Japanese gastric cancer treatment guidelines 2025 (7th edition)

Algorithm of standard treatments to be recommended in clinical practice

The algorithm is shown in Fig. 1. Description of the tumor status (T/N/M and stage) in this edition is based on the 15th edition of the Japanese Classification of Gastric Carcinoma [1], which is identical to the 8th edition of the International Union Against Cancer (UICC)/TNM Classification [2].

Summary of T, N, and M categories and stage grouping based on the 15th edition of the Japanese classification of gastric carcinoma [1]

N grade is categorized according to the number of metastatic lymph nodes among the regional lymph nodes (No. 1–12. 14v); N1: 1–2, N2: 3–6, N3a: 7–15, N3b: ≥ 16.

M1: metastasis to the distant organs, peritoneal surface (including CY1), and lymph　nodes outside the regional lymph nodes.

Stage grouping: See Table 1.

Standard gastrectomy and non-standard gastrectomy in surgery with curative intent

Standard gastrectomy

Standard gastrectomy is the principal surgical procedure performed with curative intent. It involves resection of at least two-thirds of the stomach with D2 lymph node dissection (refer to the section on “lymph node dissection” and Figs. 2, 3, 4 and 5 for the definition of D-categories).

Non-curative surgery

Non-curative surgery is offered to patients who are considered incurable. It can be semi-classified into either palliative surgery or reduction surgery depending on the aim of surgery.

Surgery for gastric cancer

Surgery for gastric cancer is defined as follows in order of the stomach volume to be resected.

• Total gastrectomy Total resection of the stomach including the cardia and pylorus.
• Subtotal gastrectomy Stomach resection on the pyloric side by cutting off the lesser curvature along almost its entire length and partially cutting off the short gastric artery.
• Distal gastrectomy Stomach resection including the pylorus. The cardia is preserved. In the standard gastrectomy, two-thirds of the stomach is resected.
• Pylorus-preserving gastrectomy (PPG) Stomach resection preserving the upper third of the stomach and the pylorus along with a portion of the antrum.
• Proximal gastrectomy (PG) Stomach resection including the cardia (esophagogastric junction). The pylorus is preserved.
• Segmental gastrectomy Circumferential resection of the stomach preserving the cardia and pylorus.
• Local resection Non-circumferential resection of the stomach.
• Non-resectional surgery Bypass surgery, gastrostomy, jejunostomy.

In addition, surgery for cancer of the gastric remnant is defined as follows.

• Completion gastrectomy Total resection of the remnant stomach including the cardia or pylorus depending on the type of previous gastrectomy.
• Subtotal resection of remnant stomach Distal resection of the remnant stomach preserving the cardia.

Determination of the extent of gastric resection

Extent of lymph node dissection

The extent of lymphadenectomy is classified by the D-level criteria into D1, D1 + , or D2, and is defined as follows according to the type of gastrectomy conducted. The indications for each of the D levels are described in the subsequent section. See the descriptions under the title “Esophagogastric junctional cancer” for the current recommendations on the extent of lymph node dissection for esophagogastric junctional carcinoma.

Definition of the D levels

The extent of systematic lymphadenectomy is defined as follows, according to the type of gastrectomy conducted. When the extent of lymphadenectomy performed does not fully comply with the D-level criteria, the lymph node station that has been additionally resected or left in situ could be recorded as in the following examples: D1 (+ No. 8a), D2 (− No. 12a). However, when entering data in the nationwide database, the D levels need to be strictly determined and should be downgraded when omitting resection of any of the lymph node stations that should have been resected to fulfill the criteria of a certain D level. (e.g., D2 (− No. 12a) should be entered as D1 +).

Total gastrectomy (Fig. 2)

D0: Lymphadenectomy less than D1.

D1: Nos. 1–7.

D1+: D1 + Nos. 8a, 9, 11p.

D2: D1 + Nos. 8a, 9, 11p, 11d, 12a.

For tumors invading the esophagus, resection of Nos. 19, 20, and 110* should be added to D2.

Distal gastrectomy (Fig. 3)

D0: Lymphadenectomy less than D1.

D1: Nos. 1, 3, 4sb, 4d, 5, 6, 7.

D1+: D1 + Nos. 8a, 9.

D2: D1 + Nos. 8a, 9, 11p, 12a.

Pylorus-preserving gastrectomy (Fig. 4)

D0: Lymphadenectomy less than D1.

D1: Nos. 1, 3, 4sb, 4d, 6**, 7.

D1+: D1 + Nos. 8a, 9.

Proximal gastrectomy (Fig. 5)

D0: Lymphadenectomy less than D1.

D1: Nos. 1, 2, 3a, 4sa, 4sb, 7.

D1+: D1 + Nos. 8a, 9, 11p.

D2: D1 + Nos. 8a, 9, 11p, 11d.

For tumors invading the esophagus, Nos. 19, 20, and 110* should additionally be dissected in D2.

*No. 110 lymph nodes (lower thoracic para-esophageal nodes) in gastric cancer invading the esophagus are those attached to the lower part of the esophagus that is removed to obtain a sufficient resection margin.

**D level should not be changed in cases in which No. 6i was incompletely dissected in pylorus-preserving gastrectomy.

Indications for lymph node dissection

In principle, D2 lymphadenectomy is indicated for cN + or ≥ cT2 tumors, and D1 or D1 + lymphadenectomy is indicated for cT1N0 tumors. Since pre- and intraoperative diagnoses regarding the depth of tumor invasion and nodal involvement remain unreliable, D2 lymphadenectomy should be performed whenever the possibility of nodal involvement cannot be dismissed.

Extent of the resection of the esophagus and stomach

One of the following procedures is selected for esophagogastric junctional cancer: proximal gastrectomy with or without lower esophageal resection; total gastrectomy with or without lower esophageal resection; or esophageal resection and proximal gastrectomy (CQ6-2).

Extent of lymphadenectomy (CQ6-1)

Although long-term results for the survival benefit of lymphadenectomy following the algorithm have not yet been obtained, it seems reasonable to follow this algorithm for the treatment of esophagogastric junctional cancer of cT2 or deeper. Nevertheless, the guidelines currently do not make either more extensive or limited lymphadenectomies inappropriate. However, even in tumors with esophageal invasion of 2 cm or less, surgeons are expected to dissect part of No. 110 lymph nodes that are attached to the portion of esophagus resected to obtain a sufficient resection margin. The definition of D level follows surgery for gastric carcinoma with esophageal invasion, but if the length of esophageal invasion exceeds 4 cm, D level should be classified according to the esophagogastric junction cancer in the Japanese Classification of Esophageal Cancer.

Vagal nerve preservation

It has been reported that preservation of the hepatic branch of the anterior vagus and/or the celiac branch of the posterior vagus contributes to improving postoperative QOL through reducing post-gastrectomy gallstone formation, diarrhea, and/or weight loss.

Omentectomy

Removal of the greater omentum is usually integrated in the standard gastrectomy for T3 or deeper tumors. For T1/T2 tumors, the omentum more than 3 cm away from the gastroepiploic artery may be preserved (CQ3-1). A clinical trial confirming the non-inferiority of omentum preservation to omentectomy for T3 or deeper tumors (JCOG1711) is now underway.

Bursectomy

Bursectomy for tumors penetrating the serosa of the posterior gastric wall had been performed with the aim of removing microscopic tumor deposits within the omental cavity. However, the survival benefit of this procedure has been refuted by a large-scale, randomized trial (JCOG1001) [10].

Combined resection of adjacent organ(s)

For tumors in which the primary or metastatic lesion directly invades adjacent organs, combined resection of the involved organ may be performed to obtain an R0 resection. Even in cases of invasion of the duodenum and head of the pancreas, pancreaticoduodenectomy is weakly recommended when the patient is in good general condition, lymph node metastasis is relatively mild, and R0 resection is possible (CQ3-3).

Approaches to the lower esophagus

A transhiatal abdominal approach has been recommended for gastric cancers invading less than 3 cm of the distal esophagus based on the results of the JCOG9502 trial, and a transthoracic approach has been considered when a greater length of esophagus is involved [11]. The results of a recently reported cooperative study by the Japan Gastric Cancer Association and the Japanese Esophageal Society suggest that dissection of the upper and middle mediastinum might be omitted when the length of esophageal invasion is 4 cm or less. Therefore, a transhiatal abdominal approach can be recommended for cases in which the length of esophageal invasion is 4 cm or less, if safe excision and reconstruction are technically possible.

Laparoscopic surgery

The non-inferiority of laparoscopic distal gastrectomy for clinical stage I gastric cancer to open distal gastrectomy was confirmed in phase 3, randomized, controlled, clinical trials conducted in Japan and Korea (JCOG0912, KLASS-01) [12, 13]. Therefore, laparoscopic distal gastrectomy for clinical stage I gastric cancer is strongly recommended as one of the standard treatment options. The feasibility of laparoscopy-assisted total or proximal gastrectomy has also been confirmed in a single-arm, confirmatory, clinical trial (JCOG1401) [14]. Since survival outcomes have also been reported [15], this guideline strongly recommends performing this procedure (CQ1-1).

For advanced gastric cancer, large-scale, randomized, clinical trials confirming safety and long-term survival of laparoscopic distal gastrectomy have been conducted in Japan, Korea, and China (JLSSG0901, KLASS-02, CLASS-01) [16–18]. Safety analyses showed that no increase in complications after surgery was observed with the laparoscopic approaches. The non-inferiority of overall survival of laparoscopic distal gastrectomy to open distal gastrectomy has also been confirmed [19–21]. This guideline strongly recommends performing laparoscopic distal gastrectomy for advanced gastric cancer of Stage II or more (CQ1-1). Regarding total gastrectomy, several retrospective studies have shown no significant differences in survival or postoperative complications compared with open surgery; therefore, this guideline weakly recommends laparoscopic total gastrectomy (CQ1-3). The results of an ongoing randomized, clinical trial (KLASS-06) are awaited.

All laparoscopic procedures must be performed by or under the guidance of a surgeon who is either qualified by the endoscopic surgical skill system of the Japanese Society of Endoscopic Surgery or acknowledged as having acquired equivalent skills.

Robotic surgery

Robotic surgery has been incorporated by numerous surgical teams and is reputed for its advantage particularly when attempting technically complex surgery. In Japan, it has been shown to decrease the incidence of surgical complications when compared with a similar group of patients who were treated by the laparoscopic approach. This observation led to the approval in 2018 of health insurance coverage for robot-assisted gastrectomy. However, since those studies were based on a single-arm trial or retrospective comparison, a clear benefit of robotic gastrectomy has not been demonstrated [19, 20, 22, 23]. A randomized, controlled study (JCOG1907) to confirm the superiority of robotic gastrectomy to laparoscopic gastrectomy in terms of reducing morbidity for clinical T1-4a N0-2 gastric cancer is ongoing [24]. At present, robotic surgery for resectable gastric cancer is weakly recommended. For robotic gastrectomy, it is necessary to fulfil the standard quality criteria for the surgeon and the facility (CQ1-2).

Total gastrectomy

• Roux-en-Y esophagojejunostomy.
• Jejunal interposition.
• Double-tract method.

Distal gastrectomy

• Billroth I gastroduodenostomy.
• Billroth II gastrojejunostomy.
• Roux-en-Y gastrojejunostomy.
• Jejunal interposition.

Pylorus-preserving gastrectomy

• Gastro-gastrostomy.

Proximal gastrectomy

• Esophagogastrostomy.
• Jejunal interposition.
• Double-tract method.

Endoscopic mucosal resection (EMR)

The lesion, together with the surrounding mucosa, is lifted by submucosal injection of fluid cushions such as normal saline and removed using a high-frequency steel snare [25, 26].

Endoscopic submucosal dissection (ESD)

The mucosa surrounding the lesion is circumferentially incised using a high-frequency electric device such as an insulation-tipped knife, and the submucosal layer is dissected from the muscularis propria layer [27–29].

Handling of resected specimens

The resected specimens should be handled according to the rules described in the Japanese Classification of Gastric Carcinoma 15th edition [1].

Definitions of differentiated-type and undifferentiated-type carcinomas

The tumor biopsy specimens and endoscopically resected tumors are classified histologically into either the differentiated type or the undifferentiated type. The former includes malignant epithelial tumor, general type, of papillary adenocarcinoma (pap) and tubular adenocarcinoma (tub1, tub2), and the latter includes that of poorly differentiated adenocarcinoma (por1, por2) and signet ring cell carcinoma (sig) according to the Japanese Classification of Gastric Carcinoma 15th edition.

When mucinous adenocarcinoma (muc) is found at the submucosal layer, the resected specimen is handled as undifferentiated type, regardless of whether it is considered to derive from the differentiated or undifferentiated type.

Histological predominance and intratumoral ulcerative findings (UL)

A tumor consisting of components of both differentiated-type and undifferentiated-type carcinoma is, nevertheless, classified into one of the two types according to quantitative predominance. In addition, when more than one histological type is found in a tumor, all histological types are to be recorded in the order of quantitative predominance, e.g., tub2 > tub1. The diagnosis of UL1 is principally made based on the histological evidence of ulcerative findings. However, the histological diagnosis of UL is sometimes difficult because of a biopsy-derived scar. Thus, endoscopic and/or radiological evidence should also be taken into account when making a conclusive diagnosis. A biopsy-derived scar is usually observed histologically as fibrosis restricted to small areas just beneath the muscularis mucosae [30]. If it cannot be discriminated from the ulcer scar, it should be classified as UL1.

Principles for indications

Endoscopic resection is considered for tumors that have a very low possibility of lymph node metastasis and are suitable for en bloc resection [31, 32].

Indications

Absolute indication

Absolute indication for EMR or ESD [33–35]

A differentiated-type adenocarcinoma without ulcerative findings (UL0), in which the depth of invasion is clinically diagnosed as T1a, and the diameter is ≤ 2 cm.

Absolute indication for ESD

• A differentiated-type adenocarcinoma without ulcerative findings (UL0), in which the depth of invasion is clinically diagnosed as T1a, and the diameter is > 2 cm.
• A differentiated-type adenocarcinoma with ulcerative findings (UL1), in which the depth of invasion is clinically diagnosed as T1a, and the diameter is ≤ 3 cm.
• An undifferentiated-type adenocarcinoma without ulcerative findings (UL0), in which the depth of invasion is clinically diagnosed as T1a, and the diameter is ≤ 2 cm.

Relative indication

A standard therapy is surgical resection for tumors that do not fulfill the absolute or expanded indications. However, endoscopic resection could be an option for elderly and high-operative-risk patients with severe comorbidities. Such cases are considered relative indications, and endoscopic resection could be performed, provided that consent is obtained from the patient after explaining the risk of residual disease in the form of lymph node metastasis.

Evaluation of curability

Two factors should be considered for curability assessment: completeness of the primary tumor removal and possibility of lymph node metastasis.

Endoscopic curability A (eCuraA)

The resection is classified as endoscopic curability A (eCuraA) when all of the following conditions are fulfilled, provided the cancer has no ulcerative findings (UL0) and is en bloc resected: i) any tumor size in case of histologically differentiated type-dominant, or ii) tumor size ≤ 2 cm in case of histologically undifferentiated type-dominant, pT1a, negative horizontal margin (HM0), negative vertical margin (VM0), and no lymphovascular infiltration (Ly0, V0).

When the cancer has ulcerative findings (UL1), the resection is still classified as eCuraA when all of the following conditions are fulfilled: iii) en bloc resection, tumor size ≤ 3 cm, histologically differentiated type-dominant, pT1a, HM0, VM0, Ly0, V0.

Based on the recent report of long-term results of a prospective cohort study [37], resections fulfilling the following conditions are also classified as eCuraA: iv) tumor size ≤ 3 cm in case of histologically differentiated type-dominant, pT1b (SM1; submucosal invasion < 500 μm from the muscularis mucosae), HM0, VM0, Ly0, V0. However, if the undifferentiated component exceeds 2 cm in length in i), or if undifferentiated components are present in the invasion to SM in iv), the endoscopic curability is classified as C-2 (eCuraC-2) [38].

Endoscopic curability B (eCuraB)

The dissection of the lesion as an “expanded indication” is classified as endoscopic curability B (eCuraB) when the criteria for eCuraA iii) and iv) are fulfilled: sum of the size of locally recurrent lesion and initial ESD specimen ≤ 30 mm [39].

Endoscopic curability C (eCuraC)

The resection is classified as endoscopic curability C (eCuraC) when it does not fulfill the conditions described above to be classified as either eCuraA or eCuraB.

The resection is classified as endoscopic curability C-1 (eCuraC-1) when it is histologically differentiated type either not resected en bloc or had a positive horizontal margin even though fulfilling other criteria to be classified as either eCuraA or eCuraB. All other eCuraC resections are subclassified as endoscopic curability C-2 (eCuraC-2).

Treatments after eCuraA or eCuraB

Follow-up with annual endoscopy is recommended after eCuraA resection [40]. Follow-up with annual or biannual endoscopy and abdominal ultrasonography or computed tomography (CT) for surveillance of metastases is recommended after eCuraB resection [41]. For both eCuraA and eCuraB resections, it has been recommended that examinations for Helicobacter pylori be performed, and that if positive, it should be eradicated [42–44]. Since the risk of metachronous gastric cancer is long-lasting, long-term follow-up is required.

Treatments after eCuraC-1

Since the risk of harboring lymph node metastasis is low, one of the following alternatives could be selected according to the institutional policy after obtaining the patient’s consent: repeat ESD, surgical resection, close observation expecting a burn effect of the initial ESD, and endoscopic coagulation using a laser or argon-plasma coagulator [45].

When the lesion is differentiated type of ≤ 3 cm and one of UL1, pT1a (M) or pT1b1 (SM1), the size of the residual mucosal lesion should be reassessed by endoscopy. When the sum of the lengths of the resected and residual lesions exceeds 3 cm, gastrectomy with lymphadenectomy should be considered the standard of care. In addition, for patients with a positive horizontal margin within the portion of submucosal invasion and for those who underwent piecemeal resection in which the resection line involved the portion of submucosal invasion, gastrectomy with lymphadenectomy should be recommended, since the histological diagnosis under these circumstances is destined to be uncertain.

Treatments after eCuraC-2

Gastrectomy with lymphadenectomy should be considered the standard of care. When surgery cannot be recommended because of old age or severe comorbidities, the risk of residual disease in the form of lymph node metastasis (Tables 2 [46] and 3 [47]) and the possibility of subsequent local recurrence and/or distant metastasis should be assessed and explained sufficiently to the patient, along with the information that recurrent disease is usually incurable and has a dismal prognosis [48].

The green zone indicates the absolute indication for endoscopic resection, the yellow zone indicates the expanded indication, and the red zone indicates the relative indication

Standard patient criteria for systemic chemotherapy

Before starting chemotherapy, the indication should be decided for each patient by checking the following items.

• Histologically proven gastric cancer
• PS 0–2. Chemotherapy is not generally recommended for patients with PS 3 or worse, and a decision beyond the scope of this recommendation should be made after discreetly considering the safety and clinical consequences for each patient (safety is of particular concern for AGC with massive ascites or extensive peritoneal metastases).
• Preserved major organ function
• No serious comorbidities
• Informed consent obtained from the patient

Routine evaluations before and during chemotherapy

1. The following should be checked or measured prior to initiation of chemotherapy: PS, body height, weight, symptoms, physical examination, laboratory data including hepatitis virus tests, and the size of tumor lesions assessed by computed tomography (CT) or other appropriate diagnostic modalities.
2. Response should be assessed using appropriate modalities such as CT, gastrointestinal endoscopy, and contrast-enhanced X-ray examination every 2 or 3 months, comparing the obtained images with those prior to initiation of chemotherapy or at the best response. Tumor response should be evaluated according to the Japanese Classification of Gastric Carcinoma or the Response Evaluation Criteria in Solid Tumors (RECIST) to decide whether to continue the ongoing chemotherapy.
3. The decision whether to continue the ongoing chemotherapy, to modify the drug dosage, or to change the treatment intervals should be made after carefully considering the adverse events and efficacy, and referring to the details of clinical trials showing the clinical significance of the treatment. Cumulative toxicities such as skin toxicities, dysgeusia, and peripheral neuropathy should be considered.
4. Appropriate management is needed for human hepatitis B virus carriers and infected patients to deliver chemotherapy according to the guidelines for reactivation of human hepatitis B virus (ref: https://www.jsh.or.jp/lib/files/medical/guidelines/jsh_guidlines/B_document-3_v2.pdf, in Japanese).

Anti-cancer agents

The following chemotherapeutic agents are proven to be beneficial for AGC: fluorouracil (5-FU), tegafur/5-chloro-2,4-dihydroxypyridine/potassium oxonate (S-1), levofolinate calcium, capecitabine, cisplatin, oxaliplatin, irinotecan, docetaxel, paclitaxel, nab-paclitaxel, trifluridine/tipiracil (FTD/TPI), trastuzumab, ramucirumab, nivolumab, pembrolizumab, trastuzumab deruxtecan, and zolbetuximab. These agents are used either as monotherapy or combination therapy based on the evidence obtained through clinical trials.

Recommended regimens

In this guideline, recommended regimens are defined as those that fulfill one of the following requirements for patients whose general condition is sufficient to meet the inclusion criteria of clinical trials.

• Clinical utility, such as superiority over, or non-inferiority in terms of overall survival proven by a domestic or international phase III clinical trial.
• Reproducible clinical benefit for a specific patient population demonstrated by multiple domestic or international clinical trials.
• The regimen recognized as one of the standard regimens that has been adopted as a control arm in multiple domestic or international phase III clinical trials.

Conditionally recommended regimens

Conditionally recommended regimens are defined as those that fulfill one of the following requirements and can substitute for the “Recommended regimens” when deemed more appropriate after considering factors such as i) general condition of the patient including disease status, age, organ functions and comorbidities, ii) social factors such as hospitalization, cost of treatment, and distance to the hospital, and iii) personal preference that derives from the type of adverse events.

• Considerable clinical benefit under a specific condition in which the patient may not tolerate the “Recommended regimen”.
• Considerable clinical benefit based on wide usage in Japan in general practice or through interpretation of relevant clinical trials, even though the evidence is not robust enough to be included in the “Recommended regimens”.

The “Recommended regimens” and “Conditionally recommended regimens” listed in Figs. 8 and 9 are selected based on voting by the seven medical oncologists who were members of the JGCA Guidelines Committee (the decision required agreement of at least 70% [5 of 7] of the medical oncologists). However, readers are not necessarily discouraged from using regimens that are not listed in these figures. The selection rule was stringent, and even the regimens that were supported by 50–69% [4 of 7] of the medical oncologists are not listed. Given the complexity of daily clinical practice, there could be situations where regimens that are not listed could, nevertheless, serve as useful options.

Due to the paucity of clinical trial results specific for elderly patients and for patients with impaired organ function or comorbidities, it is not possible to indicate with a sufficient evidence which is superior or safer, a “recommended regimen” delivered at a reduced dosage or modified treatment interval or a “conditionally recommended regimen”. Therefore, the optimal therapeutic regimen for these patients should be selected on a case-by-case basis, with the guidelines serving only as a reference. In addition, shared decision-making with patients is important when selecting a treatment method.

HER2-positive gastric cancer

Subgroup analysis of the ToGA study [55] showed that HER2 immunohistochemical staining (IHC) 3 + , or IHC2 + and in situ hybridization (ISH) positivity were more clearly associated with prolonged survival, and it is therefore recommended that patients with these findings be defined as HER2-positive for whom trastuzumab-containing chemotherapy is indicated. The frequency of HER2 positivity (IHC3 + or IHC2 + and ISH positive) in advanced and recurrent gastric cancer has been reported to be 17.8%. Drugs that can be used in combination with trastuzumab are fluoropyrimidine plus platinum. The capecitabine plus cisplatin in combination with trastuzumab regimen used in the ToGA trial, as well as S-1 plus cisplatin (SP), capecitabine plus oxaliplatin (CapeOX), and S-1 plus oxaliplatin (SOX) in combination with trastuzumab regimens, which showed reproducible efficacy in phase II trials, are “recommended” regimens [56–61] (CQ13-1).

HER2-negative gastric cancer

When the 6th edition of these guidelines was published in 2021, only HER2 was used as a biomarker for first-line chemotherapy for gastric cancer, and the recommended treatment for HER2-negative gastric cancer was combination therapy with fluoropyrimidine plus platinum.

Based on the results of the JCOG 9912 trial [62] and the SPIRITS trial [63] conducted in Japan, the S-1 plus cisplatin (SP) regimen was recommended. A capecitabine plus cisplatin (XP) regimen was also adopted as one of the standard treatments in the control groups of the ToGA trial [55] and the AVAGAST trial [64], and it was also recommended because its safety and efficacy were demonstrated in the subgroup analyses of Japanese cases in both trials. However, regimens using oxaliplatin, which is easier to administer than cisplatin because it does not require large-volume infusion, are also used. Capecitabine plus oxaliplatin (CapeOX) was shown to be effective in a subset analysis of a phase III trial in combination with epirubicin [65], and S-1 plus oxaliplatin (SOX) was shown to be almost as effective as SP in the G-SOX trial [49]. 5-FU/levofolinate calcium plus oxaliplatin (FOLFOX) therapy has been used as a control group treatment in recent comparative trials [66, 67] and is covered by insurance in Japan, so it may be an option. These combination therapies of fluoropyrimidine plus platinum were considered the “recommended” regimens for first-line chemotherapy until the previous edition of this guideline.

Currently, treatments that combine these chemotherapy regimens with nivolumab or pembrolizumab have been approved based on the results of multiple global phase III trials that included Japanese patients. The CheckMate649 trial [68] verified the superiority of CapeOX or FOLFOX plus nivolumab regimens, the ATTRACTION-04 trial [69] of SOX or CapeOX plus nivolumab regimens, and the KEYNOTE-859 trial [70] of FP or CapeOX plus pembrolizumab regimens over chemotherapy alone in terms of overall survival or progression-free survival.

Two global phase III trials have demonstrated the efficacy of combination therapy with chemotherapy and zolbetuximab in CLDN18-positive gastric cancer, and this treatment has been currently approved in Japan. The SPOTLIGHT trial [71] verified the superiority of mFOLFOX6 plus zolbetuximab therapy, and the GLOW trial [72] verified the superiority of CapeOX plus zolbetuximab therapy over the control treatment group (chemotherapy plus placebo).

Based on the above evidences, the combination of chemotherapy and immune checkpoint inhibitors, nivolumab or pembrolizumab, is recommended for first-line treatment of HER2-negative gastric cancer, and the combination of chemotherapy and zolbetuximab is recommended for CLDN18-positive cases. However, no clear research results comparing the efficacy of immune checkpoint inhibitors with zolbetuximab have been reported. It is necessary to consider that the therapeutic effects of nivolumab and pembrolizumab are strong in MSI-High/dMMR cases, whereas they tend to be weak in cases with low CPS values. The choice of chemotherapy alone in CLDN18-negative patients with low CPS levels, or combination therapy with immune checkpoint inhibitors or zolbetuximab in CLDN18-positive patients with high CPS levels, needs to be considered individually, taking into account factors such as the patient’s general condition, organ function, expected adverse events, and the patient’s wishes (CQ13-1).

CQ1-1 Is laparoscopic gastrectomy recommended for resectable gastric cancer? (Please refer to CQ1-2 for robotic gastrectomy and CQ1-3 for laparoscopic total gastrectomy for advanced gastric cancer)

Recommendation

Laparoscopic distal gastrectomy is strongly recommended as one of the standard treatments (Consensus rate 100%, 10/10, Strength of evidence A). Laparoscopic total gastrectomy or proximal gastrectomy for cStage I gastric cancer is strongly recommended (Consensus rate 78%, 7/8, Strength of evidence C). The procedures must be conducted by a qualified surgeon in the endoscopic surgical skill qualification system of the Japanese Society of Endoscopic Surgery or a surgeon with equivalent skills or under the guidance of an instructor with equivalent skills.

CQ1-2 Is robotic gastrectomy recommended for resectable gastric cancer?

Recommendation

Robotic gastrectomy is weakly recommended for resectable gastric cancer.

The procedures should be performed under the guidelines of the Japanese Society of Endoscopic Surgery and insurance approval requirements (Consensus rate 100%, 10/10, Strength of evidence C).

CQ1-3 Is laparoscopic total gastrectomy recommended for advanced gastric cancer?

Recommendation

Laparoscopic total gastrectomy is weakly recommended as a standard treatment. The procedures must be conducted by a qualified surgeon in the endoscopic surgical skill qualification system of the Japanese Society of Endoscopic Surgery or a surgeon with equivalent skills or under the guidance of an instructor with equivalent skills (Consensus rate 90%, 9/10, Strength of evidence C).

CQ1-4 Is minimally invasive surgery (laparoscopic or robotic) recommended for patients who underwent preoperative chemotherapy?

Recommendation

Minimally invasive surgery is weakly recommended for patients who received preoperative chemotherapy. The procedures must be conducted by a qualified surgeon in the endoscopic surgical skill qualification system of the Japanese Society of Endoscopic Surgery or a surgeon with equivalent skills or under the guidance of an instructor with equivalent skills (Consensus rate 100%, 10/10, Strength of evidence C).

CQ2-1 Is pylorus-preserving gastrectomy (PPG) recommended for early gastric cancer in the middle portion of the stomach?

Recommendation

PPG is weakly recommended for early gastric cancer in the middle portion of the stomach (Consensus rate 100%, 10/10, Strength of evidence C).

CQ2-2 Is proximal gastrectomy recommended for early proximal gastric cancer as function-preserving surgery?

Recommendation

Proximal gastrectomy is weakly recommended for early proximal gastric cancer as function-preserving surgery (Consensus rate 90%, 9/10, Strength of evidence C).

CQ2-3 Is subtotal distal gastrectomy with minimal preservation of the fundus recommended for cancer of the upper third of the stomach?

Recommendation

If an adequate resection margin can be ensured, subtotal distal gastrectomy with minimal preservation of the fundus is recommended for cancer of the upper third of the stomach (Consensus rate 100%, 10/10, Strength of evidence C).

CQ3-1 Is omentectomy recommended for advanced gastric cancer?

Recommendation

Omentectomy is weakly recommended for cT3-T4 gastric cancer (Consensus rate 80%, 8/10, Strength of evidence C).

CQ3-2 Is splenectomy or splenic hilar lymph node dissection recommended for advanced proximal gastric cancer?

Recommendation

It is strongly recommended not to perform splenectomy or splenic hilar lymph node dissection for tumors which have not invaded the greater curvature (Consensus rate 100%, 9/9, Strength of evidence A). Splenectomy or splenic hilar lymph node dissection is weakly recommended for tumors which have not invaded the greater curvature (Consensus rate 90%, 9/10, Strength of evidence C).

CQ3-3 Is pancreaticoduodenectomy recommended in advanced gastric cancer with invasion of the duodenum or head of the pancreas?

Recommendation

Pancreaticoduodenectomy is weakly recommended for advanced gastric cancer with invasion of the duodenum or head of the pancreas with certain conditions (Consensus rate 100%, 10/10, Strength of evidence C).

CQ4-1 Is PET-CT recommended for the staging of gastric cancer?

Recommendation

It is weakly recommended not to perform PET-CT (Consensus rate 70%, 7/10, Strength of evidence C).

CQ4-2 Is staging laparoscopy recommended for determining the treatment strategy in advanced gastric cancer?

Recommendation

Staging laparoscopy is weakly recommended to determine the treatment strategy for patients with advanced gastric cancer who are likely to have peritoneal metastasis (Consensus rate 90%, 9/10, Strength of evidence B).

CQ5-1 Is surgical treatment for oligometastases recommended?

Recommendation

Surgical resection after neoadjuvant chemotherapy is weakly recommended for a small number of paraaortic lymph node metastases confined to No.16a2/b1, if there are no other non-curable factors (Consensus rate 94.7%, 18/19, Strength of evidence C).

Surgical resection is weakly recommended for solitary liver metastasis, if there are no other non-curable factors (Consensus rate 100%, 19/19, Strength of evidence C).

CQ5-2 Is conversion surgery (including postoperative adjuvant chemotherapy) recommended?

Recommendation

At present, it is difficult to make a clear recommendation regarding conversion surgery for Stage IV patients due to a lack of evidence (Consensus rate 78.9% (15/19), Strength of evidence C).

In addition, there are no clear recommendations regarding adjuvant chemotherapy for Stage IV gastric cancer patients in whom R0 resection has been achieved through conversion surgery (Consensus rate 78.9% (15/19), Strength of evidence C).

CQ5-3 Is palliative resection, bypass surgery, or stent placement recommended for bleeding or stenosis from incurable gastric cancer?

Recommendation

Palliative resection, bypass surgery, or stent placement is weakly recommended for bleeding or stenosis from incurable gastric cancer (Consensus rate 100%, 19/19), Strength of evidence D).

CQ5-4 Is gastrectomy recommended for CY1? (Including postoperative chemotherapy)

Recommendation

If CY1 is identified during gastrectomy, upfront gastrectomy followed by postoperative chemotherapy is weekly recommended (Consensus rate: 94.7% 18/19, Strength of evidence C).

If CY1 is identified before the initial treatment by staging laparoscopy, gastrectomy is weakly recommended when CY0 is achieved after chemotherapy (Consensus rate 100%, 19/19, Strength of evidence C).

CQ6-1 Is mediastinal lymph node dissection or para-aortic lymph node dissection recommended for the surgery for esophagogastric junctional cancer?

Recommendation

In surgery for esophagogastric junctional cancer deeper than cT2,

1. Lower mediastinal lymph node dissection is weakly recommended if the esophageal invasion length is greater than 2 cm (Consensus rate 90%, 9/10, Strength of evidence C).
2. Upper, middle, and lower mediastinal lymph node dissection is weakly recommended if the esophageal invasion length is greater than 4 cm (Consensus rate 80%, 8/10, Strength of evidence C).
3. It is weakly recommended not to perform para-aortic lymph node (No.16a2) dissection, taking into consideration the entire surgical stress (Consensus rate 100%, 10/10, Strength of evidence C).

CQ6-2 Is proximal gastrectomy recommended for esophagogastric junctional cancer?

Recommendation

Proximal gastrectomy is weakly recommended for esophagogastric junctional cancer (Consensus rate 100%, 10/10, Strength of evidence C).

CQ6-3 Is laparoscopic or robotic surgery recommended for esophagogastric junctional cancer?

Recommendation

Laparoscopic or robotic surgery is weakly recommended for esophagogastric junctional cancer (Consensus rate 70%, 7/10, Strength of evidence D).

CQ7-1 Is lymph node dissection with splenectomy recommended for carcinoma of the gastric remnant?

Recommendation

Splenic hilar dissection with splenectomy is weakly recommended for advanced carcinoma of the gastric remnant with greater curvature invasion (Consensus rate 100%, 10/10, Strength of evidence C).

Not performing splenic hilar lymph node dissection with splenectomy for tumors without greater curvature invasion is weakly recommended (Consensus rate 80%, 8/10, Strength of evidence C).

CQ7-2 Is laparoscopic or robotic surgery recommended for carcinoma of the gastric remnant?

Recommendation

At present, it is difficult to make a clear recommendation to perform laparoscopic or robotic surgery for carcinoma of the gastric remnant (Consensus rate 70%, 7/10, Strength of evidence D).

CQ7-3 Is mesenteric lymph node dissection recommended for carcinoma of the gastric remnant located at the gastrojejunostomy

Recommendation

Mesenteric lymph node dissection is weakly recommended for carcinoma of the gastric remnant located at the gastrojejunostomy (Consensus rate 100%, 10/10, Strength of evidence C).

CQ8 Is reoperation recommended if the resection margin is diagnosed as positive in the permanent section?

Recommendation

It is difficult to make a clear recommendation for reoperation if the resection margin is diagnosed as positive in the permanent section (Consensus rate 100%, 10/10, Strength of evidence D).

CQ 9–1 Is vaccination with pneumococcal vaccine recommended after splenectomy?

Recommendation

Pneumococcal vaccination after splenectomy for gastric cancer surgery is weakly recommended (Consensus rate 90%, 9/10, Strength of evidence D).

CQ9-2 Is administration of vitamin B12 recommended after total gastrectomy?

Recommendation

Administration of vitamin B12 is weakly recommended after total gastrectomy (Consensus rate 90%, 9/10, Strength of evidence C).

CQ9-3 Is Helicobacter pylori eradication recommended after gastrectomy?

Recommendation

Considering the prolongation of survival, lower recurrence rate, lower incidence of metachronous gastric cancer, increase in serious adverse events, increase in adverse events (including minor ones), and increase in costs, there is no clear recommendation for Helicobacter pylori eradication therapy after gastrectomy (Consensus rate 100%, 11/11, Strength of evidence C).

CQ10-1 Is considering age recommended when deciding a surgical procedure?

Recommendation

Limited surgery with reduced lymph node dissection or minimally invasive surgery is weakly recommended for elderly patients (Consensus rate 100%, 19/19, Strength of evidence D).

CQ10-2 Is considering age recommended when deciding on the indication for systemic chemotherapy?

Recommendation

Considering age when deciding on the indication of systemic chemotherapy is weakly recommended for an elderly patient with unresectable advanced or recurrent gastric cancer, who is fit, has decision-making capacity, and is willing to undergo treatment after carefully assessing the patient’s overall condition and motivation (Consensus rate 100%, 19/19, Strength of evidence B).

In other cases, such as vulnerable or unfit patients, no clear recommendation can be made due to the range of the condition.

CQ10-3 Is considering of age recommended when deciding on the indication of endoscopic resection?

Recommendation

There are no reports directly comparing ESD with and without considering age in elderly patients with early gastric cancer, nor reports comparing observation with ESD. A recommendation regarding considering age when deciding on the indication for endoscopic resection cannot be made (Consensus rate 73.7%, 14/19, Strength of evidence D).

CQ10-4 Is perioperative nutritional/exercise therapy recommended for elderly patients or patients with sarcopenia?

Recommendation

No clear recommendations can be made regarding perioperative nutritional/exercise therapy for elderly patients or patients with sarcopenia (Consensus rate 94.7%, 18/19, Strength of evidence D).

CQ11-1 Is chemotherapy recommended for patients with impaired oral intake or massive ascites due to extensive peritoneal disease?

Recommendation

Chemotherapy is weakly recommended for patients with impaired oral intake or massive ascites after careful assessment of their general condition (Consensus rate 100%, 7/7, Strength of evidence C).

CQ11-2 Is personalized medicine based on genomic profiling tests recommended for AGC?

Recommendation

It is weakly recommended to perform appropriate genomic profiling tests in later-line treatment and to treat based on the genetic alterations found for unresectable advanced or recurrent gastric cancer patients (Consensus rate 100%, 7/7, Strength of evidence C).

CQ12 Are immune checkpoint inhibitors recommended for first-line treatment of HER2-negative AGC?

Recommendation

Chemotherapy in combination with an immune checkpoint inhibitor (nivolumab or pembrolizumab) is strongly recommended as first-line treatment for HER2-negative unresectable advanced/recurrent gastric/gastroesophageal junction cancer, taking into account biomarkers (PD-L1 (CPS), MSI, MMR, CLDN18) and the patient’s general condition (Consensus rate 100%, 7/7, Strength of evidence A).

CQ13-1 Is selection of first-line treatment based on biomarkers recommended?

Recommendation

Selection of first-line treatment based on biomarkers is strongly recommended for patients with unresectable advanced or recurrent gastric cancer (Consensus rate 100%, 7/7, Strength of evidence A).

CQ13-2 Is it recommended to select second-line or later treatments based on biomarkers obtained on pretreatment repeat biopsy?

Recommendation

No clear recommendations can be made regarding second-line or later treatment selection based on biomarker (HER2) testing by repeat biopsy for patients with unresectable advanced gastric or gastroesophageal junction adenocarcinoma (Consensus rate 85.7%, 6/7, Strength of evidence D).

CQ14 After progression of chemotherapy for unresectable advanced or recurrent gastric cancer, is it recommended to continue or re-administer drugs used in previous treatment?

Recommendation

It is strongly recommended not to continuously use or re-administer fluoropyrimidine, trastuzumab, or ramucirumab in chemotherapy for unresectable advanced or recurrent gastric cancers (Consensus rate 100%, 7/7, Strength of evidence A).

CQ15-1 Is anamorelin recommended for cachexic patients?

Recommendation

In patients with advanced gastric cancer and a non-refractory cachexia state, appropriate dosing of anamorelin is weakly recommended to promote appetite and weight gain (Consensus rate 100%, 7/7, Strength of evidence D).

CQ15-2 Is radiation recommended as palliative treatment for bleeding advanced gastric cancer?

Recommendation

For patients with incurable advanced gastric cancer with bleeding, radiation for the purpose of hemostasis is weakly recommended, taking into consideration the patient’s overall condition and prognosis (Consensus rate 100%, 7/7, Strength of evidence C).

CQ16-1 Is neoadjuvant chemotherapy for curatively resectable advanced gastric and esophagogastric junctional cancer recommended?

Recommendation

No clear recommendations can be made regarding neoadjuvant chemotherapy for curatively resectable advanced gastric and esophagogastric junctional cancer (Consensus rate 89.5%, 17/19, Strength of evidence C).

CQ16-2 Is adjuvant chemotherapy recommended for stage IV gastric cancer with R0 resection?

Recommendation

Adjuvant chemotherapy is weakly recommended for stage IV gastric cancer with R0 resection (Consensus rate 94.7%, 18/19, Strength of evidence C).

CQ17 Is continuation of antithrombotic drugs recommended compared with temporary discontinuation of the drugs when performing endoscopic resection of patients taking antithrombotic drugs?

Recommendation

No recommendation can be made regarding the usefulness of continuation of antithrombotic drugs compared with temporary discontinuation of the drugs when performing endoscopic resection of patients taking antithrombotic drugs.