Sections

Gastric Cancer

Guidelines

Guidelines Summary

Screening

Recommendations regarding gastric cancer screening vary regionally, depending on the rate of the disease. Although early-detection screening is routine in areas with high disease rates, such as Japan and Korea, no major United States organization recommends general population screening for gastric cancer. According to the National Cancer Institute, there is no evidence that screening for gastric cancer would result in a decrease in mortality in areas with relatively low incidence of the disease, such as the United States.^[69]

Risk Factors and Prevention

Environmental risk factors for gastric cancer include the following:

Smoking
Diets high in salt, smoked foods, salted fish and meat, and pickled vegetables ^[24]
Helicobacter pylori infection
Previous gastric surgery
Pernicious anemia
Adenomatous polyps
Chronic atrophic gastritis
Radiation exposure

The National Cancer Institute (NCI) concludes that evidence suggests smoking prevention or cessation would result in a decreased risk of gastric cancer. However, the impact on risk reduction of dietary changes to decrease salt and increase consumption of fruits, vegetables, and whole grains is uncertain.^[20]

Management of precancerous conditions

In 2012, the European Society of Gastrointestinal Endoscopy, a group of European gastrological societies (the European Society of Gastrointestinal Endoscopy, the European Helicobacter Study Group, the European Society of Pathology and the Sociedade Portuguesa de Endoscopia Digestiva), published guidelines for the management for precancerous conditions and lesions in the stomach. These guidelines emphasize the increased cancer risk in patients with chronic gastritis, atrophy, intestinal metaplasia, or dysplasia and focus on treatment and surveillance, but do not address general-population screening for these conditions.^[70]

The major recommendations include the following^[70]:

Magnification chromoendoscopy or narrow-band imaging (NBI) endoscopy with or without magnification may be offered for improved diagnosis of pre-neoplastic gastric conditions/lesions
At least four biopsies of the proximal and distal stomach, on the lesser and greater curvature, are needed for adequate assessment of premalignant gastric conditions
Patients with extensive atrophy and/or extensive intestinal metaplasia should be offered endoscopic surveillance every 3 years
Patients with mild to moderate atrophy/intestinal metaplasia only in antrum do not need follow-up
If H pylori infection is present, eradication should be offered to prevent high grade dysplasia or carcinoma
The use of cyclooxygenase-2 (COX-2) inhibitors or dietary supplementation with antioxidants (ascorbic acid and beta-carotene) are not endorsed as approaches to decrease the risk of progression of gastric precancerous lesions
Patients with dysplasia without a visible endoscopic lesion should be closely followed up; those with high grade immediately and 6 to 12 months thereafter; those with low grade, within 12 months
Those with dysplasia or cancer within an endoscopically visible lesion should undergo staging and resection.

Helicobacter pylori Infection

H pylori is the most common proven risk factor for non-cardiac gastric cancer. Guidelines for the management of H pylori infection have been issued by the following organizations:

American College of Gastroenterology (ACOG)
European Helicobacter Study Group
Canadian Association of Gastroenterology (CAG)

The 2017 ACOG guidelines include the following recommendations^[71]:

Evidence that eradication of H pylori infection reverses the gastric premalignant changes of gastric atrophy and intestinal metaplasia is conflicting.
Testing for H pylori infection is indicated in all patients with active peptic ulcer disease, a past history of documented peptic ulcer,low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, or a history of endoscopic resection of early gastric cancer; testing may be considered in patients with uninvestigated dyspepsia who are younger than 60 years and do not have alarm features (non-endoscopic testing)

In North America, triple therapy with a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole for 14 days remains a recommended treatment option in areas where H pylori clarithromycin resistance is known to be < 15% and in patients with no previous history of macrolide exposure for any reason. Other recommended first-line treatment regimens are as follows:

Bismuth quadruple therapy with a PPI, bismuth, tetracycline, and a nitroimidazole for 10–14 days, especially in patients with any previous macrolide exposure or penicillin allergy
Concomitant therapy consisting of a PPI, clarithromycin, amoxicillin and a nitroimidazole for 10–14 days

Suggested first-line treatment regimens are as follows:

Sequential therapy with a PPI and amoxicillin for 5–7 days followed by a PPI, clarithromycin, and a nitroimidazole for 5–7 days
Hybrid therapy with a PPI and amoxicillin for 7 days followed by a PPI, amoxicillin, clarithromycin and a nitroimidazole for 7 days
Levofloxacin triple therapy with a PPI, levofloxacin, and amoxicillin for 10–14 days
Fluoroquinolone sequential therapy with a PPI and amoxicillin for 5–7 days followed by a PPI, fluoroquinolone, and nitroimidazole for 5–7 days

The 2012 European Helicobacter Study Group guidelines note that there is strong evidence that H pylori eradication reduces the risk of gastric cancer, and that the risk of gastric cancer can be reduced more effectively by eradication before the development of preneoplastic conditions. The guidelines recommend that H pylori eradication to prevent gastric cancer be considered in the following^[72]:

First-degree relatives of family members with a diagnosis of gastric cancer
Individuals with previously treated gastric neoplasia
Individuals with severe pan-gastritis, corpus-predominant gastritis, or severe atrophy
Individuals with chronic gastric acid inhibition for more than 1 year
Individuals with other environmental risk factors for gastric cancer (eg, heavy smoking; high exposure to dust, coal, quartz, cement; work in quarries)

The guidelines recommend that antibiotic combination treatment be chosen according to local H pylori antibiotic resistance patterns. Endoscopic follow-up is recommended for the following preneoplastic high-risk conditions^[72]:

Pernicious anemia with histological confirmation of type A autoimmune atrophic gastritis
Histological and/or serological signs of subtotal or total atrophic gastritis with hypo- or achlorhydria
Gastric adenoma

Recommended follow-up intervals are as follows^[71]:

Patients with moderate to severe atrophy: Every 2–3 years
Patients with dysplasia: Every 3–6 months

The 2016 Canadian Association of Gastroenterology (CAG) consensus guidelines took note of the growing prevalence of antibiotic-resistant strains of H pylori and the increased failure of PPI triple therapies (a PPI plus two of the following antibiotics: clarithromycin, amoxicillin, or metronidazole) for 7 to 10 days as first-line therapy. In response, the guidelines gave a strong recommendation to a treatment duration of 14 days with the choice of first-line therapy based on local antibiotic resistance patterns and eradication rates. First-line therapy options include^[73]:

Bismuth quadruple therapy (PPI, bismuth, metronidazol, and tetracycline)
Nonbismuth quadruple therapy (PPI, amoxicillin, metronidazole, and clarithromycin)
PPI triple therapy only in areas with low clarithromycin resistance (< 15%) or proven high local eradication rates (>85%)

In addition, the CAG guidelines recommended against the following therapies^[73]:

Levofloxacin triple therapy (PPI, amoxicillin levofloxacin)
Sequential nonbismuth quadruple therapy (PPI and amoxicillin followed by PPI, metronidazole and clarithromycin)
The addition of probiotics to eradication therapy for the purpose of reducing adverse events or increasing eradication rates

For more information, seeHelicobacter pylori Infection Treatment.

Hereditary Cancer Predisposition Syndromes

Hereditary syndromes with a predisposition for stomach cancer include the following:

Hereditary diffuse gastric cancer (HDGC)
Lynch syndrome (hereditary nonpolyposis colorectal cancer)
Familial adenomatous polyposis (FAP)
Juvenile polyposis syndrome
Peutz-Jeghers syndrome

The following organizations have released guidelines for the evaluation and management of hereditary cancer predisposition syndromes:

National Comprehensiver Cancer Network (NCCN) ^[74]
International Gastric Cancer Linkage Consortium ^{[75, 76]}
US Multi-Society Task Force on Colorectal Cancer ^[77]

Hereditary Diffuse Gastric Cancer

HDGC is the most common genetic predisposing syndrome for gastric cancer, with germline truncating mutations of the E-cadherin gene (CDH1) detected in 30-50% of diffuse-type gastric cancers. Families that harbor these mutations have an autosomal dominant pattern of inheritance with a very high penetrance. NCCN guidelines recommendations for CDH1 mutation carriers include the following^[4]:

The efficacy of endoscopic surveillance has not been established
Prophylactic gastrectomy (without a D2 lymph node dissection) between the ages of 18 and 40 for asymptomatic carriers with a family history of HDGC
Prophylactic gastrectomy is not recommended before age 18 except in carriers with family members diagnosed with gastric cancer before age 25
For individuals who decline prophylactic gastrectomy, upper endoscopy with multiple random biopsies should be offered every 6-12 months
Women with CDH1 mutations are at increased risk for breast cancer and should be followed similar to BRCA1/BRCA2 mutation carriers

In 2015, the International Gastric Cancer Linkage Consortium updated its 2010 consensus guidelines for the clinical management of HDGC which are generally in agreement with the NCCN recommendations.^{[75, 76]}The 2010 recommendations were also endorsed in the joint guidelines for diagnosis and management of gastric cancer published by the European Society for Medical Oncology(ESM), European Socieity of Surgical Oncology (ESSO) and European Society of Therapeutic Radiation Oncology (ESTRO) in 2013.^[78]

Additional recommendation include the following^{[75, 76]}:

For those individuals with clinical features suggestive of HDGC but without a germline CDH1 mutation, intensive endoscopic surveillance should also be offered
For select carriers with a family history of colon cancer, enhanced screening should be considered with colonoscopy beginning at age 40 or 10 years younger than the youngest age of diagnosis of colon cancer in a family member, whichever is younger, and repeated at intervals of 3–5 years.
Expert histopathological confirmation of (early) signet ring cell carcinoma

Lynch Syndrome (hereditary non-polyposis colorectal cancer)

Although the NCCN guidelines note that gastric cancer is the second most common extracolonic cancer (after endometrial cancer) in patients with Lynch syndrome, they do not find clear evidence to support screening for gastric, duodenal, or small bowel cancer in these patients. In selected individuals of Asian descent (or from countries with a high background incidence of gastric cancer), clinicians may consider upper endoscopy with visualization of the duodenum at the time of colonoscopy every 3–5 years, beginning at age 40 years. Testing for H pylori, and treatment if it is found, may also be considered.^[74]

In 2014, the US Multi-Society Task Force on Colorectal Cancer, which included the American College of Gastroenterology, the American Gastroenterological Association Institute, and the American Society for Gastrointestinal Endoscopy, released consensus guidelines for the genetic evaluation and management of Lynch syndrome. With regard to gastric cancer, the task force recommendations were as follows^[77]:

Consider screening by esophagogastroduodenoscopy (EGD) with biopsy of the gastric antrum in individuals at risk for or diagnosed with Lynch syndrome at age 30−35 years
Treat H pylori infection when found
Continue surveillance every 2−3 years, based on individual patient risk factors
In view of the relatively low risk of gastric cancer and the lack of established benefit, the 2013 revised guidelines from the Mallorca group for European experts does not recommend surveillance for gastric cancer but does recommend screening individuals with Lynch syndrome for the presence of H pylori infection and subsequent eradication if detected.^[79]

Familial Adenomatous Polyposis

The NCCN guidelines recommend examining the stomach at the time of duodenoscopy. Special screening or surgery should only be considered for fundic gland polyps with high-grade dysplasia. Non-fundic gland polyps should be managed endoscopically; polyps with high-grade dysplasia that cannot be removed, or invasive cancer detected on biopsy should be referred for gastrectomy.^[77]

Juvenile Polyposis Syndrome and Peutz-Jeghers Syndrome

For both juvenile polyposis syndrome and Peutz-Jeghers syndrome, NCCN guidelines recommend EGD surveillance be considered. For individuals with juvenile polyposis syndrome initial screening should begin at age 15 and performed annually thereafter if polyps are found; if no polyps are found, the test should be repeated every 2-3 years. For Peutz-Jeghers syndrome, screening should begin in late teens and repeated every 2-3 years.^[77]

Diagnosis and Staging

NCCN recommendations for diagnosis of gastric cancer are as follows^[4]:

Endoscopy is the primary procedure for diagnosis, surveillance, and staging of gastric cancer
Endoscopic ultrasound (EUS) is preferred if early stage disease suspected or if early versus locally advanced disease needs to be determined
Multiple biopsies should be performed, especially with ulcerated lesions
Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of small lesions (eg, focal nodules ≤2 cm) can be safely performed to provide a larger specimen that may contribute to accurate staging of early-stage cancers; in addition, such excisional biopsies are potentially therapeutic
Chest/abdomen/pelvic CT with oral and IV contrast
PET/CT evaluation (skull base to mid-thigh) if no evidence of M1 disease and if clinically indicated
Biopsy of metastatic diseas,e as clinically indicated
High microsatellite instability/deficient mismatch repair (MSI-H/dMMR) testing if metastatic disease is documented or suspected
HER2 and PD-L1 testing if metastatic adenocarcinoma is documented or suspected

The European Society for Medical Oncology guidelines provide similar recommendations.^[78]

Staging Systems

Two major staging systems are commonly used in gastric cancer, as follows:

The tumor-node-metastasis (TNM) system, developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)^[31]
The Japanese Research Society staging, based on where the lymph nodes with cancer are located in the stomach.^[80]

Both the NCCN and ESMO use the TNM system for staging.^{[4, 78]}For further information, see Gastric Cancer Staging.

National Comprehensive Cancer Network

NCCN guidelines for treatment of early-stage (Tis, or T1a) gastric cancer are as follows^[4]:

Endoscopic mucosal resection or surgery are the standard treatment options
Complete surgical resection offers the potential for long-term survival
Posttreatment endoscopic surveillance is indicated

For medically fit patients with potentially resectable cT1b gastric cancer, the NCCN recommends surgery. For those with cT2 disease or higher (any N), recommendations are as follows^[4]:

Surgery only
Perioperative chemotherapy with surgery (category 1) (preferred) or
Preoperative chemoradiation with surgery (category 2B)

For surgically unresectable locoregional disease, NCCN recommendations are as follows:

Chemoradiation or
Systemic therapy or
Palliative management

For metastatic gastric cancer, the NCCN recommends palliative chemotherapy or entry into a clinical trial.^[4]

For systemic therapy, NCCN recommendations are as follows:

Perioperative chemotherapy - Preferred regimens are FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel [Taxotere]) (category 1) and a fluoropyrimidine plus oxaliplatin
Preoperative chemoradiation - Infusional fluorouracil can be replaced with capecitabine
Postoperative chemoradiation in patients who received less than a D2 lymph node dissection - Infusional fluorouracil or capecitabine before and after fluoropyrimidine-based chemoradiation
Postoperative chemoradiation in patients who have undergone primary D2 lymph node dissection - Preferred regimens are capecitabine and oxaliplatin (category 1) and fluorouracil and oxaliplatin
Chemoradiation for unresectable disease - Preferred Regimens are fluorouracil (or capecitabine) and either oxaliplatin or cisplatin

For description of chemotherapy and chemoradiotherapy regimens, see Gastric Cancer Treatment Protocols.

European Society for Medical Oncology

ESMO considers multidisciplinary treatment planning mandatory for patients with gastric cancer. The management team should include surgeons, medical and radiation oncologists, gastroenterologists, radiologists, and pathologists plus other specialists if available.^[78]

Local and locoregional gastric cancer:

Endoscopic or surgical resection alone is appropriate for selected very early tumors (stage IA).
For stage IB-III gastric cancer, perioperative therapy and radical gastrectomy is recommended.
Preoperative and postoperative chemotherapy is recommended for patients with stage ≥IB resectable gastric cancer.
A triplet chemotherapy regimen including a fluoropyrimidine, a platinum compound, and docetaxel should be given when possible.
Perioperative use of FLOT is standard of care for patients who are able to tolerate a triple cytotoxic drug regimen.
For patients unfit for triplet chemotherapy, a combination of a fluoropyrimidine with cisplatin or oxaliplatin is recommended.

Adjuvant treatment of local and locoregional disease:

For patients with stage ≥IB gastric cancer who have undergone surgery without preoperative chemotherapy, adjuvant chemotherapy is recommended.
For patients who have undergone surgery with clear margins (R0), postoperative radiation therapy (RT) has no added benefit and should not be given.
For patients who receive perioperative or postoperative chemotherapy, the addition of postoperative RT has no added benefit and should not be given.
For patients who have not received preoperative chemotherapy and have not undergone an appropriate D2 lymphadenectomy, adjuvant chemoradiation therapy (CRT) can be considered.
For patients who have undergone surgery with involved margins (R1), adjuvant RT or CRT might be considered as an individual recommendation, but is not standard.
For patients with high microsatellite instability (MSI-H) gastric cancer who have undergone curative surgery, adjuvant chemotherapy cannot be recommended, but if a response is required to downstage a tumor before surgery, FLOT is recommended.

Treatment of locally advanced unresectable or metastatic gastric cancer:

First-line chemotherapy with a platinum and fluoropyrimidine is recommended. Oxaliplatin is preferred, especially for older patients. Tegafur–gimeracil–oteracil (S-1) is commonly used in Asian patients.
Due to higher levels of toxicity and uncertain survival benefit over recommended doublet regimens, first-line taxane-based triplet chemotherapy is not recommended as a standard approach.
Irinotecan–5-fluorouracil (5-FU) can be considered an alternative option for patients who do not tolerate platinum compounds.
Trastuzumab plus chemotherapy is recommended in patients with HER2-positive tumors.
Nivolumab plus chemotherapy is recommended for advanced untreated gastric, esophagogastric junction, and esophageal cancer with a programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥5.
Pembrolizumab is approved for patients with esophagogastric junction adenocarcinoma that expresses PD-L1 CPS ≥10.

Second- and later-line treatment for locally advanced unresectable or metastatic gastric cancer:

Ramucirumab–paclitaxel is recommended for second-line treatment of gastric. Ramucirumab monotherapy is also an option.
Where ramucirumab is not available, paclitaxel, docetaxel, or irinotecan monotherapy or FOLFIRI are recommended.
Treatment with trastuzumab is not recommended after first-line therapy in HER2-positive advanced gastric cancer but trastuzumab deruxtecan may be considered (Food and Drug Administration [FDA] approved, not European Medicines Agency [EMA] approved).
Pembrolizumab is recommended for second-line treatment of patients with MSI-H/deficient mismatch repair (dMMR) gastric cancer.
For patients previously treated with two lines of therapy, trifluridine–tipiracil is recommended. Alternative treatments include a taxane or irinotecan.

Surgery for metastatic gastric cancer:

Gastrectomy is not recommended in metastatic gastric cancer unless required for palliation of symptoms.
Resection of metastases cannot be recommended in general, but might be considered as an individual approach in highly selected patients with oligometastatic disease and response to chemotherapy.

Follow-up

NCCN guidelines recommend the following in all patients after treatment for gastric cancer^[4]:

History and physical examination every 3–6 months for 1–2 years, every 6–12 months for 3–5 years
Complete blood count (CBC) and chemistry profile as clinically indicated
Routine gastric cancer–specific surveillance (ie, radiologic imaging, endoscopic evaluation, tumor markers) is not recommended beyond 5 years

NCCN guidelines recommend additional surveillance measures, depending on disease stage and treatment. For Tis successfully treated with endoscopic resection (ER), recommendations are as follows:

Upper gastrointestinal (GI) endoscopy (EGD) every 6 months for 1 year, then annually for 3 years
Routine imaging (CT chest/abdomen/pelvis with oral and IV contrast) as clinically indicated, based on symptoms and concern for recurrence

For pathologic stage I (pT1a,T1b,N0 treated by surgical resection or T1a treated by ER), recommendations are as follows:

For patients treated by ER, EGD every 6 months for 1 year, then annually for up to 5 years; tThereafter, as needed based on symptoms and/or radiographic findings
For patients treated by surgical resection, EGD as clinically indicated
CT chest/abdomen/pelvis with oral and IV contrast as clinically indicated
Monitor for nutritional deficiency (eg, vitamin B12 and iron) in surgically resected patients (especially after total gastrectomy) and treat as indicated

For stage II/III or yp stage I–III (treated with neoadjuvant ± adjuvant therapy), recommendations are as follows:

For patients who had partial or subtotal gastrectomy, EGD as clinically indicated
CT chest/abdomen/pelvis with oral and IV contrast (preferred) every 6 months for first 2 years,then annually up to 5 yearsy
Monitor for nutritional deficiency (eg, vitamin B12 and iron) in surgically resected patients (especially after total gastrectomy) and treat as indicated

ESMO recommendations for follow-up after treatment for gastric cancer are as follows^[78]:

Regular follow-up is recommended for investigation and treatment of symptoms, provision of psychological support, and early detection of recurrence.
Follow-up should be tailored to the individual patient and stage of disease.
Dietary support is recommended, with attention to vitamin and mineral deficiencies.

Medication

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Stomach and duodenum, coronal section.
Early gastric cancer in the gastric body. Courtesy of Wikimedia Commons (author Med_Chaos).

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Gastric Cancer Guidelines