CACA guidelines for holistic integrative management of gastric cancer

Abstract

According to statistics, the rates of incidence and death of gastric cancer in China have risen to the fourth worldwide, resulting in huge social burden. Regrettably, international guidelines, such as NCCN or ESMO, could not provide enough consideration to Chinese clinical practice, making it difficult to achieve individual therapy in China. In 2020, China Anti-Cancer Association (CACA) invited domestic multi-disciplinary experts and made the guideline of gastric cancer, involving surgeon, oncologist, pathologist, radiologist, herbalist, physiatrist and psychologist. This gastric cancer guideline recommends comprehensive treatment scheme with high-evidence and well-feasibility, which is mainly based on evidence-based medicine, Chinese experience and expert consensus. We provided MDT to HIM system of “prevention, screening, diagnosis, treatment, rehabilitation” for gastric cancer, which embodied the integration of research evidence, clinical experience and patient needs. The CACA guideline is more suitable for China’s clinical practice, reflecting scientificity, accessibility and Chinese characteristics, highlights the concept of integrated medicine, and has guiding value of clinical practice.

1 Gastric cancer prevention and screening

1.1 Epidemiology

According to the latest Global data (Globocan 2020) [1], gastric cancer (GC) is the 5th most prevalent type of malignancy, with 1.089 million new cases and age-standardized incidence rates of 15.8 per 100,000 for men and 7.0 per 100,000 for women; it is responsible for 769,000 new deaths and is the 4th highest cause of mortality, with an overall mortality rate of 7.7 per 100,000. The global average annual GC incidence for the past 5 years is 1.806 million cases, including 1.397 million cases (77.4%) in Asia and 689,000 cases (38.2%) in China. In 2020, GC had the 3rd highest incidence rate among all malignancies in China, with 479,000 new cases and age-standardized incidence rates of 29.5 per 100, 000 for men and 12.3 per 100,000 for women; it caused 374,000 deaths and was the 3rd leading cause of death, with a mortality rate of 15.9 per 100,000.

The incidence of GC varies with sex, age, and region. The 60 to 74 years age group has the highest incidence and mortality in China, and the incidence and mortality rates are higher in men than in women. In China, the incidence rate of GC is significantly higher in the northeastern, northern, northwestern, and eastern coastal regions than in the southern regions; it is higher in mountainous areas than in rural areas and higher in rural areas than in urban areas [2].

With the improvement of medical technologies and the implementation of screening, the early cancer detection rate has increased, and the mortality rate has decreased. In Japan and South Korea, endoscopic screening has long been implemented; as a result, the early detection of cancers (T1bN0M0 and T2N0M0) has increased yearly, with an early diagnosis rate of over 70%. In China, the early cancer detection rate is approximately 20%, and the age-standardized 5-year survival rate of GC, which is higher in rural areas than in urban areas, is improving yearly; it was 30.2%, 33.2% and 35.9% in 2000–2004, 2005–2009, and 2010–2014, respectively [3].

1.2 Etiology

1.2.1 Lifestyle

Dietary factors are associated with the risk of GC. High consumption of grilled and charred meat, a high salt intake, and the consumption of salted and smoked foods promote tumor development. Smoking and drinking are also risk factors for GC. Obesity is related to the onset and development of GC, especially cancer of the cardia.

1.2.2 Infectious factors

The World Health Organization (WHO) lists Helicobacter pylori (Hp) as a Class I carcinogen in human GC [4]. In China, Epstein-Barr virus (EBV)-related GC accounts for 6.7–10.6% of all GC cases; therefore, EBV infection could serve as a biomarker for GC treatment. The gastrointestinal microbiota and certain specific bacterial infections are associated with GC and precancerous lesions [5], and some intragastric microbiota and Hp can have a synergistic effect.

1.2.3 Environmental factors

Occupational exposure can cause GC. Workers with long-term exposure to rubber dust, rubber fumes, nitramine, asbestos, cement, and particles of metals, such as hexavalent chromium, have a significantly elevated risk of GC [6,7,8]. Other physicochemical factors, such as radiation, ionizing radiation, vinyl chloride, benzene, polycyclic aromatic hydrocarbons, and dichloromethyl ether, also have carcinogenic risks [9].

1.2.4 Genetic factors

Genetic factors play an important role in the etiology of GC. Inherited GC can take 2 forms: i.e., familial inheritance (aggregated, marked by strong genetic susceptibility) and population inheritance (sporadic, marked by weak genetic susceptibility).

1.2.5 Precancerous diseases and precancerous lesions

Some precancerous diseases, such as chronic atrophic gastritis, remnant stomach, adenomatous polyps, and persistent chronic gastric ulcer, carry a risk of GC. The associated histopathological changes, such as gastric epithelial dysplasia, intraepithelial neoplasia, and incomplete intestinal metaplasia (colonic type), are borderline precancerous lesions. Patients with pre-GC diseases, especially those with pre-GC diseases with precancerous lesions, have a significantly high risk of developing GC.

1.2.6 Racial factors

The effect of race on the risk of GC varies. Hispanic individuals and those of certain Asian ethnicities (Korean, Chinese, Vietnamese, and Japanese) have a high prevalence of intestinal metaplasia, ranging from 12.7% to 39.9%. According to the Globocan 2020 statistics, of the 1.806 million annual cases of GC worldwide in the last 5 years, 77.4% were in Asia [1].

1.3 High-risk groups

People at high risk of GC are defined as those aged ≥40 years who meet any one of the following criteria: ① from areas with a high incidence of GC; ② with Hp infection; ③ with a history of precancerous diseases; ④ with a first-degree relative with GC patient; ⑤ with exposure to other environmental risk factors for GC [10].

In addition, those who meet any of the following conditions can be regarded as at high-risk for hereditary diffuse GC: ① at least 3 family members diagnosed with GC, of whom at least 1 was diagnosed with diffuse GC or signet ring cell carcinoma; ② at least 2 family members with GC, of whom at least 1 was diagnosed with diffuse or signet ring cell carcinoma before the age of 50 years; ③ family members diagnosed with diffuse GC or signet ring cell carcinoma before the age of 35 years; ④ family members diagnosed with diffuse or signet ring cell carcinoma and lobular breast cancer at the same time; ⑤ 1 family member diagnosed with diffuse GC or signet ring cell carcinoma and another diagnosed with lobular breast cancer or colon cancer (signet ring cell carcinoma) [10].

1.4 Population screening

Screening is an important means for the early detection of GC. In South Korea and Japan, general GC screening is conducted for populations aged > 40 years and > 50 years, respectively. In China, based on the national situation, general screening is recommended in areas with a high risk of GC, and opportunistic screening in medical practice is recommended for high-risk populations [11].

1.4.1 Screening methods

Serological screening

Serum pepsinogen (PG) has been included as a marker of chronic atrophic gastritis for GC screening. In China, a PG I concentration ≤ 70 μg/L and PG I/PG II ≤ 3.0 are adopted as the screening criteria for people with a high risk of GC. Based on serological test results, the risk is stratified, and the need for further tests is determined.

Hp detection

Among the noninvasive Hp detection tests used in clinical practice, the 13C or 14C urea breath test is the most widely recommended, while the monoclonal stool antigen test is used as an alternative. The serological Hp detection test can be used to screen high-risk populations.

Endoscopic screening

Endoscopy is a precise method for the detection of GC, and biopsy aided by high-definition staining endoscopy is the best method for detecting precancerous gastric mucosa or precancerous lesions. Annual examinations are recommended in cases of low-grade intraepithelial neoplasia with unclear borders, and an examination every 6 months is recommended in cases of high-grade intraepithelial neoplasia with clear borders that has not undergone endoscopic treatment [12].

1.4.2 Screening strategy

Serum PG combined with Hp testing and coupled with an accurate gastroscopic examination is the recommended screening protocol for GC, i.e., high-risk individuals are screened using noninvasive methods first and then evaluated using a targeted, accurate endoscopic examination.

1.4.3 Screening scoring system and procedure

A new screening scoring system has been developed based on the results of a study of nearly 15,000 individuals at risk for GC in China [13]. It includes 5 variables and generates a total score of 0–23 points. Based on these scores, the screening target population is divided into 3 levels: a high-risk group (17–23 points), a medium-risk group (12–16 points), and a low-risk group (0–11 points).

With reference to screening methods previously used in China and abroad, combined with the latest clinical evidence in China, the recommended screening procedure is shown in Fig. 1.

Fig. 1

Flowchart for GC screening

1.5 The tertiary prevention strategy for GC

The primary prevention strategy reduces the prevalence of GC through etiological prevention and lifestyle interventions. For key populations with various risk factors, precancerous diseases of the stomach and precancerous lesions are treated through health promotion and changes in bad dietary habits and practices. Eradicating Hp is the most effective primary prevention strategy for reducing the incidence of GC.

The secondary prevention strategy involves reducing the mortality rate through effective screening and early detection. Currently, it is believed that the use of serum PG, gastrin-17, Hp-IgG, and other preliminary screening methods and the new screening scoring system, followed by targeted endoscopic screening, is a feasible screening strategy. The focus is on screening people with a high risk of developing precancerous diseases and precancerous lesions.

The tertiary prevention strategy is to reduce the recurrence rate and improve quality of life and the survival rate through standardized treatment and rehabilitation management. Comprehensive treatment for mid- and late-stage GC should be strengthened, and for patients with advanced disease, pain should be reduced, and quality of life should be improved. After treatment, regular follow-up should be performed to monitor metastatic recurrence, and various measures should be taken to promote rehabilitation and improve the survival rate.

2 Diagnosis of GC

2.1 Clinical manifestations

2.1.1 Symptoms

Early GC (EGC) often presents no obvious symptoms. With the development of the disease, symptoms similar to gastritis and gastric ulcer may appear; these mainly include upper abdominal fullness or discomfort or dull pain, especially after meals; loss of appetite; belching; acid reflux; nausea; vomiting; gastrointestinal bleeding; black stool, etc. In addition to the above symptoms, advanced GC (AGC) often manifests as follows: ① weight loss, anemia, and fatigue; ② stomach pain, which, when persistent, aggravated and radiating to the back, suggests possible invasion of the pancreas and celiac plexus; ③ GC perforation, accompanied by sharp abdominal pain; ④ nausea and vomiting, which are often caused by obstruction or gastric dysfunction as a result of the tumor; ⑤ gastric cardia cancer can cause chest pain and the choking feeling when eating, and antrum cancer can cause the pyloric obstruction-derived vomiting of retained food and gastric juice; ⑥ tumor invasion of the blood vessels can cause gastrointestinal bleeding, and the patient can present a positive fecal occult blood test result, black stool, and hematemesis, depending on the amount of bleeding; ⑦ other symptoms, e.g., diarrhea caused by achlorhydria or accelerated gastric emptying, menstrual abnormalities resulting from metastases in female patients, and ovarian metastases (e.g., Krukenberg tumor); additionally, a very small number of outpatient visits area associated with initial symptoms caused by brain metastasis.

2.1.2 Signs

There are usually no obvious signs in the early stage of GC, except deep tenderness in the upper abdomen. The following signs may appear in the advanced to advanced of GC: ① epigastric mass: in the pyloric antrum or gastric body, an epigastric mass can sometimes be palpated; in women, when a movable mass can be palpated in the lower abdomen, the possibility of a Krukenberg tumor should be considered; ② gastrointestinal obstruction: pyloric obstruction can be the gastric type, indicated by a succussion splash, and small intestine or mesentery metastasis can cause intestinal stenosis leading to partial or complete intestinal obstruction; ③ ascites: peritoneal bloody ascites can occur in cases of peritoneal metastasis; ④ supraclavicular lymph node (LN) enlargement; ⑤anterior rectal fossa mass; ⑥ umbilical mass (the Sister Mary Joseph sign). Among these, supraclavicular LN enlargement, ascites, lower abdominal mass, umbilical mass, anterior rectal fossa node, intestinal obstruction, weight loss, anemia, ascites, edema, fever, jaundice, malnutrition, and even cachexia are important signs of late GC.

2.2 Serological examination

Because early symptoms and signs of GC are usually not obvious, a serological examination is recommended. Commonly used detection indicators include PG, carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), alpha fetoprotein (AFP), CA724, CA125, and other tumor markers. Tumor markers play a role in GC diagnosis, determining prognosis, and monitoring efficacy, while combined detection can improve diagnostic sensitivity and specificity. When there is no obvious new or progressive lesion observed during imaging examinations but the level of tumor markers continues to rise, possible recurrence or progression of the disease should be considered, and the patient should be closely followed to determine the causes.

2.3 Endoscopic diagnosis

2.3.1 EGC

Diagnosis of the presence of GC

Based on the lesion’s mucosal manifestations, its location and scope are identified, and the Hp infection status is determined; chromoendoscopy can highlight the characteristics of the lesion and thus help identify its scope and improve the accuracy of the biopsy.

Qualitative diagnosis

When a lesion is spotted, it is necessary to perform a qualitative diagnosis. For this purpose, magnifying endoscopy with staining is recommended so that the benign and malignant nature of the lesion can be determined. The magnifying endoscopy simple diagnostic algorithm for EGC (MESDA-G) based on the vessels-plus-surface (VS) theory is recommended. The VS theory considers the surface microvessels (V) and surface microstructures (S), which have 3 forms: regular, irregular and absent. EGC observed under magnifying endoscopy is characterized by the presence of abnormal surface microvessels and/or abnormal surface microstructures at the junction of the cancer and the non-cancerous background; these microvessels manifest various morphologies such as enclosed, open, tortuous, or branched microvessel/epithelium, with asymmetrical distributions. The MESDA-G flowchart is shown in Fig. 2 [14].

Fig. 2

MESDA-G diagnosis flowchart. DL, demarcation line; IMVP, irregular microvascular pattern; IMSP, irregular microsurface pattern

The endoscopic characteristics of early cancer can be categorized as the protruding type (0-I), the nonprotruding and nonexcavated type (0-II), and the excavated type (0-III) according to the Paris Classification, updated in 2005 [15, 16]. Of these, the 0-I type is further subdivided into the pedunculated type (0-Ip) and the sessile type (0-Is), and the 0-II type is subdivided into 3 subtypes, i.e., slightly elevated (0-IIa), flat (0-IIb) and slightly depressed (0-IIc). The distinction between the 0-I type and the 0-IIa type is whether the elevation reaches 2.5 mm, while the distinction between the 0-III type and the 0-IIc type is whether the depression reaches 1.2 mm. Slightly elevated or slightly depressed lesions are divided into 0-IIc + IIa and 0-IIa + IIc subtypes according to the ratio of elevated to depressed lesions. Lesions with depression and slight depression are divided into 0-III + IIc and 0-IIc + III subtypes according to the ratio of the 2 presentations, as shown in Fig. 3.

Fig. 3

Endoscopic classification of EGC (Paris classification, 2005)

Preoperative evaluation

According to the indications for endoscopic treatment, it is necessary to perform a detailed preoperative evaluation of EGC [17] so that an appropriate treatment plan can be formulated.

Evaluation project	Content
Size of tumor	The size of the lesion is measured by comparing the diameter of the endoscope or biopsy forceps, or by using a measuring disc or forceps.
Histological type	Combined with the results of endoscopic examination and histopathological diagnosis of biopsy specimens, the tumor was divided into two types: differentiated tumor with glad and undifferentiated tumor without glad. a
Invasion depth of tumor	Preoperative endoscopic diagnosis of intramucosal carcinoma included pT1b1 lesions (SM1, vertical infiltration depth under the mucous muscle layer was less than 500um). pT1b2 (SM2, vertical infiltration depth under the mucous muscle layer was over 500um) should be taken as an important observation index for ordinary white light observation. At present, the depth of infiltration of the lesion is often judged by whether the lesion margin is upward. If necessary, depth should be further evaluated in conjunction with endoscopic ultrasonography.
Presence of ulcer	Routine white light endoscopy should determine the presence of active ulcer or ulcer scar in EGC.

Notes:

^a Endoscopically, differentiated and undifferentiated adenocarcinomas present different general morphologies and characteristics: ① General morphology: differentiated adenocarcinoma exhibits extruding proliferation and expanding growth and belongs to the elevated categories (0-IIa and 0-I) in early stage, while undifferentiated adenocarcinoma exhibits destructive proliferation and diffusive infiltration that leads to the destruction of the mucosal structure to form depressions (0-IIc). ② Color: differentiated adenocarcinomas are mostly red, while most undifferentiated carcinomas show discoloration changes. ③ Lesion edge: the depressed edge of differentiated adenocarcinoma is mostly spiny, gently sloping, and raised, while the edge of undifferentiated adenocarcinoma is mostly linear, jagged, and cliff-like.

Endoscopic ultrasonography

Endoscopic ultrasonography (EUS) can reflect stomach wall destruction at the anatomical level while allowing the direct observation of lesions. It is the preferred choice for clinical tumor (cT) staging according to the 8th edition of American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC), and it can also be used for the node (N) staging of enlarged perigastric LNs [18]. It is recommended to evaluate LNs No. 5 and No. 6 and some second-echelon LNs (LNs No. 8, No. 12) by scanning backward starting at the duodenal bulb, LNs No. 1-No. 4 by intragastric scanning, and LNs No. 9-No. 11 by identifying important anatomical landmarks, such as the celiac trunk and splenic blood vessels [19]. The assistive techniques for EUS (e.g., tissue elastography) can further identify benign and malignant LNs, and fine needle aspiration biopsy can be performed under the guidance of EUS if necessary. Moreover, EUS can detect some metastases and even small amounts of ascites and thus can assist in the evaluation of metastasis (M) staging. If non-regional LNs are suspicious, they are also considered for M staging.

Pathological examination of biopsy

If suspected EGC lesions are observed, biopsy should be conducted. The number of biopsies is based on the size of the lesion: if the lesion is > 1 cm, the number of biopsies is ≥2; if the lesion is > 2 cm, the number of biopsies is ≥3; if the lesion is > 3 cm, the number of biopsies is ≥4. The specimen should be adequately large enough, and sampling should be deep enough to reach the muscular layer of the mucosa.

2.3.2 AGC

Endoscopic classification

The Borrmann classification is usually adopted, and the classification is based on the morphology of the tumor on the mucosal surface and the manner and extent of the tumor infiltration of the gastric wall. For details, see section 2.6 (Pathological diagnosis).

Pathological examination of biopsy

To increase the positive rate of biopsy, it is recommended that 6–8 specimens should be collected from different locations according to the type of the lesion: for pedunculated lesions, tissue from the head of the lesion should be collected; for elevated lesions, tissue from the top of the lesion should be collected; for ulcerated lesions, tissue on the inner side of the ulcer should be collected.

2.4 Imaging examination and diagnosis

2.4.1 Selection of examination methods

GC imaging examination methods are divided into conventional methods (computed tomography (CT)) and alternative methods (magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, upper gastrointestinal examination), as shown in Fig. 4. Contrast-enhanced CT of the abdomen and pelvis is the preferred imaging method for GC and is the optimal method for detecting and assessing LN metastasis and peritoneal metastasis. Routine chest CT is recommended for AGC to exclude lung metastasis. When it is necessary to determine the extent of the lesion and mediastinal LN metastasis of esophagogastric junction (EGJ) cancers, contrast-enhanced chest CT scan should be performed. MRI, which is used for examination when contrast-enhanced CT is contraindicated or liver metastasis is suspected, can aid in detecting early liver metastasis and assessing the extent of advanced cancer invasion, thereby improving the diagnostic level of T staging. PET-CT can aid in the evaluation of distant metastases and is suitable when traditional imaging methods cannot provide an accurate evaluation and clinical decision-making could be affected according to different conditions, e.g., in cases of small peritoneal metastases, suspected supraclavicular and mediastinal metastases, and suspected metastases to LN No. 16. X-ray angiography is most often recommended for EGJ cancers to assist in judging the length of esophageal invasion and performing Siewert classification. In addition, small-sample studies have shown that functional imaging methods, such as MRI diffusion-weighted imaging (DWI), dual-energy CT imaging, and PET-CT imaging, can assist in the evaluation of treatment efficacy. Radiomics can effectively increase the potential of imaging workflows, improve lesion detection, and reduce the probability of errors. At present, omics imaging is mainly based on CT texture and has shown high accuracy for analyzing and predicting the pathological characteristics of GC, clarifying LN metastasis and pathological staging, and evaluating curative efficacy and prognosis.

Fig. 4

The scope of application of diagnostic imaging technology

2.4.2 Examination procedure

CT and MRI require standardized pretreatment preparation to ensure image quality, including hypotonic scanning, air/water filling, and breathing training. The scan range of CT and MRI is from the top of the diaphragm to the pelvic floor. Given the stomach’s tortuous shape, observation on 3 planes, i.e., axial, coronal, and sagittal, is necessary to clearly show the thickness, shape, and extent of the cancer and its relationship with the adjacent organs and tissues.

When contrast-enhanced abdominal and pelvic CT is necessary, 3-phase (arterial, venous, and delayed) enhancement is recommended. When the use of iodine-containing contrast agents is contraindicated, MRI is recommended as an alternative. MRI examination sequences for GC include at least 4 types, of which DWI is of great value for the detection, diagnosis and differential diagnosis, staging of lesions and evaluation of the curative effect; furthermore, it can assist in the quantitative evaluation and dynamic comparison of lesions. The imaging department should establish the quality control and standard operation procedure (SOP) for treatment and scanning before GC imaging examinations are performed (Fig. 5). Nurses should note the onset of a hypotonic effect through inquiry and observation, and the technician should assess gastric cavity filling when scanning the positioning image and should observe and manage the patient’s breathing during MRI. A mechanism for the regular analysis and evaluation of image quality should be established.

Fig. 5

SOP for imaging examinations

2.4.3 Image report specification

The imaging report should focus on comprehensive information related to clinical diagnosis and treatment, such as detection, diagnosis, clinical tumor-node-metastasis (cTNM) staging, and treatment evaluation, and should enable the Multiple Discipline Team to Holistic Integrative Medicine (MDT to HIM) to have a full involvement in image interpretation [20]. The generation of a structured report is recommended, and such reports should include the following main content:

Primary lesion

The location, distal and proximal boundaries (Siewert classification for EGJ cancers), morphology (Borrmann classification), thickness, and enhanced features of the primary lesion; the depth of invasion; the condition of the mucosa and serosal surface; and the relationship with adjacent organs should be included.

LNs

According to the report format of the Japanese Research Society for Gastric Cancer, the number of LNs with clear signs of metastasis (the number range for N staging) and the longest and shortest diameters, morphology, border, and enhancement of the largest LN should be included. The assessment of key LN metastasis involving clinical grouping decisions should be determined through MDT to HIM.

Distant metastases

The location, distribution, morphology, size, density, and enhancement characteristics of metastases, peritoneal morphology, and ascites should be included. The report of peritoneal metastases should distinguish the involvement of different areas, such as the greater omentum, perihepatic capsule, transverse mesocolon, small intestinal mesentery, and parietal peritoneum. When a small amount of ascites, smudged omental fat, or peritoneal micronodules are detected on CT or MRI, even when no diagnosis can be made, the combination of general morphological characteristics and the staging of the primary lesion can indicate the clinical risk of occult peritoneal metastasis, which can provide a basis for decision-making with further laparoscopic exploration and irrigation of the abdominal cavity. In cases of disputes, the issue should be submitted to the MDT to HIM for discussion.

2.5 Laparoscopic diagnosis and staging

Peritoneal metastasis is the most common type of distant metastasis of GC; it includes peritoneal dissemination and intraperitoneal free cancer cells. An accurate noninvasive diagnostic method for GC is still lacking, and consequently, 10–30% of patients are diagnosed with locally advanced cancer before surgery reveals peritoneal metastasis, a condition that is also called occult peritoneal metastasis [21].

Laparoscopic exploration can effectively reduce trauma while enabling the evaluation and scope of intraperitoneal metastasis. At the same time, intraoperative peritoneal lavage can be performed for cytological detection, which allows treatment strategies to be formulated or curative efficacy to be evaluated [22]. Due to the importance of laparoscopic exploration for the diagnosis of peritoneal metastasis, the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), Chinese Society of Clinical Oncology (CSCO), and other multinational guidelines have recommended the use of laparoscopic exploration for assessing the status of peritoneal metastasis, albeit the findings are still inconclusive.

2.5.1 Indications for laparoscopic staging

Existing guidelines regarding the indications for laparoscopic exploration are still inconclusive. At present, AGC remains the focus in China, and the indications for exploration should not be reduced to avoid accidental switching to open abdominal surgery or missed peritoneal metastases. Laparoscopy is recommended when peritoneal metastasis is suspected after CT examination. In addition, when neoadjuvant therapy is planned, laparoscopic staging is recommended for those with a advanced stage (cT3–4 or N+), especially those with high risk factors for peritoneal metastasis who will be undergoing preoperative treatment.

2.5.2 Contraindications for laparoscopic staging

Laparoscopic staging is contraindicated for patients with a history of abdominal or pelvic surgery, those with clear and suspected severe abdominal adhesion, and those who cannot undergo laparoscopic surgery or cannot tolerate anesthesia or CO₂ pneumoperitoneum due to poor cardiopulmonary function.

2.5.3 Ascites or peritoneal lavage fluid test

The cytological examination of ascites or peritoneal lavage fluid is currently the gold standard for the diagnosis of free cancer cells in the abdominal cavity. The surgical specifications for the examination of free cancer cells in the abdominal cavity are as follows: ① Collection of ascites: if there is sufficient amount (> 200 ml) of ascites, it is directly collected for cytological examination; if there is no ascites or the volume of ascites is less than 200 ml, then > 250 ml warm normal saline is used to sequentially rinse the bilateral diaphragmatic roofs, subhepatic area, greater omentum, bilateral paracolonic grooves, and Douglas fossa while avoiding direct flushing of the primary lesion, and > 100 ml lavage fluid each is collected from the rinses of the bilateral subdiaphragmatic areas, subhepatic area, and Douglas fossa for cytological examination. ② Specimen preparation: after the centrifugation of ascites or peritoneal lavage fluid, the cell pellet is directly smeared, fixed, and stained with hematoxylin-eosin (HE), or Pap staining is performed.

2.5.4 Record of peritoneal metastasis

Peritoneal metastasis should be recorded as follows: ① Peritoneal metastasis (P) should be recorded as PX: peritoneal metastasis status is unknown, P0: no peritoneal metastasis, or P1: with peritoneal metastasis. The degree of peritoneal dissemination can be determined according to the standard presented in the 15th edition of the Japanese Classification of Gastric Carcinoma [23] or Sugarbaker’s Peritoneal Cancer Index (PCI), but doing so is very difficult; ② The test results for peritoneal lavage cytology (CY) should be recorded as CYX: peritoneal cytology not performed; CY0: peritoneal cytology negative for carcinoma cells; CY1: peritoneal cytology positive for carcinoma cells. When a positive result is suspected but not clearly positive, it should still be recorded as CY0.

2.6 Pathological diagnosis

2.6.1 Pathological concept

• (1) Intraepithelial neoplasia/dysplasia: intraepithelial neoplasia/dysplasia refers to lesions characterized by different degrees of cellular and structural atypia of the gastric mucosal epithelium, which are gastric precancerous lesions. Intraepithelial neoplasia is divided into low-grade and high-grade types, of which the low-grade type is equivalent to mild to moderate atypical hyperplasia, and the high-grade type is equivalent to severe atypical hyperplasia, dysplasia, or carcinoma in situ.

• (2) EGC: cancer invasion is limited to the gastric mucosa or submucosa, with/without LN metastasis.

• (3) AGC: cancer tissue has invaded the gastric muscularis propria or deeper, regardless of LN metastasis.

• (4) Adenocarcinoma of EGJ (AEG): adenocarcinoma with the center located within 5 cm of the esophagogastric anatomical junction that crosses or touches the EGJ [24].

• (5) Tumor deposit: refers to an independent tumor nodule that is within the drainage area of ​​the perigastric LN and adjacent to the perigastric adipose tissue and is without identifiable LNs, blood vessels, and nerve structures, a condition that is also called extranodal soft tissue metastasis. Since the 7th edition, when TNM staging of GC is performed, tumor deposits are counted as metastasized LNs and considered an independent factor affecting the prognosis.

2.6.2 Specimen type, fixation, and sampling [25]

Specimen type

Common specimen types include endoscopic biopsy specimens, endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) specimens, and radical resection specimens.

Tissue specimen fixation

Fresh GC tissue should be fixated promptly. The collected tissue specimen should be flattened and fixed to the foam board with the mucosal surface facing up, the oral and anal directions of the specimen should be labelled, and then the mucosal surface should be facing down and fixed by complete immersion in 10 volumes of 10% buffered formalin (fixation solution) within 30 min after the tissue is isolated. The specimens should be fixed for 6 to 72 h at room temperature.

To effectively increase the detection rate of positive human epidermal growth factor receptor 2 (HER2), some experts in China have proposed the clipping method, i.e., within 10 min after the tissue is isolated, a piece of tissue containing the entire thickness of the tumor is cut along the long axis of the tumor, placed in 50 ml of fixative in a cryovial, and detected together with other tissues. Studies have shown that this method can maximally maintain tissue viability and increase the overall HER2 positive rate from 8.8% to 18.9%.

Standard for tissue collection and description

• (1) Biopsy specimens: all the mucosa is submitted for examination, and the size and number of the tissues should be described; the mucosa should be flattened and then embedded vertically for sectioning. It is recommended that each slide contain 6 to 8 continuous tissue slices to facilitate continuous observation.

• (2) EMR/ESD specimens [26, 27]

The color of the mucosa and the outline, elevation or depression, and erosion or ulceration of the lesion should be recorded; the size and general type of the lesion and the distance from the lesion to each resection edge should be recorded; the entire specimen perpendicular to the nearest resection edge should be collected; and the oral and anal directions should be labelled. Parallel cuts at intervals of 2 to 3 mm should be made, and alltissues should be collected. If the specimen is too large, then the specimen should be cut into several pieces and respectively labelled as a, b, …, etc.

• (3) Radical resection specimen

The location, size, number, general type, degree and scope of invasion, and distance from the lesion to the resection margin should be recorded, and the presence of other changes in the mucosa and serosal surface of the gastric wall outside the tumor should be observed. During tissue collection from the center of the lesion, a piece of tissue containing the entire thickness of the tumor is taken from the resection margin from the oral to the anal direction; the sample should include the tumor, the mucosa adjacent to the tumor, and both ends of the resection margin and should be cut into several pieces for embedding. To submit the resection margin of the closer separately for examination, after the closer is removed, the rest of the material should be used for observation. The deepest part of tumor invasion and suspected peripheral involvement should be the focus during tissue collection. For radical surgery specimens of EGC patients or patients with no obvious lesions after neoadjuvant treatment, it is recommended to collect all suspicious lesion areas and tumor bed areas. In cases of proximal GC, the GC’s relationship with the EGJ is recommended; if it involves the EGJ, the distance between the tumor center and the EGJ should be recorded; in cases of distal GC, the GC’s relationship with the duodenum should be reported.

• (4) LN selection and collection [23, 24]

When collecting tissues, the number, size (recommended size: ≤ 2.0 cm × 1.5 cm × 0.3 cm), and fusion and adhesion of LNs should be described. According to the 8th edition of TNM classification for GC, at least 16 LNs should be selected. A multicenter retrospective analysis of data from China shows that to ensure the accuracy of LN staging for patients with stage pN0 GC, at least 16 LNs should be submitted for examination, while for patients with stage pN1-3b GC, at least 30 LNs should be submitted for examination [28]. In addition, the LNs should be sent for examination in groups according to local anatomy to show the LN metastasis in various regions of the stomach and the quality of D2 radical surgery, thereby reflecting the standardization of LN dissection.

2.6.3 General classification

General classification of EGC

• (1) General classification of common EGC

EGC is divided into 3 types: type I (protruding growth), type II (superficial growth), and type III (excavating growth). The superficial type is further subdivided into 3 subtypes, i.e., IIa (superficial elevated), IIb (superficial flat), and IIc (superficial depressed). If 2 or more types are present, the cancer is classified as mixed-type EGC (Fig. 6).

Fig. 6

Schematic diagram of the general classifications of EGC (WHO, 2019)

• (2) General classification of special EGC

Special types of EGC mainly include superficial spreading EGC, micro GC (≤ 0.5 cm in diameter) and small GC (from 0.5 cm to 1.0 cm in diameter).

General classification of AGC

For the general classification of AGC, the Borrmann classification (Fig. 7) is recommended. Based on the morphological characteristics of GC on the mucosal surface observed with the naked eye and the way the cancer diffuses and grows in the gastric wall, the Borrmann classification divides GC into 4 types, i.e., type 1 (polypoid tumors), type 2 (ulcerated tumors), type 3 (fungating tumors), and type 4 (infiltrating, linitis plastica). The Borrmann classification of GC can reflect the cancer’s diffusive growth capacity and main direction of filtration.

Fig. 7

Schematic diagram of the Borrmann classification for AGC

2.6.4 Histological classification and grading

Histological classification

It is recommended that both the WHO (digestive system tumors) and Laurén classifications be used to classify GC histologically. The Laurén classification divides gastric adenocarcinoma into the intestinal type, diffuse type, mixed type, or indeterminate type according to its histological growth.

Histological grading

According to the degree of differentiation of its tissue cells, GC is categorized as highly differentiated (G1), moderately differentiated (G2), and poorly differentiated/undifferentiated (G3).

Serous membrane typing

The serosal typing of GC has a close and consistent relationship with the general type and growth mode and can be divided into normal type, reactive type, protruding nodular type, flat nodular type, tendonoid type, and color-diffused type, as shown in Fig. 8.

Fig. 8

Serous membrane typing of GC

2.6.5 Staging

For the clinical pathological staging of GC, the 8th edition of the TNM classification for GC jointly developed by the AJCC and the UICC is recommended. The new version of the staging classification includes cTNM, pathological staging (pTNM), and pathological staging after neoadjuvant therapy (ypTNM).

For the pathological evaluation of surgically resected specimens after neoadjuvant treatment, tumor regression should be classified into the following grades according to the amount of residual tumor cells and degree of fibrosis: grade 0 (complete remission (CR), without residual tumor cells), grade 1 (partial remission (PR), with individual cells or small-focus residual tumor cells), grade 2 (limited curative effect, residual cancer foci with fibrosis), grade 3 (poor curative effect/limited or no curative effect, with extensive residual cancer cells). However, large acellular mucus lakes may appear after radiotherapy and chemotherapy and cannot be regarded as tumor remnants.

Classification methods for EGJ cancers include the Siewert classification and the Japanese Nishi classification. In China, the Siewert classification is used; it includes type I (the tumor is centered 1–5 cm above the EGJ and grows downward and involves the EGJ), type II (the tumor is centered 1 cm above the EGJ and 2 cm below the EGJ and involves the EGJ), and type III (the tumor is centered 2–5 cm below the EGJ and grows upward, involving the EGJ). In the 8th edition of the TNM classification for GC by the AJCC/UICC, tumors that invade the EGJ and are centered 2 cm below the EGJ are staged according to the standard for esophageal cancer, and those that are centered within 2 cm below the EGJ but do not invade the EGJ and those that are centered more than 2 cm below the EGJ are staged according to the standard for GC. This guideline recommends that the current 8th edition of the pTNM staging standard be used for the classification of AEG, and the distance between the center of the tumor and the EGJ should be accurately recorded.

2.6.6 Molecular pathological detection

The standardized and individualized treatment of GC must be based on pathologically accurate diagnosis and classification. In addition to traditional histological pathological diagnostic methods, immunohistochemistry (IHC), in situ hybridization (ISH), gene sequencing and other techniques can be employed to detect various biomarkers and help pathologically diagnose GC. Currently, the IHC-related markers that are commonly used in clinical pathology practice include the following:

Markers related to diagnosis and differential diagnosis

• (1) GC with lymphoid stroma accounts for 1–7% of all GC cases. The common feature of this type of tumor is that cluster of differentiation 8⁺ (CD8⁺) lymphocyte-based infiltration or aggregation can be observed in or around the cancer tissue, suggesting a relatively good prognosis. Currently, GC with lymphoid stroma is divided into 2 categories: more than 80% of the cases are related to EBV infection, and approximately 20% of cases are related to deficient mismatch repair protein (dMMR), which can be screened based on high microsatellite instability (MSI-H) via polymerase chain reaction (PCR) assay or based on dMMR status via IHC methods.

• (2) Hepatoid adenocarcinoma and gastric adenocarcinoma with enteroblastic differentiation are likely to be GC types of the same differentiation lineage with different degrees of differentiation. They belong to the category of alpha-fetoprotein producing adenocarcinomas and represent the 2 extremes of poorly differentiated and highly or moderately differentiated lineages. The detection of a set of immune markers (e.g., hepatocyte paraffin 1 (Hep Par 1), AFP, glypican 3 (GPC3), spalt-like transcription factor 4 (SALL4), claudin 6, cytokeratin 19 (CK19) and caudal-type homeobox 2 (CDX2)) can aid in differential diagnosis.

• (3) Gastric large-cell neuroendocrine carcinoma or small-cell neuroendocrine carcinoma requires IHC tests for synaptophysin (Syn), chromogranin A (CgA), CD56, and Ki-67. Neuroendocrine cancer is divided into 2 types: highly differentiated (NET) and poorly differentiated (NEC). Of these, the NEC type often presents loss of retinoblastoma susceptibility (RB) gene expression and abnormal expression of p53, while the NET type often lacks these features, which is helpful for differential diagnosis.

• (4) Hereditary diffuse GC has the morphological characteristics of signet ring cell carcinoma and requires IHC detection (e.g., E-cadherin) and germline mutation detection (e.g., cadherin 1 (CDH1)) for screening or diagnosis. The percentage of abnormal E-cadherin expression in the Asian GC population is approximately 44.5%, and low E-cadherin expression is an independent prognostic factor for GC patients.

• (5) When vascular invasion/tumor thrombus is suspected, IHC tests for podoplanin (D2–40), CD34, and CK can be used for confirmation. If invasion of the nerves by cancer tissue is suspected, the markers neurofilament protein (NF) or S-100 protein (S-100) can be used for verification.

Markers related to molecular targeted therapy

Tumor molecular markers are substances that are synthesized and secreted as a result of gene expression in tumor cells or are produced abnormally by the body in response to the tumor. They include proteins, hormones, enzymes (isoenzymes), and oncogene products.

• (1) HER2 detection: the overall positive rate of HER2 is 14%, and that in the Chinese population is 12% [29]. HER2 is a classic target of GC targeted therapy. The ToGA trial showed that chemotherapy combined with trastuzumab treatment can significantly prolong the survival of HER2-positive AGC patients. Based on this, trastuzumab has been approved for HER2-positive gastric and EGJ cancers. IHC or ISH should be the first-choice method for the detection of HER2 expression; of these, IHC is preferred. According to the HER2 diagnostic criteria for GC, IHC 2+ or IHC 3+ does not require complete cell membrane staining. If U-shaped staining (i.e., a medium- or high-degree of staining in part of the outer cell membrane) is observed, the result can be considered positive for GC. IHC 3+ cases are directly regarded as HER2 positive, and IHC 1+ and IHC 0 are directly regarded as HER2 negative. IHC 2+ cases are regarded as indeterminate cases, and an ISH assay is required to confirm the HER2 status. If there is amplification, the result is determined to be HER2 positive, and if there is no amplification, then it is determined to be HER2 negative.

• (2) The IHC and/or ISH detection of claudin18.2, fibroblast growth factor receptor 2b (FGFR2b), vascular endothelial growth factor receptor 2 (VEGFR2), epidermal growth factor receptor (EGFR), MET, and other markers also has potential clinical application value, but further investigation and clinical verification are needed.

Markers related to GC immunotherapy

Studies have found that AGC patients who are EBV positive and have MSI and a high tumor mutational burden (TMB) are the most appropriate population for the application of immune checkpoint inhibitors [30], which can be combined for testing if necessary.

• (1) Programmed death-ligand 1 (PD-L1): for the evaluation of PD-L1 immunohistochemical results, the combined positive score (CPS) method is recommended. Patients who are PD-L1 positive, especially those with a CPS ≥ 10, can undergo pembrolizumab treatment for GC as a third-line or later treatment [31].

• (2) Epstein-Barr encoding region (EBER): EBER in situ hybridization is the gold standard for the diagnosis of EBV-related GC (EBVGC). EBVGC is highly sensitive to immunotherapy, with an objective remission rate of 100% [32]; thus, immune checkpoint inhibitor therapy is highly beneficial.

• (3) MSI/dMMR: MSI is a molecular diagnostic marker for tumor immune checkpoint inhibitor therapy, especially for the PD-1 monoclonal antibody. MSI detection includes the MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), PMS1 Homolog 2 (PMS2), and MutS homolog 6 (MSH6) genes.

• (4) TMB: A high TMB usually means the production of high frequency neoantigen and is significantly correlated with the objective remission rate of PD-1 monoclonal antibodies [33]. TMB detection is performed mainly through whole-exome sequencing or is based on a large set of mutant genomes and Panel conversion.

Chemotherapy-related markers

Routine Ki-67 detection is recommended for gastric adenocarcinoma tissue to assess the status of cancer cell proliferation and provide a reference for postoperative chemotherapy [34]. The Ki-67 positive index may be closely related to the treatment of neuroendocrine cancer and requires accurate evaluation. MSI-H GC has relatively good prognosis while the efficacy of neoadjuvant/adjuvant chemotherapy for this type is not good, which can be used as a reference index for the efficacy of postoperative chemotherapy [29].

Next-generation sequencing (NGS)

NGS can assess GC-related genetic and epigenetic changes and thus can guide GC treatment. The use of NGS for AGC is listed by the NCCN guidelines as a 2A recommendation for determining the treatment plan and/or clinical trial entry, especially for those for whom drug therapy has been ineffective or for whom limited pathological materials are available. NGS can be used to guide treatment and for MSI, TMB, and circulating tumor DNA (ctDNA) detection.

3 Treatment of GC

3.1 Endoscopic treatment

3.1.1 Indications and contraindications

Endoscopic treatment of GC is mainly used for EGC and is generally suitable for patients with an extremely low possibility of LN metastasis [35]. Endoscopic resection mainly includes EMR and ESD.

The absolute indications are as follows: well differentiated; confined to the mucosal layer (T1a); diameter < 2 cm; without ulceration. In recent years, the indications have been slightly expanded to include the following: ① EMR: mucosal carcinoma (cT1a) < 2 cm in diameter, differentiated carcinoma, without ulceration; ② ESD: intramucosal carcinoma (cT1a) >  2 cm in diameter, differentiated carcinoma, no ulceration; intramucosal carcinoma (cT1a) < 3 cm in diameter (observable with the naked eye), differentiated cancer, with ulceration; ③ Expanded indications for ESD: mucosal carcinoma (cT1a) < 2 cm in diameter (observable with the naked eye), undifferentiated, without ulceration. EUS should be used as an assessment method for ESD.

For patients who do not meet the above indications and require surgical treatment, endoscopic resection can be considered when surgery presents a great risk and serious complications are likely; however, the patient should be well informed of the risk of residual tumor and LN metastasis [36]. The use of secondary endoscopic resection for patients with local recurrence after endoscopic resection is performed under absolute indications is still under debate and must be confirmed with further investigations.

The contraindications for endoscopic treatment of EGC include the following: ① the presence of LN metastasis; ②tumor invasion of the muscularis propria; ③ the presence of coagulopathy and other conditions incompatible with endoscopic resection.

3.1.2 Evaluation of curability

Curability with endoscopic radical resection is different from that with surgical resection. With surgical resection, R0 indicates a negative margin, but with endoscopic resection, a negative margin does not mean curative resection. The curability of radical resection under endoscopic resection is determined by 2 factors, i.e., the degree of local resection and the possibility of LN metastasis, and is assessed using the eCura system (Table 1) [36].

Table 1 eCura evaluation system for endoscopic resection of GC

For curability A (eCuraA) and curability B (eCuraB), regular follow-up is adequate. In the case of endoscopic curability C-1 (eCuraC-1), the risk of LN metastasis is low. After full communication with the patient, secondary ESD or additional surgical resection can be performed. When the submucosal infiltration portion or stumps are positive, additional surgical resection should be performed due to an indeterminate pathological diagnosis. In the case of endoscopic curability C-2 (eCuraC-2), additional surgical resection should be performed in principle. When surgery cannot be performed due to the patient’s age, coexisting diseases, etc., the patient should receive a full explanation of the risk of node metastasis, local recurrence, and distant metastasis; the difficulty of achieving a cure; and the poor prognosis in cases of recurrence.

3.2 Surgical treatment

3.2.1 Principles of treatment

In EGC, except for patients who meet the indications for endoscopic treatment, the main treatment method is surgery; for local AGC, an integrated treatment strategy based on surgery should be adopted. Radical surgery includes the complete removal of the primary tumor and the thorough removal of regional LNs. Nonradical surgery mainly includes palliative surgery and reduction surgery.

Radical surgery: standard surgery aims to completely remove the primary lesion and perform D2 LN dissection; reduction surgery is defined as the removal of less than 2/3 of the stomach or an LN dissection range smaller than D2 (D1, D1+ or other); extended surgery includes combined organ resection or (and) LN dissection beyond the scope of D2.

Nonradical surgery: ① Palliative surgery is mainly for patients who have distant metastases or tumors that have invaded important organs and thus cannot be resected and who have complications such as bleeding, perforation, and obstruction. Surgical procedures include palliative gastric resection, gastrojejunostomy, and jejunal feeding tube placement. The purpose of palliative surgery is to relieve symptoms and improve quality of life. ② Reduction surgery refers to gastrectomy performed for patients who have incurable factors but no complications.

Laparoscopic and robotic surgeries have developed rapidly in recent years. For EGC, laparoscopic distal subtotal gastrectomy combined with D2 LN dissection is not only safe but can reduce bleeding, accelerate gastrointestinal recovery, and shorten hospital stays (see 3.2.5 for details). For AGC suitable for distal subtotal gastrectomy, laparoscopic surgery can be performed at large tumor centers, while for laparoscopic proximal GC resection and AGC laparoscopic total gastrectomy, clinical evidence is still lacking, and more clinical studies are required. At present, there is no large-sample prospective study confirming the therapeutic value of robotic surgery for AGC, and more evidence is needed to evaluate the advantages and effects of robotic surgery for AGC.

3.2.2 Scope of surgical resection

The scope of surgical resection is determined mainly according to tumor location, stage, size, and peripheral LN metastasis.

During surgical resection of EGC, sufficient margins should be ensured before determining the resection line, which is generally over 2 cm from the edge of the tumor. When the tumor boundary is unclear and it is difficult to determine the resection line, the preoperative endoscopic placement of titanium clips can help. If necessary, intraoperative frozen pathological examination can be conducted to ensure that the resection margin is negative.

The margin should be at least 3 cm away from the lesion for patients with limited growth of AEG and more than 5 cm away for those with infiltrating growth. If the tumor invades the esophagus or pylorus, a 5-cm margin is not necessary, and frozen pathological examination of the margin is recommended to ensure R0 resection.

Regarding the scope of EGC resection, except in cases of distal gastrectomy and total gastrectomy, patients with a clinical stage of cT1N0M0 can undergo different reduction or function-preserving gastrectomy procedures according to tumor location. There procedures mainly include pylorus-preserving gastrectomy (PPG), proximal gastrectomy, and other surgical methods (local resection and segmental resection, etc.).

Distal gastrectomy is often performed for advanced lower-stomach cancer, total gastrectomy is often performed for gastric body cancer, and total gastrectomy or proximal gastrectomy is often performed for EGJ cancer. If the tumor directly invades the surrounding organs, radical resection combined with organ resection is performed to ensure the R0 resection. Unless the tumor directly invades the spleen, preventive splenectomy for LN dissection is not recommended [37].

In standard radical resection for AGC (> T3), the greater omentum can be completely removed routinely, but for T1/T2 tumors, greater omentum resection is not necessary, and the gastrocolic ligament can be cut 3 cm from the omental vascular arch [36]. For tumors that invade the serosal layer of the posterior gastric wall, some scholars have suggested that the removal of the omental bursa can reduce the risk of peritoneal recurrence and metastasis and can improve survival. However, recent clinical trials have confirmed that resection of omental bursa fails to improve the prognosis of T3/T4a cancers [38]. Therefore, routine omental bursa resection for AGC is not recommended.

3.2.3 Radical LN dissection

LN metastasis is the most common metastasis of GC. The scope of dissection for LN metastasis in EGC is divided into D1, D1+, D2, etc., and the LN dissection grouping is determined according to the gastrectomy method.

EGC lymphadenectomy indications: ① Dl LN dissection: suitable for cT1aN0 stage EGC that does not meet the indications for EMR/ESD or for cT1bN0 stage differentiated EGC with a focus diameter ≤ 1.5 cm; ② D1+ LN dissection: suitable for cT1N0 stage EGC that does not meet the indications for D1 LN dissection; ③ D2 LN dissection: suitable for cT1 stage EGC with suspected LN metastasis during preoperative diagnosis or intraoperative detection.

The performance of D2 LN dissection for local AGC has become a consensus recommendation. The scope of LN dissection is mainly determined by the scope of gastrectomy, as shown in Table 2. At the same time, at least 16 LNs should be submitted to ensure accurate staging and prognostic determination, and the submission of more than 30 LNs for detection is preferred [39, 40].

Table 2 Scope of LN Dissection in radical surgery for GC

For LNs with a high risk of metastasis outside the range of D2 LN dissection, selective expanded LN dissection (D2 +, D3) can be considered.

D2 + surgery consensus: ① For AGC in which the tumor is located at the side of the lesser curvature of the stomach and is < 4 cm in diameter, LN No. 10 dissection is not necessary, but for middle- or upper-stomach cancer with a preoperative staging of T3 or T4 in which the tumor is located at the side of the greater curvature of stomach or is > 6 cm in diameter, LN No. 10 dissection is recommended [41]. ② When GC invades the duodenum, LN No. 13 is considered the regional LN, and for AGC with duodenal invasion, D2 + LN No. 13 dissection can be considered; however, for such patients, the R0 resection rate is generally low, and therefore, D2 + LN No. 13 dissection after the neoadjuvant therapy is recommend [42]. ③ Although LN No. 14v is not included in the scope of D2 surgery for distal GC, for patients with LN No. 6 metastasis of distal AGC or LN No. 14v enlargement during operation, D2 + LN No. 14v dissection can improve the prognosis [43]. ④ studies have confirmed that preventive LN No. 16 dissection cannot improve long-term survival [44], and if D2 + para-aortic LN dissection (PAND) is performed after neoadjuvant chemotherapy, the prognosis of some patients can be improved [45, 46]. ⑤ There is no consensus regarding the scope of LN dissection for EGJ. A Japanese multicenter study indicated that mediastinal LN metastasis is correlated with the length of esophageal invasion of the tumor. It is recommended that the mediastinal LN not be removed if the esophageal invasion length is < 2 cm; LNs No. 19, No. 20, No. 110, and No. 111 must be removed if the esophageal invasion length reaches 2 to 4 cm; the right thoracic approach and dissection of the middle and lower mediastinal LNs are recommended if the esophageal invasion length is ≥4 cm [47].

3.2.4 Digestive tract reconstruction

Digestive tract reconstruction varies for different gastrectomy methods. Against the background of not affecting the radical surgical cure, the safety of digestive tract reconstruction and its impact on the physiological function of the digestive tract need to be considered. For AGC with low malignancy and an early disease stage, the continuity of the digestive tract should be ensure while considering its physiological functions. For AGC with high malignancy and late disease stage or an increased likelihood of recurrence, the reconstruction method should be simple rather than complicated. Current common reconstruction methods for GC are shown in Table 3.

Table 3 Postoperative digestive tract reconstruction methods for AGC

Reconstruction method for distal gastrectomy: The Billroth I reconstruction is easy to perform and conforms to the physiological approach. The Billroth II anastomosis is more common and is especially suitable for tumors that have invaded the pylorus and duodenum. Due to the changes in the normal anatomical and physiological state, the incidence of complications, such as gastritis and dumping syndrome, is high; therefore, the Braun anastomosis can be performed to reduce the reflux of bile and pancreatic juice. The Roux-en-Y anastomosis offers the same advantages as the Billroth II anastomosis and can effectively reduce reflux, but it requires the jejunum to be cut off, which may cause Roux stasis syndrome. The uncut Roux-en-Y anastomosis does not require cutting off the jejunum, retains the continuity of peristalsis of the afferent loop, and can reduce discomforts such as stasis syndrome and bile reflux. Currently, the uncut Roux-en-Y anastomosis is attracting increasing attention, and it is necessary to consider the possibility of recanalizing the postoperatively blocked intestine.

Reconstruction method for total gastrectomy: The Roux-en-Y method is easy to perform and is the preferred anastomosis method, offering a low incidence of reflux esophagitis. Because food does not pass through the duodenum, it cannot directly stimulate the secretion of digestive juices and thus affect food digestion and absorption. The jejunal interposition reconstruction method addresses the drawbacks of Roux-en-Y anastomosis, but it is characterized by complicated surgery and high surgical risk, and whether it can improve the patient’s quality of life remains under dispute. More clinical studies are needed to provide supportive evidence; thus, it is recommended that this procedure be performed only at hospitals with experienced personnel.

Reconstruction method for proximal gastrectomy: Esophagogastric remnant anastomosis is the most commonly used anastomotic method. Esophagus-gastric remnant anastomosis is easy to perform and results in few anastomotic stomas and a low incidence of short-term postoperative complications; however, the esophageal reflux is common. The improved tubular gastroesophageal anastomosis significantly reduces the probability of esophageal reflux and is thus an ideal method for esophagus-gastric remnant anastomosis [48]. The double-flap reconstruction method of esophageal-gastric anastomosis (Kamikawa anastomosis), which uses the pressure difference between the esophagus and the remnant stomach to act as a 1-way valve, shows good antireflux effects, but it requires a rather complicated operation that may increase the possibility of anastomotic stenosis, and thus, further clinical verification is required. Jejunal interposition offers a good antireflux mechanism, but the operation is complicated, which increases the risk of postoperative anastomotic leakage, bleeding, and obstruction [49]. Double-channel anastomosis is a side-to-side anastomosis of the remnant stomach with the jejunum after Roux-en-Y anastomosis of the esophagus and jejunum; it can increase postoperative food intake and reduce the incidence of long-term malnutrition and anemia because it preserves the pylorus and most of distal stomach. This operation can be performed with the aid of laparoscope or completely laparoscopically. However, due to its complicated nature, this operation may increase the incidence of anastomosis-related complications; thus, it should be performed only at hospitals with experienced personnel.

3.2.5 Laparoscopic and robotic surgeries

Laparoscopic surgery

In recent years, laparoscope-assisted gastrectomy has developed rapidly. In Japan and South Korea, laparoscopic radical gastrectomy has been adopted as a routine procedure for stage I GC. Currently, the application of laparoscopy for AGC is still controversial [36]. A multicenter clinical study in China (CLASS01) suggested that for AGC, the laparoscopic distal gastrectomy combined with D2 LN dissection has the advantages of a low complication rate, fast postoperative recovery, and reduced pain [50], and its long-term effect is not inferior to that of traditional laparotomy [51]. Therefore, for AGC cases that are appropriate for distal gastrectomy, laparoscopic surgery can be performed at large and experienced hospitals; for laparoscopic proximal gastrectomy, laparoscopic total gastrectomy, and laparoscopic surgery after neoadjuvant chemotherapy, high-level evidence is still lacking, and exploratory clinical research should be conducted.

Laparoscopic radical resection of GC should follow the same principles as radical tumor resection in traditional open surgery, i.e., total resection of the tumor and surrounding tissues, adherence to the noncontact principle of tumor operation, sufficient margins, and thorough LN dissection. Based on China’s national conditions, the indications and contraindications for AGC laparoscopic surgery are as follows:

Indications for surgery: ① Exploration and staging of GC; ② Preoperatively assessed as stage I or II; ③ Gastric bypass for AGC. Indications for clinical exploratory surgery: ① Preoperatively assessed as stage IIIA or higher, or T4a in which D2 radical resection is feasible; ② Palliative resection for AGC.

Contraindications for surgery: ① Tumor has extensively infiltrated surrounding tissues; ② Emergency surgery for GC (e.g., upper gastrointestinal hemorrhage); ③ Severe heart, lung, liver, or kidney diseases; ④ Blood coagulation dysfunction; ⑤ Pregnancy; ⑥ Intolerance of CO₂ pneumoperitoneum.

Robotic surgery

Robotic surgery is still in its infancy and lacks standardized operating procedures and long-term efficacy confirmed by large prospective randomized controlled studies. Therefore, robotic GC surgery should be considered with caution, and it is recommended that robotic surgery performed large and experienced hospitals. Indications for robotic surgery: ① Stage I or II GC; ② Large hospitals with rich experience with robotic surgery can perform explorative surgery for stage IIIA patients. Contraindications for robotic surgery are the same as those for laparoscopic surgery.

3.2.6 Function-preserving surgery

Function-preserving surgery for EGC first considers the radical cure of the tumor while considering postoperative gastric function and quality of life. There are 3 requirements: ① Reducing the scope of gastrectomy; ② Preserving the pylorus; ③ Preserving the vagus nerve. The surgical methods include PPG, proximal gastrectomy, and segmental gastric resection or partial gastric resection.

PPG

PPG is a surgical procedure that preserves the gastric cardia and pylorus and removes the midsection of the stomach to maximally preserve gastric function and improve quality of life. It is suitable for EGC located in the middle 1/3rd of the stomach and with a distance between the distal end of the tumor and the pylorus > 4 cm (cT1N0) or for benign gastric diseases, and the margin requirements and LN dissection scope for EGC should be followed. Based on the accurate assessment of LN metastasis, LN No. 6 is subclassified into LNs No. 6a, No. 6i and No. 6v. Studies have found that when PPG is performed for EGC in the middle stomach, the dissection of LN No. 6i is unnecessary, and the extent of surgery can be reduced. The safety and long-term efficacy of laparoscopic PPG (LPPG) for midsegment EGC are not inferior to those of laparoscopic distal gastrectomy, but large-scale prospective studies are still lacking. It is recommended that LPPG be performed at experienced hospitals.

Other function-preserving gastrectomy procedures

Gastric function-preserving surgeries, such as segmental gastrectomy and local resection, are more common in case reports, and their safety and long-term efficacy still need to be further reviewed; therefore, this guideline does not recommend these procedures.

3.2.7 Nonradical surgical treatment

Palliative surgery

Palliative surgery refers to nonradical surgery aimed at relieving symptoms and improving quality of life. It is performed to address serious disease-caused complications, such as obstruction, bleeding, and perforation. For those unable to undergo radical surgery, gastric bypass surgeries, such as palliative gastrectomy or gastrointestinal anastomosis, can be used to relieve symptoms; for those who cannot tolerate surgery, endoscopic stent placement, jejunostomy, or indwelling nasal jejunal feeding tube placement can be performed.

Reduction surgery

Reduction surgery refers to nonradical gastrectomy for GC with nonradical factors (e.g., unresectable liver metastasis and peritoneal metastasis, etc.) but no serious comorbidities; it aims to reduce the tumor burden, delay the onset of symptoms, and prolong survival. Clinical evidence of prognostic improvement with reduction surgery is insufficient, and drug therapy is still the standard therapy for stage IV GC. For GC with a single noncurable factor, R0 or R1 surgery can be considered.

3.2.8 Conversion therapy and surgical intervention for stage IV GC

In the past, most treatments for AGC have involved palliative chemotherapy or palliative surgery. With the increasing benefits of conversion therapy, treatment strategies have undergone fundamental changes. Conversion therapy aims to treat advanced cases for which R0 surgery would be difficult through active and effective chemotherapy, radiotherapy, molecular targeted therapy, or immunotherapy and other integrated therapies. After the primary tumor is degraded and the metastasis is controlled, R0 surgery is performed to improve the survival rate. Conversion therapy includes screening the beneficiary population, formulating conversion treatment plans, evaluating curative effects, and determining the timing of conversion surgery. Given the complexity and uncertain efficacy of conversion therapy, multidisciplinary integrated diagnosis and treatment (MDT to HIM) should be applied to the entire process, and the plan should be continuously adjusted according to efficacy to realize the individualization and maximize the benefits of conversion therapy for stage IV GC patients.

Preoperative classification of stage IV GC

The Yoshida classification is a clinical classification based on whether conversion therapy is feasible for AGC (Fig. 9) [52].

Fig. 9

Yoshida classification for stage IV GC

Category 1 (potentially resectable, suitable for conversion therapy): 1 liver metastasis, few para-aortic LN (16a1, 16b2) metastases, or positive free cancer cells in the intraperitoneal cavity (CY1). In such cases, neoadjuvant or conversion therapy should be provided first, followed by the R0 resection of primary and metastatic gastric lesions.

Category 2 (marginally resectable, high conversion rate): 2 or more liver metastases, or metastases > 5 cm in diameter, or distant metastases. Such cases should be regarded as important targets for conversion therapy. After CR or PR is achieved, R0 resection of the primary gastric tumor and metastases should be performed.

Category 3 (potentially unresectable, possibly suitable for conversion therapy): limited peritoneal implantation but no metastases in other organs. Treatments include systemic chemotherapy, molecular targeted therapy, or combined intraperitoneal chemotherapy. Those who have achieved CR or PR or whose free cancer cells in the abdominal cavity become negative can still undergo R0 surgery, cytoreductive surgery (CRS), or reduction surgery.

Category 4 (incurable, low conversion rate): diffuse peritoneal metastasis and metastasis to other organs. Few such cases are sensitive to conversion therapy, and in most cases, R0 resection is difficult to attain. Depending on the situation, palliative chemotherapy or optimal supportive treatment can be provided.

Conversion therapy for peritoneal metastases

The prognosis of stage IV GC with peritoneal metastasis is extremely poor, with a median survival of approximately 6 months. Conversion therapy lowers the stage of the primary tumor and controls peritoneal metastases through chemotherapy and regional therapy so that R0 surgery can be performed and survival can be improved.

• (1) Conversion therapy strategy

P0CY1 patients can be treated with neoadjuvant intraperitoneal-systemic chemotherapy (NIPS) or hyperthermic intraperitoneal chemotherapy (HIPEC). After CY1 becomes negative, R0 surgery can be performed, which can achieve the optimal outcome of conversion therapy and significantly prolong survival (with a median survival of 47.5 months) [53].

NIPS is actively recommended for patients with P1CY0/1 and PCI ≤ 12 on laparoscopic exploration; patients with PCI < 6 after treatment can undergo resection of the primary tumor and CRS combined with HIPEC; for those who progress after conversion therapy, palliative chemotherapy or optimal supportive therapy can be adopted. In patients with PCI > 12 on laparoscopic exploration, conversion therapy can have only limited effectiveness [54], and integrated treatment programs (e.g., palliative chemotherapy or best supportive care) should be adopted according to MDT to HIM; only in cases of primary tumor bleeding, perforation, or obstruction, should palliative surgery be considered.

• (2) Treatment plan

Paclitaxel-based 3-drug chemotherapy is the basis of conversion therapy for stage IV GC. Paclitaxel intraperitoneal infusion and intravenous chemotherapy combined with S-1 oral administration can effectively prolong the median survival of patients with peritoneally metastasized GC to 17.7 months; patients with ascites show particular benefit [55]. Other paclitaxel-based 3-drug intravenous chemotherapy regimens are also options.

Numerous studies have shown that adjuvant surgical treatment after full control of the tumor through intravenous chemotherapy combined with local treatments, such as intraperitoneal perfusion (IP) and HIPEC, can achieve significant survival benefits.

Preventive treatment for high-risk cases of peritoneal metastasis

More than 50% of patients with stage T3 or T4 GC have peritoneal metastases after radical surgery. Stage T3-T4, N+, extranodal invasion, Borrmann Type III/IV, Lauren classification diffuse type, signet ring cell carcinoma, etc., are high risk factors for peritoneal metastasis. To prevent peritoneal metastasis and recurrence, the addition of regional chemotherapy to perioperative chemotherapy offers a increased effectiveness. For high-risk patients, especially those with CY1, intraoperative D2 or/and early postoperative preventive regional treatments can reduce the recurrence rate of peritoneal metastases. For IP and HIPEC, the treatment should consider both the medication’s sensitivity and its characteristics, such as a large molecular weight, sustained release, and biological agent classification; the dosage can be adjusted appropriately according to the patient’s age, physical condition, drug tolerance, and Myeloid proliferative capacity capacity. Commonly used drugs include taxanes, platinum derivatives, fluorouracils and anthracyclines (epirubicin), etc., and they can be combined with Nocardia rubra cell wall skeleton, Pseudomonas aeruginosa, and other biological agents; furthermore, the use of IP with simultaneous subcutaneous injection can achieve a better curative effect [56, 57]. Preventive HIPEC should be performed intraoperatively or within 48 h after surgery and completed within a week; it should be used no more than 2 times and should be delivered in 3000 ml of 43 °C normal saline with chemotherapy drugs via continuous perfusion for 90 min. However, the efficacy of preventive HIPEC still needs further clinical verification.

Treatment strategies for liver metastases

Liver metastasis of GC (LMGC) is often accompanied by peritoneal and LN metastasis or infiltration of adjacent organs and most often involves the right and left hepatic lobes, with multifocal distribution. In the majority of cases, LMGC should be regarded as a systemic disease, and if conditions permit, a PET-CT examination should be performed to confirm systemic metastases. Diagnostic laparoscopic exploration combined with the cytological examination of peritoneal lavage fluid can help identify occult peritoneal metastases and partial liver metastases [58].

• (1) Treatment strategy: the intrahepatic recurrence rate is high after the resection of liver metastases. It is recommended that systemic chemotherapy be administered before surgery to reduce the stage of the primary gastric tumor or control liver metastases. The 3-drug intravenous chemotherapy regimen based on paclitaxel and multiapproach integrated treatments, such as hepatic artery infusion chemotherapy, radiofrequency ablation, or hepatic artery embolization, can be selected to improve the R0 resection rate for primary and metastatic lesions. R0 resection is the best way to prolong survival in LMGC, and systemic treatment should be continued after surgery.

• (2) Surgical indications: surgical treatment is recommended only when the conditions for R0 resection are met [59]: ① GC with synchronous liver metastasis without other noncurable factors, such as peritoneal or other distant metastases; ② GC with metachronous liver metastases without metastasis and recurrence in other sites; ③ Sufficient retained liver function is possible after the resection of liver metastases; ④ intrahepatic metastases ≤3; the largest lesion is ≤4 cm; confinement to 1 lobe without the involvement of large vessels.

Para-aortic LN metastasis

Para-aortic LN metastasis (PALN) includes the LNs No. 16a2 and B1 and has a metastasis rate of 14–32%. In such cases, direct PAND is not recommended. Only after conversion therapy can the R0 resection rate and curative effect be significantly improved [60].

• (1) Treatment strategy: when PALN metastasis is not accompanied by other noncurable factors, conversion therapy based on chemotherapy and surgery is adopted, and multidisciplinary integrated diagnosis and treatment (MDT to HIM) is required throughout the entire course.

• (2) Treatment plan: a preoperative 2-drug SOX (S-1+ oxaliplatin) or 3-drug DCS (docetaxel + cisplatin +S-1) regimen can be adopted depending on the patient’s condition. If the treatment is effective, for patients with PALN metastasis limited to LNs No.16a2 and b1 but without peritoneum or liver and other distant metastases, radical D2 + PAND can benefit survival, but the surgeon must have abundant extended D2 lymphadenectomy experience.

3.2.9 Surgical treatment of gastric stump cancer (GSC)

Definition of GSC

GSC refers to new cancer that arises in the remnant stomach after surgery. A more generally accepted definition is as follows: cancer that occurs in the remnant stomach more than 5 years after surgery for benign gastric lesions or more than 10 years after surgery for malignant gastric lesions. The incidence of GSC is 1.0–5.0% after distal gastrectomy, 6.3% after proximal gastrectomy, and 2.7% after PPG, and males are predominantly affected. The 5-year survival rate after radical operation is 22.0–54.0%, and that for early GSC and advanced GSC is 82.5–100.0% and 26.0–34.1%, respectively. The main factors affecting the prognosis include tumor histological type, degree of invasion, perigastric LN metastasis, whether radical resection has been performed, etc.

Lymphatic drainage and LN metastasis pattern of the remnant stomach

The collateral lymphatic circulation route formed after gastrectomy changes the original lymphatic drainage route of the stomach. The lymphatic flow of the remnant stomach is dominated by the left gastric artery, splenic artery, and left inferior phrenic artery [61]. The Billroth I operation drains to the peripheral LNs through the duodenal wall, while the Billroth II operation drains to the mesenteric root LNs through the jejunum [62]. As a result, the characteristics of LN metastasis of GSC are as follows: ① Splenic artery and splenic hilar LN metastases; ② LN No. 16 metastasis; ③ Mesenteric root LN metastases; ④ Mediastinal LN metastases. For GSC after initial benign disease, the rate of metastasis to first-echelon LNs No. 1–4 is high; for GSC after initial malignant disease, the rate of metastasis to the second-echelon LNs is generally higher than that to the first-echelon LNs, e.g., LNs No. 10, 11, mesenteric root LNs, and LNs No. 16a2 and b1 [62].

Surgical treatment and key points for GSC

ESD can be performed for early GSC without LN metastasis [63], with reference to the standard for primary EGC. For advanced GSC, total resection of the remnant stomach and combined resection of the invaded organs should be performed, and LNs in the area that were not fully dissected during the first operation should be redissected. The mesenteric root LNs near the anastomotic stoma after the Billroth II operation have a high metastasis rate and should be prioritized for dissection. For patients with advanced GSC who cannot tolerate R0 resection, neoadjuvant radiotherapy and chemotherapy are performed first, and then surgery is conducted, following the same standard used for primary AGC. For patients with unresectable AGC who are symptomatic, palliative resection, gastric bypass surgery, stent placement, indwelling jejunal feeding tube, etc., are performed. For asymptomatic patients with unresectable AGC, integrated treatment based on systemic drug therapy can be performed after MDT discussion.

Due to tissue healing and keloid fibroblast repair, adhesion of the remnant stomach to surrounding tissues, such as the liver, pancreas, colon, and diaphragm, poses a challenge in GSC surgery. After D2 lymphadenectomy, the anatomical layers disappear, making systemic lymphadenectomy for GSC more difficult. In addition, the length of the duodenal stump and the adhesion of the stump to the pancreas during the Billroth I reconstruction after distal gastrectomy and the adhesion of the stump to the esophagogastric anastomotic stoma after proximal gastrectomy greatly increase the risk of surgery. Due to the difficulty of distinguishing adhesion from cancer infiltration, to ensure the R0 resection rate, detailed examination, research, and assessment should be performed before surgery support the formulation of a reasonable plan. Intraoperative frozen pathological examination is also helpful for diagnosis.

3.2.10 Surgical treatment of AEG

AEG definition and classification

AEG refers to an adenocarcinoma that is centered within 5 cm above or below the anatomic EGJ and crosses or touches the EGJ. Anatomically, the EGJ refers to the point at which the tubular esophagus becomes the sacculated stomach, i.e., the end of the esophagus and the start of the stomach, which is equivalent to the lower edge of the His angle or esophageal sphincter and is not necessarily consistent with the histological squamocolumnar junction. The Siewert classification is mostly used for AEG, and the specific staging method is provided in the 8th edition of the TNM classification for GC by the AJCC/UICC.

Surgical treatment for AEG

According to the Siewert classification (hereinafter referred to as types I, II, and III), difficulties during surgical treatment for AEG include the surgical path, resection range, digestive tract reconstruction method, safe distance of resection margin, and range of LN dissection.

Possible surgical approaches include the right-thoracic single incision approach, the upper abdomen and right chest 2-incision approach, the combined left thoracic-abdominal incision approach, and the transabdominal approach. Type I: the right thoracic approach is preferred. Because type I has a high rate of mediastinal LN metastasis, this transthoracic approach offers certain advantages in mediastinal LN dissection. Type II: the surgical approach for use with this AEG type still under debate; however, the transabdominal-hiatal approach is preferred for patients with an esophagus involvement distance < 3 cm, and the right thoracic approach is recommended for patients with an esophagus involvement distance ≥3 cm. Type III: the transabdominal-hiatal approach is preferred.

The radical resection range and digestive tract reconstruction should be determined based on tumor size, location, etc. For type I, transthoracic esophageal resection with proximal subtotal gastrectomy should be adopted, and this method can also be applied to some type II cases. For type II or III, total gastrectomy is recommended when the long diameter is > 4 cm, and transabdominal proximal subtotal gastrectomy is recommended when the long diameter is ≤4 cm. If the tumor directly invades the surrounding organs, radical combined organ resection should be performed. The preferred digestive tract reconstruction method is related to the scope of resection. After total gastrectomy, Roux-en-Y anastomosis is recommended; after proximal gastrectomy, esophagus-gastric remnant anastomosis or double-channel anastomosis is recommended. The distance between the resection edge of the esophagus and the upper edge of the EGJ tumor is currently not defined. For type I or type II with esophagus involvement ≥3 cm, the recommended esophagus margin distance should be ≥5 cm; for type III or type II cases with an esophagus involvement < 3 cm, the recommended esophagus margin distance should be ≥2 cm, and intraoperative frozen pathological examination is recommended to confirm negative margins. Intraoperative frozen pathological examination is of great value to ensure the oncological safety of the esophageal and gastric resection margins, especially for patients with late-stage local lesions.

According to the Siewert classification, LN dissection specifications are as follows: For type I, the standard for esophageal cancer applies; for type III, the standard for GC applies; for type II, the applicable standard is still under debate. Thoracic LN dissection specifications are as follows: for type I, the standard for middle and lower esophageal cancer applies, and complete upper-, middle-, and lower-mediastinal LN dissections should be performed; for type II, lower mediastinal LN dissection should be performed; for type III, lower paraesophageal LN dissection (LNs No. 19, 20) should be performed. For abdominal LN dissection, the specifications are as follows: for type I, abdominal LN dissection of LNs No. 1, 2, 3a, 7, 19, 20 should be performed; for types II and III, D2 LN dissection is required, and D1 /D1+ LN dissection should be performed when the staging is cT1N0 and the long diameter of the tumor is < 4 cm.

Thoracic laparoscopy combined with radical resection can be selectively performed for types I and II. Laparoscopic AEG resection still lacks high-quality clinical evidence and thus should be performed at hospitals with experienced staff and based on clinical studies.

3.2.11 Surgical complications

Anastomosis-related complications

Anastomosis-related complications seriously affect postoperative rehabilitation and efficacy and can even cause unplanned reoperation or patient death. The clinical incidence of anastomosis-related complications is approximately 1.2–14.6% and mainly includes anastomotic bleeding, stenosis, and leakage.

• (1) Anastomotic bleeding

The incidence of anastomotic bleeding is approximately 0.2–2.0% [64]. Bleeding usually occurs within 12 to 24 h after surgery. The preventive measures are as follows: 1) choosing an anastomosis at the contralateral mesangium of the intestinal tube; 2) appropriately exposing the surrounding tissues so that embedding of the omentum or fat tissue in the anastomotic stoma can be avoided; 3) carefully selecting the stapler and the staple cartridge; 4) if necessary, suturing and reinforcing the anastomotic stoma to enhance the hemostatic effect; 5) if anastomotic bleeding is suspected during the operation, intraoperative gastroscopy can be used for confirmation.

Treatment measures include conservative medical treatment, active volume expansion, antishock measures, oral or gastric infusion of iced saline water containing norepinephrine, injection of somatostatin and thrombin, etc.; at the same time, emergency gastroscopy can be actively performed to confirm the diagnosis and enable endoscopic hemostasis. In cases of a large amount of bleeding and unsatisfactory medical treatment, surgery should be decisively performed for exploration and to stop the bleeding. For patients with a poor general condition and a high estimated risk of secondary operation, interventional therapy can be performed.

• (2) Anastomotic leakage

The incidence rate of anastomotic leakage is 0.5–14.6% [65]; it most often occurs in cases with a high esophagojejunal anastomosis within 7–10 days after surgery. The outflow of intestinal contents, saliva, or oral methylene blue from the drainage tube or the leakage of contrast agent into upper gastrointestinal tract on radiography with diatrizoate meglumine can confirm the diagnosis. In addition, noncontrast-enhanced CT may also show an opaque dark area of fluid around the anastomotic stoma. Preventive measures include correcting anemia and hypoproteinemia, controlling blood sugar, and stopping the use of glucocorticoids preoperatively; improving local tissue conditions; and the appropriate timing of surgery after neoadjuvant therapy (at appropriately a 3- to 6-week interval) [66]. Additional measure include preoperatively indwelling a gastric tube for decompression in patients with pyloric stenosis and irrigating the stomach with concentrated saline water to reduce edema; avoiding excessively dissociating or exposing the intestinal tube to avoid anastomotic ischemia; ensuring that the anastomotic stoma is in a tension-free state during anastomosis; and suturing and reinforcing anastomotic stoma and installing drainage tube if necessary. Treatment principles include adequate drainage, anti-infection measures, and nutritional support so that infection can be controlled and the leakage site can heal. Surgical intervention can be performed if necessary.

• (3) Anastomotic stenosis

Anastomotic stenosis is common in esophagojejunal anastomosis and Billroth I anastomosis, and angiography or gastroscopy can be used to confirm the diagnosis and evaluate the location and extent of the stenosis. Preventive measures include improving the condition of the esophagus or intestinal tissues before surgery, selecting the appropriate stapler for the size of intestinal tube, avoiding excessive tissue compression or misalignment of the mucous membrane during anastomosis, ensuring a tension-free anastomotic stoma and the absence of blood supply obstruction during the operation, and ensuring that the anastomotic stoma is unobstructed after the anastomosis. Four weeks after the operation, the patient can consume a solid diet, which expands the anastomotic stoma through the mechanical action of the food. Treatments are as follows: treatments based on the cause and degree of anastomotic stenosis, fasting for stenosis caused by inflammatory edema, and strengthening nutritional support to reduce edema; endoscopic balloon dilatation, endoscopic stenosis scar resection, or endoscopic stent implantation for cicatricial stenosis; and surgical treatment if necessary.

Duodenal stump fistula

The incidence rate of duodenal stump fistula is 1–4%, and it often causes fatal complications, such as severe intra-abdominal infection and shock, with a mortality of approximately 10% [67]. Duodenal stump fistula usually appears 2–7 days after surgery; bile-like or turbid, purulent fluid drains into the abdominal drainage tube, abdominal puncture or incision in the right upper abdomen; abdominal ultrasonography or CT shows fluid in the right upper abdomen; and upper gastrointestinal radiography shows contrast agent leaking from the duodenal stump. Preventive measures are as follows: paying attention to preoperative preparation; correcting malnutrition; eliminating local inflammatory edema and other factors that are not conducive to trauma healing; selecting reliable and stable devices and strictly abiding by SOPs; maximally suturing, embedding and reinforcing the stump with purse-string sutures; and adding the Braun anastomosis when the Billroth II operation is performed to reduce pressure on the afferent loop.

Pancreatic fistula

In radical GC surgery, treatment of the duodenal stump, separation of the pancreatic capsule, adhesion between the posterior gastric wall and the pancreas, and dissection of LNs near the pancreas may damage the pancreatic parenchyma and even the pancreatic duct, resulting in postoperative pancreatic fistula. Reports indicate that the incidence of pancreatic fistula after radical GC surgery in recent years is 20.7%, and this rate is even higher when surgery is combined with splenectomy and pancreatectomy [68]. On the 3rd day or later after surgery, if the amylase concentration in the peritoneal drainage fluid is more than 3 times higher than the normal upper limit for serum amylase, pancreatic fistula can be diagnosed, with further classification into no pancreatic fistula, Grade BL, Grade B, and Grade C. Continuous monitoring of pancreatin concentration in the drainage fluid after surgery is a simple and effective method for the early detection of pancreatic fistula. For patients with the Grade BL pancreatic fistula, routine postoperative treatment should be continued to keep the drainage tube unobstructed. In most cases, the amylase concentration in the abdominal drainage fluid can be decreased to less than 3 times that of the serum concentration at 5 days after surgery, and postoperative recovery is not generally affected. For patients with Grade B or C pancreatic fistulas, smooth drainage of the abdominal cavity should first be ensured; simultaneously, fasting and gastrointestinal decompression should occur; water, electrolyte and acid-base balances should be maintained; and pancreatic secretion-inhibiting drugs, antibiotics, and nutritional support should be administered. For those with poor drainage and significant peripancreatic effusion, percutaneous drainage during intervention or another operation should be adopted.

Delayed gastric emptying (gastroparesis)

Postoperative delayed gastric emptying is a gastric motility disorder and may be related to gastric denervation. The diagnostic criteria are as follows: (1) without mechanical obstruction of the outflow tract; (2) gastric drainage exceeding 800 ml/d for more than 10 days; (3) without obvious water and electrolyte balance disorders; (4) without underlying diseases that cause gastroparesis (diabetes, hypothyroidism, connective tissue diseases, etc.); (5) without use of drugs that affect smooth muscle contraction. Gastroscopy and imaging examination (radiography) can assist in the diagnosis. Treatment measures include fasting, gastrointestinal decompression, etc., while giving nutritional support and maintaining water, electrolyte, and acid-base balances. If accompanied by other diseases, such as diabetes and hypothyroidism, the patient should be treated, and prokinetic agents are mainly used; therefore, the gastrointestinal motility can be improved through gastroscopic stimulation, jejunal tube feeding, and acupuncture. In most cases, delayed gastric emptying can be cured through conservative treatment, and in very rare cases, surgery is required.

Postoperative intestinal obstruction

The incidence of postoperative intestinal obstruction can reach 11.7–38.5%, and it is often caused by an excessively long afferent loop; intestinal volvulus; internal hernia and intussusception derived from abdominal gastrointestinal adhesions; surgical operation and reconstruction methods; and paralytic intestinal obstruction caused by electrolyte disturbances and peritonitis [69]. Preventive measures include complete hemostasis on surgical wound, closing the mesenteric hiatus, avoiding intestinal volvulus and the compression on intestinal tube by drainage tube; encouraging the patient to get out of bed early to promote the recovery of gastrointestinal function. Laparoscopic surgery, omentum preservation, and appropriately selecting digestive tract reconstruction methods can reduce the incidence of intestinal adhesion and obstruction. In most cases, postoperative intestinal obstruction can be improved through conservative treatment, and surgery should be actively performed in the case of recurrent adhesive intestinal obstruction, or in the presence or with the tendency of intestinal strangulation. The formation of internal hernias is inclined to cause closed-loop intestinal obstruction, and surgery should be performed immediately after the diagnosis is established.

Postoperative gallbladder complications

After radical gastrectomy, gallbladder stones, cholestasis and cholecystitis can occur. For GC patients with preoperative gallbladder stones or biliary sludge, or gallbladder-related symptoms, preventive cholecystectomy is recommended [70].

Gallbladder complications can include fever, upper right abdominal pain, elevated white blood cells, and even peritoneal irritation signs. Ultrasonography, CT, and other imaging examinations can be used to rule out other complications, such as anastomotic leakage. If postoperative acute cholecystitis is highly suspected, surgical intervention or cholecystostomy should be performed as soon as possible, but cholecystectomy is not mandatory.

Lymphatic leakage (chyle leakage)

Intraoperative damage to lymphatic vessels can cause lymphatic leakage, which has an incidence of 0.3–0.4% after D2 radical surgery and 3.9% after the D2 + surgery [71]. It manifests primarily an increase in abdominal drainage related to the diet after surgery, alkalic drainage fluid, a total protein concentration of > 32 g/L, a total fat concentration of > 33 g/L, and a large amount of lipid microspheres in an abdominal drainage fluid smear stained with Sudan III dye, which is used to confirm the diagnosis [72]. Preventive measures include correcting anemia and hypoproteinemia before surgery, choosing an appropriate surgical procedure, and carefully closing and ligating lymphatic vessels when dissecting LNs, especially the lymphatic vessel network of the chyle cistern and surrounding areas. For cases with a high risk of lymphatic leakage after surgery, early enteral nutrition is not recommended to avoid lymphatic leakage [73]. In addition, during the removal of LNs No. 7, No. 8a, and No. 12a, lymphatic leakage is more likely to occur; therefore, after removal, close attention should be paid to the presence of white fluid leakage, and if such leakage is observed, prompt suturing is recommended. Lymphatic leakage can be treated mainly with conservative treatment, and appropriate nutritional support (e.g., fasting or low-fat diet) is key. Somatostatin can be used, antibiotics should be used as early as possible for infections, and surgical exploration and treatment are required in the rare cases of refractory lymphatic leakage.

3.3 Medications for GC

Drug therapy for GC is categorized into adjuvant therapy, neoadjuvant therapy, conversion therapy (Section 3.2.8) and treatments for AGC, including chemotherapy, targeted therapy, and immunotherapy. Systemic chemotherapy and targeted therapy drugs are commonly used.

3.3.1 Adjuvant therapy

Adjuvant chemotherapy is suitable for patients with pathological stage II or III GC after D2 radical resection. This guideline recommends the twodrug regimen that combines fluorouracil with platinum (Table 4). For patients with a poor physical condition, advanced age, or intolerance of the combined regimen, single-drug regimen with oral fluorouracil is used. Combined chemotherapy should be completed within 6 months, and single-drug chemotherapy should not exceed 1 year. For those who have not achieved D2 lymph node dissection or R0 resection (not due to distant metastasis), postoperative chemoradiotherapy is recommended, or multidisciplinary team discussion is recommended to determine a holistic integrated treatment plan (MDT to HIM).

Table 4 Indications and recommended regimens for postoperative adjuvant chemotherapy

Postoperative adjuvant chemotherapy is not recommended for patients with stage Ia GC. There is no sufficient evidence that postoperative adjuvant chemotherapy is appropriate for patients in stage Ib. For LN-positive patients (pTIN1M0), adjuvant chemotherapy can be considered. For patients who are at pT2N0M0, are young (< 40 years old), have poor histological differentiation, and present infiltration of the nerve bundles, blood vessels, and lymphatic vessels, adjuvant chemotherapy, mostly with single-drug regimens, may reduce recurrence.

For stage II GC, the recommended regimen is S-1 monotherapy (oral administration up to 1 year after surgery) or capecitabine combined with oxaliplatin [74, 75], and other two drug regimens of fluorouracil combined with platinum-based drugs can also be considered. According to the results of the RESOLVE study, for local AGC at cT4a/N + M0 or cT4b/N × M0, the 8-cycle oxaliplatin combined with S-1 (SOX) adjuvant chemotherapy after D2 radical surgery is not inferior to the oxaliplatin combined with capecitabine (XELOX) regimen [76]. According to the results of the JACCORGC-07 study, the 6-cycle regimen of docetaxel combined with S-1 followed by S-1 oral monotherapy (DS followed by S-1) offers improved survival of stage III patients compared to the S-1 monotherapy regimen [77]. Observational studies have shown that for stage II GC patients, single-agent regimens offer survival benefits similar to those of combination chemotherapy, but combination chemotherapy confers more profound benefits for stage III GC patients. Therefore, when selecting single-drug regimen or combined chemotherapy, it is necessary to comprehensively consider the patient’s physical condition, age, underlying disease, and pathological type.

For LN-positive GC patients after D2 resection, postoperative chemotherapy combined with radiotherapy does not further improve survival [78]. For patients without D2 or R0 resection (not due to distant metastasis), postoperative chemoradiotherapy [79] or multidisciplinary integrated diagnosis and treatment are recommended.

Other adjuvant drugss, such as thymalfasin, can induce the maturation and differentiation of T cells and stimulate the production of various cytokines in peripheral blood, which can enhance the body’s immunity and thus lead to a certain sensitization effcet to chemoradiotherapy [80, 81]. Based on some studies, some biological agents, such as subcutaneous injection of Nocardia rubra cell-wall skeleton, are recommended to enhance immunity and coordinate systemic medications.

3.3.2 Neoadjuvant therapy

For local AEG (cT3–4a, N+) without obvious distant metastasis, neoadjuvant chemotherapy is recommended (Table 5). Regimens include the 2-drug combination regimen (fluorouracil combined with platinum or docetaxel) and the 3-drug combination regimen (docetaxel, oxaliplatin, and fluorouracil, i.e., the FLOT regimen). For AEG, neoadjuvant chemoradiotherapy is recommended. For cT4bNanyM0, Iva stage patients, multidisciplinary integrated diagnosis and treatment (MDT to HIM) is recommended to develop individualized treatment plans.

Table 5 Indications and recommended regimens for neoadjuvant therapy

The application of targeted therapy and immunotherapy as neoadjuvant therapy is still in the clinical study stage and lacks support from high-level clinical research; therefore, it is not recommended as a perioperative treatment option. The prognosis of HER2-positive GC is poor, but the perioperative treatment of HER2-positive is rather effective [93]. Local AGC treated with chemotherapy combined with trastuzumab can achieve a better pathological remission rate. Compared with FLOT alone, FLOT combined with two HER2-targeted drugs (trastuzumab and pertuzumab) during the perioperative period can significantly increase the pathologic complete response (pCR) rate of HER2-positive resectable AEG patients and the proportion of LN-negative patients (ypN0) [94], and it offers promise for improving DFS and OS. Preoperative neoadjuvant immunotherapy is safe for the treatment of gastrointestinal tumors and can effectively induce pathological remission and even achieve CR [95]. However, it still lacks sufficient evidence and needs to be verified by clinical trials.

3.3.3 Treatment of advancedGC

First-line treatment for advanced GC

The first-line treatment for advanced GC is suitable for GC that is unresectable or has distant metastasis and has not received systemic treatment (Table 6). For the first-line treatment of advanced HER2+ GC, the trastuzumab combined with chemotherapy regimen is used; it is recommended that patients with a combined positive score (CPS) for programmed death ligand 1 (PD-L1) ≥ 5 receive chemotherapy combined with programmed death 1 (PD-1) inhibitor immunotherapy as the first-line treatment; GC patients without relevant molecular markers can be treated with fluorouracil combined with platinum and/or paclitaxel as the first-line chemotherapy.

Table 6 Indications and recommended regimens for the first-line treatment of advanced GC patients

For stage IV GC patients with a good physical condition, high tumor burden, or distant oligometastasis, when radical resection is possible, chemotherapy with the 3-drug regimen can be used to effectively improve the ORR and prolong DFS and OS, which has been verified in Chinese patient groups [108, 109], but the incidence of adverse reactions has also increased accordingly. For elderly patients and those with poor physical condition, the dose of chemotherapeutic drugs can be reduced to 60% of the original dose without affecting OS [110], and the efficacy of the dose-reduced 2-drug regimen is still better than that of single-agent therapy [111, 112].

Second- and later-line treatments for advanced GC

Second- and later-line treatments for late-stage GC are suitable for patients with disease progression after initial chemotherapy (Table 7). The continuation of anti-HER-2 therapy for HER2+ patients is not recommended, and re-biopsy is recommended to confirm the HER2 status. Patients with unstable microsatellites can be treated with PD-1 inhibitors, and those without relevant molecular markers can be treated with second-line chemotherapy combined with anti-angiogenic drugs. For later-line treatment, apatinib, TAS-102, and immune checkpoint inhibitors (ICIs) can be used. Given the high heterogeneity of GC, patients are encouraged to actively participate in clinical studies.

Table 7 Indications and recommended regimens for second- and later-line treatments for late-stage GC

For the end-line treatment of GC, apatinib [128], TAS-102 [128], and ICI [128] can be used.

3.3.4 Complications of drug therapy

Blood system complications

Bone marrow suppression is the most common dosage-limited toxic side effect of chemotherapy, and it varies with different chemotherapeutic agents. The earliest manifestation is the decrease in granulocytes, the decrease in platelets appears later, the decrease of red blood cells was not obvious. Generally, when the white blood cell concentration is < 3.5 × 10⁹/L and the platelet concentration is < 80.0 × 10⁹/L, it indicates that bone marrow-suppressing chemotherapeutic agents are not suitable for use in chemotherapy. When the white blood cell concentration is < 2.0 × 10⁹/L and the granulocyte concentration is < 1.0 × 10⁹/L, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can be used; the preventive use of these substances can reduce the occurrence of neutropenia in patients with nonmyeloid malignancies while ensuring the relative dose intensity of chemotherapy. When the white blood cell concentration is reduced to < 1.0 × 10⁹/L, especially when the granulocyte concentration is < 0.5 × 10⁹/L for more than 5 days, the possibility of serious bacterial, fungal or viral infections can increase significantly, and antibiotics can be used accordingly to prevent infection; once fever occurs, blood cultures and drug sensitivity tests should be performed immediately, and broad-spectrum antibiotics should be prescribed. When platelet concentrations are < 50.0 × 10⁹/L, especially when they are < 20.0 × 10⁹/L, there is a risk of bleeding, and the patient should receive treatment with recombinant human interleukin-11 derivatives or recombinant human thrombopoietin and platelet should be transfused if necessary.

Digestive tract complications

• (1) Nausea and vomiting

Nausea and vomiting are the most common early toxic side effects. Severe vomiting can cause dehydration, electrolyte imbalance and weight loss and can aggravate the patient’s fear of chemotherapy. The intervention goal for vomiting is prevention, and antiemetics should be provided before chemotherapy. An antiemetic plan should be formulated based on the strength of the drug’s emetic activity and the patient’s characteristics. For vomiting caused by moderately to highly emetic drugs, 5-HT3 receptor antagonists are the most important antiemetic drugs and can be combined with corticosteroids. When the antiemetic is not effective, the presence of other factors that cause nausea/vomiting, such as intestinal obstruction or brain metastasis, should be considered. Attention should be paid to the side effects of antiemetic drugs, such as constipation, especially when the patient has taken antiemetic drugs for multiple days, and laxatives should be prescribed when necessary.

• (2) Digestive tract mucositis

Chemotherapeutic drugs can damage mucosal epithelial tissues that are actively proliferating and cause digestive tract mucositis, leading to pain, reduced consumption of food, and even swallowing difficulties and bleeding of the digestive tract. Fluorouracil often causes mucositis. The patient should be instructed to maintain oral hygiene and gargle with Dobell’s solution or 5% sodium bicarbonate solution; in cases of canker sores, the traditional Chinese medicine (TCM) Shuang-liao-hou-feng-san or watermelon frost spray and oral adhesive pellicles can be used. In cases of fungal infection, 1:1000 nystatin solution can be applied to the affected area or used as a gargle.

• (3) Diarrhea

Chemotherapeutic drugs, 5-FU in particular, tend to cause diarrhea, and high doses or continuous administration may lead to bloody diarrhea, for which montmorillonite powder (Smecta) or oral loperamide (Imodium) can be administered, along with supplementation with electrolytes, especially potassium. Diarrhea caused by irinotecan usually occurs 24 h after the medication is administered. The median onset time of irinotecan-caused diarrhea is the 5th day after administration; it lasts 4 days on average and can occur intermittently throughout the course of chemotherapy. In cases of delayed-onset diarrhea, loperamide is immediately prescribed, along with a large amount of supplemental fluid. If delayed-onset diarrhea lasts more than 48 h, prophylactic oral broad-spectrum antibiotics should be administered, along with parenteral supportive treatment and other anti-diarrhea drugs, such as octreotide.

Skin complications

Adverse skin reactions caused by drugs include rashes, hand-foot skin reactions, dryness, itching, hair loss, pigmentation/hypopigmentation, and paronychia/nail changes. Among these, hand-foot skin reactions are the most concerned in clinical practice, and the main manifestations include palm and plantar erythema and paresthesia, also known as palmoplantar erythema syndrome. Preventive measures include wearing loose footwear and gloves, wearing soft-soled shoes to reduce friction on the feet, avoiding exposure to environments with excessive heat and high pressure, frequently applying moisturizing and lubricating lotion, and seeking help from a dermatologist in cases of blisters and ulcers. When thickening of the skin on the hands and feet is the main manifestation, urea cream can be applied topically. The topical application of hormone-containing ointments can help reduce redness and pain. Some studies have found that large doses of vitamin B6 are effective for preventing and reducing capecitabine-related skin reactions on the hands and feet .

Liver complications

There are 3 main types of chemotherapy-derived liver toxicity: ① hepatocyte insufficiency and chemical hepatitis; ② venous occlusive diseases; ③ chronic liver fibrosis. In addition to increase in transaminase, liver function tests can show increased levels of direct or indirect bilirubin, which manifests as hepatocellular jaundice or is accompanied by intrahepatic obstructive jaundice and acute toxic hepatitis in severe cases. Antitumor drugs that cause liver toxicity mainly include oxaliplatin, irinotecan, paclitaxel, and docetaxel. Oxaliplatin mainly causes liver damage derived from vascular damage, leading to sinusoidal obstruction syndrome (SOS), while irinotecan most commonly causes steatohepatitis.

According to the clinical medication routine and the mechanism of liver-protecting drugs, commonly used liver-protecting drugs are divided into 5 categories: anti-inflammatory drugs, detoxification and antioxidant drugs, liver cell-membrane protectants, choleretic drugs, and enzyme-lowering drugs. For liver damage caused by the intermittent use of intravenous chemotherapeutic drugs, the use of 1 or 2 kinds of detoxification liver protection drugs plus anti-inflammatory liver protection drugs in the acute phase is recommended; these drugs can be changed to anti-inflammatory liver protection drugs plus essential phospholipid drugs after serum biochemical indicators improve.

Cardiac complications

The anticancer drugs that cause cardiotoxicity are mainly anthracyclines. In addition, paclitaxel, docetaxel, 5-fluorouracil, and trastuzumab can cause myocardial damage. Short-term acute cardiotoxic reactions mainly manifest as sinus tachycardia, arrhythmia, conduction block, ST-segment decline on the electrocardiogram, and low T waves, while delayed cardiotoxic reactions mainly manifest as congestive heart failure (CHF). Approximately 80% of patients show improved heart function after they stop taking anticancer drugs or undergo heart failure treatment. The drugs used to antagonize the cardiotoxic reactions of chemotherapeutics include coenzyme Q10, fructose 1,6-bisphosphate, creatine phosphate sodium, and amifostine. Acute toxicity is often reversible after the medication is discontinued and symptomatic treatment is administered. The application of digitalis and diuretics can alleviate CHF but cannot reverse it.

Nervous system complications

Anti-tumor drugs that cause neurotoxicity include oxaliplatin, cisplatin, paclitaxel, docetaxel, 5-fluorouracil, etc. Peripheral sensory nerve abnormalities caused by oxaliplatin can be acute or cumulative. In acute cases, neurotoxicity manifests as paresthesia in the distal extremities and/or the perioral region, occasionally, it manifests as reversible acute throat sensory dysfunction, which can be triggered or worsened by cold or contact with cold objects. During chemotherapy, patients should not eat or drink cold food or drinks or make contact with cold water or other cold objects. In subsequent treatment, the infusion time can be extended from 2 h to 6 h, which can ease symptoms. The dose-limiting toxicity of oxaliplatin includes dose-related, cumulative, and reversible peripheral neurotoxicity that mainly manifests as hypoesthesia and (or) paresthesia and can be triggered or aggravated by cold and is more profound when the cumulative dose is over 800 mg/m; however, it can recover a few months after the treatment is stopped.

The neurotoxicity of cisplatin, which manifests as tinnitus, deafness, and high-frequency hearing loss, is related to the dosage and can be treated by stopping cisplatin and administering amifostine.

Extravasation of chemotherapeutic drugs

Extravasation refers to the overflow of chemotherapeutic drugs from blood vessels into surrounding tissues or the accidental injection of drugs into undesignated tissues. The degree of tissue damage depends on the type, concentration, and injection volume of the drug.

The following factors need to be considered to prevent extravasation: (1) For drugs that can induce blistering, an indwelling peripherally inserted central catheter (PICC) should be placed before chemotherapy; (2) small and fragile veins should be avoided; (3) the catheter should not be inserted into a limb with lymphedema or neuropathic weakness, and veins close to tendons, nerves, or arteries and those in areas with high venous pressure should be avoided; (4) before the administration of cytotoxic drugs, the catheter should be flushed with 0.9% sodium chloride or 5% glucose solution at a free flow rate for 5 min, and flushing should be repeated after the drugs are administered; (5) patients should be instructed to immediately notify the nurse and stop the medication if they feel pain or discomfort.

Complications of immunotherapy

The use of PD-1 inhibitors may cause some normal cells of the body to be attacked by the immune system, which generates immune-related adverse events (irAEs). irAEs can affect all organs and tissues of the body; toxicities of the skin, colon, endocrine organs, liver, and lungs are most common, while nervous system and cardiovascular system impacts are rare. IrAEs are sensitive to glucocorticoid therapy, and in clinical practice, the use of steroids should be judged according to the severity of the toxicity. If glucocorticoid therapy fails, other immunosuppressive therapy, such as the tumor necrosis factor-α (TNF-α) inhibitor infliximab can be considered. Superprogression is a progression pattern caused by immunotherapy; it manifests as the explosive growth of tumors within a short period after treatment. It has a poor prognosis, and its predictive markers and potential mechanisms are still under investigation.

3.4 Radiotherapy

As a multidisciplinary integrated diagnostic and treatment method, radiotherapy plays an important role. The value of postoperative radiotherapy for locally advanced GC not reaching D2 lymph node dissection has been verified, but with the introduction of D2 surgery and the publication of the ARTIST-II study results, the value of radiotherapy for GC with D2 surgery has gradually come into question. For locally advanced GC or AEG patients, several phase II/III studies in China and abroad have confirmed that neoadjuvant chemoradiotherapy can significantly improve the tumor downgrading rate, R0 resection rate, and OS without significantly increasing surgical complications.

3.4.1 Indications for radiotherapy

Indications for preoperative radiotherapy

• (1) Locally advanced GC that can be surgically removed or is potentially resectable;

• (2) Clinical diagnosis: T3, T4 and (or) regional LN metastasis; no distant metastasis.

Indications for postoperative radiotherapy

• (1) Indications after radical resection: no distant metastasis; < D2 operation and T3, T4 and/or LN metastasis according to postoperative pathology;

• (2) After R1 or R2 surgical resection.

Indications for palliative radiotherapy

For GC with distant metastasis, radiotherapy can be used to relieve obstruction, compression, bleeding or pain.

Local regional recurrence

For patients who cannot undergo surgery at the recurrence site and have not received radiotherapy in the past, chemoradiotherapy can be used for 6 to 8 weeks. Evaluate the efficacy after 6 to 8 weeks of chemoradiotherapy, and strive for reoperation.

3.4.2 Radiotherapy technology and target area

Radiotherapy technology

Intensity-modulated radiotherapy includes volumetric modulated arc therapy (VMAT), helical tomotherapy (TOMO), etc.; has better conformability and uniformity of dose distribution than 3-dimensional conformal radiotherapy (3D-CRT), and allows the radiotherapy dosing mode of simultaneous integrated boost (SIB), i.e., increasing the radiation dose to gastric tumors without increasing the radiation dose to normal tissues.

Positioning before treatment

After 3 h of fasting, the patient is asked to assume the supine position and hold his or her elbows up to his or her forehead, and this position is fixed with thermoplastic body film or a vacuum pad/foam. Oral contrast agent or intravenous angiography can help to localize the target area during CT. 4D-CT positioning can also be selected, and the management of respiratory movements should be considered to avoid gastric filling and uncertainty due to changes in respiratory movement.

Radiotherapy target area

• (1) Preoperative radiotherapy

Gross tumor volume (GTV): combined with gastroscopy, ultrasonography, CT and MRI to determine the initial tumor primary lesion of GC. GTV with positive lymph nodes (GTVnd): based on CT scan, positive lymph nodes revealed by PET-CT should be included if possible, and the scope of the clinical target volume (CTV) is determined based on the location of the primary tumor and the degree of invasion, lymph node metastasis, etc. CTV includes GTV, GTVnd and the high-risk lymphatic drainage area (Table 8).

Table 8 Radiation ranges of lymphatic drainage areas corresponding to different primary tumor sites

• (2) Postoperative radiotherapy

he CTV area for postoperative radiotherapy for GC should be considered in combination with the original tumor site, surgical resection and dissection range, digestive tract reconstruction method, and postoperative pathological conditions, including those of the tumor bed, anastomotic stoma, and lymphatic drainage area; however, the remnant stomach is not recommended to be included in the target area (Table 9).

Table 9 Radiation range of postoperative radiotherapy for different disease stages

The range of the lymphatic drainage area should be selected according to the JGCA definition of lymph node divisions and the position of the primary lesion (Table 10). If there are residual LNs after R2 resection, then the corresponding lymphatic drainage area aside should be included in addition to the aforementioned area. The range of the internal target volume (ITV) margin enlargement should be determined with reference to the breathing amplitude and filling state of the lung, and then the positioning error, system error and whether image-guided radiotherapy is used, are combined to determine the range of the planning target volume(PTV).

Table 10 Selection of the postoperative radiotherapy area according to the location of the primary lesion

• (3) In cases of palliative treatment, only the primary focus and the metastatic lesions causing symptoms are irradiated.

3.4.3 Radiotherapy dose and regimen

Radiotherapy dose

• (1) Preoperative radiotherapy dose: recommended dose of tumor (DT) 41.4–45 Gy, 1.8 Gy each time, 23–25 sessions in total;

• (2) Postoperative radiotherapy dose: recommended DT 45–50.4 Gy, 1.8 Gy each time, 25–28 sessions in total; for tumors and/or residuals, local conformal boosting irradiation of DT 5–10 Gy after SIB is recommended.

• (3) Radical radiotherapy dose: recommended DT 54–60 Gy, 2 Gy each time, 27–30 sessions in total.

• (4) Radiotherapy for metastasis and brain metastasis: 30 Gy/10 f or 40 Gy/20 f or SRS.

Concurrent chemotherapy

Fluorouracil is used for concurrent chemotherapy, and oral or intravenous tegafur or fluorouracil can be administered.

(1) Tegafur dose:

Body surface area	Dosage (by Tegafur)
<  1.25m2	40 mg every time
≥ 1.25m2 and ≤ 1.5 m2	50 mg every time
≥ 1.5m2	60 mg every time

(2) Capecitabine dose: oral administration (bid) of 800 mg/m² on the day of radiotherapy.

Normal tissue limit (may be modified according to the actual clinical situation).

Organ	Limit dosage
Lung	V20 < 25%
Heart	V30 < 30%
Spinal cord	Dmax ≤45Gy
Kidney	V20 < 25%
Small intestine	V45 <  195 cc
Liver	V30 < 30% Dmean <25Gy

3.5 Treatment of special types of GC

In addition to common histological types of GC, there are GCs with special histological types and clinicopathological characteristics, such as gastric neuroendocrine carcinoma (NEC), hepatoid adenocarcinoma of the stomach (HAS), lymphoepithelioma-like gastric carcinoma (LELGC), hereditary diffuse GC (HDGC), and Borrmann type 4 GC. These special types have a low incidence, which makes conducting related large-scale research difficult; therefore, no high-level evidence regarding their treatment is available to date. Here, only the existing expert consensus is presented. For the diagnosis of special types of GC, please see Section 2.6: Pathological Diagnosis.

3.5.1 Gastric NEC

The diagnosis of gastric NEC relies mainly on pathological morphology and IHC examination. It can be categorized into 2 types: large cell and small cell. At the time of diagnosis, NEC is generally in the middle and advanceds and is prone to liver metastasis; consequently, the overall survival of NEC patients is short, and their prognosis is extremely poor. The prognosis is relatively good in cases of single-lesion tiny tumors (< 1 cm) but poor in cases of large tumors (> 2 cm).

For localized gastric NEC, radical resection is the first choice. Chemotherapy is an important treatment method for patients after gastric NEC surgery and those with inoperable tumors. However, at present, there is no standard chemotherapy regimen for gastric NEC. Etoposide combined with cisplatin (the EP regimen) is widely used in clinical practice. Some reports have shown that irinotecan combined with cisplatin has achieved good results for the treatment of NEC, and some reports have shown that cisplatin combined with S-1 chemotherapy prolongs survival.

3.5.2 Has

HAS is a special type of GC with features that differentiate it from hepatoid adenocarcinoma. It accounts for 6.63% of the GC patient population in China and manifests as a large tumor with poor differentiation; deep invasion; inclination toward LN invasion, liver metastases, and recurrences; and short survival. Approximately 70%–80% of patients with HAS have increased serum AFP, which can reach a level thousands of times the normal range. The diagnosis of HAS relies primarily on IHC. Even with early diagnosis, the prognosis of HAS is poor. The principle underlying HAS treatment is comprehensive treatment based on surgery, and even with liver metastases, R0 resection is the best way to prolong survival. However, since most patients are in the middle and advanceds when they are diagnosed and thus have lost the opportunity for radical surgery, the most common treatment is chemotherapy. Given that HAS is characterized by pathological duality that includes characteristics of both GC and liver cancer, systemic chemotherapy combined with local interventional chemotherapy is generally adopted; immunotherapy, such as PD-1 inhibitors, can also be used.

3.5.3 LELGC

LELGC, also known as gastric carcinoma with lymphoid stroma (GCLS) or gastric medullary carcinoma (GMC), is a malignant GC with significant lymphocyte infiltration that accounts for 3.8% of GC cases. More than 80% of cases are related to EBV infection, and some are related to MSI. LELGC patients have a significantly better prognosis than those with ordinary gastric adenocarcinomas.

The diagnosis of LELGC relies mainly on histopathological and IHC detection. Because LELGC has clear boundaries and early clinical staging, surgical resection supplemented by chemotherapy is the main treatment method, and the chemotherapy regimen is based on that for GC. Compared to the prognosis of ordinary EGC, that of early LELGC is similar, but that of advanced LELGC is significantly better. Even if the lesion has infiltrated the entire layer of gastric wall, the 5-year survival rate can still reach 79.8%.

3.5.4 HDGC

HDGC accounts for 1–3% of all GC cases and has been reported only sporadically in China. It is an autosomal dominant cancer susceptibility syndrome caused by inherited alterations in genes and is mainly related to germline mutations of the E-cadherin gene (CDH1). Integrated treatment combining surgery and chemotherapy can improve survival. HDGC has a low degree of differentiation and a multifocal distribution and can affect all parts of the stomach. After local resection, residuals and recurrence are likely. Therefore, total gastrectomy supplemented with postoperative chemotherapy is recommended.

3.5.5 Borrmann type 4 GC

Borrmann type 4 GC has clinicopathological characteristics and biological behaviors that are different from those of other types of GC. It exhibits extensive invasive growth in the gastric wall and often first involves the submucosa, then spreads along the gastric wall to the entire stomach cavity. Its unique growth pattern and pathological characteristics make the early diagnosis of lesions difficult, with a diagnostic sensitivity ranging from 33% to 73%. Compared with other types of GC, Borrmann type 4 GC is more likely to have LN and peritoneal metastases; consequently, its 5-year survival is only 9.6%. Most Borrmann type 4 GC patients are in the advanced when they are treated; therefore, neoadjuvant chemotherapy is unable to improve survival. Curability is the most important prognostic factor. Therefore, D2 surgery is still the main means for improving the survival of Borrmann 4 GC patients. High-quality studies on the effect of adjuvant therapy on the prognosis of Borrmann 4 GC patients are rare, but it is generally believed that postoperative chemotherapy has some effect.

4 Rehabilitation for GC

GC is both a systemic disease characterized by the abnormal growth of local tissues and a disease marked by body-organ-tissue systemic regulation disorder; therefore, it has both systemic and systematic characteristics. Consequently, holistic integrated medicine could offer a breakthrough in the diagnosis and treatment of GC. The integrated diagnosis and treatment of GC is patient-centered; is based on the biological behavior of GC; relies on medical evidence, such as big data analysis, multicenter clinical trials, and clinical experience; pays equal attention to prevention and treatment; integrates the advantages of nutrition, society, psychology, and other disciplines; attaches importance to the integration of traditional Chinese and Western medicines; and promotes the standardization, rationalization, and integration of GC diagnosis and treatment through cross-linked integration models.

4.1 Follow-up

4.1.1 Follow-up strategy

Follow-up requires the cooperation of both doctors and patients. The objective, frequency, and general content of follow-up should be clarified before discharge and recorded on the discharge certificate or discharge guidelines. The specific content is as follows:

Projects	Items
Follow-up time	() once every 3–6 months; () once every 6–12 months; () once annually
Follow-up content (alternative)	Chest radiography, Color Doppler ultrasound, KUB film, Laparoscopic exploration, Endoscopy, Ultrasonic endoscope, Histopathology, MRI, CT, PET-CT, ECT, CEA, CA199, CA724, CA242, CA125, CA50, Fecal occult blood testing, ALP, Ascites

4.1.2 Frequency of follow-up

EGC after radical resection: once every 6 months for the first 3 years; once annuanlly from 3 to 5 years after surgery.

AGC radical surgery and palliative treatment in cases of unresectable tumor: once every 3 months for the first 2 years; once every 6 months from 2 to 5 years after surgery; and once a year after 5 years. Regular follow-up helps identify metastatic and recurring GC that can potentially be cured, detect tumor recurrence and secondary GC earlier, and provide timely intervention to improve the overall survival and quality of life of GC patients [129].

Patients with stage IV GC, recurrent GC, or worsening symptoms should be closely monitored or undergo follow-up every 3 months.

4.1.3 Follow-up content

Medical history consultation, physical examination, performance status (PS) score, blood routine, biochemistry, Hp test, CEA, and CA19–9 are required at each annual follow-up [130]. Chest, abdomen, and pelvic enhanced CT or (and) ultrasonography should be performed for EGC patients at the 6 and 12 months after R0 surgery and then once a year from the 2nd year to the 5th year. For AGC patients who have undergone radical surgery or palliative treatment for unresectable tumors, chest, abdomen, and pelvic contrast-enhanced CT should be performed once every 6 to 12 months for the first 2 years. Endoscopic examinations should be performed in the 1st, 3rd, and 5th year after surgery. If necessary, other examinations (e.g., bone scan and PET-CT) can also be performed.

① Medical history: quality of life score (gastrointestinal symptom rating scale (GSRS) score or Visick score); other treatments and their effects; and physical examination, including PS score, body weight, nutritional status score (NRS2002), and nutrition assessment (vitamin B12, iron).

② Blood tests: blood routine, biochemical series, CEA, CA199, CA724, CA125, CA424, CA50, vitamin B12, iron ions.

③ Hp detection [130]: Routine follow-up after radical GC resection.

④ Gastroscopy and biopsy are recommended within 1 year after surgery. If there is evidence of high-grade intraepithelial neoplasia or GC recurrence in each pathological biopsy with gastroscopy, reexamination is required within 1 year. Endoscopic examination should be performed once a year, and in cases of chief complaints or clinical indications, the following examinations should be performed in a timely manner: ① chest, abdominal, and pelvic contrast-enhanced CT; ② PET-CT and MRI examinations are only recommended for clinically suspected recurrence with negative routine imaging examinations (e.g., a continuous increase in CEA when the results of other examinations, such as abdominal CT, are negative). PET/CT is not recommended as a routine follow-up monitoring method.

4.2 Nutritional assessment and treatment

The incidence of malnutrition among GC patients is 87%, and that of cachexia can be as high as 65–85%; these incidences are among the highest for all types of tumors, and 92.7% of all cases have a Scored Patient-Generated Subjective Global Assessment score ≥ 2. For most GC patients undergoing surgery, nutrition therapy should be extended, and 5–7 days of preoperative immunization nutrition therapy, at least 7 days of postoperative enteral nutrition (EN) and/or parenteral nutrition (PN) therapy, and even lifelong oral nutritional supplements (ONSs) are recommended.

4.2.1 Nutritional assessment

Nutritional status is a basic vital sign that should be routinely evaluated upon admission, and both diagnoses (i.e., the diagnosis of primary disease and the diagnosis of nutritional status [131]) should be routinely recorded. The diagnosis of nutritional status should include nutritional intake, weight change, body mass index (BMI), nutrition-related symptoms, physical fitness, systemic inflammation, etc. A 3-level diagnosis, i.e., nutrition screening, nutrition assessment, and comprehensive evaluation [132], is recommended. Any validated tools and methods can be used for the nutrition diagnosis, but the PG-SGA is preferred.

4.2.2 Nutritional treatment

The implementation of nutritional therapy should follow the 5-step principle. Nutrition education is the preferred option, followed by EN and parenteral nutrition (PN); EN is the first choice, followed by PN; oral administration is the first choice, followed by tube feeding. When the current step cannot meet 60% of the target energy demand for 3 to 5 days, the next step should be selected. When patients who have undergone surgery cannot eat for more than 7 days during the perioperative period, even without signs of nutritional deficiency, EN should be supplemented; if the intake is less than 60% of the recommended intake for more than 10 days, EN should also be supplemented. In case of one of the following conditions, surgery should be postponed to implement preoperative EN: ① Weight loss within 6 months > 10%; ② BMI < 18.5; ③a rating of C on the PG-SGA; ④ No liver and kidney dysfunction but albumin < 30 g/L.

Preoperative nutritional therapy

Indications: ① malnutrition and nutritional risk; ② predicted inability to consume nutrition orally for more than 5 days during the perioperative period, or an oral intake less than 50% of the recommended intake for more than 7 days. EN is preferred, including ONS and tube feeding. When oral intake and tube feeding cannot meet the energy and nutrition requirement (< 50% calorie requirement) for more than 7 days, combined PN is recommended; when EN is contraindicated (e.g., due to intestinal obstruction), PN should be used as soon as possible for 7–14 days. Most patients do not need to fast from food and drink from the night before surgery, and those who are not at risk of aspiration can drink clear liquids 2 h before anesthesia and consume solid food 6 h before anesthesia. Oral intake of carbohydrates the night before surgery or 2 h before surgery can help reduce anxiety, improve postoperative insulin resistance (IR), and even shorten the length of hospital stay.

Postoperative nutritional therapy

Most patients can resume the oral intake of liquids within a few hours after surgery, and EN can be started within 24 h after surgery. For patients with malnutrition who need EN due to major surgery of the upper gastrointestinal tract and pancreas, a nasointestinal tube or needle-catheter jejunostomy (NCJ) should be implanted for nutritional therapy. The standard whole-protein formula is suitable for most patients, and homemade food is not recommended.

Conservative treatment of terminal GC

Patients with terminal GC often also present gastrointestinal obstruction; if obstructions in the cardia or pylorus cannot be treated surgically or with stent placement, NCJ is recommend. NCJ is critical for postoperative supplementation of early EN, preventing and controlling postoperative complications, reducing medical expenses, and shortening the length of hospitalization; furthermore, it is of great benefit for later chemoradiotherapy, since it can increase nutritional supply, improve the tolerance of chemoradiotherapy, and reduce adverse reactions. NCJ can be continued until the end of postoperative adjuvant chemoradiotherapy.

Nutrition therapy during at-home rehabilitation

It is recommended to increase food diversity and the intake of high-quality protein, vegetables, fruits, and whole grains; reduce the intake of saturated fatty acids, red meat, and alcohol; have small, frequent meals; chew thoroughly and eat slowly; record weight every 2 weeks and maintain a BMI of 18.5–23.9 kg/m²; pay special attention to outpatient nutrition consultation (at least once every 3 months); and develop ONS habits.

4.2.3 Energy requirements

The recommended total daily energy consumption during the perioperative period is 30 kcal/kg∙d. Approximately 50–70% of energy should come from carbohydrates, and 30–50% should come from fats; the protein requirement should be increased from 1.0–1.2 g/kg∙d (0.15–0.2 g nitrogen) before surgery to 1.2–1.8 g/kg∙d (0.2–0.3 g nitrogen) after surgery; for carbohydrates, 3 to 4 g/kg∙d (not less than 2 g/kg∙d) is necessary to meet energy demands, and the total amount should not be less than 100 g; the total amount of fats should be 1.5–2 g/kg∙d, but no more than 2 g/kg∙d, and the daily intake of an appropriate amount of minerals and vitamins should be ensured. When total intravenous nutrition is used, the energy supply should be reduced to 25 kcal/kg∙d [131].

4.2.4 Immunonutrition preparations and formulas

GC surgery is very traumatic, resulting in a decrease in immunity and an increased risk of postoperative mortality and infection. Enhancing immune function can reduce the occurrence of complications, and therefore, immunonutrition is preferred. The nutritional therapy preparations and formulas for GC patients are generally not different from those used for patients with other tumors. During the perioperative period, immunonutrition is more effective than a standard diet. Commonly used immunonutrients include arginine, glutamine, omega-3 PUFAs, nucleic acids, and antioxidant micronutrients (vitamin E, vitamin C, β-carotene, zinc, and selenium). The integrated use of these immunonutrients should be emphasized, and combinations of first 4 types are recommended, while the outcomes of combinations of 1, 2, or 3 types have yet to be verified.

4.2.5 Evaluation of the efficacy of nutritional therapy

Efficacy evaluation requires the dynamic monitoring of changes in various nutrition-related parameters before, after, and during nutrition treatment [133]. The clinical effects of nutritional therapy appear slowly; therefore, a 4-week course of treatment is recommended. After treatment, the time required for each parameter to respond to treatment varies; therefore, the evaluation interval should also differ accordingly. Response parameters can be divided into 3 categories:

• (1) Rapid response parameters: laboratory examination items, food intake, physical fitness, etc., to be examined once every 1–2 weeks.

• (2) Moderate response parameters: anthropological measurement (e.g., weight, calf circumference), body composition analysis, imaging examinations, tumor lesion volume, metabolic activity, quality of life, psychological changes, etc., to be reexamined once every 4–12 weeks.

• (3) Slow response parameters: survival, to be evaluated once a year.

Severely malnourished patients should visit the outpatient clinic or receive regular telephone follow-up after being discharged from the hospital, at least once every 3 months.

4.3 Enhanced recovery after surgery (ERAS)

4.3.1 ERAS whole-process management during the perioperative period

ERAS involves various diagnostic and treatment links aimed at establishing a MDT to HIM team of experts in surgery, anesthesiology, nursing, nutrition, rehabilitation therapy, and psychological support to formulate a personalized ERAS program to promote fast and safe postoperative rehabilitation. ERAS attaches importance to multidisciplinary cooperation to optimize perioperative management. The most important measures are as follows: ① A multimodal analgesia scheme to avoid or reduce the use of opioid analgesics; ② Avoidance or reduction of the use of nasogastric tubes; ③ Early ambulation after surgery; ④ Early resumption of oral eating and drinking after surgery; ⑤ Avoidance of too much or too little intravenous infusion, etc.

4.3.2 Preoperative preparation

Preoperative education

Most patients have varying degrees of panic and anxiety about surgery. Before the surgery, detailed information about the anesthesia and operation process and the purpose and main aspects of ERAS should be provided to the patient and family members to relieve the patient’s nervousness and anxiety and encourage the patient’s understanding and cooperation, thereby promoting rapid postoperative recovery.

Preoperative nutritional support treatment

Malnutrition is an independent prognostic factor for postoperative complications [134]. The necessary preoperative nutritional support is an important aspect of ERAS. If any of the following conditions are found during the preoperative nutritional assessment, then preoperative nutritional support (≥ 1 week) should be considered [135]: ① Plasma Alb < 30.0 g/L; ② > 10% decrease in body weight in the past 6 months; ③ BMI < 18.5 kg/m2; ④ C rating on the PG-SGA. Supportive EN treatment is preferred [136]. Hb < 7.0 g/L is an indication for blood transfusion therapy.

Preoperative gastrointestinal preparation

Preoperative mechanical bowel preparation is a kind of stress stimulus that leads to dehydration disturbs the water and electrolyte balance while destroying the internal intestinal environment, effects that are especially profound among elderly patients [137]. There is currently no evidence that it can benefit patients. However, for patients with pyloric obstruction, gastric lavage with warm saline through a nasogastric tube is recommended to reduce gastric wall tissue edema and gastric retention. For patients with suspected transverse colon invasion who are scheduled to undergo combined organ resection, preoperative bowel preparation is recommended. For patients with chronic constipation, preoperative enema with normal saline is recommended to avoid difficulty with defecation after surgery.

Fasting from food and drink before surgery

Fasting from food for 12 h and from liquids for 6 h before surgery are traditional routine measures before gastric surgery. However, they do not reduce the incidence of postoperative complications and cause IR and postoperative discomfort [138]. Therefore, patients without gastrointestinal motility dysfunction or intestinal obstruction can consume solid food up to 6 h before surgery and water up to 2 h before surgery. For those without diabetes, the oral administration of 400 ml of 12.5% carbohydrate drink before anesthesia is recommended. The oral administration of 800 ml of 12.5% carbohydrate drink 10 h before surgery can ease preoperative hunger, thirst, and anxiety; shorten the hospital stay; and reduce postoperative IR [139,140,141].

Preventive use of antibiotics

The administration of antibiotics 0.5–1.0 h before surgery is recommended. If the operation time is longer than 3 h or more than 2 times the half-life of the antibiotic, or if the volume of intraoperative blood loss is greater than 1500 ml, a single dose of antibiotics should be added [142,143,144].

4.3.3 Intraoperative management

Operative method selection

Operative methods include laparotomy, laparoscopy, and robotic surgery. Laparoscopic or minimally invasive robotic surgery is recommended for GC patients with T1-T3 invasion and the possibility of R0 resection [145,146,147].

Anesthesia plan and fluid therapy

General anesthesia or systemic anesthesia combined with extradural nerve block can be adopted. Continuous anesthesia should be implemented under EEG dual-spectrum monitoring, and low tidal volume ventilation should be used during the operation. To ensure the stability of tissue perfusion and blood volume, controlled fluid infusion is performed. Excessive intravenous fluid infusion should be avoided to prevent tissue edema while avoiding insufficient blood volume caused by the intravenous infusion of too little fluid [145].

Nasogastric tube placement

Gastrointestinal decompression is not related to surgical complications. Not placing a nasogastric tube during surgery can reduce pulmonary complications, shorten the time to anal exhaust, accelerate the recovery of oral eating, and decrease the length of the hospital stay [135, 148, 149]. Postoperatively, the prevention and treatment of nausea, vomiting, and abdominal distension should be emphasized. For patients with preoperative pyloric obstruction, intraoperative gastric wall edema, risk of anastomotic leakage and bleeding, postoperative gastric retention, abdominal distension, or severe nausea and vomiting, a nasogastric tube can be considered for decompression.

Abdominal drainage tube placement

Due to the large scope of LN dissection in GC surgery and the abundant exudation on the wound surface, preventive abdominal drainage tubes are often clinically used to drain abdominal effusion to prevent abdominal infection and for the early detection of anastomotic leakage and the monitoring of postoperative bleeding. Studies have shown that the placement of an abdominal drainage tube after GC surgery has no effect on flatulence, length of hospital stay, and the incidence of complications within 30 days after surgery [150,151,152]. Therefore, it is recommended that the use of an abdominal drainage tube be based on the intraoperative situation.

Avoiding intraoperative hypothermia

The avoidance of intraoperative hypothermia can reduce the impact on neuroendocrine metabolism and coagulation. Routine monitoring of body temperature during the operation and necessary heat preservation measures are recommended. Intraperitoneal irrigation fluid should be warmed to 37 °C before its use during surgery.

4.3.4 Postoperative management

Postoperative analgesia

Postoperative pain in the upper abdominal surgical area has a strong impact on the patient’s breathing and early ambulation. Effective analgesia can relieve nervousness and anxiety and improve compliance with early eating and early ambulation [153]. Multimodal analgesia is recommended, and nonsteroidal anti-inflammatory drugs are the basic source of postoperative analgesia. Oral acetaminophen, local incision infiltration of ropivacaine, and the addition of midthoracic epidural analgesia are other options. Opioids have serious adverse reactions, can affect the recovery of intestinal function, and cause respiratory depression, dizziness, nausea, vomiting, etc.; therefore, their use should be avoided or minimized [154, 155].

Perioperative fluid therapy

Fluid balance can improve the prognosis of gastrectomy. Both hypovolemia, which leads to insufficient tissue perfusion and organ function damage, and hypervolemia, which causes tissue edema and increased cardiac load, should be avoided. Intraoperatively, a goal-orientated appropriate circulatory volume and tissue oxygen supply should be maintained to achieve the goal of ERAS [156].

Drainage tube management

Minimizing and removing catheters as soon as possible can help reduce complications (e.g., infections) and the impact on postoperative activities. Routine use of a nasogastric tube is not recommended after surgery; instead, nasogastric tubes should be selectively used only in cases of gastric emptying disorders [28]. If there are no special circumstances, removal of the bladder catheter 1–2 days after surgery and other indwelling drainage tubes early after the operation is recommended. In cases of surgical wound infection or the presence of high-risk factors for anastomotic leakage, the indwelling time of the drainage tube can be extended.

Resumption of oral eating as soon as possible after surgery

The resumption of oral eating and drinking as soon as possible after GC surgery is recommended. EN during the early postoperative period can promote the early recovery of intestinal function, maintain the function of intestinal mucosa, prevent the imbalance and displacement of gastrointestinal microbiota, reduce the incidence of postoperative infections, and shorten the hospital stay. After surgery, the patient should drink a small amount of water after awakening; on the first day after the operation, the patient should consume 500–1000 ml of liquid or a small amount of clear liquid food, and this amount should increase daily. When the daily intake reaches the physiological requirement of 2000–2500 ml/day, intravenous nutritional infusion can be stopped. After the resumption of flatulence, the liquid diet can be changed to semi-liquid diet, and the food intake should be gradually increased according to gastrointestinal tolerance. Preoperatively malnourished patients should be treated with EN or PN support until the oral nutrition intake can meet 60% of their energy needs.

Promoting the recovery of gastrointestinal function after surgery

Postoperative gastrointestinal function recovery time is one of the main factors that determine the length of postoperative hospital stay. Measures to prevent postoperative intestinal paralysis include multimodal analgesia, reducing the use of opioids, controlling fluid intake, minimally invasive surgery, minimizing the indwelling of nasogastric and abdominal drainage tubes, early oral eating and early ambulation. There is no high-quality evidence to support the use of a specific drug to stimulate the recovery of gastrointestinal function after gastrectomy.

Early ambulation after surgery

Early ambulation can promote the recovery of multiple systems and gastrointestinal function and can prevent lung infections and the formation of bedsores and deep vein thrombosis. To encourage the patient to ambulate early, preoperative education, multimodal analgesia, and the removal of catheters early are important. Once the patient is alert after surgery, her or she can adopt a semi-reclining position or engage in appropriate on-the-bed exercises, without the need to lie in bed in the supine position for 6 h after the pillow is removed. On the 1st day after surgery, the patient is encouraged to ambulate early and to establish daily activity targets, with a continuous increase in daily activities.

Discharge criteria and follow-up

Basic criteria: no need for liquid therapy, resumption of a semi-liquid diet, good effect of oral analgesics, good wound healing, no evidence of infection, good organ function, and good mobility. For ERAS patients, follow-up and monitoring should be strengthened, and patients should receive instructions for incision care through telephone calls or outpatient clinic visits. Telephone follow-up should be made within 48 h after discharge, and outpatient follow-up should take place 1 week after discharge, when instructions for adjuvant treatment are also provided.

4.4 Postoperative care

4.4.1 In-hospital care

Observation of the patient’s condition

On the first day after surgery, the patient’s blood pressure, pulse, and respiration should be monitored with ECG until blood pressure is stable. The patient’s state of consciousness, body temperature, urine output, and blood, exudate, and drainage from the incision should also be observed.

Effective measures for patient comfort

• (1) Position: a semi-recumbent position should be adopted after the operation. After the patient’s blood pressure is stable, a low semi-recumbent position can be adopted so that the patient’s abdominal muscles are relaxed and tension in the abdominal incision is reduced to relieve pain while facilitating breathing and drainage.

• (2) Analgesia: see section 4.3.4.1

• (3) Rest: a good rest environment should be created for the patient to ensure that he or she can rest and sleep well.

Encouraging early ambulation

Please see section 4.3.4.6.

Postoperative diet care

After bowel movement is restored, the gastric tube can be removed, and the patient can consume a small amount of water or rice water on the day of the operation; 1 day after the operation, the patient can consume half the normal amount of liquid diet, 50–80 ml each time; on the 3rd day after the operation, the patient can consume the full amount of liquid diet, and egg soup, vegetable soup, and lotus root powder soup are appropriate. If the patient does not experience discomfort, such as abdominal pain and bloating after eating, he or she can consume a semi-liquid diet (e.g., porridge) on the 4th day after surgery. From the 10th to the 14th day after surgery, the patient can eat soft foods. Gas-producing foods and raw, cold, hard, or irritating foods should be avoided. Small but frequent meals are recommended, starting at 5 or 6 meals per day and gradually reducing the number of meals while increasing the size of each meal to gradually resume a diet that is normal in terms of size and frequency. After total gastrectomy, the capacity of the intestinal tube acting as the stomach is small, and at the very beginning, the liquid diet should be small in size and not oily, and patient should be observed for abdominal discomfort after each meal. For ERAS, please refer to section 4.3.4.

Early EN care

• (1) Nasogastric tube care: the nasogastric tube should be properly fastened to keep it unobstructed. To prevent the tube from becoming blocked, it should be flushed with normal saline or 20–30 ml of warm water before and after each nutrient infusion and once every 4 h.

• (2) Control of the temperature, concentration and flow rate of nutrient solution: the temperature of the nutrient solution should be close to the body temperature. An excessively high concentration of nutrient solution can induce dumping syndrome.

• (3) The occurrence of complications such as nausea, vomiting, abdominal pain, abdominal distension, diarrhea, and electrolyte imbalance should be closely monitored.

Drainage tube care

• (1) Properly fasten and accurately label each drainage tube.

• (2) Keep the drainage tube unobstructed by avoiding compression, bending, and twisting.

• (3) Monitor and record the amount, color, and nature of drainage fluid.

Prevention of venous thromboembolism

Venous thromboembolism, including deep vein thrombosis and pulmonary thromboembolism, is a high-risk complication in surgical patients and should be prevented. The postoperative preventive measures are as follows:

• (1) After the patient is returned to the ward, his or her lower limbs should be massaged by squeezing the muscles from the distal end to the proximal end to facilitate the circulation of venous blood.

• (2) The affected limbs should be raised, and heat should be applied to the lower limbs if necessary to promote blood circulation.

• (3) The patient should be encouraged to frequently roll over in bed or engage in frequent knee, ankle, and toe joint flexion and extension activities as soon as possible and to perform deep breathing and coughing to increase diaphragm movement and decrease chest pressure.

• (4) The patient should be encouraged to ambulate as early as possible after surgery, and the range of motion and muscle strength of each joint of the limbs should be gradually increased.

• (5) Signs of venous thrombosis, such as swelling of the thighs, skin darkening, and tenderness and swelling of the calves, should be closely monitored.

• (6) Mechanical preventive measures: when necessary, mechanical methods, such as progressive compression stockings and intermittent pneumatic compression devices, can be used to reduce the incidence of deep vein thrombosis of the lower extremities.

• (7) Preventive medications: anticoagulant drugs can be used according to a doctor’s advice. During drug use, the clotting time, blood routine, etc., should be monitored, and bleeding of the gums, nose, surgical incision, urinary system, digestive tract, and injection site should be closely observed.

4.4.2 Home care

To meet the patient’s needs, nursing staff should refer to Maslow’s hierarchy of needs; guide the patient’s home rehabilitation care by comprehensively considering the patient’s disease condition, education and personality characteristics; provide diverse and continuous care at different levels; provide discharge instructions focusing on the patient’s physical and psychological needs; and improve the patient’s knowledge of the disease prognosis through telephone calls and home visits.

Diet adjustment

• (1) Thorough chewing and slow swallowing: the completely milling of food and mixing with saliva help complete primary digestion without burdening the remnant stomach or jejunum while avoiding digestion and absorption disorders.

• (2) Consumption of small and frequent meals: large meals tend to cause upper abdominal discomfort, nausea, belching, abdominal pain, and bloating. The consumption of 5–6 meals a day is conducive to digestion and absorption while increasing the total calorie intake to prevent weight loss.

• (3) Consumption of an easy-to-digest diet with sufficient energy: foods must be adequately nutritious and high in protein and vitamins. Raw, cold, hard, fried, spicy, sour, gas-producing, and other irritating foods, as well as strong tea, should be avoided.

• (4) Separate consumption of solids and liquids: drinking soup and beverages while eating food should be avoided. Beverages can be consumed 30 min before and after a meal. Drinking too quickly or drinking a large amount of sugary fluids at a time should also be avoided.

Psychological adjustment care

Patients are often pessimistic about tumors and their prognosis and should be encouraged to express their feelings, improve their psychological state, and practice good self-regulation. Family members and friends should provide care and support.

4.5 TCM treatment

4.5.1 Principles of treatment

Basic treatment is based on the Fu-zheng-Kang-Ai decoction principle. Syndrome differentiation and GC treatment should be based on the combination of disease differentiation and syndrome differentiation while considering the effects of other treatments on the body. TCM treatment for EGC patients can assist with surgery and chemotherapy by rebuilding qi and strengthening the body; for patients with middle- and late-stage tumors, in addition to rebuilding qi, TCM treatment can eliminate pathogenic factors while modifying the treatment according to the symptoms associated with recurrence.

4.5.2 Syndrome differentiation and treatment

Differentiation and treatment of GC after surgery

Postoperative symptoms often include insufficient qi and blood; weak spleen and stomach, manifesting as a pale or sallow complexion, white lips and nails; fatigue; lack of qi and disinclination to talk; diet stagnation; spontaneous sweating; numbness of the limbs; tongue dryness; and weak pulse. After supplementing qi to nourish the blood and the initiation of oral food intake, medicine to invigorate the spleen and stomach is prescribed to promote the patient’s rapid recovery while facilitating other treatments. Perioperative adjuvant TCM treatment can reduce recurrence, prevent metastasis, and prolong survival. Bazhen decoction or Danggui Buxue decoction is recommended for patients with qi and blood deficiency; Buzhong Yiqi decoction is recommended for those with weak spleen and stomach; and Dachengqi decoction is recommended for those with diet stagnation.

Differentiation and treatment of GC after chemoradiotherapy

Chemoradiotherapy has an effect on the body’s qi, blood, essence, and fluid, resulting in dysfunction of the internal organs that manifests as stomach fullness and discomfort, poor appetite, nausea and vomiting, irregular bowel movements, fatigue, loose stools, bloating after meals, sallow complexion, etc. The use of TCM to invigorate the spleen and stomach, nourish the qi and blood, and nourish the liver and kidney can alleviate and improve clinical symptoms, such as bone marrow suppression and gastrointestinal dysfunction, and can improve the effect of chemotherapy.

• (1) Hand and foot skin reactions

The main pathogenesis of this disease is heat-toxicity in the blood, and the treatment is based on clearing away heat and providing detoxifying and dampness-drying medications. Huanglian Jiedu decoction is recommended for heat-lodging skin; spleen-clearing and dampness-drying drinks are recommended for damp-heat accumulation in the spleen; blood nourishing and skin moisturizing drinks are recommended for blood-heat and endogenous dryness.

• (2) Cardiotoxicity

The pathogenesis of cardiotoxicity is mainly deficiency of qi and blood (fatigue, diarrhea, nausea or vomiting, weak waist and knees, dizziness and headache, cold limbs, numbness of hands and feet, nausea and vomiting, low appetite, fat tongue, white and moist fur of the tongue, deep thready pulse), and heart-yang deficiency (palpitations, chest tightness, shortness of breath, pale complexion, cold limbs and aversion to cold, pale tongue, white fur, and deep thready and feeble pulse), which should be treated according to the principle of supplementing both qi and blood and invigorating qi and warming yang. For the yang deficiency of spleen and kidney, the modified Anticancer decoction for rebuilding qi is recommended; for the deficiency of heart yang, Anticancer decoction for rebuilding qi is recommended.

• (3) Skin rash

The pathogenesis of skin rash is mainly deficiency of qi and blood, internal accumulation of blood heat, or external invasion of rheumatism and heat toxins to the skin. The clinical treatment should adopt different methods and prescriptions for different syndromes. For the skin invasion of wind-heat, Shufeng decoction is recommended; for damp-heat accumulation, the Longdan Xiegan decoction is recommended; for yin deficiency and blood dryness, Xijiao Dihuang decoction is recommended.

• (4) Diarrhea

Dampness is the main cause of diarrhea, and the pathogenesis is abundant dampness due to splenic asthenia. Common causes include exogenous cold, heat, and dampness; internal damage caused by improper diet and emotions; and dysfunction of internal organs. The main treatment is invigorating the spleen and drying the dampness. For diet stagnation, Baohe pills are recommended; for internal damage caused by damp heat, Gegen Qinlian decoction is recommended; for liver-qi overrestriction of the spleen, the Important Formula for Painful Diarrhea is recommended; for kidney-yang deficiency, Sishen pills are recommended.

4.5.3 Strengthening the body (Fuzheng) and rehabilitation

For drug therapy to strengthen and rehabilitate the body through TCM, please refer to the aforementioned medicines for syndrome differentiation. Avoidance of spicy food, tobacco, and alcohol is recommended, as is the consumption of small but frequent meals and the adjustment of emotions toward happiness. If conditions permit, participation in gentle activities such as Tai Chi, Wu Qin Xi, and Yi Jin Jing is encouraged so that qi can be guided and adjusted. When necessary, acupuncture and moxibustion therapy can be used as auxiliary treatments.

Chinese massage (Tuina) and massage

For rehabilitation after GC surgery, Tuina and massage can alleviate adverse reactions related to chemoradiotherapy:

• (1) For patients with postoperative gastrointestinal reactions such as gastric fullness, loss of appetite, nausea, vomiting, and diarrhea, adopting the supine position and rubbing the abdomen in a clockwise direction while focusing on the acupoints of Zhongwan and Tianshu is recommended. For patients with severe vomiting, additional rubbing from Fengfu to Dazhui or rubbing the acupoints of Pishu, Ganshu, Sanjiaoshu, and Weishu is recommedned according to the degree of soreness.

• (2) In cases of bone marrow suppression, aleukemia and thrombocytopenia, dizziness, fatigue, sore limbs, loss of appetite, low fever, and other symptoms caused by chemotherapy, the patients should adopt a seated position, and the acupoints of Xinshu, Ganshu, Shenshu, and Pishu should be alternately pressed with both thumbs. When performing Tuina, the operator should hold the patient’s wrist in one hand and press the Shenmen acupoint with the other hand; the patient should then move to the supine position, and finger-pressing of the Zusanli, Fuliu, Sanyinjiao, and Fenglong acupoint should be performed for a few minutes.

• (3) To improve the patient’s fatigue after gastrointestinal surgery and promote the recovery of gastrointestinal function, the patient should take a sitting position and be massaged on both sides of the spine from top to bottom by professionally trained nursing staff using finger-pressing, squeezing-pressing, kneading, and palm-pressing on various acupoints, including Feishu, Xinshu, Ganshu, Pishu, Weishu, Shenshu, Mingmen, Yaoyangguan, etc.; pressure should increase from light to heavy until the patient experiences the sensations of soreness, swelling, and numbness. In addition, abdominal massage should be performed: before eating, the patient should take the supine position, and the nursing staff should use 2 overlapped hands from the 3-transverse-finger position on the right side of the umbilicus to that position below the umbilicus to massage first the ascending colon, then the transverse colon and descending colon, and finally, the sigmoid colon.

Acupuncture

For the rehabilitative treatment of patients after GC surgery, acupuncture and moxibustion can alleviate adverse reactions related to chemoradiotherapy. Contraindications include: ① excessive nervousness or hunger; ② pregnancy, in cases of waist or abdomen acupuncture; ③ bleeding diseases or a bleeding tendency; and ④ skin infections or local tumors. Additionally, acupuncture should not go too deep in the abdomen to prevent damage to internal organs.

• (1) For postoperative abdominal distension, gastric paralysis, and constipation, the Zusanli, Shangjuxu, Tianshu, Zhongwan, Qihai, Hegu, and Taichong acupoints should be selected.

• (2) For diarrhea and vomiting after chemotherapy, the Zusanli and Neiguan acupoints should be selected (these can be combined with conventional antiemetic treatment).

• (3) For peripheral neuropathy after chemotherapy, the Sanyinjiao, Taichong, Zusanli, Baxie, Bafeng, Hegu, and Kunlun acupoints should be selected (can be combined with Western medicine to nourish the nerves, supplement B vitamins, etc.).

• (4) For bone marrow suppression after chemotherapy, the Zusanli and Sanyinjiao acupoints on both sides are selected as the major acupoints, and Dazhui, Pishu, Geshu, Neiguan, Yinlingquan, Guanyuan, Qihai, and Xuehai are selected as the matching acupoints. The reinforcing method should be adopted, and after insertion, the needle is slowly twisted first and then gently lifted until the patient has the sensations of soreness and swelling. If necessary, warm acupuncture and moxibustion can be used.

4.6 Psychological rehabilitation

4.6.1 Medication

Mental health problems, especially depression and anxiety, are very common in GC patients and can reduce the therapeutic effect and quality of life and increase the cost of treatment.

First, the primary biological causes of mental health and psychological problems should be addressed. These include abnormal physiological indicators caused by cancer, surgery, and anticancer drug treatment and may include vitamin B12 deficiency, hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypercalcemia, etc. In addition, certain persistent side effects (e.g., pain, nausea, vomiting, etc.) caused by anticancer drugs or treatments are also important causes of mental health issues. Priority should be given to resolving reversible problems (e.g., providing supportive symptomatic treatment, switching to another systemic anticancer treatment, etc.) so that the symptoms can be relieved.

Second, if the current anticancer treatment is effective and should not be discontinued, special treatment for mood or mental symptoms can be considered. The principle should be the same as those used when treating other psychiatric patients. Joint psychiatric consultations should be organized. Before drug treatment begins, psychological intervention methods (e.g., cognitive behavioral therapy) should be considered.

Psychiatric drugs should be selected based on specific clinical conditions, and special attention should be paid to their interactions with chemotherapeutic drugs. Current and future possible risks, such as bone marrow suppression, should be considered to determine which drugs should be used, used with caution, or not used at all.

4.6.2 Psychotherapy

The provision of supportive psychological intervention throughout the course of the disease (e.g., caring about changes in the patient’s condition, patiently listening to the patient’s appeals, understanding the patient’s feelings, and providing disease-related knowledge to reduce the patient’s sense of uncertainty) is recommended; especially when the patient is experiencing severe physical symptoms, it is very important to provide timely supportive psychology intervention and educational intervention.

Supportive psychological intervention is an intermittent or continuous therapeutic intervention that helps patients deal with painful emotions, build on their strengths, and promote an adaptive response to diseases. Educational intervention refers to psychological interventions provided through health education, including treatment-related information, coping strategies, behavioral training, communication skills, and available resources. It is recommended that medical staff provide educational interventions through consultation and care and the dissemination of disease information. The integration of supportive interventions with educational interventions and other psychological interventions can achieve better outcomes.