The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer

China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts' consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow-up visits for gastric cancer.
susceptibility to hereditary gastric cancer syndrome. However, since it has a complex microenvironment and is a heterogeneous disease, there exist differences between the Western and Eastern gastric cancer populations as to the etiology, epidemiological characteristics, primary tumor site, histopathology, treatment strategies, prognoses, molecular biological characteristics, and immunological characteristics. The incidence of proximal gastric cancer is rising in the West, and that of non-proximal locations are rising in the East, especially in Japan and China. In the East, gastric cancer is often diagnosed in its early stages in countries like Japan and Korea, but, in China more than 80% of gastric cancer patients are already in advanced stages at the time of diagnosis; for which many may miss the opportunity of radical resection or may have high risks of postoperative metastasis and relapse. In addition, there are differences in the treatment practices among different regions in China. As such, the purpose of this guideline is to standardize the treatment for the different stages of gastric cancer in the Chinese population.

## Diagnosis

## Basic principles
The tumor-node-metastasis (TNM) staging system from the American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) is the internationally accepted standard for gastric cancer staging, and the 8th edition is used throughout this guideline. Initial evaluation of gastric cancer mainly includes imaging and pathological examinations for qualitative, location, and staging diagnosis. Other examinations include complete physical examination, blood chemistry tests, endoscopy (endoscopic ultrasound and fine-needle biopsy), metastatic lesion biopsy, diagnostic laparoscopy, and diagnostic intra-peritoneal fluid examination. Histopathological examination is the gold-standard for gastric cancer diagnosis and a basic requirement prior to treatment initiation. Thoracic, abdominal, and pelvic computed tomography (CT) is the primary diagnostic modality used for pre-treatment clinical staging. Magnetic resonance imaging (MRI), laparoscopic exploration, and positron emission tomography (PET) scan are alternatives to CT for the diagnosis of liver, peritoneal, and systemic metastases. The imaging report should describe observations to support the clinical stage evaluation and classification (cTNM). The postoperative histopathological diagnosis (pTNM) should provide information for identifying the histological subtype of the tumor and full assessment of the tumor (including location, lymph node status, and the number of lymph nodes retrieved), which are important for prognostication and planification of personalized treatment strategies. At present, the molecular classification of gastric cancer is based on the human epidermal growth factor receptor 2 (HER2) expression in the tumoral tissue, and it is the basis for selecting anti-HER2 targeted therapy. All cases pathologically diagnosed as gastric or esophagogastric junction (EGJ) adenocarcinoma should undergo HER2 assessment. Notes a. When repeated gastroscopic biopsies are unable to confirm the pathological diagnosis, cytological examination of the ascites/pleural effusion or the pathological examination of the metastatic lesions can be used as the basis for qualitative diagnosis. b. Ensure that the gastric cavity is fully dilated and expanded by drinking 500 mL of liquid, water preferably, prior to the examination. A multiphase and multi-planar enhanced contrast scan should be used for diagnosis. Plain abdominal CT scans are not recommended. If patients have contraindications to the contrast agent used for enhanced CT scan, MRI or EUS is recommended. c. Chest CT can detect and show lung metastasis better than X-rays [bib_ref] Guidelines for the management of oesophageal and gastric cancer, Allum [/bib_ref]. For carcinoma of the EGJ, an enhanced CT scan of the chest should be performed to judge the range and metastatic status of mediastinal lymph nodes. d. EUS should be carried out in qualified centers only.

## Imaging and endoscopy
In the 8th edition of the AJCC/UICC staging system for gastric cancer [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge..., Amin [/bib_ref] , esophageal cancer, and EGJ cancer, EUS is recommended as the preferred cT staging modality for the clinical evaluation of the depth of tumor invasion; EUS cT staging not only enables direct observation of the lesions but can also provide visual descriptions about the different anatomical layers of the gastric wall. The tumor is mostly manifested in the non-homogeneous hypoechoic region, which is usually accompanied by the destruction of the corresponding layers of the gastric wall. Simultaneously, EUS can detect enlarged perigastric lymph nodes and metastatic lesions in the gastricneighboring parts of the liver and peritoneal cavity. In all, EUS is helpful for the diagnosis, clinical stag-ing, and assessment of response of gastric cancer to neoadjuvant therapy. Systematic analysis has identified the overall sensitivity and specificity of EUS in distinguishing between T1/2 and T3/4 cancers as 0.86 and 0.90, between T1 and T2 cancers as 0. [bib_ref] A randomized phase II trial of neoadjuvant chemotherapy compared with chemoradiation therapy..., Wang [/bib_ref] and 0.90, and between T1a and T1b cancers as 0.87 and 0.75, respectively [bib_ref] Diagnostic accuracy of endoscopic ultrasonography (EUS) for the preoperative locoregional staging of..., Mocellin [/bib_ref]. e. When liver metastasis is suspected on a CT scan, abdominal MRI is recommended for further confirmation [bib_ref] Diagnostic accuracy and sensitivity of diffusion-weighted and of gadoxetic acidenhanced 3-T MR..., Kim [/bib_ref]. If the patients' conditions permit, a hepatocyte-specific contrast agent can be used to increase the diagnostic sensitivity. f. Diagnostic laparoscopic exploration and examination of intraperitoneal washings are recommended for detecting occult metastasis and when peritoneal metastasis is suspected [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge..., Amin [/bib_ref]. For intraperitoneal lavage, 200 mL of normal saline can be infused into the different quadrants of the abdominal cavity, and the surgeons can collect more than 50 mL of the lavage fluid for cytological examinations. g. According to the RECIST 1.1 guidelines [bib_ref] New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eisenhauer [/bib_ref] , the nodules of the liver, lung, or peritoneal metastasis with a long-axis diameter  1 cm or lymph nodes with a short-axis diameter  1.5 cm should be used as target lesions for treatment evaluation. The thickness of primary lesions can be used as a reference for therapeutic assessment but should not be considered as target lesion. h. Small-scale studies have demonstrated that functional imaging parameters such as the apparent diffusion coefficient value of diffusion MRI [bib_ref] Response to chemotherapy in gastric adenocarcinoma with diffusion-weighted MRI and (18) F-FDG-PET/CT:..., Giganti [/bib_ref] and iodine concentration of energy spectral CT [bib_ref] Evaluating the response of gastric carcinomas to neoadjuvant chemotherapy using iodine concentration..., Tang [/bib_ref] can assist in evaluating the curative effect of gastric cancer therapies and can be used as reference indexes for evaluation in atypical cases. Notes a. Endoscopic mucosal resection (EMR)/endoscopic sub-mucosal dissection (ESD) has become the new alternative treatment of early-stage gastric cancer [bib_ref] Risk factors for underdiagnosis of gastric intraepithelial neoplasia and early gastric carcinoma..., Xu [/bib_ref]. EMR/ESD specimens should be meticulously resected, collected, and prepared based on standard protocols [bib_ref] Pathological standardization of endoscopic mucosal dissection for early gastric cancer and precancerous..., Sun [/bib_ref]. b. According to the 8th edition of the AJCC/UICC staging system for gastric cancer [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge..., Amin [/bib_ref] , esophageal cancer, and EGJ carcinoma, the staging criteria for EGJ carcinoma or gastric-cardia carcinoma are defined as follows: (1) if the tumor invades the gastroesophageal boundary and the tumor's epicenter is within 2 cm from the EGJ, staging criteria for esophageal cancer should be adopted; [bib_ref] A novel nomogram individually predicting disease-specific survival after D2 gastrectomy for advanced..., Wang [/bib_ref] if the tumor invades the gastroesophageal boundary but its epicenter is located > 2 cm from the EGJ, the staging criteria for gastric cancer should be adopted. It is worth noting, that among the total number of gastric cancer cases analyzed by the AJCC/UICC committee for providing such definition, the number of Chinese cases analyzed were very limited and may be a source for potential bias. The data from a single-center study regarding Chinese patients with gastric-cardia cancer showed that the biological behavior and clinical characteristics of EGJ carcinoma (Siewert II cardiac cancer) had greater similarities to gastric cancer than to esophageal cancer [bib_ref] Recent advances in proximal gastric carcinoma, Huang [/bib_ref]. However, studies comprising of larger cohort of patients are required for validation. c. To avoid inaccuracy for staging tumors according to the AJCC/UICC pTNM staging system,  16 lymph nodes should be pathologically evaluated. For a more accurate evaluation, the preferred number of lymph nodes should be > 30 [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge..., Amin [/bib_ref]. In order to help clinicians to accurately determine the range of lymph node metastasis, it is recommended that surgeons and pathologists to collect and group the perigastric lymph nodes according to their respective stations, which should be accordingly mentioned in the postopera-tive pathological report in addition to providing the total number of metastatic lymph nodes and total number of lymph nodes examined. For instance, this can be based on the following example: Lymph node station no. : number of metastatic lymph nodes/number of examined lymph nodes. d. When the pathological diagnosis is difficult, the specimens should be sent to a more specialized center/ hospital for further evaluation. To enable a proper assessment of the specimen, the items to be sent should include (1) the original pathological report (for cross-checking analysis with the pathological slides), (2) sufficient pathological glass slides and/or paraffin blocks, and (3) the detailed surgical records. e. According to the Lauren classification [bib_ref] The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type..., Lauren [/bib_ref] , gastric adenocarcinoma is classified as intestinal type, diffuse type, and mixed type based on its histological growth patterns. f. According to the 8th edition of the AJCC/UICC staging system [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge..., Amin [/bib_ref] , gastric cancer invading the muscularis propria is to be classified as "T2", but there is no detailed classification for tumors invading into the superficial muscularis propria layer and deeper muscularis propria. Based on the results of a large-cohort domestic singlecenter study [bib_ref] A novel subclassification of pT2 gastric cancers according to the depth of..., Sun [/bib_ref] , the prognoses of patients with tumor invading the deeper sub-mucosal layer were significantly worse than those of patients with tumor invading the superficial sub-mucosal layer. Therefore, when the tumor invasion is limited to the muscularis propria, specific mentions as to whether the tumor has invaded the superficial or deep sub-mucosal layer should be recorded in the final pathological report. This will be helpful in evaluating the patient's prognosis and for the planification of personalized treatment strategies. g. This guideline defines a positive surgical margin as the presence of cancer cells within a 1 mm distance from the resected margin. h. The detection of carcinomatous nodules in subserous adipose tissues adjacent to the primary tumor site is to be considered as regional lymph node metastasis even if there is no evidence of residual lymph node tissues [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge..., Amin [/bib_ref]. It is recommended that regional metastatic lymph nodes and carcinomatous nodules are to be recorded separately. i. If tissues obtained from non-neighboring regions of the stomach is pathologically confirmed as being metastatic, these are to be regarded as distant metastasis (pM1), which includes metastatic tissues from distant lymph node stations and cancerous cells detected in other organs (including intraperitoneal washings or peritoneal seedings). Gross evidence of metastasis seen during surgery can be recorded in the final pathological report as distant metastasis (cM) and can be reported as pTpNcM0-1. j. The classification, description, and evaluation proposals from the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Gastric Cancer, the AJCC/UICC pTNM staging system [bib_ref] The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge..., Amin [/bib_ref] , and the latest version of the Japanese Gastric Cancer Treatment Guidelines has been well accepted by Chinese pathologists as they have been observed to be highly applicable in Chinese patients, particularly in relation to the grading of tumor regression based on the degree of tumor cell residues and fibrosis. Of note, the pathological staging of gastric cancer after neoadjuvant therapy from the 8th AJCC/UICC staging system has fully considered the limitations of existing assessment methods and their association with prognosis and has simplified the ypTNM classification to a certain extent. k. Early-stage gastric cancer is defined as gastric cancer confined to the mucosa and submucosa, regardless of whether there is evidence of regional lymph node metastasis. l. Advanced gastric cancer is defined as a tumor which has invaded the muscularis propria or deeper layer of the gastric wall. The Borrmann classification includes four subtypes: Borrmann Type I, nodular polypoid tumor; Type II, local ulcerative tumor with easily identified margin; Type III, infiltrating ulcerative tumor with poorly defined margins; and Type IV, poorly demarcated, infiltrative, and diffuse tumor (local Borrmann Type IV, gastric tumor infiltrating the linitis plastica). m. When the pathological diagnosis is difficult to determine, gastric cancer-related markers can be used for confirming the diagnosis, differential diagnosis, prognostic evaluation, and follow-up/treatment needs. n. The 8th edition of the AJCC/UICC staging system for gastric cancer requires the recording of the HP infection status and thus, it should be assessed and recorded in medical institutions having such facilities [bib_ref] Expert consensus on selection of related immunohistochemical markers for gastric cancer, Xue [/bib_ref].

## Molecular classification

## Molecular classification grade i recommendations

## Grade iii recommendations
After a pathological diagnosis of gastric cancer, molecular profiling should be conducted and treatment should be guided according to the molecular classification Notes a. HER2-positive tumor is a unique subtype of gastric cancer, and its diagnostic and treatment modalities are different from HER2-negative gastric cancer. b. HER2-positive late-stage gastric cancer patients may have survival benefits from trastuzumab therapy [bib_ref] Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive..., Bang [/bib_ref]. The level of HER2 gene amplification can be used to predict the sensitivity to trastuzumab therapy and potential survival benefits for these patients [bib_ref] Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive..., Bang [/bib_ref] [bib_ref] HER2 status in gastric cancers: a retrospective analysis from four Chinese representative..., Sheng [/bib_ref] [bib_ref] HER2 status in gastric and gastroesophageal junction cancer assessed by local and..., Huang [/bib_ref] [bib_ref] HER2-positive patients receiving trastuzumab treatment have a comparable prognosis with HER2-negative advanced..., Qiu [/bib_ref] [bib_ref] Liquid biopsy: a powerful tool to monitor trastuzumab resistance in HER2-positive metastatic..., Shen [/bib_ref]. c. For primary lesions after neoadjuvant therapy as well as recurrent and/or metastatic lesions, if sufficient specimens can be obtained, it is recommended to reassess the HER2 amplification level [bib_ref] Human epidermal growth factor receptor 2 testing in gastric cancer: recommendations of..., Kim [/bib_ref]. d. Both gastroscopic biopsy specimens and surgical specimens can be used for HER2 assessment [bib_ref] Matched biopsy and resection specimens of gastric and gastroesophageal adenocarcinoma show high..., Wang [/bib_ref]. e. Immunohistochemistry (IHC) and in situ hybridization (ISH) for HER2 assessment should be strictly performed in accordance with the Guidelines for HER2 detection in gastric cancer (2016 edition). The related tests (IHC, FISH/double signal in situ hybridization [DSISH]) should be performed using the China Food and Drug Administration (CFDA) approved kits. f. The positive rate of HER2 overexpression in gastric cancer reported worldwide is between 7.3 and 20.2%, but in Chinese gastric cancer patients, it ranges between 7 and 12% [bib_ref] Clinicopathologic significance of HER-2/neu protein expression and gene amplification in gastric carcinoma, Yan [/bib_ref] [bib_ref] Prognosis significance of HER-2/neu overexpression/amplification in Chinese patients with curatively resected gastric..., Zhou [/bib_ref]. The results of retrospective studies have shown that HER2 positive expression was associated with old age, males, intestinal type, and tumors located in the upper third of the stomach [bib_ref] HER2 status in gastric cancers: a retrospective analysis from four Chinese representative..., Sheng [/bib_ref] [bib_ref] Lauren classification combined with HER2 status is a better prognostic factor in..., Qiu [/bib_ref]. Different studies have used different HER2 evaluation criteria. As a result, there is no consensus concerning the prognostic/predictive value of HER2 for gastric cancer. Studies have shown that HER2 was associated with poor prognosis in early-stage gastric cancer patients and was not an independent prognostic factor for advanced gastric cancer patients [bib_ref] The prognostic significance of the overexpression of HER-2/neu in Korean gastric carcinomas..., Im [/bib_ref] [bib_ref] Advanced HER2-positive gastric cancer: current and future targeted therapies, Cid [/bib_ref]. A retrospective study comprising of 838 gastric cancer patients from all stages demonstrated that the best survival outcomes were observed for patients with HER2-negative intestinal-type gastric cancer, whereas the worst survival outcomes were for those with HER2-positive diffuse-type gastric cancer [bib_ref] Lauren classification combined with HER2 status is a better prognostic factor in..., Qiu [/bib_ref]. g. In a meta-analysis [bib_ref] Microsatellite instability and survival in gastric cancer: a systematic review and meta-analysis, Zhu [/bib_ref] 

## Comprehensive treatment of gastric cancer

## Treatment of non-metastatic gastric cancer

## Treatment of resectable gastric cancer
The treatment of resectable gastric cancer is based on the evaluated clinical stage. The primary choice of treatment for early-stage gastric cancer is endoscopic treatment, which includes EMR or ESD. For patients unsuitable for endoscopic treatment, laparotomy or laparoscopy can be performed. Patients identified as having metastatic lymph nodes, confirmed by postoperative pathology, should undergo postoperative chemotherapy. The standard treatment for locally advanced gastric cancer is D2 gastrectomy followed by postoperative adjuvant chemotherapy. Neoadjuvant therapy is also among one of the recommendations for advanced resectable gastric cancer patients (clinical stage III or above). However, for patients with progressive disease unable to undergo R0 resection after neoadjuvant treatment, till present, there is no adequate evidence-based data to support remedial therapy, but the best treatment plan can be formulated through a multidisciplinary team (MDT) discussion based on the individual's condition. Radiochemotherapy is an alternative choice for patients with resectable tumors but unsuitable for surgery due to individual factors. However, personalized treatment should be tailored so as to provide an optimal treatment strategy. (3) non-ulcerative and undifferentiated cT1a tumor < 2 cm, for which vascular invasion is absent and the probability for potential lymph node metastasis is low. For larger lesions which have a high probability of incomplete resection by EMR, ESD is recommended [bib_ref] The effectiveness and safety of endoscopic submucosal dissection compared with endoscopic mucosal..., Park [/bib_ref]. c. Some Chinese scholars are exploring the efficacy of ESD in T1b patients, for which the incidence rate of lymph node metastasis is relatively low (about 15%-25%). As such, T1b patients who are unsuitable for surgery or chemoradiotherapy due to old age or underlying disease conditions can be enrolled and treated in clinical trials at specialized institutions.
d. Indications for radical surgery are complete resection of all lesions, tumor diameter < 2 cm, well-differentiated tumor, invasion depth characterized as pT1a, non-ulcerative lesions, negative surgical margin, and absence of lymphatic and vascular invasion. e. Indications for extended radical resection are that the completely resected specimen should meet the following criteria: (1) non-ulcerative lesion > 2 cm, well-differentiated pT1a tumor; (2) ulcerative lesion < 3 cm, well-differentiated pT1a tumor; (3) non-ulcerative lesion < 2 cm, undifferentiated pT1a tumor; (4) well-differentiated lesions < 3 cm, classified as pT1b-SM1 (< 500 m from the muscularis mucosae), having negative resection margin and without lymphatic and vascular invasion [bib_ref] The effectiveness and safety of endoscopic submucosal dissection compared with endoscopic mucosal..., Park [/bib_ref]. f. Non-radical resection refers to tumors that fail to meet any of the indications for radical or extended radical resection and should undergo additional elective surgery. However, for tumors considered as being nonradically resected mainly because the tumor could not be removed as a single piece or for those which are completely resected but have positive horizontal margins, additional surgery resection may not be the only choice. According to the current diagnosis and treatment principles, these patients can undergo additional ESD, electric resection, or continuous close follow-up visits after providing signed consent forms [bib_ref] Endoscopic and oncologic outcomes after endoscopic resection for early gastric cancer: 1370..., Ahn [/bib_ref]. Roux-en-Y anastomoses with jejunal pouch reconstruction (Evidence 2B) Jejunal interposition for gastric replacement (Evidence 2B) * For patients with metastatic lymph nodes in the middle and lower portions of the stomach, and preoperative stage evaluation considered as cT3 or cT4 ** Proximal gastrectomy D1+ is recommended for early-stage proximal gastric cancer *** For patients with primary tumor > 6 cm, located at the greater curvature, in the upper or middle portions of the stomach, and preoperative stage evaluation considered as cT3 or cT4

## Notes

## Principles of surgery
- The scope of gastrectomy is based on the location of the tumor, with an aim to ensure adequate surgical resection margin. In the past, a surgical margin of  4 cm from the tumor was recommended. Based on data from recent studies, the recommendations for an adequate distance of resection margin for Borrmann I-II gastric cancers are to be  3 cm, and for Borrmann III-IV it should be  5 cm. If the tumor has invaded the esophagus or pylorus, a resection margin of 5 cm is not obligatory only when R0 resection can be assured and the frozen pathological examinations of the resection margins are negative. - For EGJ adenocarcinoma which has invaded < 3 cm into the esophagus or the body of the stomach, nonendoscopic surgery is recommended. Transthoracic surgery is not recommended because of the risks of complications and mortality are significantly increased, without significant improvement in survival [bib_ref] Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia..., Sasako [/bib_ref].
- The resection of perigastric lymph nodes and those alongside accompanying vessels of the abdominal cavity should be performed according to the type of gastrectomy. D1 gastrectomy includes the resection of the required part of the stomach (with adequate resection margin), greater and lesser omentum, and the following perigastric lymph nodes: the right and left para-cardial lymph nodes, lesser and greater curvature lymph nodes, lymph nodes along the left gastric artery, suprapyloric, and infrapyloric lymph nodes along the right gastric artery. D2 gastrectomy includes the structures resected in D1 gastrectomy and, in addition, the resection of the lymph nodes along the common hepatic artery, celiac artery, splenic hilum, and splenic artery. D2 lymph node dissection is the standard recommendation for resectable gastric cancer classified as being cT1N+ and cT2-4N-/+. It is recommended that  16 lymph nodes should be pathologically examined to ensure accurate staging and prognostication [bib_ref] Does a minimum number of 16 retrieved nodes affect survival in curatively..., Biondi [/bib_ref]. It is worth mentioning that proximal gastrectomy is recommended for early-stage patients (T1-2N0), and in the 4th edition of the Japanese Gastric Cancer Treatment Guidelines, D1 or D1+ lymphadenectomy is recommended for this group of patients. However, after a study has demonstrated that the rates of lymph node metastasis for EGJ adenocarcinoma having diameter < 4 cm (the majority was Siewert II tumors) at stations 4sa, 4sb, 4d, 5, 6 were less than 1% [bib_ref] Results of a nation-wide retrospective study of lymphadenectomy for esophagogastric junction carcinoma, Yamashita [/bib_ref] , in the latest edition of the Japanese Gastric Cancer Treatment Guidelines, the recommended scope of D2 proximal gastrectomy was revised to D1 resection including lymph node stations 3b, 8a, 9, and 11p. - There is great controversy over the necessity for splenic hilar lymph node dissection. The rate of splenic hilar lymph node metastasis varies greatly in different reports [bib_ref] Analysis of splenic hilar lymph node metastasis in advanced gastric cancer and..., Zhang [/bib_ref] [bib_ref] Prognostic impact of prophylactic splenectomy for upper-third gastric cancer: a cohort study, Ito [/bib_ref] [bib_ref] Differences of the lymphatic distribution and surgical outcomes between remnant gastric cancers..., Komatsu [/bib_ref] [bib_ref] Is it necessary to dissect the posterior lymph nodes along the splenic..., Lin [/bib_ref] [bib_ref] Splenic hilar lymph node metastasis independently predicts poor survival for patients with..., Zhu [/bib_ref]. At present, it is recommended that splenic hilar lymph node dissection should not be performed for patients with stage cT1-2 gastric cancer [bib_ref] Frequency of lymph node metastasis to the splenic hilus and effect of..., Sasada [/bib_ref]. The Expert Committee recommends that splenic hilar lymph node dissection should be performed in the following cases: the primary tumor is > 6 cm, located at the greater curvature and middle-upper part of the stomach, and preoperatively staged as T3-4. Splenectomy for the purpose of lymph node dissection is not recommended [bib_ref] Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric..., Sano [/bib_ref]. - Whether it is necessary to dissect lymph nodes at the root of the superior mesenteric vein (station 14v) in advanced gastric cancer remains controversial. Although station 14v is not within the routine scope of D2 lymphadenectomy in the 3rd edition of the Japanese Gastric Cancer Treatment Guidelines, it has been observed that D2+ station 14v lymph node dissection may improve overall survival (OS) in clinically staged III/IV patients with middle-and lower-third gastric cancer [bib_ref] Improved survival after adding dissection of the superior mesenteric vein lymph node..., Eom [/bib_ref]. The Expert Committee recommends these indications for the dissection of station 14v lymph nodes: clinically staged III patients with tumors located at the middle and lower parts of the stomach, and having lymph node metastasis, especially for those with metastasis to the infrapyloric lymph nodes. - Although it has been reported that preventive para-aortic lymph node dissection cannot improve the long-term survival of patients with resectable advanced gastric cancer [bib_ref] D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer, Sasako [/bib_ref] , the value of therapeutic para-aortic lymph node dissection is still controversial. Suitable patients should be encouraged to participate in clinical trials.

## Laparoscopic surgery
- For distal gastrectomy of gastric cancer classified as cT1N0 and cT1N1, laparoscopic surgery is equivalent to open surgery in terms of safety and shortterm prognosis. Therefore, laparoscopic surgery is recommended as a routine surgical technique. - Till present, there is no large-scale prospective study regarding laparoscopic total gastrectomy for earlystage gastric cancer. Although there is not sufficient scientific-based evidence, the Expert Committee suggests that it can be performed in experienced medical centers. - For advanced gastric cancer, small-scale studies and large-scale retrospective studies have reported that laparoscopic surgery had an advantage over open surgery in regards to short-term efficacy, but their long-term efficacy was equivalent [bib_ref] Long-term results of laparoscopic gastrectomy for gastric cancer: a large-scale case-control and..., Kim [/bib_ref] [bib_ref] Laparoscopic versus open subtotal gastrectomy for distal gastric cancer: five-year results of..., Huscher [/bib_ref]. Preliminary results of an ongoing phase III clinical study have shown that laparoscopic distal gastrectomy combined with D2 lymphadenectomy was safe [bib_ref] Morbidity and mortality of laparoscopic versus open D2 distal gastrectomy for advanced..., Hu [/bib_ref] , but the long-term survival is yet to be published. The Expert Committee recommends that laparoscopic surgery for advanced gastric cancer should be carried out in large experienced medical centers, where standardized technical facilities and safety can be guaranteed.

## Digestive tract reconstruction
- The type of digestive tract reconstruction performed is to depend on the patient's physical condition and the surgeon's experience as far as it does not affect the radicality of the gastrectomy.
- Billroth I and Billroth II surgeries are mostly adopted for distal gastrectomy. For tumors located in the lower third of the stomach, especially those invading the pylorus and the duodenum, Billroth II surgery is recommended because these patients can have a second chance for surgery in case of tumor recurrence [bib_ref] Comparison of Billroth I and Billroth II reconstructions after laparoscopy-assisted distal gastrectomy:..., Kang [/bib_ref]. Roux-en-Y anastomosis can effectively reduce bile reflux and prevent the occurrence of remnant gastritis. However, this operation is relatively complex, and the risk of postoperative retention syndrome may be increased [bib_ref] Long-term benefits of Roux-en-Y pouch reconstruction after total gastrectomy: a randomized trial, Fein [/bib_ref]. - Gastroesophageal anastomosis is frequently used for proximal gastrectomy, but the risk of esophageal reflux is common and serious. Modified tubular gastroesophageal anastomosis can significantly reduce the risk of severe esophageal reflux. Compared with gastroesophageal anastomosis, the Jejunal interposition method can reduce the occurrence of moderate or severe esophageal reflux, but this operation is complicated and the risks for frequent abdominal discomfort, upper abdominal fullness, and hiccups are common [bib_ref] Billroth 1 versus Roux-en-Y reconstructions: a quality-of-life survey at 5 years, Nunobe [/bib_ref]. Therefore, its advantages remain to be confirmed. If required, it is suggested that the Jejunal interposition method should be carried out in large experienced medical centers. - Roux-en-Y is the preferred reconstruction method for total gastrectomy. It has been reported that, in addition to Roux-en-Y anastomosis, the reconstruction of the Jejunal pouch digestive tract may improve the patients' postoperative quality of life [bib_ref] Long-term benefits of Roux-en-Y pouch reconstruction after total gastrectomy: a randomized trial, Fein [/bib_ref]. The Jejunal interposition method as a replacement for the stomach is complicated, and there is still controversy concerning its efficacy in improving the patients' quality of life. If required, it is suggested that this procedure should be carried out in large experienced medical centers. should be treated with 5-fluorouracil (5-FU)-based regimen or capecitabine in combination with cisplatin followed by concurrent chemoradiotherapy. - For locally advanced gastric cancer patients who fail to meet the R0 resection criteria, postoperative chemoradiotherapy is recommended [bib_ref] The prognostic significance of an R1 resection in gastric cancer patients treated..., Stiekema [/bib_ref] or an MDT discussion should be performed to decide the optimal treatment.
Preoperative and perioperative chemotherapy for advanced gastric cancer - Perioperative therapy (neoadjuvant chemotherapy/ radiotherapy + surgery + adjuvant chemotherapy/ radiotherapy) for gastric cancer has been proven to be superior to surgery alone in Western countries [bib_ref] Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer, Cunningham [/bib_ref] [bib_ref] Preoperative treatment and surgery in gastric cancer: friends or foes?, D&apos;ugo [/bib_ref]. Preoperative chemotherapy prior to radical gastrectomy in Asian countries has also demonstrated significantly improved tumor remission rates and R0 resection rates with safer profiles [bib_ref] A phase II study of perioperative S-1 combined with weekly docetaxel in..., Kim [/bib_ref] [bib_ref] A phase II study of a modified FOLFOX6 regimen as neoadjuvant chemotherapy..., Wang [/bib_ref]. The survival benefits of perioperative chemo-/radiotherapy as compared with postoperative chemotherapy for radical D2 gastrectomy remains to be determined with large phase III clinical trials. - The present recommendations for preoperative chemotherapy include epirubicin + cisplatin + 5-FU (ECF) [bib_ref] Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer, Cunningham [/bib_ref] , cisplatin + 5-FU (PF) [bib_ref] Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC..., Ychou [/bib_ref] , modified ECF (mECF) [bib_ref] Report of two protocol planned interim analyses in a randomised multicentre phase..., Sumpter [/bib_ref] , oxaliplatin + capecitabine (XELOX) [bib_ref] Capecitabine and oxaliplatin for advanced esophagogastric cancer, Cunningham [/bib_ref] , oxaliplatin + 5-FU (FOLFOX) [bib_ref] Neoadjuvant chemotherapy with FOLFOX: improved outcomes in Chinese patients with locally advanced..., Li [/bib_ref] , and oxaliplatin + S-1 (SOX) [bib_ref] Efficacy and safety of SOX regimen as neoadjuvant chemotherapy for advanced gastric..., Li [/bib_ref]. despite the absence of distant metastasis after neoadjuvant chemotherapy, either postoperative chemoradiotherapy is recommended or the following treatment should be decided by an MDT discussion. If chemoradiotherapy is performed prior to the surgery, the following treatment should be decided by an MDT discussion or else palliative treatment is recommended.

## Comprehensive treatment of unresectable gastric cancer

## Notes
- Gastric adenocarcinomas are considered unresectable if (1) the primary tumor shows extensive invasion and cannot be separated from the surrounding normal tissues or has encased major vascular structures; (2) regional lymph node metastases are fixed and fused in groups and/or are not within the scope of surgical resection;
(3) the patient shows contraindications to surgery or refuses surgical intervention due to poor general condition, malnutrition, severe hypoproteinemia, severe anemia, or severe underlying diseases. if they are: (1) associated with these tumor-related factors: (a) extensive invasion of the primary tumor which cannot be separated from the surrounding normal tissues or has encased major vascular structures; (b) regional lymph node metastases are fixed and fused in groups and/or are not within the scope of surgical resection; (2) contraindicated to surgery or refusal for surgical intervention due to poor general condition, malnutrition, severe hypoproteinemia, severe anemia, severe underlying diseases. - Combined examination modalities are recommended for accurate clinical stage evaluation and for judging the resectability of the tumor. Special consideration should be made regarding peritoneal metastasis/ dissemination as they are common, particularly in advanced stage (T3-4 or N+) patients, and laparoscopic exploration with a cytological examination of the intraperitoneal washings is recommended prior to treatment initiation.
- Concurrent chemoradiotherapy is recommended for patients with unresectable locally advanced gastric cancer who have a good general condition. Studies have shown that, in terms of tumor downstaging and pathological remission, concurrent chemoradiotherapy was superior to chemotherapy or radiotherapy alone, and the survival time of these patients could be prolonged if a local control of the tumor could be achieved. For those patients who had a favorable response to radiotherapy, the tumor should be reevaluated to judge the potential for surgical resectability. Further, there have been reported studies demonstrating survival benefits for locally advanced patients with a good general condition who had radical or even palliative resection [bib_ref] Combined modality treatment of gastric cancer, Gunderson [/bib_ref]. - For patients who are unsuitable for concurrent chemoradiotherapy due to extensive tumor or lymph nodes invasion, whereby wide irradiation fields may cause more harm than benefits, chemotherapy or radiotherapy alone can be considered as an alternative [bib_ref] Multicenter phase 2 study of peri-irradiation chemotherapy plus intensity modulated radiation therapy..., Liu [/bib_ref]. For patients with favorable responses, an MDT discussion is recommended after the treatment to judge the potential for surgical resection. If the tumor is still unresectable, sequential or concurrent chemoradiotherapy may be considered, and tumor resectability should be re-evaluated after the treatment. - Radiologists should perform a comprehensive evaluation based on the patients' physical condition and the scope of the irradiation field before performing sequential or concurrent chemoradiotherapy. In general, concurrent chemoradiotherapy is superior to radiotherapy alone [bib_ref] Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer, Moertel [/bib_ref]. Radiotherapy alone should be used when patients cannot tolerate concurrent chemoradiotherapy. However, patients who had prior chemotherapy may have poor tolerance to radiotherapy, and dualdrug regimen combined with concurrent chemoradiotherapy may reduce the completion rate of radiotherapy. In this situation, single-drug 5-FU regimen with concurrent chemoradiotherapy can be considered. - Appropriate radiotherapy planning can be considered. For patients with potentially resectable disease, in addition to the visible tumors (primary, metastatic tumors or lymph nodes) confirmed by imaging examinations, appropriate external expansion of the irradiation field can be considered to include regions of lymphatic drainage. For unresectable patients, the irradiation field should comprise of visually identified tumors only, and preventive irradiation of lymph nodes should not be considered. The recommended dosage for preoperative radiotherapy is DT 40-45 Gy. After treatment, the tumor should be reassessed to judge whether the patient can undergo surgery or continue radiotherapy. The recommended total dose of radical radiotherapy is DT 50-60 Gy. The recommended dose for palliative radiotherapy is DT 30-40 Gy. As a note, the dosage and scope of irradiation should be based on the patient's general condition, the size of the irradiation field, expected lifespan, and possible irradiation damage to normal tissues and organs. - For patients who can tolerate chemotherapy, it has been observed that, as compared with best supportive care, chemotherapy can prolong the survival of metastatic gastric cancer patients [bib_ref] Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on..., Wagner [/bib_ref]. As such, for patients presenting with severe gastrointestinal obstruction, hemorrhage, or obstructive jaundice at first diagnosis, it is suggested that nutrition tube, stent implantation, gastrointestinal bypass surgery, local palliative radiotherapy, acid inhibition, hemostasis, and analgesia should be prescribed, preferentially within the first 2-4 weeks of presentation, as longer duration may result in tumor progression. Chemotherapy can be considered when the patient' general condition improves. If not, best supportive care can be continued. The main chemotherapy drug regimen includes 5-fluorouracil-based, platinumbased, taxanes-based, irinotecan regimen. Combined chemotherapy can result in a response rate of 30%-54% and a median OS of 8-13 months [bib_ref] Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on..., Wagner [/bib_ref].
Although combined chemotherapy is more effective than single-drug chemotherapy, 5-FU alone can still be considered for those patients who cannot tolerate combined chemotherapy [bib_ref] Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either..., Al-Batran [/bib_ref].
- Radiotherapy can significantly alleviate some clinical symptoms of late-stage gastric cancer patients, such as hemorrhage, severe cancer pain, dysphagia, and obstruction and can improve the patients' general condition and quality of life [bib_ref] Clinical benefit of palliative radiation therapy in advanced gastric cancer, Kim [/bib_ref]. Palliative radiotherapy may be considered for those patients with old age, advanced disease, decreased cardio-pulmonary functions, multiple underlying diseases, and difficulty to sustain surgical intervention. - Three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) are recommended as related studies have demonstrated that, compared with conventional twodimensional radiotherapy, 3D-CRT or IMRT was excellent at targeting the dose distribution area and at protecting normal organ tissue, especially in the gastrointestinal tract, liver, and kidneys, against adverse events from irradiation [bib_ref] Comparison of intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy as adjuvant therapy for..., Minn [/bib_ref].

## Treatment of metastatic gastric cancer
For the patients who cannot undergo radical resection or with metastatic/recurrent disease, comprehensive treatment based on systemic antitumor therapy is recommended. Other therapeutics such as palliative surgery, radiotherapy, radiofrequency ablation, intraperitoneal perfusion, and arterial embolization may help to prolong survival and improve quality of life. Therefore, we must emphasize that treatments for such patients should be discussed by an MDT to assess the optimal personalized treatment strategy. At present, drugs for gastric cancer include mainly chemotherapeutic and molecular targeted drugs for which their applicability is supported by sufficient scientific-based evidence and experiences in clinical practice. Programmed cell death protein 1 (PD-1) monoclonal antibody has already been approved by the US Food and Drug Administration (FDA) and in Japan as the third-line treatment for advanced gastric cancer, but in China, its approval by the CFDA is yet to be given. Accordingly, these patients are encouraged to participate in immunotherapy-based clinical trials. The treatment of metastatic gastric cancer is challenging, especially since the available second-and third-line regimens are limited and are yet to demonstrate significant efficacies. There are still no effective molecular targeted drugs for the first-line treatment of HER2-negative patients, and these patients should be encouraged to participate in clinical trials. In addition, the stomach is an important digestive organ where the primary lesion may directly affect the nutritional status, leading to complications such as bleeding, digestive tract obstruction, and/or perforation. Therefore, maintenance of nutritional status, as well as active prevention and timely treatment of complications, should be given special attention during the entire antitumor treatment process.

## Choice of antitumor drug treatment for late-stage metastatic gastric cancer

## Notes
- Difference in antitumor treatment for late-stage gastric cancer may arise due to heterogeneity in ethnicity and tumor location. Therefore, these patients should be encouraged to participate in clinical trials. - Fluoropyrimidine, platinum, and taxanes are the main therapeutic drugs for late-stage gastric cancer. Usually, first-line regimens are based on fluoropyrimidine combined with platinum and/or taxanes to constitute a two-or three-drug regimen. Adequate clinical evidence is available to support the recommendation of fluoropyrimidine combined with platinum. Fluoropyrimidine combined with taxanes have also demonstrated adequate efficacy and safety in clinical studies [bib_ref] Capecitabine and oxaliplatin for advanced esophagogastric cancer, Cunningham [/bib_ref] [bib_ref] Capecitabine/ cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric..., Kang [/bib_ref] [bib_ref] Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin..., Van Cutsem [/bib_ref] [bib_ref] Randomized multicenter phase III study of a modified docetaxel and cisplatin plus..., Wang [/bib_ref] [bib_ref] S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric..., Koizumi [/bib_ref] [bib_ref] Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric..., Ajani [/bib_ref] [bib_ref] Efficacy and safety of capecitabine as maintenance treatment after first-line chemotherapy using..., Qiu [/bib_ref]. In China, the two-drug therapy consisting of fluoropyrimidine and platinum is recommended, and the selection of first-line chemotherapy regimens should be based on the patients' physical condition, age, and any underlying disease. - There is no sufficient evidence to recommend chemotherapeutic drugs based on the prediction of chemotherapeutic response according to the Lauren classification, molecular classification, in vitro drug susceptibility test, xenograft transplantation model, xenobiotic metabolism, or metabolomics. Patients suspected of fluoropyrimidine metabolic disorders are advised to undergo a dihydropyrimidine dehydrogenase deficiency (DPD) test. - The standard treatment for late-stage gastric cancer usually lasts 4-6 months, and these patients should be regularly followed-up after disease control. Although there is no large-scale clinical study to demonstrate the OS benefit of maintenance treatment with sequential monotherapy after standard chemotherapy over standard chemotherapy alone, a preliminary study has shown that maintenance therapy could improve the patients' quality of life by decreasing adverse events [bib_ref] Docetaxel and irinotecan as second-line therapy for advanced oesophagogastric cancer, Hawkes [/bib_ref]. - Peritoneal metastasis is the most common type of metastasis observed in late-stage gastric cancer patients and is considered as a leading cause of death. For those with symptomatic ascites, drainage and hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) can be considered. For patients with asymptomatic ascites, first-, second-, or third-line chemotherapeutic regimens can be used. The Phoenix-GC study compared HIPEC plus intravenous paclitaxel and S-1 with standard SP regimen (intravenous infusion of cisplatin combined with oral S-1) in patients with peritoneal metastasis as a first-line therapy [bib_ref] Phase III trial comparing intraperitoneal and intravenous paclitaxel Plus S-1 versus cisplatin..., Ishigami [/bib_ref]. Survival benefits were observed in the subgroup with moderate amount of ascites. However, the median OS of the entire studied population was not prolonged (17.7 vs. 15.2 months, P = 0.080). As a result, HIPEC is not recommended for routine use in clinical practice. - Most patients who were given second-line chemotherapy had an ECOG score of 0-1, and few had a score of 2 when they were enrolled in phase III clinical trials. Therefore, the risks and benefits of secondline treatments for the patients in poor physical condition should be carefully considered. - Regarding the second-line chemotherapy, at present, there are monotherapy regimens that have been recommended based on the results from phase III clinical trials [bib_ref] Docetaxel and irinotecan as second-line therapy for advanced oesophagogastric cancer, Hawkes [/bib_ref] [bib_ref] Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with..., Hironaka [/bib_ref]. In some smallscale phase II clinical trials, it was observed that dual-drug chemotherapy for the patients with an ECOG score of 0-1 had better tumor control with an acceptable toxicity profile as compared with the observational arm. As such, combination chemotherapy can be considered for patients in good physical condition if the risks and benefits of the treatment are fully weighed-up. - Clinical studies regarding the third-line treatment for advanced gastric cancer involved a limited number of patients. As such, the benefit of chemotherapy remains to be further clarified. In clinical practice, it is emphasized that the risks and benefits of treatment should be carefully weighed-up depending on the patients' physical condition, underlying diseases, tumor-related symptoms, and risk of complications.
It is suggested that monotherapy should be prioritized. - The ToGA trial showed that, compared with chemotherapy alone, trastuzumab in combination with firstline chemotherapy improved the efficacy and survival in HER2-overexpressed late-stage gastric cancer patients [bib_ref] Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive..., Bang [/bib_ref]. Many phase II clinical studies have demonstrated the efficacy and safety of trastuzumab in combination with other different chemotherapy regimens. For HER2-positive metastatic gastric cancer patients with first-line chemotherapy failure and who had no prior treatment with trastuzumab, data from a phase II clinical study have demonstrated treatment efficacy and safety for using paclitaxel in combination with trastuzumab [bib_ref] Phase II study of the effectiveness and safety of trastuzumab and paclitaxel..., Nishikawa [/bib_ref]. However, if trastuzumab was used in the first-line therapy, there is no high-level evidence to suggest its cross-line application. Preliminary results of a multi-center prospective observational study from China have shown that continued application of trastuzumab in the second-line therapy could prolong the median progression-free survival (PFS) [bib_ref] Efficacy of trastuzumab beyond progression in HER2 positive advanced gastric cancer: a..., Li [/bib_ref]. The Chinese Society of Clinical Oncology, the Chinese Anti-Cancer Associa-tion Gastric Cancer Specialized Committee, and the Chinese Anti-Cancer Association Tumor Pathology Specialized Committee jointly led the publication of the "consensus of Chinese experts on molecular targeted treatment of HER2-positive advanced gastric cancer", which can help oncologists to improve the diagnosis and treatment of HER2-positive gastric cancer. - HER2-targeted drugs, such as anti-HER2 monoclonal antibody pertuzumab, small-molecule tyrosine kinase inhibitor lapatinib [bib_ref] Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified..., Satoh [/bib_ref] [bib_ref] Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor..., Hecht [/bib_ref] , drug-coupled anti-HER2 monoclonal antibody TDM-1 [bib_ref] A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1)..., Kang [/bib_ref] , did not show positive results in phase III clinical trials and are not recommended for clinical use. - Anti-angiogenic drugs include anti-VEGF antibody (bevacizumab), anti-VEGFR antibody (ramucirumab), and small-molecule tyrosine kinase inhibitor (regorafenib, apatinib, and so on). The REGARD study showed that compared with placebo, ramucirumab alone as a second-line drug could prolong the survival of metastatic gastric cancer patients with tolerable adverse events [bib_ref] Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD):..., Fuchs [/bib_ref]. The RAINBOW study showed that compared with paclitaxel alone, secondline ramucirumab combined with paclitaxel could prolong survival even further [bib_ref] Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated..., Wilke [/bib_ref] , which led to the approval of ramucirumab by the US FDA as a secondline treatment for late-stage gastric cancer. A phase III clinical study which enrolled 273 patients who had treatment failure after using second-line/subsequent-lines chemotherapeutic regimens showed that apatinib, compared with the placebo, could prolong the median progression-free survival (mPFS) (2.6 vs. 1.8 months, P < 0.001) and increase the disease control rate (42.05% vs. 8.79%, P < 0.001) [bib_ref] Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory..., Li [/bib_ref]. Accordingly, on October 10, 2014, the CFDA approved the use of apatinib, a highly selective VEGFR-2 inhibitor, as a third-line/above therapy for late-stage gastric cancer patients. In the Clinical Application of Apatinib, the CSCO Experts panel provides clinicians with references regarding the application and safety of apatinib. - The use of immunological checkpoint inhibitors has been supported by prospective studies. Based on the results of the ONO-4538-12 study [bib_ref] Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to,..., Kang [/bib_ref] , nivolumab was approved as a third-line treatment for advanced gastric cancer in Japan. In contrast with placebo, nivolumab significantly reduced the risk of death by 37%, and the observed 1-year survival rate was also higher in the nivolumab arm (26.2%) than in the placebo arm (10.9%). Based on the results of the KEY-NOTE-059 study [bib_ref] Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced..., Fuchs [/bib_ref] , the US FDA approved pembrolizumab as a third-line drug for the treatment of metastatic gastric/EGJ adenocarcinoma expressing PD-L1 level  1%. In one study, when 259 gastric cancer patients who were refractory to previous treatments were given pembrolizumab as a single agent, they demonstrated satisfactory mPFS, mOS, and ORR of 2 months, 6 months, and 12%, respectively (PD-L1 positive rate, 16%) [bib_ref] Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced..., Fuchs [/bib_ref]. In 2017, the US FDA approved pembrolizumab for MSI-H or dMMR solid tumors as a third-line treatment. However, the KEYNOTE-061 study showed that pembrolizumab, as a second-line therapy, did not prolong OS or mPFS in PD-L1-positive patients compared with standard chemotherapy. As such, there is still controversy concerning the actual benefit from immunologic checkpoint inhibitors [bib_ref] Prognostic value of programmed death-1, programmed death-ligand 1, programmed deathligand 2 expression,..., Gao [/bib_ref]. - The risk of malnutrition is high in gastric cancer. The guidelines from the China Anti-cancer Association for Cancer Nutrition and Support Therapy [bib_ref] Guidelines for nutrition therapy in patients with gastric cancer, Shi [/bib_ref] recommend that the nutritional status of patients with gastric cancer should be screened and evaluated. Patients with a moderate or severe malnutritional risk should undergo appropriate nutritional therapy alongside chemotherapy, and when necessary, chemotherapy should be delayed [bib_ref] Guidelines for nutrition therapy in patients with gastric cancer, Shi [/bib_ref].

## Comprehensive treatment of recurrent or metastatic gastric cancer with solitary distant metastasis
A solitary distant metastatic lesion is defined as one that has the possibility of being locally treated, regardless of the primary gastric lesion and regional lymph nodes [bib_ref] Oligometastases and oligo-recurrence: the new era of cancer therapy, Niibe [/bib_ref] [bib_ref] Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study, Milano [/bib_ref].
There are no large-scale prospective randomized controlled clinical study data to provide scientific-based evidence for the treatment of gastric cancer with solitary distant metastasis. Most of the evidences are from retrospective or small-scale studies. Therefore, the optimal therapeutic option for such patients should be discussed through an MDT, and the patients should be encouraged to participate in clinical trials.

## Treatment of gastric cancer with postoperative local recurrence or solitary distant metastasis

## Notes
- Local recurrence is defined as the re-occurrence of tumor at the resection site after radical gastrectomy. Most studies regarding local recurrence of gastric cancer were retrospective and came from single institutions, and there is a lack of large-scale prospective study. Preliminary results suggest that surgery may be an important prognostic factor as the mOS of these surgically operated patients reached 25.8 months, while those non-surgical patients were only 6.0 months [bib_ref] Attempted salvage resection for recurrent gastric or gastroesophageal cancer, Badgwell [/bib_ref]. Although some local recurrent diseases can be surgically treated, the indications for surgical intervention must be strictly followed. - Patients with local recurrence who did not receive any previous radiotherapy may gain great greater survival benefits from concurrent chemoradiotherapy. A retrospective study identified that gastric cancer patients with local recurrence at the anastomotic site who underwent concurrent chemoradiotherapy achieved an ORR of 61.9% and mOS of 35 months. Compared with chemotherapy alone, concurrent chemoradiotherapy resulted in a higher ORR (87.8% vs. 63.0%, P = 0.01), longer mOS (13.4 months vs. 5.4 months, P = 0.06), and better control of symptoms such as pain, bleeding, and obstruction (85.0% vs. 55.9%, P = 0.006) [bib_ref] Concurrent involved-field radiotherapy and XELOX versus XELOX chemotherapy alone in gastric cancer..., Yuan [/bib_ref].
- Liver metastasis that occurs more than 6 months after radical gastrectomy is described as metachronous liver metastasis. Solitary liver metastasis is defined as liver metastasis confined to a single lobe, only one lesion being  4 cm in diameter, and has no involvement with the surrounding blood vessels and bile ducts. There are few clinical studies on gastric cancer patients with solitary liver metastasis after gastrectomy. Both the results of retrospective studies and meta-analysis have shown that the survival of patients undergoing liver surgery was longer than those patients not receiving liver surgery (mOS: 22-26 months vs. 3-7 months, respectively, P < 0.001). However, there were no survival differences observed between patients with metachronous and synchronous liver metastasis [bib_ref] Survival benefit of surgical treatment for liver metastases from gastric cancer, Shinohara [/bib_ref] [bib_ref] Influence of surgical resection of hepatic metastases from gastric adenocarcinoma on long-term..., Markar [/bib_ref]. Radiofrequency ablation (RFA) is a local treatment for solitary liver metastasis. Retrospective studies have shown that, compared with systemic chemotherapy, RFA could significantly prolong the mOS of patients with metachronous liver metastasis (25 months vs. 12 months, P = 0.015). Literature has also identified that patients receiving RFA combined with systemic chemotherapy could achieve an mPFS of 9.8 months and an mOS of 20.9 months [bib_ref] Combination of percutaneous radiofrequency ablation and systemic chemotherapy are effective treatment modalities..., Hwang [/bib_ref]. A multi-center retrospective study in Japan has shown that the patients with solitary or multiple liver metastases could have an mOS of up to 3.40 years and an mRFS of up to 0.98 years after surgical resection and/or local treatment. The survival difference between surgical resection and non-surgical local treatment was not significant, but the patients with N0/N1 disease could benefit significantly from surgery or local treatment. Therefore, surgery and/ or local treatment may be an effective treatment for patients with solitary liver metastasis after gastric cancer surgery. However, it is not clear whether postoperative systemic chemotherapy should be given. - Ovarian resection combined with antitumor drug therapy is important for female gastric cancer patients with postoperative metachronous ovarian metastasis. It has been shown that, compared with systemic chemotherapy alone, ovarian resection combined with chemotherapy could significantly prolong mOS (9 months vs. 19 months) [bib_ref] Comparison of surgery plus chemotherapy and palliative chemotherapy alone for advanced gastric..., Cho [/bib_ref]. The surgical benefits for patients with metachronous ovarian metastasis may be superior to those with simultaneous ovarian metastasis (mOS, 36 months vs.17 months) [bib_ref] Krukenberg tumors of gastric origin: the rationale of surgical resection and perioperative..., Rosa [/bib_ref].

## Treatment of stage iv gastric cancer with single distant metastasis at initial diagnosis

## Site stratification grade i recommendations grade ii recommendations grade iii recommendations
Peritoneal cytology positive (P0CY1)* ECOG performance score = 0-1, radical resection of the primary lesion and regional lymph nodes [bib_ref] Phase II trial of combined treatment consisting of preoperative S-1 plus cisplatin..., Satoh [/bib_ref]. Results from the JCOG0405 study showed that the 5-year survival rate for gastric cancer patients with solitary para-aortic lymph node metastasis was 57% if they had undergone 2 cycles of neoadjuvant chemotherapy using S-1 and cisplatin followed by subsequent D2 gastrectomy with para-aortic lymph node dissection [bib_ref] Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic..., Tsuburaya [/bib_ref].
Observations from the JCOG1002 studyhave shown that the addition of docetaxel to S-1 plus cisplatin regimen resulted in a clinical remission rate of 57.7%, R0 resection rate of 84.6%, and pathological remission rate of 50.0%, but no data for the 5-year survival rate was provided. As such, this double-drug regimen (S-1 + cisplatin) is still considered as the first choice of treatment for this group of patients. A prospective study conducted by the Zhongshan Hospital Affiliated to Fudan University demonstrated that the PFS of patients with solitary para-aortic lymph node metastasis after neoadjuvant chemotherapy and radical surgery could reach up to 18.1 months [bib_ref] A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed..., Wang [/bib_ref].
In the REGATTA study, the subgroup analysis of lymph node metastasis, as the only incurable factor, also demonstrated good efficacy of surgical resection [bib_ref] Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a..., Fujitani [/bib_ref]. Data from larger-scale clinical trials are needed to confirm the role of surgery in patients with paraaortic lymph node metastasis as the only incurable factor. - The data from randomized controlled trials on patients with solitary liver metastasis is still lacking. Some retrospective studies and meta-analysis have confirmed that for some highly selected patients with solitary liver metastasis treated with systemic chemotherapy in combination with R0 resection of the primary and metastatic lesions, greater survival benefits could be observed [bib_ref] Liver resection for metastatic gastric cancer: experience with 42 patients including eight..., Koga [/bib_ref] [bib_ref] Meta-analysis of prognosis after surgical treatment in gastric cancer patients with liver..., Shen [/bib_ref] [bib_ref] Prognostic analysis of combined curative resection of the stomach and liver lesions..., Wang [/bib_ref]. However, there are no definite conclusions about the timing, indications, and surgical methods. For patients unsuitable for surgery, clinicians should carefully assess other local treatments in combination with systemic therapies. It is highly recommended that treatment decisions are made through an MDT discussion. - There is no large-scale, prospective, randomized controlled clinical trial regarding the treatment for gastric cancer patients with solitary distant liver metastasis. Some retrospective studies have confirmed that after strict screening, for selective patients, survival benefits could be gained through radical resection of the primary lesion and metastatic lesion versus palliative resection of the primary tumor only. A systematic review showed that the 5-year survival rate for patients undergoing radical resection of the primary tumor and liver metastasis could reach up to 23.8%, with a median survival time of 22 months [bib_ref] data, including large and complex data types  gold Open Access which..., Petrelli [/bib_ref]. A systematic review of 39 retrospective studies found that the resection of liver metastasis could significantly improve prognosis (hazard ratio [HR] = 0.50; P < 0.001), especially for those with solitary liver metastasis and in the Eastern population [bib_ref] Influence of surgical resection of hepatic metastases from gastric adenocarcinoma on long-term..., Markar [/bib_ref]. Another meta-analysis also demonstrated that the prognosis of patients undergoing hepatectomy for metastatic liver lesion was significantly better than that of those who did not undergo surgery, with a median survival of 23.7 months vs. 7.6 months [bib_ref] Influence of surgical resection of hepatic metastases from gastric adenocarcinoma on long-term..., Markar [/bib_ref].
In 2017, the EORTC and JCOG conducted a questionnaire survey in 17 European countries and 55 research centers in Japan and found that, regarding gastric cancer patients with liver metastasis whose primary and metastatic lesions could be removed, most centers recommend these patients to receive preoperative chemotherapy followed by primary and metastatic resection. Retrospective studies have shown that T1-3 disease, H1, R0 resection followed by systemic chemotherapy were important prognostic factors for gastric cancer patients with liver metastasis [bib_ref] Gastric cancer and synchronous hepatic metastases: is it possible to recognize candidates..., Tiberio [/bib_ref] [bib_ref] Factors influencing survival after hepatectomy for metastases from gastric cancer, Tiberio [/bib_ref]. In addition, it has been found that the HER2 gene amplification rate in gastric cancer patients with liver metastasis was higher and that these patients would be more likely to gain a survival benefit from anti-HER2 targeted therapy [bib_ref] Impact of HER2 expression on outcome in gastric cancer patients with liver..., Jiang [/bib_ref]. - Krukenberg tumors are the metastatic lesion of gastric cancer that have been metastasized to the ovary (one or both). For gastric cancer patients with single-ovary metastasis, systemic chemotherapy is regarded as the main treatment. Findings from some retrospective studies performed on these patients have confirmed that systemic chemotherapy combined with surgical resection of the primary tumor and/or ovarian metastasis could provide some survival benefits, extending their mOS from 6-9 months to 19-23.7 months [bib_ref] Efficacy of modern chemotherapy and prognostic factors in patients with ovarian metastases..., Brieau [/bib_ref]. Their most determining prognostic factors were an ECOG performance score of 0-1, R0 resection (radical resection of the primary lesion and the ovarian metastatic lesion), and postoperative systemic chemotherapy [bib_ref] Comparison of surgery plus chemotherapy and palliative chemotherapy alone for advanced gastric..., Cho [/bib_ref]. Some highly selected patients with single-ovarian metastasis may benefit from surgery combined with systemic chemotherapy. However, the selection of patients, timing of treatments, and methods for such operations are still unclear. Follow-up visits c for advanced gastric cancer patients after radical resection, or non-resectable gastric cancer patients after palliative treatment

## Follow-up visits
Once every 3 months in the first 2 years, followed by once every 6 months until 5 years
Once every year for more than 5 years after treatment

## Notes
- The main objective of follow-up/monitoring is for the timely identification and intervention for the plausibility of radical treatment in gastric cancer patients with local recurrence, metastasis, or secondary recurrence after showing a satisfactory response to the treatment administered, with the aim to improve their OS and quality of life [bib_ref] Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up, Smyth [/bib_ref]. Large-scale evidence-based data supporting the best follow-up visit/ monitoring strategy is still lacking. - Planification of follow-up visits should be made on an individualized basis relating the specific conditions of the patient [bib_ref] Gastric cancer, version 3.2016, NCCN clinical practice guidelines in oncology, Ajani [/bib_ref]. Routine tumor follow-up/ monitoring is not recommended for patients with poor physical conditions and is unsuitable for antitumor treatment in the event of recurrence. - HP infection has been found to have a direct implication on the prognosis of gastric cancer patients. It is recommended that HP detection should be performed as a routine examination in follow-up visits. - The postoperative follow-up visits for advanced gastric cancer patients who have undergone radical resection is similar, irrespective whether or not they have had neoadjuvant chemo-/radiotherapy. - The main purpose of follow-up gastroscopy after gastrectomy is to assess the status of the anastomoses and to timely identify any abnormalities. Local recurrence at the anastomotic site is rare. However, for any abnormalities observed, an adequately sized local biopsy should be performed. - The follow-up strategies of gastroscopy are as follow: (1) gastroscopy is recommended within 1 year after surgery; (2) patients are advised to undergo annual follow-up gastroscopy; (3) if there is evidence of high-grade atypical hyperplasia or signs of gastric cancer recurrence, adequately sized biopsy should be made, and a follow-up gastroscopy should be performed within 1 year if no cancerous tissue was observed. - PET/CT and MRI are currently not recommended as routine follow-up/monitoring imaging modalities. They are only recommended for suspected recurrence when there is no clear evidence from conventional imaging examinations (CT or ultrasound) despite a continuous elevation of blood tumor markers (e.g., CEA and CA19-9).

## Recommendation grades from the 2018 csco clinical practice guidelines for common malignant tumors
Recommendation grade

## Criteria
Grade I Evidence level 1A and some Evidence level 2A: Grade I recommendations include Evidence level 1A and some Evidence level 2A which obtained high consensus from the expert panel and has suitable applicability for Chinese gastric cancer patients Specifically, in the CSCO Guidelines, Grade I recommendations include the following: universally accepted measures with clear indications for diagnosis and treatment, has adequate applicability for Chinese gastric cancer patients, and is included in the National Reimbursement Drug List (NRDL). The priority for allocating Grade I recommendations is solely for the benefits of the patients and is independent to changes regarding commercial medical insurance Grade II Evidence level 1B and some Evidence level 2A: Grade II recommendations include Evidence level 1B and some Evidence level 2A which obtained satisfactory consensus with minimum disagreements from the expert panel and has limited applicability for Chinese gastric cancer patients Specifically, Grade II recommendations include the following: high-level evidence provided by multi-center studies that have been randomly controlled internationally or domestically (in China), but may have limited applicability for Chinese patients or low potency ratio, in addition to drugs or treatments that may exceed the purchasing power of the general public of gastric cancer patients; treatments that are expensive but may have substantial benefits for the patients are also regarded as Grade II recommendations
Grade III Evidence level 2B and 3: Despite the lack of strong evidence-based data, however, these are recommendations that have obtained satisfactory consensus with minimum disagreements from the expert panel and are provided as a reference for medical personnel usage

## Not recommended/ objection
Recommendations for which the expert panel has uniform consensus that there is adequate evidence to prove that the drugs or medical technologies do not have sufficient benefits or may even cause harm to Chinese patients. These are labeled as "experts do not recommend" or, when applicable as "experts' disapproval". It can be allocated to any grade recommendations