Sections

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 US 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.^[67]

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 ^[10]
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.^[22]

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.^[68]

The major recommendations include the following^[68]:

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^[69]:

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^[70]:

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^[70]:

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^[69]:

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^[71]:

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^[71]:

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

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) ^[72]
International Gastric Cancer Linkage Consortium ^{[73, 74]}
US Multi-Society Task Force on Colorectal Cancer ^[75]

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.^{[73, 74]}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.^[76]

Additional recommendation include the following^{[73, 74]}:

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.^[72]

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^[75]:

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.^[77]

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.^[75]

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.^[75]

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.^[76]

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)^[30]
The Japanese Research Society staging, based on where the lymph nodes with cancer are located in the stomach.^[78]

Both the NCCN and ESMO use the TNM system for staging.^{[4, 76]}For further information, see Gastric Cancer Staging.

Treatment Management

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.

The European Society for Medical Oncology recommendations for treatment are as follows^[76]:

Multidisciplinary treatment planning is mandatory; the management team should include surgeons, medical and radiation oncologists, gastroenterologists, radiologists, and pathologists plus other specialists if available.
For stage IB–III gastric cancer, radical gastrectomy is indicated and perioperative therapy is recommended. Medically fit patients should undergo D2 resections in high-volume surgical centers.
T1a gastric cancers may be amenable to endoscopic resection if they are well-differentiated, ≤2 cm, confined to the mucosa, and not ulcerated.
With T1 tumors that do not meet the criteria for endoscopic therapy, lymph node dissection during open surgery can be limited to perigastric nodes and include local N2 nodes; sentinel lymph node mapping may further modify these approaches.
The preferred treatment for operable gastric cancers beyond stage T1N0 is surgery with both preoperative and postoperative chemotherapy
For patients with stage IB disease or higher who do not receive preoperative chemotherapy, the treatment options include either chemoradiotherapy or chemotherapy in the adjuvant setting
Radical gastrectomy is indicated for resectable stage IB–III disease, although subtotal gastrectomy may be performed if a macroscopic proximal margin of 5 cm can be achieved between the tumor and the es.ophagogastric junction (8 cm for diffuse-type cancers).
In Asian countries, dissection leads to superior outcomes compared with D1 resection. In Western countries, medically fit patients should undergo D2 dissection in specialized, high-volume centers.
Pre- and postoperative chemotherapy with a platinum and fluoropyrimidine combination is recommended for patients with stage IB or higher resectable gastric cancer; capecitabine-containing regimens can also be suggested.
For inoperable or metastatic gastric cancer, treatment is with palliative chemotherapy, or best supportive care if the patient is unfit for treatment
In HER-2 negative disease, combination regimens based upon a platinum–fluoropyrimidine doublet are generally used; triplet regimens are controversial, but the addition of an anthracycline (eg, epirubicin) has demonstrated benefit
In HER-2 positive disease, recommended chemotherapy is with trastuzumab plus cisplatin and either 5-fluorouracil or capecitabine
Second-line chemotherapy options include irinotecan and docetaxel or paclitaxel

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