Gastric Cancer

Gastric cancer was once the second most common cancer in the world. In most developed countries, however, rates of stomach cancer have declined dramatically over the past half century. In the United States, stomach malignancy is currently the 15th most common cancer.[2]

Decreases in gastric cancer have been attributed in part to widespread use of refrigeration, which has had several beneficial effects: increased consumption of fresh fruits and vegetables; decreased intake of salt, which had been used as a food preservative; and decreased contamination of food by carcinogenic compounds arising from the decay of unrefrigerated meat products. Salt and salted foods may damage the gastric mucosa, leading to inflammation and an associated increase in DNA synthesis and cell proliferation. Other factors likely contributing to the decline in stomach cancer rates include lower rates of chronic Helicobacter pylori infection, thanks to improved sanitation and use of antibiotics, and increased screening in some countries.[5]

Nevertheless, gastric cancer remains difficult to cure in Western countries, primarily because most patients present with advanced disease. Even patients who present in the most favorable condition and who undergo curative surgical resection often die of recurrent disease. However, two studies have demonstrated improved survival with adjuvant therapy: a US study using postoperative chemoradiation[6] and a European study using preoperative and postoperative chemotherapy.[7]

For patient education resources, see Stomach Cancer.

Management of stomach cancer requires a thorough understanding of gastric anatomy. An image depicting stomach anatomy can be seen below.

Stomach and duodenum, coronal section.

The stomach begins at the gastroesophageal junction and ends at the duodenum. The stomach has three parts: the uppermost part is the cardia; the middle and largest part is the body, or fundus; and the distal portion, the pylorus, connects to the duodenum. These anatomic zones have distinct histologic features. The cardia contains predominantly mucin-secreting cells. The fundus contains mucoid cells, chief cells, and parietal cells. The pylorus is composed of mucus-producing cells and endocrine cells.

The stomach wall is made up of five layers. From the lumen out, the layers are as follows:

• Mucosa
• Submucosa
• Muscularis
• Subserosa
• Serosa

Externally, the peritoneum of the greater sac covers the anterior surface of the stomach. A portion of the lesser sac drapes posteriorly over the stomach. The gastroesophageal junction has limited or no serosal covering.

The right portion of the anterior gastric surface is adjacent to the left lobe of the liver and the anterior abdominal wall. The left portion of the stomach is adjacent to the spleen, the left adrenal gland, the superior portion of the left kidney, the ventral portion of the pancreas, and the transverse colon.

The site of stomach cancer is classified on the basis of its relationship to the long axis of the stomach. Approximately 40% of cancers develop in the lower part, 40% in the middle part, and 15% in the upper part; 10% involve more than one part of the organ. Most of the decrease in gastric cancer incidence and mortality in the United States has involved cancer in the lower part of the stomach; the incidence of adenocarcinoma in the cardia has actually shown a gradual increase.

Ooi et al identified three oncogenic pathways that are deregulated in the majority (>70%) of gastric cancers: the proliferation/stem cell, NF-kappaβ, and Wnt/beta-catenin pathways. Their study suggests that interactions between these pathways may play an important role in influencing disease behavior and patient survival.[8]

The intestinal type of non-cardia gastric cancer is generally thought to arise from Helicobacter pylori infection, which initiates a sequence that progresses from chronic non-atrophic gastritis to atrophic gastritis, then intestinal metaplasia, and finally dysplasia. This progression is known as Correa’s cascade. In a population-based cohort study, Swedish researchers found that after a 2-year latency, patients with precancerous gastric lesions were at higher risk for gastric cancer than the general Swedish population, and that risk increased steadily with progression through Correa’s cascade. The researchers estimated that the 20-year gastric cancer risk in patients with particular gastroscopy findings was as follows[9] :

• Normal mucosa – One in 256
• Gastritis – One in 85
• Atrophic gastritis – One in 50
• Intestinal metaplasia – One in 39
• Dysplasia – One in 19

Hematogenous and lymphatic spread

Understanding the vascular supply of the stomach allows understanding of the routes of hematogenous spread. The vascular supply of the stomach is derived from the celiac artery. The left gastric artery, a branch of the celiac artery, supplies the upper right portion of the stomach. The common hepatic artery branches into the right gastric artery, which supplies the lower portion of the stomach, and the right gastroepiploic branch, which supplies the lower portion of the greater curvature.

Understanding the lymphatic drainage can clarify the areas at risk for nodal involvement by cancer. The lymphatic drainage of the stomach is complex. Primary lymphatic drainage is along the celiac axis. Minor drainage occurs along the splenic hilum, suprapancreatic nodal groups, porta hepatis, and gastroduodenal areas.

United States

The American Cancer Society estimates that about 26,560 cases of stomach cancer (16,160 in men and 10,400 in women) will be diagnosed in 2021.[10] Median age at diagnosis is 68 years.[2] Gastric cancer is the 15th most common cancer in the US.[2]

International

Once the second most common cancer worldwide, stomach cancer has dropped to sixth place, after cancers of the lung, breast, prostate, colon and rectum, and skin (non-melanoma).[5] Stomach cancer is the third most common cause of death from cancer.[5] The World Health Organization estimates that in 2018, gastric cancer accounted for 783,000 deaths worldwide.[1]

Tremendous geographic variation exists in the incidence of this disease around the world. Rates of the disease are low in Northern America and Northern Europe, and highest in Asian countries (eg, Mongolia, Japan, the Republic of Korea). The highest death rates are recorded in western Asian countries (Iran, Turkmenistan, Kyrgyzstan).[5]  

Using data from 92 cancer registries in 34 countries representing 10 world regions, Arnold et al predicted that overall gastric cancer incidence rates will continue falling in most countries, including high-incidence countries such as Japan as well as low-incidence ones such as Australia. By 2035, incidence rates in 16 of those 34 countries will fall below the rare disease threshold (defined as 6 per 100,000 person-years).[11]

Nevertheless, the absolute number of new gastric cancer cases is expected to increase in the majority of countries. New cases could double in Canada, Cyprus, South Korea, Slovakia, and Thailand, while dropping slightly in a few other countries (eg, Bulgaria, Lithuania).[11]

While decreasing or stable incidence rates were consistently observed in people aged 50 years and above, Arnold et al predicted increases in incidence in those younger than 50 years in 15 of 34 countries, including Belarus, Chile, the Netherlands, Canada, and the United Kingdom.[11]

In the United States, gastric cancer represents 1.5% of all new cancer cases but 1.8% of cancer deaths. The overall 5-year relative survival rate, which was 14.3% in 1975, rose to 32.0% by 2010-2016. During that period, the 5-year relative survival rate by stage at diagnosis was 69.5% for localized disease,  32.0% for regional disease, and 5.5% for distant disease.[2] Worldwide, gastric cancer is the third leading cause of cancer death, with the highest rates reported in East Asia, South America and Eastern Europe.[1]

Race

The rates of gastric cancer are higher in Asian and South American countries than in the United States; in Japan, for example, stomach cancer is the most common cancer site in males.[5]  Japan, Chile, and Venezuela have developed a very rigorous early screening program that detects patients with early-stage disease (ie, low tumor burden). These patients appear to do quite well. In fact, in many Asian studies, patients with resected stage II and III disease tend to have better outcomes than similarly staged patients treated in Western countries. Some researchers suggest that this reflects a fundamental biologic difference in the disease as it manifests in Western countries.

In the United States, the incidence of stomach cancer in males is highest in blacks, followed by Asians and Pacific Islanders, Hispanics, and American Indian/Alaska natives. In females, rates are highest in Asians and Pacific Islanders, followed by blacks and Hispanics and American Indian/Alaska natives. In both males and females, rates are lowest in whites.[2]

Sex- and age-related demographics

In the United States, gastric cancer affects slightly more men than women; the American Cancer Society estimated that in 2020, 16,980 new cases would be diagnosed in men and 10,620 in women.[10]  Worldwide, however, gastric cancer rates are about twice as high in men as in women.[5]

The median age at gastric cancer diagnosis in the United States is 68 years; fewer than 2% of cases occur in persons younger than 35 years.[2]  The gastric cancers that occur in younger patients may represent a more aggressive variant or may suggest a genetic predisposition to development of the disease.

Unfortunately, only a minority of patients with gastric cancer who undergo surgical resection will be cured of their disease. Most patients have a recurrence.

Patterns of failure

Several studies have investigated the patterns of failure after surgical resection alone. Studies that depend solely on the physical examination, laboratory studies, and imaging studies may overestimate the percentage of patients with distant failure and underestimate the incidence of local failure, which is more difficult to detect.

A reoperation series from the University of Minnesota may offer a more accurate understanding of the biology of the disease. In this series of patients, researchers surgically reexplored patients 6 months after the initial surgery and meticulously recorded the patterns of disease spread. The total local-regional failure rate approached 67%. The gastric bed was the site of failure in 54% of these cases, and the regional lymph nodes were the site of failure in 42%. Approximately 26% of patients had evidence of distant failure. The patterns of failure included local tumor regrowth, tumor bed recurrences, regional lymph node failures, and distant failures (ie, hematogenous failures and peritoneal spread). Primary tumors involving the gastroesophageal junction tended to fail in the liver and the lungs. Lesions involving the esophagus failed in the liver.[12]

In the United States, about 25% of stomach cancer patients present with localized disease, 31% present with regional disease, and 32% present with distant metastatic disease; the remainder of cases surveyed were listed as unstaged.[3]

Early disease has no associated symptoms; however, some patients with incidental complaints are diagnosed with early gastric cancer. Most symptoms of gastric cancer reflect advanced disease. Patients may complain of one or more of the following:

• Indigestion
• Nausea or vomiting
• Dysphagia
• Postprandial fullness
• Loss of appetite
• Melena
• Hematemesis
• Weight loss

Late complications include the following:

• Pathologic peritoneal and pleural effusions
• Obstruction of the gastric outlet, gastroesophageal junction, or small bowel
• Bleeding in the stomach from esophageal varices or at the anastomosis after surgery
• Intrahepatic jaundice caused by hepatomegaly
• Extrahepatic jaundice
• Inanition resulting from starvation or cachexia of tumor origin

All physical signs are late events. By the time they develop, the disease is almost invariably too far advanced for curative procedures.

Signs may include a palpable enlarged stomach with succussion splash; hepatomegaly; periumbilical metastasis (Sister Mary Joseph nodule); and enlarged lymph nodes such as Virchow nodes (ie, left supraclavicular) and Irish node (anterior axillary). Blumer shelf (ie, shelflike tumor of the anterior rectal wall) may also be present. Some patients experience weight loss, and others may present with melena or pallor from anemia.

Paraneoplastic syndromes such as dermatomyositis, acanthosis nigricans, and circinate erythemas are poor prognostic features.

Other associated abnormalities include peripheral thrombophlebitis and microangiopathic hemolytic anemia.

Gastric cancer may often be multifactorial, involving both inherited predisposition and environmental factors.[13] Environmental factors implicated in the development of gastric cancer include the following:

• Diet
• Helicobacter pylori infection
• Previous gastric surgery
• Pernicious anemia
• Adenomatous polyps
• Chronic atrophic gastritis
• Radiation exposure

Diet

A diet rich in pickled vegetables, salted fish, salt, and smoked meats correlates with an increased incidence of gastric cancer.[13]

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.[14]

Smoking

Smoking is associated with an increased incidence of stomach cancer in a dose-dependent manner, both for number of cigarettes and for duration of smoking. Smoking increases the risk of cardiac and noncardiac forms of stomach cancer.[15] Cessation of smoking reduces the risk. A meta-analysis of 40 studies estimated that the risk was increased by approximately 1.5- to 1.6-fold and was higher in men.[16]

Helicobacter pylori infection

Chronic bacterial infection with H pylori is the strongest risk factor for stomach cancer.

H pylori may infect 50% of the world's population, but many fewer than 5% of infected individuals develop cancer. It may be that only a particular strain of H pylori is strongly associated with malignancy, probably because it is capable of producing the greatest amount of inflammation. In addition, full malignant transformation of affected parts of the stomach may require that the human host have a particular genotype of interleukin (IL) to cause the increased inflammation and an increased suppression of gastric acid secretion. For example, IL-17A and IL-17F are inflammatory cytokines that play a critical role in inflammation. Wu et al found that carriage of IL-17F 7488GA and GG genotypes were associated with an increased risk of gastric cancer.[17]

H pylori infection is associated with chronic atrophic gastritis, and patients with a history of prolonged gastritis have a sixfold increased risk of developing gastric cancer. Interestingly, this association is particularly strong for tumors located in the antrum, body, and fundus of the stomach but does not seem to hold for tumors originating in the cardia.[18]

A large-scale, long-term study from Korea—which along with China and Japan is a high-risk country for gastric cancer—concluded that in patients with a family history of gastric cancer, treatment of H pylori infection more than halves their risk of developing gastric cancer. In the study, which included 1676 patients ages 40 to 65 years with confirmed H pylori infection and at least one first-degree relative with gastric cancer, patients were randomized to triple antibiotic therapy or placebo and followed with surveillance endoscopy every 2 years.[19, 20]

Over a median follow-up of 9.2 years, gastric cancer developed in 1.2% of patients in the treatment group, versus 2.7% of those in the placebo group. Among patients with persistent infection (n = 979), gastric cancer developed in 2.9%, compared with 0.8% of those in whom the infection had been eradicated (hazard ratio, 0.27).[19, 20]

A study by Cheung et al found that risk of gastric cancer was increased in patients who used proton pump inhibitors (PPIs) long-term after successful treatment for H pylori infection.[21] In the study, which included 63,397 patients from a territory-wide Hong Kong health database with a median follow-up of 7.6 years, PPIs use was associated with more than a doubled risk of gastric cancer (hazard ratio [HR] 2.44; 95% confidence index [CI], 1.42 to 4.20). The risk increased with duration of PPIs use, as follows:

• ≥1 year - HR 5.04 (95% CI 1.23–20.61)
• ≥2 years - HR 6.65 (95% CI 1.62–27.26)
• ≥3 years - HR 8.34 (95% CI 2.02–34.41) 

The relevance of this study to clinical practice remains uncertain, however, as the results could be due to residual confounding or detection bias.[22]

Previous gastric surgery

Previous surgery is implicated as a risk factor. The rationale is that surgery alters the normal pH of the stomach, which may in turn lead to metaplastic and dysplastic changes in luminal cells.[23]

Retrospective studies demonstrate that a small percentage of patients who undergo gastric polyp removal have evidence of invasive carcinoma within the polyp. This discovery has led some researchers to conclude that polyps might represent premalignant conditions.

Genetic factors

Some 10% of stomach cancer cases are familial in origin. Genetic factors involved in gastric cancer remain poorly understood, though specific mutations have been identified in a subset of gastric cancer patients. For example, germline truncating mutations of the E-cadherin gene (CDH1) are detected in 50% of diffuse-type gastric cancers, and families that harbor these mutations have an autosomal dominant pattern of inheritance with a very high penetrance.[24]

Other hereditary syndromes with a predisposition for stomach cancer include the following:

• Hereditary nonpolyposis colorectal cancer
• Li-Fraumeni syndrome
• Familial adenomatous polyposis
• Peutz-Jeghers syndrome

Other factors

See the list below:

• Infection with the Epstein-Barr virus may be associated with a rare (< 1%) form of stomach cancer, lymphoepithelioma-like carcinoma.
• Pernicious anemia associated with advanced atrophic gastritis and intrinsic factor deficiency is a risk factor for gastric carcinoma.
• Gastric cancer may develop in the remaining portion of the stomach following a partial gastrectomy for gastric ulcer.  Benign gastric ulcers may themselves develop into malignancy.
• Obesity increases the risk of gastric cardia cancer.
• Radiation exposure: Survivors of atomic bomb blasts have had an increased rate of stomach cancer. Other populations exposed to radiation may also have an increased rate of stomach cancer.

Bisphosphonates

A large cohort study examined whether use of oral bisphosphonates was associated with an increased risk of esophageal or gastric cancers. No significant difference was observed for increased risk of esophageal or gastric cancers between the bisphosphonate cohort and the control group.[25]

Direct mortality rate within 30 days after a surgical procedure for gastric cancer has been reduced substantially over the last 40 years. Most major centers report a direct mortality rate of 1-2%.

Early postoperative complications include anastomotic failure, bleeding, ileus, transit failure at the anastomosis, cholecystitis (often occult sepsis without localizing signs), pancreatitis, pulmonary infections, and thromboembolism. Further surgery may be required for anastomotic leaks.

Late mechanicophysiologic complications include dumping syndrome, vitamin B-12 deficiency, reflux esophagitis, and bone disorders, especially osteoporosis.

Postgastrectomy patients often are immunologically deficient, as measured by blastogenic and delayed cutaneous hypersensitivity responses.

Studies for staging of stomach cancer may include the following[4] :

• Upper gastrointestinal (GI) tract endoscopy and biopsy
• Chest/abdomen/pelvic computed tomography (CT) with oral and intravenous contrast
• Positron emission tomography (PET) – CT evaluation if no evidence of M1 disease is found, and if clinically indicated
• Complete blood cell count (CBC) and comprehensive chemistry profile
• Endoscopic ultrasound if no evidence of M1 disease is found
• Endoscopic resection for early-stage cancers
• Biopsy of metastatic disease as clinically indicated
• Microsatellite instability (MSI) and deficient mismatch repair (dMMR) testing if metastatic disease is documented/suspected
• HER2-neu and programmed death ligand 1 (PD-L1) testing if metastatic adenocarcinoma is documented or suspected

Esophagogastroduodenoscopy has a diagnostic accuracy of 95%. This relatively safe and simple procedure provides a permanent color photographic record of the lesion. This procedure is also the primary method for obtaining a tissue diagnosis of suspected lesions. Biopsy of any ulcerated lesion should include at least 6 specimens taken from around the lesion because of variable malignant transformation. In selected cases, endoscopic ultrasound may be helpful in assessing depth of penetration of the tumor or involvement of adjacent structures.

Double-contrast upper GI series and barium swallows may be helpful in delineating the extent of disease when obstructive symptoms are present or when bulky proximal tumors prevent passage of the endoscope to examine the stomach distal to an obstruction (more common with gastroesophageal [GE]-junction tumors). These studies are only 75% accurate and should for the most part be used only when upper GI endoscopy is not feasible.

Chest radiograph is done to evaluate for metastatic lesions.

CT scan or MRI of the chest, abdomen, and pelvis assess the local disease process as well as evaluate potential areas of spread (ie, enlarged lymph nodes, possible liver metastases).

Endoscopic ultrasound allows for a more precise preoperative assessment of the tumor stage. Endoscopic sonography is becoming increasingly useful as a staging tool when the CT scan fails to find evidence of T3, T4, or metastatic disease. Institutions that favor neoadjuvant chemoradiotherapy for patients with locally advanced disease rely on endoscopic ultrasound data to improve patient stratification.

In a study of peritoneal cancer (PC) diagnosis, investigators found that the administration of carbonated water for dual-time point imaging may improve the accuracy of FDG PET/CT scanning for PC in patients previously diagnosed with colorectal cancer (CRC).[26]

Adenocarcinoma of the stomach constitutes 90-95% of all gastric malignancies. The second most common gastric malignancies are lymphomas. Gastrointestinal stromal tumors formerly classified as either leiomyomas or leiomyosarcomas account for 2% of gastric neoplasms (see Gastric Stromal Tumors). Carcinoids (1%), adenoacanthomas (1%), and squamous cell carcinomas (1%) are the remaining tumor histologic types.[3]

Adenocarcinoma of the stomach is subclassified according to histologic description as follows: tubular, papillary, mucinous, or signet-ring cells, and undifferentiated lesions.

Pathology specimens are also classified by gross appearance. In general, researchers consider gastric cancers ulcerative, polypoid, scirrhous (ie, diffuse linitis plastica), superficial spreading, multicentric, or Barrett ectopic adenocarcinoma.

Researchers also employ a variety of other classification schemes. The Lauren system classifies gastric cancer pathology as either type I (intestinal) or type II (diffuse). An appealing feature of classifying patients according to the Lauren system is that the descriptive pathologic entities have clinically relevant differences.

Intestinal, expansive, epidemic-type gastric cancer is associated with chronic atrophic gastritis, retained glandular structure, little invasiveness, and a sharp margin. The pathologic presentation classified as epidemic by the Lauren system is associated with most environmental risk factors, carries a better prognosis, and shows no familial history.

The second type, diffuse, infiltrative, endemic cancer, consists of scattered cell clusters with poor differentiation and dangerously deceptive margins. Margins that appear clear to the operating surgeon and examining pathologist often are determined retrospectively to be involved. The endemic-type tumor invades large areas of the stomach. This type of tumor is also not recognizably influenced by environment or diet, is more virulent in women, and occurs more often in relatively young patients. This pathologic entity is associated with genetic factors (such as E-cadherin), blood groups, and a family history of gastric cancer.

In 2013, researchers identified a possible third type of gastric adenocarcinoma. In an analysis of 248 gastric tumors using microarray-based gene-expression profiling, Lei et al found that this third subtype of gastric adenocarcinoma (which they termed the "metabolic" subtype; the other 2 subtypes are mesenchymal and proliferative) preferentially responds to 5-fluorouracil (5-FU). The researchers validated their findings in an independent set of 70 gastric tumors.[27, 28, 29] They believe that the preferential sensitivity of metabolic-subtype gastric cancers to 5-FU may be due to their significantly lower expression of thymidylate synthase and dihydropyrimidine dehydrogenase relative to the other 2 subtypes.[27]

The 2017 American Joint Committee on Cancer (AJCC) Cancer Staging Manual presents the following TNM classification system for staging gastric carcinoma[30] :

Primary tumor (T)

See the list below:

• TX - Primary tumor cannot be assessed
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ, intraepithelial tumor without invasion of lamina propria
• T1 - Tumor invades lamina propria, muscularis mucosae, or submucosa
• T1a - Tumor invades lamina propria or muscularis mucosae
• T1b - Tumor invades submucosa
• T2 - Tumor invades muscularis propria
• T3 - Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures
• T4 - Tumor invades serosa (visceral peritoneum) or adjacent structures
• T4a - Tumor invades serosa (visceral peritoneum)
• T4b - Tumor invades adjacent structures/organs

Regional lymph nodes (N)

See the list below:

• NX - Regional lymph node(s) cannot be assessed
• N0 - No regional lymph node metastases
• N1 - Metastases in 1-2 regional lymph nodes
• N2 - Metastases in 3-6 regional lymph nodes
• N3 - Metastases in 7 or more regional lymph nodes
• N3a - Metastases in 7-15 regional lymph nodes
• N3b - Metastases in 16 or more regional lymph nodes

Distant metastasis

See the list below:

• M0 - No distant metastasis
• M1 - Distant metastasis

Prognostic features

Two important factors influencing survival in resectable gastric cancer are depth of cancer invasion through the gastric wall and presence or absence of regional lymph node involvement.

In about 5% of primary gastric cancers, a broad region of the gastric wall or even the entire stomach is extensively infiltrated by malignancy, resulting in a rigid thickened stomach, termed linitis plastica. Patients with linitis plastica have an extremely poor prognosis.[31]

Margins positive for presence of cancer are associated with a very poor prognosis.

The greater the number of involved lymph nodes, the more likely the patient is to develop local and systemic failure after surgery.

In a study by Shen and colleagues,[32] the depth of tumor invasion and gross appearance, size, and location of the tumor were 4 pathologic factors independently correlated with the number of metastatic lymph nodes associated with gastric cancer.

Lee and colleagues found that surgical stage, as estimated during curative resection for gastric cancer, complemented the pathologically determined stage for determining prognosis. Survival was significantly poorer among patients with pathologic Stages II, IIIa, and IIIb disease in whom intraoperative staging overestimated the extent of pathological stage.[33]

Clinical Staging

See the list below:

• Stage 0 - Tis, N0, M0
• Stage I - T1-2, N0, M0
• Stage IIA - T1-2, N1-3, M0
• Stage IIB - T3, N0, M0 or T4a, N0, M0
• Stage III - T3, N0, M0 or; T4a, N1-3, M0
• Stage IVA - T4b, any N, M0
• Stage IVB - Any T, any N, M1

For pathologic and post-neoadjuvant therapy stage grouping, see Gastric Cancer Staging

Survival rates

See the list below:

• Stage IA - 94%
• Stage IB - 88%
• Stage IIA - 82%
• Stage IIB - 68%
• Stage IIIA - 54%
• Stage IIIB - 36%
• Stage IIIC - 18%
• Stage IV -  5%

Spread patterns

Cancer of the stomach can spread directly, via lymphatics, or hematogenously. Features of spread include the following:

• Direct extension into the omenta, pancreas, diaphragm, transverse colon or mesocolon, and duodenum is common
• If the lesion extends beyond the gastric wall to a free peritoneal (ie, serosal) surface, then peritoneal involvement is frequent
• The visible gross lesion frequently underestimates the true extent of the disease
• The abundant lymphatic channels within the submucosal and subserosal layers of the gastric wall allow for easy microscopic spread
• The submucosal plexus is prominent in the esophagus and the subserosal plexus is prominent in the duodenum, allowing proximal and distal spread
• Lymphatic drainage is through numerous pathways and can involve multiple nodal groups (eg, gastric, gastroepiploic, celiac, porta hepatic, splenic, suprapancreatic, pancreaticoduodenal, paraesophageal, and paraaortic lymph nodes)
• Hematogenous spread commonly results in liver metastases

The goal of obtaining laboratory studies is to assist in determining optimal therapy. Useful studies may include the following:

• A complete blood cell count (CBC) can identify anemia, which is present in approximately 30% of patients and may be caused by bleeding, liver dysfunction, or poor nutrition
• Electrolyte panels and liver function tests also are essential to better characterize the patient's clinical state
• Carcinoembryonic antigen (CEA) is increased in 45-50% of cases
• Cancer antigen (CA) 19-9 is elevated in about 20% of cases

Distinctive serum glycan patterns may have the potential to serve as markers for gastric cancer risk. In a study of 72 serum samples from patients with gastric cancer, nonatrophic gastritis, or duodenal ulcer, Ozcan and colleagues found that abnormal patterns of serum glycans (sugars attached to proteins) may be useful as a screening tool for identifying patients with Helicobacter pylori infection who are at risk for stomach cancer.[34, 35]

A total of 19 significant differences in serum glycan expression were found between gastric cancer patients and individuals with asymptomatic nonatrophic gastritis. High-mannose–type glycans, glycans with 1 complex type antenna, and bigalactosylated biantennary glycans tended to be lower in gastric cancer patients, whereas levels of nongalactosylated biantennary glycans were higher. Altered serum glycan levels were also seen in study patients with ulcers.[34, 35]

Surgical resection is the principal therapy for gastric cancer, as it offers the only potential for cure.[4] The most common procedures are total, subtotal, or distal gastrectomy. The choice of procedure and the extent of nodal dissection are determined by the ability to obtain clear microscopic margins. In patients who present with regionally advanced disease, removal of involved adjacent organs (eg, the spleen) may be required.

Neoadjuvant chemotherapy has an established role in the management of gastric cancer. Perioperative chemotherapy, or postoperative chemotherapy plus chemoradiation, are preferred for localized gastric cancer. Because of lower toxicity, two-drug cytotoxic regimens (eg, fluoropyrimidine and oxaliplatin) are preferred for patients with advanced disease.[4]

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

In general, most surgeons in the United States perform a total gastrectomy (if required for negative margins), an esophagogastrectomy for tumors of the cardia and gastroesophageal junction, or a subtotal gastrectomy for tumors of the distal stomach. A randomized trial comparing subtotal with total gastrectomy for distal gastric cancer revealed similar morbidity, mortality, and 5-year survival rates.[36]

Because of the extensive lymphatic network around the stomach and the propensity for this tumor to extend microscopically, traditional teaching is to attempt to maintain a 5-cm surgical margin proximally and distally to the primary lesion.

Lymph node dissection

The extent of the lymph node dissection is somewhat controversial. Many studies demonstrate that nodal involvement indicates a poor prognosis, and more aggressive surgical approaches to attempt to remove involved lymph nodes are gaining popularity.

Two randomized trials compared D1 (perigastric lymph nodes) with D2 (hepatic, left gastric, celiac, and splenic arteries, as well as those in the splenic hilum) lymphadenectomy in patients who were treated for curative intent. In the largest of these trials, postoperative morbidity (43% versus 25%) and mortality (10% versus 4%) were higher in the D2 group.[37, 38]

Most critics argue that these studies were underpowered and overestimated benefit. In addition, a  more recent randomized trial found a much lower rate of complications than those earlier trials. Degiuli et al reported complication rates of 17.9% and 12% with D2 and D1 dissections, respectively—a statistically insignificant difference— and postoperative mortality rates of 2.2% and 3%, respectively.[39]

D2 dissections are recommended by the National Comprehensive Cancer Network (NCCN) over D1 dissections.[4] A pancreas- and spleen-preserving D2 lymphadenectomy is suggested, as it provides greater staging information, and may provide a survival benefit while avoiding its excess morbidity when possible.

D1 gastrectomy is associated with less anastomotic leaks, a lower postoperative complication rate, a lower reoperation rate, decreased length of hospital stay, and a lower 30-day mortality rate. The 5-year survival rate in patients who underwent D1 gastrectomy was similar to the D2 cohort.[40]

Neoadjuvant chemotherapy may allow downstaging of disease to increase resectability, decrease micrometastatic disease burden prior to surgery, allow patient tolerability prior to surgery, determine chemotherapy sensitivity, reduce the rate of local and distant recurrences, and ultimately improve survival. However, the choice of preoperative and postoperative chemotherapy versus postoperative chemoradiation therapy remains controversial. 

A European randomized trial demonstrated survival benefit when patients were treated with three cycles of preoperative chemotherapy (epirubicin, cisplatin, and 5-fluorouracil) followed by surgery and then three cycles of postoperative chemotherapy compared with surgery alone. The benefit was comparable to that obtained with postoperative chemoradiation in a US trial.[7] However, the Gastric Chemotherapy Group for Japan did not demonstrate a significant survival benefit with neoadjuvant chemotherapy.

A meta-analysis of 15 randomized controlled trials concluded that the addition of neoadjuvant chemotherapy to surgery reduces overall mortality at 3 and 5 years in patients with advanced gastric cancer (relative risk [RR] = 0.74 and 0.82, respectively) and reduces overall mortality at 1, 2, 3, and 5 years in patients with esophagogastric cancer (RR = 0.79, 0.83, 0.84, 0.91 respectively). In patients with esophagogastric cancer, neoadjuvant therapy reduces the overall recurrence rate (RR = 0.80). However, neoadjuvant therapy does not influence morbidity and perioperative mortality rates in either gastric or esophagogastric cancer.[41]

Some authors suggest that intraoperative radiotherapy (IORT) shows promising results. This alternative method of delivering radiotherapy allows for a high dose to be given in a single fraction while in the operating room so that other critical structures can be avoided.

The National Cancer Institute randomized patients with grossly resected stage III/IV gastric cancer to receive either 20 Gy of IORT or 50 Gy of postoperative external beam radiation. Local failure was delayed in the patients treated with IORT (21 mo vs 8 mo). Although the median survival duration also was higher (21 mo vs 10 mo), this figure did not reach statistical significance.[42]

Moertel and colleagues randomized postoperative patients with advanced gastric cancer to receive 40 Grays (Gy) of radiotherapy or 40 Gy of radiotherapy with 5-FU as a radiosensitizer and demonstrated improved survival associated with the combined-modality therapy.[43]

The British Stomach Cancer Group reported lower rates of local recurrence in patients who received postoperative radiotherapy than in those who underwent surgery alone.[44]

The update of the initial Gastrointestinal Tumor Study Group series revealed higher 4-year survival rates in patients with unresectable gastric cancer who received combined-modality therapy than in those who received chemotherapy alone (18% vs 6%).[45]

In a series from the Mayo Clinic, patients were randomized to receive postoperative radiotherapy with 5-FU or surgery alone, and improved survival was demonstrated in patients receiving adjuvant therapy (23% vs 4%).[46]

Adjuvant radiotherapy is associated with improvements in both overall and relapse-free survival and reductions in locoregional failure.[47]

Numerous randomized clinical trials comparing combination chemotherapy in the postoperative setting to surgery alone did not demonstrate a consistent survival benefit.

Meta-analyses have shown a hint of statistical benefit. In one meta-analysis of 13 randomized trials, adjuvant systemic chemotherapy was associated with a significant survival benefit (odds ratio for death, 0.80; 95% CI, 0.66-0.97). In subgroup analysis, there was a trend toward a larger magnitude of effect for trials in which at least two thirds of the patients had node-positive disease.[48]

In the open-label randomized Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC), treatment with capecitabine and oxaliplatin (XELOX) after surgery for advanced gastric cancer cut the risk of death by 34% over 5 years, as compared with surgery alone. In CLASSIC, patients with stage II to IIIB gastric cancer who had undergone curative D2 gastrectomy were assigned to adjuvant XELOX for eight cycles or surgery alone. The XELOX regimen consisted of oral capecitabine (1000 mg/m² twice daily on days 1-14 of each cycle) plus intravenous oxaliplatin (130 mg/m² on day 1 of each cycle) for 6 months.[49]  However, D2 surgeries are not common in the United States due to morbidity concerns and a lack of level 1 evidence of a survival advantage.

A postoperative chemoradiation study was prompted in part by the patterns of local failure often preceding systemic spread. A randomized phase III study performed in the United States, Intergroup 0116, demonstrated a survival benefit associated with postoperative chemoradiotherapy compared with surgery alone (en bloc resection).[6]

In Intergroup 0116, patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive a bolus of 5-fluorouracil (5-FU) and leucovorin (LV) and radiotherapy or observation. Patients who received the adjuvant chemoradiotherapy demonstrated improved disease-free survival (from 32% to 49%) and improved overall survival rates (from 41% to 52%) compared to those who were merely observed. This regimen is considered the standard of care in the United States.

The phase III CALGB 80101 study found that in patients who had undergone curative resection of gastric or gastroesophageal junction adenocarcinoma, postoperative chemoradiotherapy with epirubicin, cisplatin, and infusional 5-FU before and after radiotherapy did not improve survival compared with standard 5-FU and LV before and after radiotherapy. With a median follow-up duration of 6.5 years, 5-year overall survival rates were 44% in both treatment arms.[50]

Many patients present with distant metastases, carcinomatosis, unresectable hepatic metastases, pulmonary metastases, or direct infiltration into organs that cannot be resected completely.

In the palliative setting, radiotherapy provides relief from bleeding, obstruction, and pain in 50-75% of patients. The median duration of palliation is 4-18 months.

Surgical procedures such as wide local excision, partial gastrectomy, total gastrectomy, simple laparotomy, gastrointestinal anastomosis, and bypass also are performed with palliative intent, with a goal of allowing oral intake of food and alleviating pain.

Chemotherapy and biologic therapy

Platinum-based chemotherapy, in combinations such as epirubicin/cisplatin/5-FU or docetaxel/cisplatin/5-FU, represents the current first-line regimen. Other active regimens include irinotecan and cisplatin and other combinations with oxaliplatin and irinotecan. Results of cisplatin-based chemotherapy have been largely discouraging, with median time to progression of 3-4 months and overall survival of approximately 6-9 months despite reported response rates of up to 45%. For metastatic gastric cancer, the NCCN recommends palliative chemotherapy or entry into a clinical trial.[4]

Early results reported in 2007 by Japanese clinicians suggest some improvement in both response rates and survival with the oral fluoropyrimidine S-1 used alone or in combination with cisplatin.[51] (S-1 combines three investigational drugs: tegafur, a prodrug of 5-FU; gimeracil, an inhibitor of fluorouracil degradation; and oteracil or potassium oxanate, a GI tract adverse-effect modulator.) A 2017 systematic review and meta-analysis found evidence of a modest survival benefit with S-1 compared with 5-FU-containing regimens.[52]  However, studies of S-1 have largely been limited to Japan, China, and Korea.

Novel treatment strategies may be guided by the use of gene signatures.[53]  Kim et al reported that combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of metastatic gastric cancer to treatment with cisplatin and 5-FU.[54] ​

Ishido et al reported that in patients receiving S-1 chemotherapy after gastrectomy for advanced gastric cancer, intratumoral mRNA expression of thymidylate synthase (TS) is an independent prognostic factor for response to chemotherapy. In 39 patients who received postoperative S-1, recurrence-free survival and overall survival were significantly longer in patients with low TS expression than in those with high TS expression (P=0.021 and 0.016, respectively), whereas in 40 patients treated with surgery only, TS expression did not correlate with survival.[55]

Ramucirumab

The angiogenesis inhibitor ramucirumab (Cyramza) is approved by the US Food and Drug Administration (FDA) for the treatment of advanced stomach cancer or gastroesophageal (GE) junction adenocarcinoma in patients with unresectable or metastatic disease following therapy with a fluoropyrimidine- or platinum-containing regimen.[56]  

Approval was based on two clinical trials. In one study (n=355), patients treated with ramucirumab (two thirds of patients) had better median overall survival (5.2 vs 3.8 mo) and better progression-free survival compared with patients who received placebo. A second study that compared the efficacy of ramucirumab plus paclitaxel with that of paclitaxel alone also showed improved overall survival in the group that received ramucirumab. The most common adverse events associated with ramucirumab included diarrhea and hypertension.[56]

Pembrolizumab

Pembrolizumab (Keytruda) was approved in 2017 for gastric or GE junction carcinoma in patients expressing PD-L1 with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. Approval was based on the phase 2, single-arm KEYNOTE-059 study, in which 143 of 259 patients had PD–L1-positive tumors (CPS ≥1) and microsatellite stable tumor status or undetermined microsatellite instability or mismatch repair status. The objective response rate (ORR) in these patients was 13.3%, comprising 1.4% complete responses and 11.9% partial responses. In the 19 patients who were responders, the duration of response ranged from 2.8+ to 19.4+ months, with 58% having responses 6 months or longer and 26% having responses 12 months or longer.[57]

Rapid progression of cancer (ie, hyperprogression) occurs in a fraction of patients treated with PD-1/PD-L1 inhibitors such as pembrolizumab, including approximately 10% of those with advanced gastric cancer. Kamada et al propose that hyperprogression may occur when when PD-1 blockade activates and expands the population of tumor-infiltrating PD-1+ regulatory T (Treg) cells, which then overwhelm tumor-reactive PD-1+ effector T cells. These authors report that the presence of actively proliferating PD-1+ effector Treg cells in tumors is a reliable marker for hyperprogression, and suggest that inhibiting Treg cell proliferation (eg, with nivolumab plus ipilimumab) could be an important strategy for prevention and treatment of hyperprogression in high-risk patients receiving PD-1 inhibitor therapy.[58]

Trastuzumab

Overexpression of human epidermal growth factor receptor 2 (HER2) is a significant negative prognostic factor for gastric cancer. In the international ToGA trial (trastuzumab with chemotherapy in HER2-positive advanced gastric cancer), about 22% of patients with advanced gastric cancer were found to have tumors that overexpressed HER2. In this phase III trial, 594 patients with HER2-positive advanced gastric cancer were randomized to receive standard chemotherapy alone or chemotherapy plus trastuzumab (Herceptin). Overall survival with trastuzumab was 13.8 months, compared with 11.1 months in the chemotherapy group (hazard ratio [HR], 0.74, P = 0.0046).[59]

Although modest, this 2.7-month improvement in overall survival is clinically meaningful in this group of patients, who have a poor prognosis. In addition to the impact on overall survival, trastuzumab improved all of the secondary end points, including progression-free survival (increased from 5.2 mo to 6.7 mo; P = 0.002) and overall response rate (increased from 34.5% to 47%; P = 0.0017).

Trastuzumab was approved in 2010 for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. It is administered in combination with cisplatin and capecitabine or 5-FU in patients who have not received prior treatment for metastatic disease. 

Trastuzumab deruxtecan

The first HER2-directed antibody conjugate was approved by the FDA in January 2021. It is approved for locally advanced and metastatic HER2-positive gastric or GE junction adenocarcinoma in patients who were previously treated with a trastuzumab-based regimen.

Approval was based on the phase 2 DESTINY-Gastric01 trial, which randomized patients (n=187) to receive either trastuzumab deruxtecan or physician’s choice of chemotherapy. Objective response was higher in the trastuzumab deruxtecan group compared with the chemotherapy group (51% versus 14%). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (12.5 months versus 8.4 months).[60]

Bevacizumab

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) has been evaluated for use in advanced gastric cancer. The Avastin in Gastric Cancer (AVAGAST) trial, a randomized study of bevacizumab added to capecitabine and cisplatin as first-line treatment of advanced gastric cancer in 774 patients, showed a trend toward achieving its primary endpoint of improving median survival, but did not reach statistical significance (12.1 months with bevacizumab vs 10.1 months with placebo-chemotherapy; HR, 0.87, P = 0.1). However, other endpoints were met and favored bevacizumab, including median progression-free survival (6.7 vs 5.3 months; HR, 0.80; P = 0.0037) and overall response rate (46.0% vs 37.4%; P = 0.0315).[61]

An evaluation of biomarkers performed as part of AVAGAST identified two strong candidates for use in predicting response to bevacizumab. Patients with high baseline plasma levels of VEGF-A showed a trend toward improved overall survival (HR, 0.72) versus patients with low VEGF-A levels (HR, 1.01; interaction P = 0.07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival (HR, 0.75) versus patients with high neuropilin-1 expression (HR, 1.07; interaction P = 0.06). Subgroup analyses demonstrated that for both biomarkers, significance was present only in patients from non-Asian regions.[62]

Tipiracil/trifluridine

The FDA approved tipiracil/trifluridine in 2019 for metastatic gastric or GE junction adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine; a platinum agent; either a taxane or irinotecan; and if appropriate, HER2/neu-targeted therapy.

Approval of tipiracil/trifluridine was based on the phase 3 TAGS (TAS-102 Gastric Study) clinical trial (n=507). Patients in the tipiracil/trifluridine group had a median overall survival 5.7 months compared with 3.6 months in the placebo group (one-sided P=0.00029, two-sided P=0.00058).[63]  

Nivolumab

The FDA approved nivolumab in April 2021 for first-line immunotherapy in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. In the phase 3 CheckMate 649 trial, which involved 1581 previously untreated patients with unresectable HER2-negative gastric cancer, GE junction cancer, or esophageal adenocarcinoma, 60% of which had a PD-L1 combined positive score (CPS) ≥5, nivolumab plus oxaliplatin-based chemotherapy was associated with significantly better overall survival (OS) than chemotherapy alone (13.8 months vs 11.6 months, respectively; P = 0.0002). In patients with a PD-L1 CPS ≥5, progression-free survival (PFS) was also significantly improved with nivolumab plus chemotherapy (median 7.7 months vs 6.0 months, P < 0.0001).[64, 65]

In contrast, the phase 3 ATTRACTION-4 study, conducted in Japan, Korea, and Taiwan, which involved involved 724 previously untreated patients with HER2-negative gastric or GE junction cancer, nivolumab plus chemotherapy did not significantly improve OS, but did significantly improve PFS, at a median 10.5 months vs 8.3 months with chemotherapy alone (P = 0.0007).[64]

Specialists recommend obtaining consultations freely in the management of most malignancies, and gastric carcinoma is no exception. The gastroenterologist, surgical oncologist, radiation oncologist, and medical oncologist work closely as a team.

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect. A review of eight trials by Rothwell et al found allocation to aspirin reduced death caused by cancer. A latent period of more than 5 years was observed for stomach cancer.[66]

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]

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 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]

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.

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

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Class Summary

Antineoplastic agents inhibit cell growth and proliferation.

Fluorouracil (Adrucil)

Fluoropyrimidine analog. Cell cycle-specific with activity in the S-phase as single agent and has for many years been combined with biochemical modulator leucovorin.Has activity as single agent that inhibits DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. Shown to be effective in adjuvant setting. Classic antimetabolite anticancer drug with chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis. 5-FU inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. These effects depend on intracellular conversion of 5-FU into 5-FdUMP, 5-FUTP, and 5-FdUTP. 5-FdUMP inhibits thymidylate synthase (key enzyme in DNA synthesis), which leads to accumulation of dUMP, which then gets misincorporated into the DNA in the form of 5-FdUTP resulting in inhibition of DNA synthesis and function with cytotoxic DNA strandbreaks. 5-FUTP is incorporated into RNA and interferes with RNA processing.

Capecitabine (Xeloda)

Fluoropyrimidine carbamate prodrug of 5-fluorouracil (5-FU). Capecitabine itself is inactive. Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA and to a lesser degree with RNA synthesis.

Class Summary

Platinum compounds inhibit cell growth and proliferation.

Carboplatin

Analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.

Cisplatin

Cisplatin is a platinum-containing compound that exerts an antineoplastic effect by covalently binding to DNA, with preferential binding to N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. The platinum complex also can bind to nucleus and cytoplasmic protein.

Oxaliplatin (Eloxatin)

Cisplatin is a platinum-containing compound that exerts an antineoplastic effect by covalently binding to DNA, with preferential binding to N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. The platinum complex also can bind to nucleus and cytoplasmic protein.

Class Summary

Anthracyclines inhibit cell growth and proliferation.

Epirubicin (Ellence)

Doxorubicin is an anthracycline antibiotic that inhibits DNA and RNA synthesis. It acts throughout the entire cell cycle and by direct intercalating into DNA triggers DNA breakage by topoisomerase II, causing subsequent cytocydal activity.

Class Summary

Topoisomerase inhibitors inhibit cell growth and proliferation.

Irinotecan (Camptosar)

Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminate tree. Inactive in its parent form. Converted by the carboxylesterase enzyme to its active metabolite from, SN-38. SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by topoisomerase I, inhibiting DNA replication.

Class Summary

Antimicrotubular agents inhibit cell growth and proliferation.

Paclitaxel

Taxanes alone or in combination with other agents have demonstrated efficacy in the treatment of hormone-refractory prostate cancer. Mechanisms of action are tubulin polymerization and microtubule stabilization.

Class Summary

Monoclonal antibodies are a form of drug delivery that specifically targets the tumor cells, thus reducing the systemic side effects of chemotherapy and at the same time being more effective than routine forms of chemotherapy agents.

Trastuzumab (Herceptin)

Trastuzumab is a monoclonal antibody that binds to the human epidermal growth factor receptor 2 protein (HER-2) extracellular domain. It inhibits the proliferation of cells overexpressing HER-2 protein.

Trastuzumab deruxtecan (Enhertu, Fam-trastuzumab deruxtecan-nxki)

This conjugate comprises trastuzumab, a humanized anti-HER2 monoclonal antibody, attached to deruxteca, which is composed of a cleavable linker and topoisomerase inhibitor (DXd). The drug binds to HER2 on tumors and undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, DXd causes DNA damage and apoptotic cell death. It is approved for locally advanced and metastatic HER2-positive gastric or GE junction adenocarcinoma in patients who were previously treated with a trastuzumab-based regimen.

Class Summary

Vascular endothelial growth factor inhibitors reduce tumor vascularity and growth.

Ramucirumab (Cyramza)

Ramucirumab is a monoclonal antibody that inhibits activation of vascular endothelial growth factor receptor 2 (VEGFR2). Has high affinity for VEGFR2 binding and blocks binding of VEFGR ligands, VEGF-A, VEGF-C and VEGF-D.  

Class Summary

PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound.

Nivolumab (Opdivo)

Indicated in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. 

Pembrolizumab (Keytruda)

Indicated in combination with fluoropyrimidine- and platinum-containing chemotherapy as first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma that is not amenable to surgical resection or definitive chemoradiation. Also indicated as a single agent for recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express programmed death ligand 1 (PD-L1) with a Combined Positive Score (CPS) 10 or greater, as determined by an FDA-approved test, with disease progression after 1 or more prior lines of systemic therapy.

Class Summary

Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation.

Tipiracil/trifluridine (Lonsurf)

Tipiracil is a thymidine phosphorylase inhibitor that increases trifluridine exposure by inhibiting its metabolism. Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA, interferes with DNA synthesis, and inhibits cell proliferation. It is indicated for metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.