Gastric Cancer
Gastric and gastro-oesophageal junction adenocarcinoma
DefinitionClick to collapse
Gastric cancer is a malignancy arising from the stomach, with over 95% of cases classified as adenocarcinomas [1]. The stomach is anatomic organ located in the upper gastrointestinal tract with defined subsites including the cardia, fundus, body, antrum, and pylorus. Gastric cancer is typically classified based on anatomic location (cardia/proximal or noncardia/distal) and histologic type (diffuse or intestinal) [1,3,16]. The stomach wall consists of five layers: mucosa, submucosa, muscularis propria, subserosa, and serosa. Tumors may arise from the gastric mucosa and invade through successive layers, with depth of invasion determining T-stage [ST-1]. Tumors involving the esophagogastric junction (EGJ) are further classified using the Siewert system: Siewert Type I (adenocarcinoma of the lower esophagus with epicenter 1–5 cm above the anatomic EGJ), Siewert Type II (true carcinoma of the cardia at the EGJ, with epicenter within 1 cm above and 2 cm below the EGJ), and Siewert Type III (subcardial carcinoma with epicenter 2–5 cm below the EGJ, which infiltrates the EGJ and lower esophagus from below) [GAST-C 1 of 5]. Using the AJCC 8th edition staging, tumors involving the EGJ with an epicenter located >2 cm into the proximal stomach are staged as gastric carcinomas, while those with an epicenter ≤2 cm into the proximal stomach are staged as esophageal carcinomas [MS-4]. Gastric cancers located within the gastric cardia that do not involve the EGJ are staged as gastric carcinomas [MS-4]. The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum [ST-1]. Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure but is classified using the depth of greatest invasion in any of these sites [ST-1]. The gastric lymphatic drainage includes perigastric lymph nodes (D1) along the lesser and greater curvature, and nodes along the named vessels of the celiac axis (D2) including the left gastric artery, common hepatic artery, celiac artery, and splenic artery [GAST-C 2 of 5].
EpidemiologyClick to collapse
SubtypesClick to collapse
Intestinal-type adenocarcinoma
Characterized by variably differentiated tumor cells arranged in a tubular or glandular pattern with scattered goblet cells present. This type tends to form a mass lesion and is more prevalent in high-risk geographic areas. Intestinal type accounts for most of the geographic variation seen with gastric cancer [MS-2,1,3,16].
Diffuse-type adenocarcinoma
Characterized by poorly differentiated and discohesive tumor cells with a signet-ring or non-signet-ring morphology diffusely infiltrating the gastric wall in a desmoplastic stroma. More prevalent in low-risk areas and mostly associated with heritable genetic abnormalities [MS-2,3,9,14-16].
EBV-associated gastric cancer
An estimated 8% to 10% of gastric cancers are associated with Epstein-Barr virus (EBV) infection, making EBV-positive gastric cancer the largest group of EBV-associated malignancies [MS-16,185,186]. EBV-positive tumors occur preferentially in the proximal stomach and are associated with diffuse-type histology and early onset [MS-16,11].
MSI-H/dMMR gastric cancer
Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) gastric cancers represent a distinct molecular subset with elevated mutation burden and favorable response to immune checkpoint inhibitors [MS-14,150-153,155-157].
HER2-overexpressing/amplified gastric cancer
Gastric cancers overexpressing HER2 protein or harboring ERBB2 gene amplification. Unlike in breast cancer, the prognostic significance of HER2 status in gastric cancer is unclear [MS-12,131-140].
CLDN18.2-positive gastric cancer
Gastric cancers expressing claudin 18 isoform 2 (CLDN18.2), a tight junction transmembrane protein typically expressed in normal gastric epithelia and retained during malignant transformation [MS-15,173,174].
Genomically stable (GS) subtype
A molecular subtype identified by The Cancer Genome Atlas (TCGA) data, characterized by distinct genomic features from other subtypes [MS-11,116].
Chromosomally unstable (CIN) subtype
A molecular subtype characterized by frequent somatic copy number alterations and gene amplifications, identified through TCGA and other molecular studies [MS-11,116,117].
Molecular PathogenesisClick to collapse
The molecular pathogenesis of gastric cancer involves an accumulation of genetic aberrations during gastric carcinogenesis, resulting in overexpression of growth factors and/or receptors, loss of tumor suppressor genes, alterations in the cell cycle, and changes in DNA repair and damage response [MS-11,116,117]. Genome instability, including increased chromosomal instability and microsatellite instability (MSI), is often associated with these changes [MS-11,117,118]. The Cancer Genome Atlas (TCGA) identified four molecular subtypes of gastric adenocarcinoma [MS-11,116]. MSI-H occurs in approximately 22% of gastric adenocarcinomas based on TCGA data, and a pan-cancer analysis reported an incidence of 19% in MSI-H/dMMR gastric tumors [MS-14,116,154]. MSI-H tumors are associated with elevated mutation burden due to loss of functional mismatch repair (MMR) at microsatellite mutational hotspots [MS-14,118]. MMR deficiency is evaluated by IHC for nuclear expression of MLH1, MSH2, MSH6, and PMS2 proteins [GAST-B 5 of 7,159]. MSI status is assessed by PCR using validated microsatellite markers including mononucleotide repeats BAT25, BAT26, MONO27, NR21, and NR24 [MS-14,158]. EBV-associated gastric cancer occurs in 8% to 10% of cases [MS-16,185,186]. HER2 (ERBB2) amplification and overexpression is observed in 12% to 23% of gastric cancers, with intestinal type more frequently positive [MS-12,132-144]. PD-L1 expression is frequently observed in intestinal subtype and is associated with MSI-H and EBV positivity [MS-14,164-168]. CLDN18.2, a tight junction protein, is retained during malignant transformation and represents a therapeutic target expressed in 24% to 38% of advanced gastric cancers [MS-15,173-178]. MSI-H/dMMR is frequently associated with increased immune checkpoint ligand expression [MS-11,119-121]. HER2 positivity also varies with histologic subtype: intestinal (33%) versus diffuse/mixed (8%; P=.001) [139]. Tumor mutational burden-high (TMB-H, ≥10 mutations/megabase) status serves as a biomarker for checkpoint inhibitor response [GAST-F 5 of 9,342]. The presence of NTRK1/2/3 gene fusions, RET gene fusions, and BRAF V600E mutations are additional molecular alterations with therapeutic implications [GAST-B 6 of 7]. Chromosomal instability in gastric cancer contributes to tumor development, progression, and therapy resistance through multiple signaling pathways [MS-11,117].
Risk FactorsClick to collapse
Helicobacter pylori infection
H. pylori infection is a well-established risk factor for gastric cancer, particularly intestinal type [MS-2,2,3,9,14-16]. The guideline recommends testing for H. pylori infection and eradicating in all patients with early gastric cancer if positive [GAST-1,i]. If H. pylori testing is positive, recommendations should be discussed with family members as appropriate, and close family members should be tested [GAST-1,i]. H. pylori eradication for the prevention of metachronous gastric cancer has been supported by prospective trial data [64].
Tobacco smoking
Tobacco smoking is associated with gastric cancer, particularly intestinal type [MS-2,2,3,9,14-16]. The guideline includes smoking cessation advice, counseling, and pharmacotherapy as indicated for all patients [GAST-1,g]. Smoking cessation is recommended as appropriate throughout survivorship [GAST-I 3 of 4].
High salt intake
High salt intake is associated with gastric cancer, particularly intestinal type [MS-2,2,3,9,14-16].
Other dietary factors
Various dietary factors are associated with gastric cancer risk, though specific factors beyond salt intake and H. pylori are not individually enumerated in this guideline [MS-2,2,3,9,14-16].
Heavy alcohol use
The role of alcohol as a risk factor for gastric cancer is without consensus. Meta-analyses have shown no appreciable association between light or moderate alcohol consumption and gastric cancer risk, but demonstrated a positive association between heavy alcohol use and gastric cancer, particularly non-cardia gastric cancer [MS-2,17-20].
Family history/Hereditary cancer predisposition syndromes
It is estimated that 1% to 3% of gastric cancers are associated with inherited cancer predisposition syndromes, including hereditary diffuse gastric cancer, Lynch syndrome, juvenile polyposis syndrome, and familial adenomatous polyposis syndrome [MS-3]. Genetic risk assessment principles are outlined in GAST-D, referencing CDH1 pathogenic variant carriers and the NCCN Guidelines for Genetic/Familial High-Risk Assessment. Patients with MSI-H or dMMR tumors should be referred to a genetics counselor [GAST-B 5 of 7,13,160].
Age
Age is a risk factor, with MSI-H/dMMR status associated with age ≥68 years [MS-14,116,119,150-153]. However, evidence suggests the incidence of early-onset gastric cancer may be rising in the US and other western countries [MS-2,11,12].
Male sex
Males have higher incidence of gastric cancer than females [MS-2,1]. HER2 positivity was significantly higher in males versus females [MS-13,139].
Race/Ethnicity
The highest gastric cancer incidence rates occur in Northeast Asia, South and Central America, and Eastern Europe, with particularly high rates in Japan, Korea, and China [MS-2,5,6,9]. In the US, diffuse type gastric cancer incidence rate per 100,000 in US Whites was 4.4 [1]. Differences between US and Asian populations in HER2 testing and other biomarkers have been observed [MS-13].
Clinical FeaturesClick to collapse
Typical Presentation
Gastric cancer is often diagnosed at an advanced stage in most countries where population screening is not routine. Approximately 50% of patients present with advanced disease at diagnosis and will likely have a poor outcome. The disease generally carries a poor prognosis because of late diagnosis. In Japan and South Korea, where population screening is performed widely, early detection often results in improved outcomes. In the United States, survival rates from gastric cancer remain poor as early detection continues to pose a major challenge for health care professionals. Over 95% of gastric cancers are adenocarcinomas, typically classified based on anatomic location (cardia/proximal or noncardia/distal) and histologic type (diffuse or intestinal). The diffuse type, characterized by poorly differentiated and discohesive tumor cells with signet-ring or non-signet-ring morphology, is more prevalent in low-risk areas and is mostly associated with heritable genetic abnormalities. The intestinal type, which forms a mass lesion with variably differentiated tumor cells arranged in a tubular or glandular pattern, occurs more frequently in high-risk areas. Intestinal type gastric cancer is often related to environmental factors such as H. pylori infection, tobacco smoking, high salt intake, and other dietary factors [1-3]. A dramatic shift in the type and location of upper gastrointestinal tract tumors has occurred in North America and Europe, with a marked decline in intestinal type gastric cancers of the distal stomach but rising incidence rates of diffuse type gastric cancer of the proximal stomach [1,3,21-23].
Symptoms
Vague upper abdominal discomfort
Nonspecific upper abdominal symptoms that may be attributed to benign conditions, contributing to diagnostic delay
Dyspepsia
Epigastric discomfort, early satiety, or postprandial fullness may be present
Weight loss
Unintentional weight loss is a common presenting symptom, especially in advanced disease
Anorexia
Loss of appetite may be an early or late symptom
Dysphagia
Difficulty swallowing, particularly with proximal or EGJ tumors
Hematemesis or melena
Acute severe bleeding may occur, directly from the tumor or as a consequence of therapy; patients with acute severe bleeding should undergo prompt endoscopic assessment
Signs
Alkaline phosphatase ≥100 U/L
An elevated alkaline phosphatase level ≥100 U/L is identified as a measure of poor outcome in gastric cancer
Palpable abdominal mass
May be present in advanced locoregional or metastatic disease
Hepatomegaly
May indicate hepatic metastatic disease
Virchow node
Left supraclavicular lymphadenopathy suggesting distant metastatic disease
Red FlagsClick to collapse
Acute severe hematemesis or melena requiring prompt endoscopic assessment
Dysphagia suggesting proximal or EGJ involvement
New-onset significant weight loss
Palpable abdominal mass
Ascites on examination suggesting peritoneal disease
Virchow node (left supraclavicular lymphadenopathy) suggesting distant metastatic disease
Palpable left supraclavicular lymph node (suggests advanced disease)
Family history suggestive of hereditary diffuse gastric cancer syndrome (CDH1 pathogenic variant) or other cancer predisposition syndromes including Lynch syndrome, juvenile polyposis syndrome, and familial adenomatous polyposis syndrome
Evidence of locally advanced disease: infiltration of the root of the mesentery, para-aortic lymph node involvement highly suspicious on imaging or confirmed by biopsy, invasion or encasement of major vascular structures (excluding splenic vessels), or distant metastasis or peritoneal seeding including positive peritoneal cytology
InvestigationsClick to collapse
Diagnostic
Esophagogastroduodenoscopy (EGD) and biopsies
Essential for diagnosis and staging; multiple biopsies (6–8) using standard-size endoscopy forceps should be performed to provide adequately sized material for histologic and molecular interpretation, especially in ulcerated lesions. Larger forceps may improve yield. The location of the tumor in the stomach and relative to the EGJ should be carefully recorded.
Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD)
ER is essential for the accurate staging of early-stage cancers (T1a or T1b). EMR or ESD of focal nodules ≤2 cm can be safely performed to provide a larger specimen for pathologic assessment, providing greater information on degree of differentiation, LVI, and depth of infiltration, thereby providing accurate T-staging. Such excisional biopsies have the potential of being therapeutic.
Endoscopic ultrasound (EUS)
Recommended if early-stage disease suspected or if early versus locally advanced disease needs to be determined. Important in initial clinical staging, providing evidence of depth of tumor invasion (T-category), presence of abnormal or enlarged lymph nodes (N-assessment), and occasionally signs of distant spread (M-category) or ascites. Hypoechoic expansion of gastric wall layers identifies tumor location. Accuracy of EUS: 57%-88% for T staging and 30%-90% for N staging. EUS is especially important in patients being considered for ER.
Biopsy of metastatic disease
Performed as clinically indicated to confirm metastatic disease and for biomarker testing
Diagnostic laparoscopy with cytology
Laparoscopy with cytology is performed to evaluate for peritoneal spread when considering local therapy. Indicated for clinical stage T1b or higher. Not indicated if a palliative resection is planned. Positive peritoneal cytology (in the absence of visible peritoneal implants) is associated with poor prognosis and is defined as pM1 disease. In a study of 657 patients with potentially resectable gastric adenocarcinoma, metastatic disease (M1) was detected in 31% by laparoscopic staging.
History and physical examination
Complete history and physical examination is part of the initial workup for all newly diagnosed patients
Complete blood count (CBC) and comprehensive chemistry profile
Part of the standard initial workup; alkaline phosphatase level ≥100 U/L identified as a measure of poor outcome
Staging
Chest/abdomen/pelvis CT with oral and IV contrast
Part of routine preoperative staging; has an overall accuracy of 43% to 82% for measuring depth of invasion. CT with contrast should be considered if there were findings on the pre-treatment CT that merit more accurate anatomic assessment after treatment.
FDG-PET/CT evaluation (skull base to mid-thigh)
Recommended for locally advanced or metastatic disease or if clinically indicated. May not be appropriate for T1 disease. Combined FDG-PET/CT imaging offers advantages over FDG-PET or CT alone, with a significantly higher accuracy rate in preoperative staging (68%) than FDG-PET (47%) or CT (53%) alone. FDG-PET has lower accuracy due to low FDG uptake in diffuse and mucinous tumor types. Significantly lower sensitivity compared to CT in detection of local lymph node involvement (56% vs 78%), though improved specificity (92% vs 62%). FDG-PET does not replace staging laparoscopy given inability to detect peritoneal disease.
Chest/abdomen CT with oral and IV contrast (response assessment)
Performed after completion of perioperative systemic therapy and before surgical intervention for response assessment. Not required if FDG-PET/CT is done. Pelvis CT if clinically indicated.
FDG-PET/CT for response assessment
Performed 5-8 weeks after therapy as clinically indicated for patients with MSI-H/dMMR tumors treated with neoadjuvant ICI
Biomarkers
Universal testing for microsatellite instability (MSI) by PCR or NGS, or mismatch repair (MMR) by immunohistochemistry (IHC)
MSI-H or dMMR gastric tumors have different prognosis and treatment implications including response to immune checkpoint inhibitors. MSI-H/dMMR status is associated with earlier stage, ≥68 years of age, intestinal subtype, and distal stomach location. Testing performed on formalin-fixed paraffin-embedded (FFPE) tissue. Results interpreted as MSI-H or dMMR in accordance with CAP DNA Mismatch Repair Biomarker Reporting Guidelines. Testing should be performed only in CLIA-approved laboratories. Patients with MSI-H or dMMR tumors should be referred to genetics counselor.
Universal testing for PD-L1 by IHC
PD-L1 testing is used to identify patients who may benefit from immune checkpoint inhibitor therapy. Combined positive score (CPS) ≥1 indicates PD-L1 expression. CPS and tumor area positivity (TAP) score have high concordance and may be interchangeable. A minimum of 100 tumor cells must be present for adequate evaluation. A companion diagnostic test should be used to analyze FFPE tumor tissue.
HER2 (ERBB2) testing
HER2 overexpression or amplification is a target for trastuzumab therapy. HER2 testing using IHC and, if needed, ISH/FISH is recommended. IHC scoring ranges from 0 to 3+. Score of 0 or 1+ = negative; 2+ = equivocal (requires ISH); 3+ = positive. Cases with ERBB2:CEP17 ratio ≥2 or average ERBB2 copy number ≥6 signals/cell are ISH positive. IHC/ISH/targeted gene PCR is the preferred initial approach.
CLDN18.2 testing
Claudin 18 isoform 2 (CLDN18.2) is a target for zolbetuximab therapy. Tumors considered CLDN18.2 positive if ≥75% of viable tumor cells demonstrate moderate to strong membrane CLDN18.2 staining (2+ or 3+ intensity) by IHC on FFPE tissue. CLDN18.2-positive tumors represent 24%-38% of advanced gastric and EGJ adenocarcinomas.
Next-generation sequencing (NGS)
Offers the opportunity to assess numerous mutations simultaneously, along with amplification, deletions, TMB, and MSI status. NGS testing through a CLIA-approved laboratory may be considered later in the clinical course with sufficient tumor tissue. IHC/ISH/targeted gene PCR is the preferred initial approach.
Circulating tumor DNA (ctDNA) testing
When limited tissue is available or patients with metastatic/advanced gastric cancer cannot undergo traditional biopsy, multigene panel testing (MGPT) performed in a CLIA-approved laboratory may be considered. A negative result should be interpreted with caution as it does not exclude the presence of tumor.
Tumor Epstein-Barr virus (EBV) status
Emerging potential biomarker for personalized treatment strategies; EBV testing should be performed if the morphology of the tumor contains prominent lymphoid stroma. Not currently recommended for clinical care routine testing.
StagingClick to collapse
American Joint Committee on Cancer (AJCC) 8th Edition (2017) TNM Staging Classification for Carcinoma of the Stomach. This system includes clinical staging (cTNM), pathologic staging (pTNM), and post-neoadjuvant pathologic staging (ypTNM). Tumors involving the EGJ with an epicenter located >2 cm into the proximal stomach are staged as gastric carcinomas. Tumors involving the EGJ with an epicenter ≤2 cm into the proximal stomach are staged as esophageal carcinomas. Cancers within the gastric cardia not involving the EGJ are staged as gastric carcinomas.
T Categories
| Stage | Description |
|---|---|
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria, high-grade dysplasia |
| T1 | Tumor invades the lamina propria, muscularis mucosae, or submucosa |
| T1a | Tumor invades the lamina propria or muscularis mucosae |
| T1b | Tumor invades the submucosa. Superficial pT1b is defined as ≤500 μm invasion of submucosa; deep pT1b is defined as >500 μm invasion of submucosa. |
| T2 | Tumor invades the muscularis propria. A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures; in this case, the tumor is classified as T3. |
| T3 | Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures |
| T4 | Tumor invades the serosa (visceral peritoneum) or adjacent structures |
| T4a | Tumor invades the serosa (visceral peritoneum). If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified as T4a. |
| T4b | Tumor invades adjacent structures/organs. The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. |
N Categories
| Stage | Description |
|---|---|
| NX | Regional lymph node(s) cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Metastasis in 1 to 2 regional lymph nodes |
| N2 | Metastasis in 3 to 6 regional lymph nodes |
| N3 | Metastasis in 7 or more regional lymph nodes |
| N3a | Metastasis in 7 to 15 regional lymph nodes |
| N3b | Metastasis in 16 or more regional lymph nodes |
M Categories
| Stage | Description |
|---|---|
| M0 | No distant metastasis |
| M1 | Distant metastasis. Positive peritoneal cytology (in the absence of visible peritoneal implants) is defined as pM1 disease. |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Clinical Stage 0 | cTis, cN0, cM0 | Carcinoma in situ confined to epithelium without lamina propria invasion | None | Curative |
| Clinical Stage I | cT1, cN0, cM0 or cT2, cN0, cM0 | Early-stage tumor confined to gastric wall with no nodal involvement | None | Curative |
| Clinical Stage IIA | cT1, cN1-N3, cM0; cT2, cN1-N3, cM0 | Locoregional disease with varying T and N involvement | None | Curative |
| Clinical Stage IIB | cT3, cN0, cM0; cT4a, cN0, cM0 | Locoregional disease without nodal involvement but higher T stage | None | Curative |
| Clinical Stage III | cT3, cN1-N3, cM0; cT4a, cN1-N3, cM0 | Locally advanced disease with significant nodal involvement | None | Curative |
| Clinical Stage IVA | cT4b, any cN, cM0 | Tumor invading adjacent structures | None | May be curative in selected cases |
| Clinical Stage IVB | Any cT, any cN, cM1 | Distant metastatic disease | None | Palliative |
| Pathologic Stage 0 | pTis, pN0, pM0 | Carcinoma in situ, no nodal or distant metastasis | None | Curative; observation |
| Pathologic Stage IA | pT1, pN0, pM0 | Tumor confined to mucosa or submucosa without nodal involvement | None | Curative; observation or ER |
| Pathologic Stage IB | pT1, pN1, pM0; pT2, pN0, pM0 | Early tumor with minimal nodal involvement or deeper invasion without nodes | None | Curative |
| Pathologic Stage IIA | pT1, pN2, pM0; pT2, pN1, pM0; pT3, pN0, pM0 | Intermediate-stage disease | None | Curative |
| Pathologic Stage IIB | pT1, pN3a, pM0; pT2, pN2, pM0; pT3, pN1, pM0; pT4a, pN0, pM0 | Locally advanced disease with moderate nodal burden | None | Curative |
| Pathologic Stage IIIA | pT2, pN3a, pM0; pT3, pN2, pM0; pT4a, pN1 or pN2, pM0; pT4b, pN0, pM0 | Advanced locoregional disease | None | Curative |
| Pathologic Stage IIIB | pT1, pN3b, pM0; pT2, pN3b, pM0; pT3, pN3a, pM0; pT4a, pN3a, pM0; pT4b, pN1 or pN2, pM0 | Advanced locoregional disease with high nodal burden | None | Curative |
| Pathologic Stage IIIC | pT3, pN3b, pM0; pT4a, pN3b, pM0; pT4b, pN3a or pN3b, pM0 | Very advanced locoregional disease | None | Curative |
| Pathologic Stage IV | Any pT, any pN, pM1 | Metastatic disease | None | Palliative |
| Post-Neoadjuvant Stage I | ypT1, ypN0, M0; ypT2, ypN0, M0 | Response to neoadjuvant therapy with minimal residual disease | None | Curative |
| Post-Neoadjuvant Stage II | ypT3, ypN0, M0; ypT2, ypN1, M0; ypT1, ypN2, M0; ypT4a, ypN0, M0; ypT3, ypN1, M0; ypT2, ypN2, M0; ypT1, ypN3, M0 | Moderate residual disease after neoadjuvant therapy | None | Curative |
| Post-Neoadjuvant Stage III | ypT4a, ypN1, M0; ypT3, ypN2, M0; ypT2, ypN3, M0; ypT4b, ypN0, M0; ypT4b, ypN1, M0; ypT4a, ypN2, M0; ypT3, ypN3, M0; ypT4b, ypN2, M0; ypT4b, ypN3, M0 | Significant residual disease after neoadjuvant therapy | None | Curative |
| Post-Neoadjuvant Stage IV | Any ypT, any ypN, M1 | Metastatic disease after neoadjuvant therapy | None | Palliative |
Staging Pearls
- Intramural extension to the duodenum or esophagus is not considered invasion of an adjacent structure but is classified using the depth of the greatest invasion in any of these sites
- If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified as T4a
- Positive peritoneal cytology (in the absence of visible peritoneal implants) is defined as M1 disease
- A tumor penetrating the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures, is classified as T3
- The yp prefix is used to indicate cases in which staging is performed following preoperative therapy
- Superficial pT1b is defined as ≤500 μm invasion of submucosa and deep pT1b is defined as >500 μm invasion of submucosa
- The staging system was validated using the International Gastric Cancer Association (IGCA) database of >25,000 patients with gastric cancer
- New cTNM and ypTNM stage groupings were added in the 8th edition to overcome the lack of validated clinical staging and post-neoadjuvant staging in the 7th edition
- EUS is not reliable for predicting superficial or deep submucosal invasion, so endoscopic resection is recommended to provide accurate staging
- Pathologic regression after neoadjuvant therapy is assessed using a 4-tiered scoring system: 0 (complete response), 1 (near complete), 2 (partial response), 3 (poor or no response)
Management PrinciplesClick to collapse
The NCCN Guidelines emphasize a multidisciplinary team (MDT) approach as essential for the treatment of localized gastric cancer. Treatment philosophy integrates surgery, systemic therapy, and radiation therapy based on disease stage, biomarker status, and patient fitness. Best supportive care is an integral part of treatment, especially in patients with unresectable, recurrent, or metastatic disease. The primary goal for localized disease is curative resection with negative margins, often combined with perioperative systemic therapy. For advanced disease, systemic therapy aims to prolong survival and improve quality of life. Clinical trial participation is strongly encouraged throughout the disease course. The panel believes that combined modality therapy for localized esophagogastric cancer is optimally delivered with an infrastructure that encourages multidisciplinary treatment decision-making by members of all relevant disciplines taking care of these patients.
Curative
Patients with localized disease (cTis, cT1a, or cT1b-high to cT4a, N any, M0) who are medically fit and potentially resectable.
Multimodal therapy with the primary intent of achieving cure. For early-stage (cTis or cT1a) tumors, endoscopic resection (ER) may be sufficient. For resectable T1b or higher tumors, surgery is the primary treatment, with perioperative systemic therapy (category 1) recommended for cT2 or higher, any N. For MSI-H/dMMR tumors, neoadjuvant or perioperative immune checkpoint inhibitor (ICI) therapy may be considered. Postoperative management is dictated by pathologic stage and extent of lymph node dissection.
Palliative
Patients with unresectable locoregional disease, metastatic disease (cM1), or those who are nonsurgical candidates.
Treatment focuses on symptom control, prolonging survival, and improving quality of life. Options include systemic therapy, chemoradiation (for locally unresectable disease not previously treated), and best supportive care. The selection of therapy is heavily dependent on performance status, biomarker status (HER2, PD-L1, CLDN18.2, MSI/MMR), and prior treatment. A multimodality interdisciplinary approach to palliative care is encouraged.
The NCCN Panel believes that comprehensive care for gastric cancer requires expertise in several disciplines, including surgical oncology, medical oncology, radiation oncology, gastroenterology, radiology, and pathology. The presence of nutritional services, social workers, nurses, palliative care specialists, and other supporting disciplines is also desirable. The infrastructure should encourage multidisciplinary treatment decision-making with joint review of patient data. Frequent meetings (once a week or every 2 weeks) are encouraged. All relevant disciplines should be encouraged to participate. Long-term therapeutic strategies should be developed after adequate staging procedures are completed but ideally prior to any therapy. A brief documentation of the consensus recommendation(s) by the MDT may be useful. Recommendations made by the MDT may be considered advisory to the primary treating physicians. Re-presentation of select patient outcomes after therapy is an effective educational method.
Performance status is a critical factor in treatment decision-making. The Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) and the Karnofsky Performance Status Scale (KPS) are commonly used. Patients with a KPS score <60% or an ECOG PS score ≥3 should be offered palliative/best supportive care only. Systemic therapy or chemoradiation (only if locally unresectable and not previously received) can be offered in addition to palliative/best supportive care for patients with better performance status (KPS score of ≥60% or ECOG PS score ≤2). The choice of systemic therapy regimens is dependent on performance status and medical comorbidities. Two-drug cytotoxic regimens are preferred for patients with advanced disease due to lower toxicity. The use of three cytotoxic drugs should be reserved for patients who are medically fit with excellent PS and easy access to frequent toxicity evaluations.
Management PathwaysClick to collapse
Branching: Clinical T-stage, Medical fitness for surgery
Branching: Clinical T-stage, Biomarker status (MSI-H/dMMR)
Branching: Surgical resectability after staging
Branching: Medical fitness for surgery
Branching: HER2 status, PD-L1 CPS, MSI-H/dMMR status, CLDN18.2 status
Branching: Prior therapy, HER2 status, Biomarker status (MSI-H, TMB-H, NTRK, BRAF, RET)
Branching: Peritoneal Cancer Index (PCI), Disease response to systemic therapy
Branching: Pattern of recurrence (locoregional vs. metastatic)
Pretreatment EvaluationClick to collapse
Clinical and Laboratory
Imaging and Endoscopy
Biomarker and Pathology Testing
Consultations
SurgeryClick to collapse
Surgery is the primary treatment option for patients with localized gastric cancer with the goal of achieving a complete resection with negative margins (R0 resection).
The primary goal is R0 resection; however, only 50% of patients will achieve this.
The type of resection (subtotal vs. total gastrectomy) and extent of lymph node dissection (D1 vs. D2) are key considerations.
Adequate gastric resection with lymphadenectomy is standard for T1b–T3 tumors. T4b tumors require en bloc resection of involved structures.
Gastric resection should include regional lymphatics with a goal of examining ≥16 lymph nodes (retrieval and assessment of >30 nodes is desirable).
Routine splenectomy is not indicated unless the spleen is involved or extensive hilar adenopathy is noted.
Surgery for palliation should be reserved for symptoms (obstruction, uncontrollable bleeding) when nonsurgical options are not feasible.
Procedures
Distal Gastrectomy
Subtotal Gastrectomy
Total Gastrectomy
Endoscopic Resection (EMR or ESD)
Cytoreductive Surgery (CRS) with HIPEC
Radiation TherapyClick to collapse
Radiation therapy (RT) is primarily used in the postoperative adjuvant setting for patients who received less than a D2 lymph node dissection, and for palliation of symptoms (bleeding, pain, dysphagia) in patients with advanced disease. It is also a component of definitive chemoradiation for patients with locally advanced, surgically unresectable disease who are not candidates for surgery.
Principles
- Treatment recommendations should be made after joint consultation and discussion by a multidisciplinary team.
- All available information from pretreatment diagnostic studies (CT, EUS, EGD, FDG-PET/CT) should be used to determine the target volume.
- CT simulation and conformal treatment planning (3D-CRT or IMRT) should be used.
- Image guidance may be used to enhance clinical targeting.
- In general, Siewert Type I and II tumors should be managed with RT guidelines applicable to esophageal and EGJ cancers. Siewert Type III tumors may be managed with either esophageal/EGJ or gastric cancer RT guidelines depending on tumor bulk.
- Treatment interruptions or dose reductions for manageable acute toxicities should be avoided. Careful patient monitoring and aggressive supportive care are preferable.
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Adjuvant Postoperative Chemoradiation | 45–50.4 Gy | 1.8 Gy | 25–28 | Daily, 5 days per week | Patients with R0 or R1 resection for gastric or EGJ adenocarcinoma who received less than a D2 lymph node dissection. Recommended for all patients following an R1 resection. Also an option for patients with pT2, N0 tumors with high-risk features. |
| Definitive Chemoradiation for Unresectable Disease | 45–50.4 Gy | 1.8 Gy | 25–28 | Daily, 5 days per week | Patients with locally advanced, surgically unresectable disease who are not candidates for surgery. |
| Palliative Radiation | Variable (e.g., 30 Gy in 10 fractions) | Variable | Variable | Variable | Symptom control for bleeding, pain, or dysphagia in patients with advanced disease. |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Adjuvant Chemoradiation with Concurrent Fluoropyrimidine | 45–50.4 Gy in 25–28 fractions | Fluoropyrimidine (infusional fluorouracil or capecitabine). Leucovorin is indicated with certain fluorouracil-based regimens. | Postoperative adjuvant therapy after less than D2 dissection (category 1). | INT-0116 (Macdonald et al., N Engl J Med 2001). | Grade 3–4 hematologic (54%) and GI (33%) toxicities were reported in the original trial. Nausea, diarrhea, and hematologic toxicity are common. |
| Definitive Chemoradiation with Fluoropyrimidine ± Platinum | 45–50.4 Gy in 25–28 fractions | Preferred: Fluoropyrimidine, Fluorouracil and oxaliplatin, Fluorouracil and cisplatin. Other: Fluoropyrimidine and paclitaxel (category 2B). | Unresectable locally advanced disease if not previously received. | PRODIGE5/ACCORD17 (Conroy et al., Lancet Oncol 2014) for FOLFOX vs fluorouracil/cisplatin in esophageal cancer (extrapolated). | Myelosuppression, esophagitis, nausea, diarrhea. |
Systemic TherapyClick to collapse
Systemic therapy is a cornerstone of treatment for both localized (perioperative) and advanced/metastatic gastric cancer. Regimens are chosen based on disease setting, performance status, comorbidities, and biomarker status (HER2, PD-L1, MSI/MMR, CLDN18.2). Two-drug cytotoxic regimens are preferred for advanced disease due to lower toxicity. The use of three cytotoxic drugs should be reserved for medically fit patients with excellent performance status. An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy.
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Post-Treatment Response Assessment and Additional Management
Timing
After completion of neoadjuvant or perioperative systemic therapy, prior to surgery (if planned). For patients undergoing non-operative management (e.g., immunotherapy for MSI-H/dMMR), surveillance should include EGD with biopsy (EUS as clinically indicated) every 12 weeks for 2 years and then every 6 months until year 5.
Response Logic
-
Patients who receive neoadjuvant or perioperative therapy should be restaged before proceeding to surgery. Restaging includes chest/abdomen/pelvis CT with oral and IV contrast. FDG-PET/CT as clinically indicated.
-
If restaging shows resectable disease, proceed with surgery (preferred) or palliative management.
-
If restaging shows unresectable or metastatic disease, proceed to palliative management.
-
For patients with MSI-H/dMMR tumors treated with neoadjuvant ICI, radiologic and endoscopic complete responses may occur. However, current imaging and endoscopic assessment methods do not reliably predict pathologic complete response. Gastrectomy with appropriate lymphadenectomy remains the standard approach outside of prospective organ-preservation clinical trials. Multidisciplinary evaluation is recommended when considering non-operative management.
Imaging Recommendations
-
Chest/abdomen/pelvis CT with oral and IV contrast is recommended for restaging after perioperative therapy.
-
FDG-PET/CT can be performed as clinically indicated.
-
CT with contrast should be considered if there were findings on the pre-treatment CT that merit more accurate anatomic assessment after treatment (such as small pulmonary nodules) or if post-treatment PET identified new findings.
Biopsy Or Salvage Logic
-
Endoscopic surveillance following definitive treatment requires careful attention to detail for mucosal surface changes, and multiple (4–6) biopsies of any visualized abnormalities.
-
EUS performed in conjunction with endoscopy exams has a high sensitivity for detecting recurrent disease. EUS-guided FNA should be performed if suspicious lymph nodes or areas of wall thickening are seen.
-
Post-treatment endoscopic biopsy may not accurately diagnose the presence of residual disease but still provides useful information.
-
If disease persists or recurs, treatment options depend on the pattern (locoregional vs. metastatic) and prior therapies received.
SurveillanceClick to collapse
Clinical Follow Up Schedule
- Tis (successfully treated by ER): H&P every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years [GAST-7]
- p stage I (T1a, T1b, N0 treated by surgical resection or by ER): H&P every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years [GAST-7]
- p stage II/III or yp stage I-III (treated with neoadjuvant ± adjuvant therapy): H&P every 3-6 months for 1-2 years, then every 6-12 months for 3-5 years [GAST-7]
- For all patients: CBC and chemistry profile as clinically indicated [GAST-7]
- For patients undergoing non-operative management (eg, immunotherapy): EGD with biopsy (EUS as clinically indicated) every 12 weeks for 2 years and then every 6 months until year 5 [21,22, GAST-A 3 of 4]
Imaging Strategy
- Tis: Routine imaging (CT chest/abdomen/pelvis with oral and IV contrast) as clinically indicated based on symptoms and concern for recurrence [GAST-7]
- p stage I: CT chest/abdomen/pelvis with oral and IV contrast as clinically indicated [GAST-7]; for patients treated by ER, EGD every 6 months for 1 year, then annually for up to 5 years [GAST-7]
- p stage II/III or yp stage I-III: CT chest/abdomen/pelvis with oral and IV contrast every 6 months for first 2 years, then annually for up to 5 years [GAST-7]; CT scan preferred; alternative imaging such as PET/CT or MRI as clinically indicated for patients who cannot undergo CT scan [GAST-7, footnote jj]
- For patients undergoing total gastrectomy: endoscopy as clinically indicated for routine surveillance unless patients are symptomatic [GAST-7, footnote gg]
Laboratory Monitoring
- CBC and chemistry profile as clinically indicated for all patients [GAST-7]
- Monitor for nutritional deficiency in patients who have undergone surgical resection, especially after total gastrectomy [GAST-7, footnote kk]
- B12 level at least every 6 months if not on parenteral B12 supplement [GAST-I]
- CBC and iron levels at least annually [GAST-I]
- Vitamin D testing as clinically indicated [GAST-I]
Supportive Follow Up
- Follow-up with appropriate practitioners or specialists should be established for lifelong monitoring and management of potential nutritional sequelae of gastrectomy, which may include vitamin B12, iron, zinc, calcium, and vitamin D deficiencies [GAST-H, footnote kk]
- Consider routine supplementation with daily multivitamin/mineral complex, vitamin B12, calcium, and vitamin D [GAST-H, footnote kk]
- Osteoporosis screening at 3 years post-gastrectomy and in individuals who are post-menopausal or >50 years of age [GAST-I]
- Encourage healthy body weight, physically active lifestyle, healthy diet with emphasis on plant sources, limit alcohol, smoking cessation [GAST-I]
- Additional preventive health measures and immunizations as indicated under care of or in conjunction with primary care physician [GAST-I]
- Survivorship care planning with delineation of roles of oncologists, PCPs, and subspecialty care physicians [GAST-I]
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Bleeding (hematemesis or melena) | Acute severe bleeding should undergo prompt endoscopic assessment [1]. Widely available endoscopic treatment options include injection therapy, mechanical therapy (eg, endoscopic clips), ablative therapy (eg, argon plasma coagulation), or a combination of methods [404]. Angiographic embolization techniques may be useful where endoscopy is not helpful [406]. EBRT has been shown to effectively manage acute and chronic GI bleeding [407,408]. Proton pump inhibitors can be prescribed but there are no definitive data supporting their use at this time. Palliative gastrectomy is an option in select patients. |
| Malignant gastric obstruction | Primary goals are to reduce nausea and vomiting and allow resumption of oral diet. Treatment options include: endoscopic placement of enteral stent for gastric outlet obstruction or esophageal stent for EGJ/gastric cardia obstruction [409-413]; surgery (gastrojejunostomy [6,409] or gastrectomy in select patients [202]); EBRT; chemotherapy. Endoscopic placement of SEMS is a safe and effective minimally invasive palliative treatment [410-413]. When obstruction cannot be alleviated, venting gastrostomy may be performed for gastric decompression [415]. Pericardiocentesis if ascites present to reduce risk of infectious complications [418,419]. |
| Pain | May be treated with EBRT or chemotherapy. Tumor-related pain should be assessed and treated in accordance with NCCN Guidelines for Adult Cancer Pain. Severe uncontrolled pain following gastric stent placement should be treated with endoscopic removal of the stent [414]. |
| Nausea and vomiting | Treat in accordance with NCCN Guidelines for Antiemesis. May be associated with luminal obstruction, so endoscopic or fluoroscopic evaluation should be performed to determine if obstruction is present. |
| Nutritional deficiency following gastrectomy | Lifelong monitoring and management for nutritional sequelae is required, particularly after total gastrectomy. May include vitamin B12, iron, zinc, calcium, and vitamin D deficiencies. Routine supplementation with daily multivitamin/mineral complex, vitamin B12, calcium, and vitamin D is recommended [391-396,400]. Follow-up with appropriate practitioners should be established for lifelong monitoring [GAST-H, GAST-I]. |
| Dumping syndrome | Occurs following total gastrectomy. Early dumping (within 30 minutes of eating) presents with palpitations, diarrhea, nausea, cramps; late dumping (within 2-3 hours) presents with dizziness, hunger, cold sweats, faintness [397]. Management includes frequent meals, diet high in protein and fiber, low in simple carbohydrates/concentrated sweets, avoid fluid consumption with meals [GAST-I]. |
Supportive CareClick to collapse
The goal of best supportive care is to prevent and relieve suffering and to support the best possible quality of life for patients and their families, regardless of the stage of the disease or the need for other therapies. For gastric cancer, interventions undertaken to relieve major symptoms may result in prolongation of life, particularly when a multimodality interdisciplinary approach is pursued [GAST-J]. The multidisciplinary team approach is essential, involving surgical oncology, medical oncology, gastroenterology, radiation oncology, radiology, pathology, nutritional services, social workers, nursing, and palliative care specialists [49, GAST-E].
Nutritional assessment and counseling should be provided to all patients [GAST-1]. For patients undergoing gastrectomy, lifelong monitoring and management of nutritional sequelae is essential, including vitamin B12, iron, zinc, calcium, and vitamin D deficiencies. Consider routine supplementation with a daily multivitamin/mineral complex, vitamin B12, calcium, and vitamin D [391-396, GAST-H, GAST-I]. Patients with total gastrectomy are at highest risk. In patients at higher risk of postoperative nutritional intolerance or anastomotic complications, feeding jejunostomy may be considered [18,19, GAST-A, GAST-3A]. Long-term anemia and deficiencies in nutrients such as iron, vitamin B12, vitamin D, and zinc can occur after gastrectomy [391-394]. Supplementation of vitamin B12 and iron is safe and effective for reversing these deficiencies [395,396]. Dietary changes including frequent meals throughout the day, avoidance of fluid intake with meals, and consumption of a diet high in protein and fiber and low in simple carbohydrates are recommended for dumping syndrome management [GAST-I].
Antiemetics should be given on a prophylactic basis during radiation treatment courses [GAST-G]. Patients experiencing nausea and vomiting should be treated in accordance with the NCCN Guidelines for Antiemesis. Nausea and vomiting may be associated with luminal obstruction, so endoscopic or fluoroscopic evaluation should be performed to determine if obstruction is present [GAST-J].
The document does not provide specific G-CSF guidance. Myelosuppression management is referenced through general supportive care principles and NCCN Guidelines for the Management of Immune Checkpoint Inhibitor-Related Toxicities. Dose modifications of chemotherapy regimens for hematologic toxicities should follow standard institutional protocols.
The document does not provide specific VTE prophylaxis guidance. Standard institutional and NCCN supportive care guidelines should be followed.
EBRT and chemotherapy may provide pain control. If the patient is experiencing tumor-related pain, pain should be assessed and treated in accordance with the NCCN Guidelines for Adult Cancer Pain. Severe uncontrolled pain following gastric stent placement should be treated with endoscopic removal of the stent [GAST-J]. Duloxetine can be considered for painful chemotherapy-induced neuropathy but is ineffective for numbness or tingling [GAST-I].
All patients should be assessed for distress using the NCCN Distress Thermometer and Problem List, which includes social determinants of health [GAST-1, footnote j]. See NCCN Guidelines for Distress Management (DIS-A). Survivorship care planning should include information regarding follow-up care, surveillance, screening recommendations, and post-treatment needs [GAST-I]. Maintenance of a therapeutic relationship with a primary care physician throughout life is encouraged.
The document does not provide specific dental care guidance for gastric cancer patients. Standard dental care recommendations for cancer survivors should be followed.
PrognosisClick to collapse
Gastric cancer generally carries a poor prognosis since it is often diagnosed at an advanced stage. Globally, there were more than 968,000 new cases resulting in approximately 660,000 deaths in 2022, making gastric cancer the fifth most frequently diagnosed cancer and the fifth leading cause of cancer-related deaths in the world [1]. In the United States, approximately 30,300 people will be diagnosed and 10,780 people are expected to die of this disease in 2025 [4,10]. Despite overall declining rates, evidence suggests that the incidence of early-onset gastric cancer may be rising in the United States and other western countries [11,12]. In Japan and South Korea, where population screening is performed widely, early detection often results in improved outcomes [1,6]. In the United States, survival rates from gastric cancer remain poor as early detection continues to pose a major challenge for health care professionals [2]. Approximately 50% of patients present with advanced disease at diagnosis and will likely have a poor outcome. Other measures of poor outcome include poor performance status, presence of metastases, and an alkaline phosphatase level ≥100 U/L [47]. Nearly 80% of patients have involvement of the regional lymph nodes and the number of positive lymph nodes has a profound influence on survival [48].
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Tis (successfully treated by ER) | Prognosis approximates a non-cancer cohort | The prognosis of R0-resected Tis disease approximates a non-cancer cohort [GAST-H]. These patients have extremely favorable outcomes when treated with endoscopic resection alone. |
| Stage I (T1a/T1b, N0) | Generally favorable but heterogeneous | T1a,N0 and T1b disease do not perform as well as Tis disease. Following the KLASS-01 trial, 5-year OS rates were 94.2% for laparoscopic and 93.3% for open surgery in stage I disease [227]. Surveillance recommendations vary according to depth of invasion and treatment modality. |
| Stage II/III (resectable, locoregional) | 30%-78% depending on substage and treatment | Outcomes depend heavily on pathological stage, lymph node status, and receipt of perioperative systemic therapy. Perioperative chemotherapy (FLOT) improved median OS to 50 months versus 35 months with ECF (HR, 0.77; 95% CI, 0.63-0.94) in the FLOT4 trial [54]. Postoperative chemotherapy with capecitabine and oxaliplatin after D2 dissection yielded 5-year DFS of 68% versus 53% for surgery alone in the CLASSIC trial [62,63]. |
| Stage IV (metastatic disease) | Generally poor | Patients with metastatic disease are considered nonsurgical candidates. First-line systemic therapy is the mainstay of treatment. Median OS has improved to approximately 13-15 months with modern first-line regimens incorporating immunotherapy and/or targeted therapy in appropriate patients [28,29,30]. Best supportive care alone yields median OS of approximately 3-5 months [270-273]. |
| MSI-H/dMMR tumors | Generally better prognosis | Better prognosis has been reported with MSI-H/dMMR gastric tumors compared to microsatellite stable/MMR-proficient tumors [150,151,155], including for those with MSI-H/dMMR who receive immunotherapy [156,157]. In KEYNOTE-062, median OS was not reached in patients with MSI-H tumors receiving pembrolizumab versus 8.5 months with chemotherapy [358]. |
Prognostic Factors
- Number of positive lymph nodes - has a profound influence on survival [48]
- Performance status
- Presence of metastases
- Alkaline phosphatase level ≥100 U/L [47]
- Resection margin status (R0 vs R1 vs R2)
- Pathologic stage (ypTNM staging system for patients receiving preoperative therapy) [25]
- HER2 status - prognostic significance unclear but affects treatment options [131-140]
- MSI-H/dMMR status - associated with better prognosis and earlier stage [116,119,150-155]
- EBV status - several studies suggest better OS rates compared to other genotypes [187-191]
- Histologic subtype (intestinal vs diffuse)
- Microscopic lymph node involvement
- Pathologic response to neoadjuvant chemotherapy - response to neoadjuvant chemotherapy was the only independent predictor of OS in patients who underwent curative resection [122]
- Depth of submucosal invasion (superficial ≤500 μm vs deep >500 μm pT1b)
- DLN (number of lymph nodes assessed ≥16, preferably >30)
Follow UpClick to collapse
Post Curative Treatment
Follow-up/surveillance strategies after curative intent resection (R0) for gastric cancer remain controversial, with sparse prospective data to construct evidence-based algorithms that balance benefits and risks (including cost) within this cohort [GAST-H]. The guidance provided is based on currently available retrospectively analyzed literature and expert consensus. H. pylori eradication: All patients positive for H. pylori who underwent curative ER or gastric subtotal resection must receive an H. pylori eradication regimen. The choice and duration of the eradication regimen should follow the latest American College of Gastroenterology or Maastricht Consensus Report H. pylori guidelines [1,64, GAST-H]. After 5 years, additional follow-up may be considered based on risk factors and comorbidities. Routine gastric cancer-specific surveillance (radiologic imaging, endoscopic evaluation, tumor markers) is not recommended beyond 5 years [GAST-I].
Surveillance Rationale
The majority of gastric cancer relapses occur within 2 years (70%-80%) and almost all recurrences by 5 years (~90%) after completion of local therapy. However, a study of 1573 patients showed that 7.6% of recurrences occurred >5 years after treatment [68, GAST-H]. Therefore, after 5 years additional follow-up may be considered based on risk factors and comorbidities. Surveillance strategies provided in the guideline are based on currently available retrospectively analyzed literature [65-74] and expert consensus. Differences in follow-up for early-stage gastric cancer reflect a heterogeneous potential for relapse and overall survival. R0-resected Tis disease has a prognosis that approximates a non-cancer cohort, whereas T1a,N0 and T1b disease do not have such a favorable prognosis. Thus, recommendations vary according to the depth of invasion and treatment modality received.
Late Effects Screening
- Vitamin B12 deficiency - monitor B12 level at least every 6 months if not on parenteral B12 supplement [GAST-I]
- Iron deficiency - monitor CBC and iron levels at least annually; supplement iron orally or intravenously as clinically indicated [GAST-I]
- Vitamin D and calcium deficiency - supplement vitamin D following local practice for dose and monitoring levels; ensure adequate calcium intake [GAST-I]
- Osteopenia/osteoporosis screening - consider bone density testing at 3 years post-gastrectomy and in individuals who are post-menopausal or >50 years of age [GAST-I]
- Small intestinal bacterial overgrowth - consider treatment with antibiotics (rifaximin 550 mg TID x 7-10 days preferred) [GAST-I]
- Other micronutrient deficiencies - supplement with daily multivitamin/mineral complex including vitamins A, C, E, D, folate, thiamine, magnesium, zinc, selenium, copper, and iron [GAST-I]
- Dumping syndrome monitoring and management [GAST-I]
- Chemotherapy-induced neuropathy screening [GAST-I]
- Cancer screening for average-risk survivors: breast, colorectal, prostate, lung cancer screening per respective NCCN Guidelines [GAST-I]
Recurrence Patterns
Most gastric cancer relapses occur within 2 years (70%-80%) after completion of local therapy, and almost all recurrences occur by 5 years (~90%) [65,67,72, GAST-H]. A study of 1573 patients showed that 7.6% of recurrences occurred >5 years after treatment [68]. Recurrence patterns include locoregional recurrence (which can be considered for surgery if isolated and patient is medically fit [GAST-8, footnote mm]) and metastatic disease. Positive peritoneal cytology even in the absence of visible peritoneal implants should be considered as M1 disease [2,44-46]. Patterns of initial recurrence in completely resected gastric adenocarcinoma include local recurrence, peritoneal recurrence, and distant metastases [72].
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| ToGA | Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer | 2010 | 594 | Trastuzumab plus chemotherapy (cisplatin plus fluorouracil or capecitabine) | Chemotherapy alone | HER2 overexpression-positive (IHC 3+ or IHC 2+/FISH+) locally advanced, recurrent, or metastatic gastric or EGJ adenocarcinoma | Overall survival | Median OS 13.8 vs 11 months (P = .046) | In subgroup with IHC 2+/FISH+ or IHC 3+, median OS was 16 vs 11.8 months (HR, 0.65) | Established trastuzumab in combination with cisplatin and fluoropyrimidine as standard first-line therapy for HER2-positive disease [27] | Lancet |
| FLOT4 | Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma | 2019 | 716 | FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) | ECF (epirubicin, cisplatin, fluorouracil) | Resectable non-metastatic gastric or EGJ adenocarcinoma (≥cT2 and/or N+) | Overall survival | Median OS 50 vs 35 months (HR, 0.77; 95% CI, 0.63-0.94) | Pathologic CR rate 16% vs 6% (P = .02); similar grade 3-4 AE rates (27% vs 27%) [54,246] | Established FLOT as preferred perioperative regimen (category 1); ECF no longer recommended in this setting | Lancet |
| MATTERHORN | Perioperative durvalumab in gastric and gastroesophageal junction cancer | 2025 | 948 | Durvalumab plus FLOT perioperatively | Placebo plus FLOT | Untreated resectable gastric or EGJ adenocarcinoma | Event-free survival | At 24 months, EFS rate 67.4% vs 58.5% (HR for event or death, 0.71; P < .001) | PD-L1 TAP ≥1%: HR for EFS 0.70 (95% CI: 0.57-0.87); PD-L1 TAP <1%: HR 0.77 (95% CI: 0.40-1.46); diffuse type showed no EFS benefit (HR, 0.93) [55] | Established FLOT + durvalumab as preferred perioperative option for PD-L1 CPS ≥1 or TAP ≥1% (category 1); category 2B for diffuse type | N Engl J Med |
| CheckMate 649 | First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma | 2021 | 1581 | Nivolumab plus chemotherapy (capecitabine and oxaliplatin or mFOLFOX) | Chemotherapy alone | Previously untreated, HER2-negative, unresectable gastric, EGJ, or esophageal adenocarcinoma | Overall survival and progression-free survival | PD-L1 CPS ≥5: Median OS 14.4 vs 11.1 months (HR, 0.70); 3-year follow-up consistent [360,361] | PFS 8.3 vs 6.1 months (HR, 0.70); ORR 60% vs 45%; CR 13% vs 7% [361]; MSI-H tumors: OS 38.7 vs 12.3 months (HR, 0.34) [361] | Established nivolumab plus fluoropyrimidine- and oxaliplatin-based chemotherapy as first-line preferred option for PD-L1 CPS ≥1 (category 1 for CPS ≥5) | Lancet |
| KEYNOTE-811 | Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma | 2021 | 698 | Pembrolizumab plus trastuzumab and chemotherapy (fluorouracil/cisplatin or capecitabine/oxaliplatin) | Placebo plus trastuzumab and chemotherapy | Previously untreated advanced HER2-positive gastric or EGJ adenocarcinoma | Progression-free survival and overall survival | Median PFS 10 vs 8.1 months (P = .0002); Median OS 20 vs 16.9 months (HR, 0.87; 95% CI, 0.72-1.06; P = .084) | ORR 72.6% vs 59.8%; CR 14% vs 11%; PD-L1 CPS ≥1 subgroup favored pembrolizumab [25,26,352,353] | FDA approval (2023) for PD-L1 CPS ≥1; established as category 1 preferred option for HER2-positive, PD-L1 CPS ≥1 first-line therapy | Lancet |
| KEYNOTE-859 | Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer | 2023 | 1581 | Pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy | Placebo plus chemotherapy | Treatment-naive advanced HER2-negative gastric or EGJ adenocarcinoma | Overall survival | PD-L1 CPS ≥1: median OS 13 vs 11.4 months (HR, 0.74; P < .0001); PD-L1 CPS ≥10: 15.7 vs 11.8 months (HR, 0.65; P < .0001) | PFS CPS ≥1: 6.9 vs 5.6 months (HR, 0.72; P < .0001); ORR 52% vs 43% [29] | FDA approval for first-line HER2-negative gastric or EGJ cancer; category 1 preferred option for PD-L1 CPS ≥1 | Lancet Oncol |
| SPOTLIGHT | Zolbetuximab plus mFOLFOX6 in CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma | 2023 | 565 | Zolbetuximab plus mFOLFOX6 | Placebo plus mFOLFOX6 | Treatment-naive, HER2-negative, CLDN18.2-positive, locally advanced unresectable or metastatic gastric or EGJ adenocarcinoma | Progression-free survival and overall survival | Median PFS 10.61 vs 8.67 months (HR, 0.75; P = .0066); Median OS 18.23 vs 15.54 months (HR, 0.75; P = .0053) | ORR and median DOR similar between groups [31] | FDA approval in combination with fluoropyrimidine- and platinum-based therapy for CLDN18.2-positive, HER2-negative first-line disease | Lancet |
| GLOW | Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma | 2023 | 507 | Zolbetuximab plus CAPOX | Placebo plus CAPOX | Untreated, locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive gastric or EGJ adenocarcinoma | Progression-free survival and overall survival | Median PFS 8.21 vs 6.8 months (HR, 0.687; P = .0007); Median OS 14.39 vs 12.16 months (HR, 0.771; P = .0118) | ORR 42.5% vs 40.3%; DOR 6.14 vs 6.08 months [32] | Confirmed zolbetuximab benefit; FDA approval in combination with CAPOX for CLDN18.2-positive, HER2-negative first-line disease | Nat Med |
| RAINBOW | Ramucirumab plus paclitaxel versus placebo plus paclitaxel in previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma | 2014 | 665 | Ramucirumab plus paclitaxel | Paclitaxel alone | Metastatic gastric or EGJ adenocarcinoma progressing on first-line chemotherapy | Overall survival | Median OS 9.63 vs 7.36 months (P < .0001) | PFS 4.4 vs 2.86 months; ORR 28% vs 6% (P = .0001); neutropenia and hypertension more common with ramucirumab [363] | Established ramucirumab plus paclitaxel as category 1 preferred second-line option | Lancet Oncol |
| DESTINY-Gastric01 | Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer | 2020 | 188 | Fam-trastuzumab deruxtecan-nxki | Physician's choice (paclitaxel or irinotecan) | Progressive disease following at least two prior lines of therapy, including trastuzumab, with HER2-positive gastric or EGJ adenocarcinoma | Overall response rate | ORR 40.5% vs 11%; OS 12.5 vs 8.4 months (P = .0097); median PFS 5.6 vs 3.5 months | Median DOR 11.3 vs 3.9 months; ILD/pneumonitis occurred in 12 patients resulting in 1 drug-related death [366] | FDA approval for HER2-positive solid tumors in second-line or subsequent therapy; category 1 preferred option | N Engl J Med |
| INT-0116 | Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction | 2001 | 556 | Surgery followed by postoperative chemoradiation (bolus fluorouracil and leucovorin before and after concurrent chemoradiation) | Surgery alone | Stage IB-IV (M0) gastric or EGJ adenocarcinoma post-surgery, not previously receiving preoperative therapy | Overall survival | Median OS 36 vs 27 months (P = .005); survival remained improved >10 years [58,59] | 3-year OS 50% vs 41%; 3-year RFS 48% vs 31%; local failure 19% vs 29% [58] | Established postoperative chemoradiation as standard for patients not receiving preoperative therapy who underwent less than D2 dissection | N Engl J Med |
| CLASSIC | Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy | 2012 | 1035 | Surgery followed by adjuvant capecitabine and oxaliplatin | Surgery alone | Stage II or IIIB gastric cancer post-curative D2 gastrectomy | Disease-free survival | 5-year DFS 68% vs 53% (P < .0001); 5-year OS 78% vs 69% | 3-year DFS 74% vs 59% (P < .0001) [62,63] | Established capecitabine and oxaliplatin as category 1 preferred postoperative chemotherapy after D2 dissection | Lancet |
| REGARD | Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma | 2014 | 355 | Ramucirumab | Placebo | Advanced gastric or EGJ adenocarcinoma progressing after first-line chemotherapy | Overall survival | Median OS 5.2 vs 3.8 months (P = .047) | Hypertension more common with ramucirumab (16% vs 8%) [333] | Established ramucirumab as category 1 second-line option (monotherapy or with paclitaxel) | Lancet |
| TAGS | Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer | 2018 | 507 | Trifluridine and tipiracil plus best supportive care | Placebo plus best supportive care | Heavily pretreated metastatic gastric or EGJ cancer | Overall survival | Median OS 5.7 vs 3.6 months (HR, 0.69; 95% CI, 0.56-0.85; P = .0003) | PFS 2.0 vs 1.8 months (HR, 0.57; P < .0001); ORR 4.5% vs 2.1%; disease control rate 44.1% vs 14.5% [330] | FDA approval for third-line or subsequent therapy; category 1 preferred option for heavily pretreated patients with low-volume disease who can swallow pills | Lancet Oncol |
| RATIONALE-305 | Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma | 2024 | 997 | Tislelizumab plus chemotherapy (capecitabine plus oxaliplatin or fluorouracil plus cisplatin) | Placebo plus chemotherapy | Unresectable locally advanced or metastatic gastric or EGJ adenocarcinoma | Overall survival | Median OS 15 vs 12.9 months (HR, 0.80; P = .001) | PFS 6.9 vs 6.2 months (HR, 0.78); PD-L1 TAP ≥5%: OS 17.2 vs 12.6 months (HR, 0.74; P = .006) [171] | FDA approval for PD-L1 CPS ≥1; category 1 preferred option for PD-L1 CPS ≥5 | BMJ |
| DANTE/IKF-s633 | Perioperative atezolizumab plus FLOT for resectable esophagogastric cancer (interim results) | 2024 | Not provided in source | Atezolizumab plus FLOT perioperatively | Not described in this source | Resectable esophagogastric cancer | Not fully described | Referenced as ongoing/interim [251] | Not described | Not yet established; referenced as evidence supporting caution with ICI in this setting for certain PD-L1 negative subgroups | J Clin Oncol |
| CRITICS | Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer | 2018 | 788 | Preoperative chemotherapy followed by postoperative chemoradiation | Perioperative chemotherapy (3 preoperative and 3 postoperative cycles) | Resectable gastric adenocarcinoma receiving preoperative chemotherapy | Overall survival | Median OS 37 vs 43 months (HR, 1.01; 95% CI, 0.84-1.22; P = .90) | 5-year OS 46% vs 58% (HR, 1.62; P = .0004) [243,247] | Adding RT to postoperative chemotherapy confers no survival benefit following adequate preoperative chemotherapy and surgery | Lancet Oncol |
Clinical PearlsClick to collapse
- Pearl 1: Universal testing for MSI by PCR/NGS or MMR by IHC is recommended in ALL newly diagnosed patients, not just advanced disease [GAST-1]. Universal testing for PD-L1 is also recommended in all newly diagnosed patients [GAST-1].
- Pearl 2: EUS is not reliable for predicting superficial or deep submucosal invasion; endoscopic resection is recommended to provide accurate staging, with superficial pT1b defined as ≤500 μm invasion and deep pT1b defined as >500 μm invasion [GAST-2A footnote p].
- Pearl 3: For medically fit patients, if unfavorable histology after ER (poorly differentiated or diffuse type), consider surgery rather than surveillance [GAST-2A footnote u].
- Pearl 4: Gastrectomy for curative intent should include assessment of at least 16 regional lymph nodes; retrieval and assessment of >30 nodes is desirable. These standards apply to both open and minimally invasive gastrectomy [GAST-B 2 of 7, GAST-C 2 of 5].
- Pearl 5: Minimally invasive gastrectomy has demonstrated comparable oncologic outcomes to open surgery in selected patients with clinically operable disease. Recommend caution using minimally invasive approaches for clinically T4b or N2 bulky gastric cancer [GAST-C 2 of 5].
- Pearl 6: Laparoscopy with cytology is indicated for clinical stage T1b or higher when considering local therapy. Positive peritoneal cytology in the absence of visible peritoneal implants is defined as M1 disease [GAST-1 footnote n, GAST-C 1 of 5].
- Pearl 7: In patients at higher risk of postoperative nutritional intolerance or anastomotic complications, feeding jejunostomy may be considered [GAST-3A footnote z]. The panel previously recommended feeding jejunostomy generally but now considers it only for higher-risk patients.
- Pearl 8: For patients with MSI-H/dMMR tumors treated with neoadjuvant ICI, gastrectomy with appropriate lymphadenectomy remains the standard approach outside of prospective organ-preservation clinical trials [GAST-2A footnote s].
Special SituationsClick to collapse
MSI-H/dMMR tumors in perioperative setting
MSI-H/dMMR tumors in metastatic setting
HER2-positive disease
CLDN18.2-positive disease
Peritoneal carcinoma as only disease
Postoperative chemoradiation vs chemotherapy
Diffuse type gastric cancer with FLOT + durvalumab
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer, Version 3.2026
NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities
AJCC Cancer Staging Manual, 8th Edition
NCCN Guidelines for Distress Management
NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric
NCCN Guidelines for Adult Cancer Pain
NCCN Guidelines for Antiemesis
NCCN Guidelines for Survivorship
NCCN Guidelines for Smoking Cessation
NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers
H. pylori guidelines
Maastricht Consensus Report H. pylori guidelines
Cancer Protocol Templates
Protective FactorsClick to collapse
- H. pylori eradication therapy for prevention of metachronous gastric cancer [64, GAST-1, footnote i]
- Improved food preservation and access to clean drinking water (associated with declining intestinal type gastric cancer rates in North America and Western Europe) [MS-2, 1, 3, 16, 23]
- Diet with low promotion of gastric cancer [MS-2, 1, 16, 23]