.5 years, and upon confirmation of low-grade dysplasia, argon plasma coagulation of submucosal tumors (metaplastic foci) of the esophagus [72].

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

Comments: it is difficult to assess the exact contribution of various measures to the prevention of esophageal squamous cell carcinoma due to the lack of large, well-designed population-based studies.

- patients after radical treatment (surgery or chemoradiotherapy) – every 3–6 months for the first 2 years, then every 6–12 months for the next 3–5 years, and annually thereafter [12];

- patients with early cancer who underwent endoscopic mucosal resection or submucosal dissection – EGD every 3 months in the first year, every 6 months in the second and third years, and annually thereafter [12, 73].

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

Comments:

Scope of examination:

1) medical history and physical examination;

2) EGD 3 months after resection of the primary tumor, thereafter twice a year for 3 years, and then once a year up to 5 years;

3) abdominal and pelvic ultrasound (comprehensive) every 3–6 months depending on the risk of progression;

4) targeted chest X-ray every 6 months;

5) chest and abdominopelvic CT with intravenous bolus contrast once 6–12 months after surgery (depending on the risk of progression).

6. Organization of Medical Care

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

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

2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

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

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

If a malignant disease of the esophagus is suspected or detected in a patient, general practitioners, district general practitioners, family physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient oncological care center, a primary oncological office, or a primary oncological department of a medical organization to receive primary specialized health care.

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.

In the event that the medical organization housing the outpatient oncological care center (primary oncological office, primary oncological department) is unable to obtain biopsy (surgical) material or perform other diagnostic tests, the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases of the esophagus.

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

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

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

The timeframe for initiating specialized, excluding high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to patients with oncological diseases of the esophagus 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 malignant neoplasm of the esophagus (in the absence of medical indications for outpatient pathological-anatomical studies).

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

In a medical organization providing medical care to patients with oncological diseases of the esophagus, the tactics of medical examination and treatment shall be determined by a concilium of oncologists and radiotherapists, involving other specialist physicians as 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 complications of esophageal cancer requiring emergency and urgent specialized medical care;

2) presence of complications resulting from esophageal cancer treatment (surgery, radiation therapy, drug therapy, etc.).

An indication for planned inpatient admission to a medical organization is:

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

2) presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy, including brachytherapy, teletherapy, and other types of radiation therapy, drug therapy, etc.) requiring monitoring in a 24-hour or day hospital setting.

Indications for discharging a patient from a medical organization are:

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

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

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

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.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for specialized medical care provided to adults with esophageal and cardial cancer (ICD-10 codes: C15, C16.0)

References

Appendix A1. Working Group Composition

1. Aleksandrov E.D., oncologist at the Department of Clinical Radiology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

2. Besova N.S., PhD in Medical Sciences, Senior Researcher at the Oncology Department of Drug Treatment Methods (Chemotherapy) No. 2, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

3. Bolotina L.V., MD, PhD, Head of the Chemotherapy Department, Tumor Drug Treatment Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

4. Vladimirova L.Yu. Professor, MD, PhD, Head of the Tumor Drug Treatment Division, Head of the Antitumor Drug Therapy Department, National Medical Research Center of Oncology of the Russian Ministry of Health,

5. Gamayunov S.V., PhD in Medical Sciences, Chief Physician of the Nizhny Novgorod Regional Clinical Oncology Dispensary

6. Grinevich V.N., PhD in Medical Sciences, Head of the Oncopathology Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Head of the Pathological Anatomy Department, Moscow Clinical Scientific Center named after A.S. Loginov, Moscow Healthcare Department, Russian Society of Oncopathologists.

7. Kolesnikov Evgeny Nikolaevich, MD, PhD, Associate Professor, Head of the Abdominal Oncology Department No. 1, National Medical Research Center of Oncology of the Russian Ministry of Health

8. Kononets P.V., PhD in Medical Sciences, Head of the Thoraco-Abdominal Division, Director of the Research Institute of Clinical Oncology named after Academician of RAS and RAMS N.N. Trapeznikov, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

9. Levchenko E.V., MD, PhD, Professor, Head of the Thoracic Department, National Medical Research Center of Oncology named after N.N. Petrov of the Russian Ministry of Health.

10. Malikhova O.A., MD, PhD, Professor, Head of the Endoscopy Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

11. Pirogov S.S., PhD in Medical Sciences, Head of the Endoscopy Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

12. Pokataev I.A., MD, PhD, Head of the Chemotherapy Service, First Oncology Hospital, City Clinical Hospital named after S.S. Yudin, Moscow Healthcare Department.

13. Ryabov A.B., MD, PhD, Deputy General Director for Surgery, National Medical Research Radiological Center of the Russian Ministry of Health

14. Sakun Pavel Georgievich, PhD in Medical Sciences, Head of the Radiology Department, National Medical Research Center of Oncology of the Russian Ministry of Health,

15. Semenova A.I., PhD in Medical Sciences, Senior Researcher, National Medical Research Center of Oncology named after N.N. Petrov of the Russian Ministry of Health

16. Sobolev D.D., PhD in Medical Sciences, Researcher at the Thoraco-Abdominal Surgical Department, Division of Thoraco-Abdominal Oncosurgery, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

17. Stilidi I.S., MD, PhD, Corresponding Member of the RAS, Director of the National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

18. Tryakin A.A., MD, PhD, Head of the Oncology Department of Drug Treatment Methods (Chemotherapy) No. 2, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health; Russian Society of Clinical Oncology (RUSSCO).

19. Tyuryaeva E.I., PhD in Medical Sciences, Oncologist, Research Institute of Oncology named after N.N. Petrov of the Russian Ministry of Health.

20. Fedenko A.A., MD, DSc, 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

21. Khandogin N.V., MD, PhD, Oncologist, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

22. Khomyakov V.M., MD, PhD, Head of the Thoracoabdominal Surgery Department, Department of Thoracoabdominal Cancer Surgery, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

23. Falaleeva N.A., MD, PhD, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

24. Fedyanin M.Yu., MD, DSc, Head of the Chemotherapy Service, Moscow Multidisciplinary Clinical Center "Kommunarka" of the Moscow Healthcare Department

25. Filonenko E.V., Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

26. Chernykh M.V., MD, PhD, Deputy Director for Radiation Therapy, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health; Associate Professor, Department of Oncology, Radiotherapy, and Plastic Surgery, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health.

Healthcare Organization Section:

1. Nevolskikh A.A., MD, DSc, 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 S.A., MD, DSc, Professor of the Russian Academy of Sciences, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

3. Khaylova Zh.V., MD, PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Gevorkyan T.G. Deputy Director of the Research Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology.

Medical Rehabilitation and Supportive Care Section:

1. Romanov A.I., MD, DSc, Professor, Academician of the Russian Academy of Sciences, Chief Physician of the Rehabilitation Center of the Presidential Administration of the Russian Federation.

2. Ivanova G.E., MD, DSc, Chief Specialist in Medical Rehabilitation of the Russian Ministry of Health, Head of the Department of Medical and Social Stroke Rehabilitation, Research Institute of Cerebrovascular Pathology and Rehabilitation, P.I. RSLMU of the Russian Ministry of Health.

3. Obukhova O.A., MD, PhD, Physiotherapist, Head of the Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

No conflict of interest declared by any member 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 therapists;

5) pathologists;

6) clinical pharmacologists;

7) general practitioners (physicians);

8) endoscopists;

9) thoracic surgeons;

10) geneticists;

11) medical university students, residents, and postgraduate students.

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

Table A1. Levels of evidence certainty in accordance with the methodological recommendations for the development and updating of clinical guidelines (Order of the Russian Ministry of Health No. 103n dated February 28, 2019).

Table A2. Grades of recommendation in accordance with 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 analyzed.

Method of recommendation validation:

• external expert review,

• internal expert review.

Description of the recommendation validation method

The draft of these recommendations was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Comments were received from primary care pediatric oncologists regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a practical tool for 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 peer review: the draft recommendations were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

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

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 medicine data regarding 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. The decision to update is made by the Ministry of Health of the Russian Federation based on proposals submitted by medical professional non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicinal products and medical devices, as well as the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure 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. Reference Materials

Table 11. Main chemotherapy regimens used as monotherapy or in combination with radiation therapy in the treatment of esophageal cancer [139]

¹ in patients with squamous cell carcinoma or adenocarcinoma of the esophagus with PD-L1 CPS ≥5 expression who underwent R0 surgical resection following chemoradiotherapy and did not achieve a complete pathological response.

² in patients with adenocarcinoma of the esophagus and esophagogastric junction with PD-L1 CPS ≥5 or MSI expression.

³ first-line therapy, patients with squamous cell carcinoma with PD-L1 CPS ≥1 or TPS ≥1% expression.

⁴ second and subsequent lines of therapy in patients with squamous cell carcinoma with PD-L1 CPS ≥10 or TPS ≥1% expression.

⁵ the regimen can be used as neoadjuvant/perioperative chemotherapy in patients with MSI adenocarcinomas.

⁶ as first-line therapy in patients with adenocarcinoma with CPS ≥10 or MSI.

⁷ in case of HER2neu overexpression, trastuzumab may be added to regimens at standard doses.

⁸ The regimen requires supportive care with filgrastim** for 3-6 days, or empegfilgrastim** subcutaneously once, or lipegfilgrastim 6 mg subcutaneously once, or pegfilgrastim 6 mg once. Colony-stimulating factors may be started immediately after the completion of the fluorouracil** infusion.

⁹ first-line, adenocarcinoma, HER2neu overexpression combined with PD-L1 CPS ≥1 expression.

¹⁰ second-line therapy for esophageal squamous cell carcinoma, especially in patients who have not previously received fluorouracil or capecitabine.

Table 1. Rehabilitation Routing Scale (RRS) for somatic patients, including patients with malignant neoplasms.

¹ Six-minute walk test

² Exercise Stress Tests

Appendix B. Physician Action Algorithms

Diagram 1. Flowchart for the diagnosis and treatment of a patient with esophageal and/or cardia cancer

Appendix C. Patient Information

Recommendations for chemotherapy complications - contact an oncologist specializing in chemotherapy

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

• monitor complete blood count within 24 hours;

• start antibiotics (systemic anti-infectives) as prescribed by the oncologist.

2. For stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• frequent mouth rinsing (every hour) with chamomile, oak bark, or sage decoctions, lubricate the oral cavity with sea buckthorn (peach) oil;

• treat the oral cavity as prescribed by your oncologist.

3. In case of diarrhea:

• diet: exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meat, flour products, fermented milk products, and rice water are permitted. Drink plenty of fluids;

• take medications as prescribed by the medical oncologist.

4. In case of nausea:

• take medications as prescribed by the medical oncologist.

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

Appendix G1. ECOG/WHO Scale for assessing the general condition of the patient

Russian name: ECOG Performance Status Scale.

Original name (if any): The ECOG Scale of Performance Status.

Source (official developer website, publication with validation): Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655 [74].

Type: rating scale.

Purpose: Assessment of the patient's general condition.

Content (template) and Key (interpretation).

Notes: none.

Appendix D2. Nutritional status assessment scale NRS-2002

Russian title: NRS-2002 scale for nutritional risk screening.

Original title (if any): NRS-2002.

Source (official developer website, validation publication): Kondrup J., Allison S.P., Elia M., Vellas B., Plauth M. Educational and Clinical Practice Committee, European Society of Parenteral and Enteral Nutrition (ESPEN). ESPEN Guidelines for Nutrition Screening 2002 Clinical Nutrition (2003) 22(4): 415–421 [75].

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 G1 and G2.

Key (interpretation): NRS-2002.

Table G1. Primary screening

Table G2. Final screening

Notes:

1. Patient's age 70 years or older – add 1 point to the total score.

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

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

Notes: none.

Appendix G3. NRS 2002 SCALE

Patient Nutritional Risk Screening Scale (NRS).

Reference: Kondrup J, Allison SP, Elia M, Vellas B, Plauth M. ESPEN guidelines for nutrition screening 2002. Clin Nutr. 2003; 22(4): 415-421. doi: 10.1016/s0261-5614(03)00098-0.

Type: rating scale.

Purpose: recommended for assessing the nutritional status of hospitalized patients

Contents:

1) Initial screening

2) Final screening

Notes and interpretation:

1. Patient's age 70 years or older – add 1 point to the total score.

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

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

Appendix G4. Malnutrition Universal Screening Tool (MUST)

Name: Malnutrition Universal Screening Tool (MUST) (Malnutrition Universal Screening Tool).

Source: Stratton R.J., Hackston A., Longmore D., et al. (2004) Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the "malnutrition universal screening tool" ("MUST") for adults. Br J Nutr 92, 799 – 808.

Type: scale.

Purpose: recommended for assessing the nutritional status of outpatients.

Contents:

1. Body mass index, kg/m²

• >20.0 – 0 points

• 18.5–20.0 – 1 point

• <18.5 – 2 points

2. Unintentional weight loss in the preceding 3–6 months

• <5% – 0 points

• 5–10% – 1 point

• >>10% – 2 points

3. Presence of an acute disease AND no food intake >5 days / probability of no food intake >5 days = 2 points

Key (interpretation):

0 points — low risk of malnutrition. Routine care. Repeat screening: in an inpatient setting — weekly; for independent community-dwelling individuals — annually for risk groups.

1 point – moderate risk of malnutrition. Monitoring: hospital – monitoring food and water intake for 3 days, followed by re-screening (dietary adjustment if necessary). Re-screening: hospital – weekly, at home – every 2–3 months.

≥2 points – high risk of malnutrition. Malnutrition correction: Initial consultation/examination by a clinical nutritionist / physical and rehabilitation medicine physician, additional protein and nutrient administration (sip feeding) as needed, dietary adjustment