HELICOBACTER PYLORI INFECTION

H. pylori is a gram-negative microaerophilic bacterium that infects nearly half of the world’s population and is recognized as the primary etiologic agent for gastric cancer (see Chapter 50). Indeed, H. pylori has been classified as a class I (or definite) carcinogen by the International Agency for Research on Cancer (IARC), a branch of the World Health Organization (WHO). Infection with H. pylori has been found in every population studied, although the prevalence is higher in developing countries.^21,22

The natural history of chronic H. pylori infection includes three possible outcomes²³: (1) superficial gastritis, in which most patients remaining asymptomatic; (2) duodenal ulcer phenotype, which occurs in 10% to 15% of infected subjects; and (3) gastric ulcer/gastric cancer phenotype, which is the least common in the United States. In general, the risk for gastric cancer is dependent on the types of gastritis, and an increased risk is associated with a low acid state. H. pylori–induced duodenal ulcer disease is associated with a high gastric acid output as well as a reduced risk for developing gastric cancer.²⁴ Patients with H. pylori–associated gastric ulcer disease exhibit low gastric acid output, and their ulcers are typically associated with preneoplastic changes of atrophic gastritis and metaplasia. Overall, studies suggest that H. pylori–infected patients are at risk for development of chronic atrophic gastritis at a rate of 1% to 3% per year of infection.^17,25,26 Thus, those patients who are genetically predisposed to forming atrophic gastritis in response to H. pylori infection are predisposed to gastric cancer. Although Helicobacter infection is associated with both intestinal-type and diffuse-type adenocarcinomas, the mechanisms responsible for the formation of intestinal-type adenocarcinoma have been better studied and are focused on here. The association of H. pylori with mucosa-associated lymphoid tissue (MALT) lymphoma is discussed briefly at the end of this chapter and in more detail in Chapter 29.

The increased risk of development of gastric adenocarcinoma due to H. pylori infection depends on multiple factors including the strain of bacteria, host genetic factors, the duration of infection, and the presence or absence of other environmental risk factors (e.g., poor diet, smoking, etc.). In a Japanese cohort of 1526 patients with peptic ulcer disease, nonulcer dyspepsia, and gastric hyperplasia, only those infected with H. pylori developed gastric adenocarcinoma during follow-up (2.9% vs. 0%, P < 0.001).²⁷ Additional cohort studies from China and Taiwan have reported similar findings.^28,29 At least in Western countries, the association between H. pylori and gastric cancer appears to be confined to noncardia gastric tumors.³⁰

Potential mechanisms for H. pylori–induced gastric carcinogenesis include host factors, bacterial factors, environmental factors, and interactions among all three factors. Our latest understanding suggests that a combination of a virulent bacterial strain, a genetically permissive host, and a favorable gastric environment are necessary for disease to occur. The most important factor appears to be the induction of chronic inflammation by H. pylori infection. Several aspects of the inflammatory milieu have been implicated as carcinogens; they include increased oxidative stress and the formation of oxygen free radicals leading to DNA damage, increased CD4⁺ T cells and myeloid cells, and elevated proinflammatory cytokine production, all leading to accelerated cell turnover, reduced apoptosis, and the potential for faulty or incomplete DNA repair.³¹ Indeed, recent studies suggest that animals with deficient DNA repair mechanisms display more severe gastric dysplasia after chronic infection with H. pylori.³² Thus, evidence to date clearly indicates that the most important cofactor in the induction of Helicobacter-related disease is the host immune response. Indeed, chronic inflammation has been linked to a large number of cancers.

H. pylori infection leads to innate and adaptive immune responses (see Chapter 2). Initiation of the innate immune response to H. pylori is just beginning to be unraveled. Classically, the innate immune system consists of professional antigen presenting cells (APCs) such as macrophages, dendritic cells, and in some cases epithelial cells. Recent work supports a role for pattern recognition receptors (Toll-like receptors [TLRs]) in the initial response to Helicobacter colonization and the subsequent induction of the adaptive response. The most convincing evidence to date implicates TLR2 as the major TLR in Helicobacter species recognition.³³ A role for TLRs 4, 5, and 9 remains more controversial.^34–37 TLR4, along with CD14 and MD-2, serves as the receptor for Escherichia coli lipopolysaccharide (LPS) and probably H. pylori LPS and thus may be involved as well.

Chronic inflammation appears necessary for the progression through atrophy to gastric cancer. Disease mechanisms are difficult to study in human infection, and therefore much of our understanding of the immune response to Helicobacter organisms comes from work performed in the mouse model of infection. Different inbred strains of mice respond to infection with varying degrees of disease susceptibility, and several knockout models have helped to elucidate the roles of individual components of the immune response in disease.

The C57BL/6 mouse is a susceptible inbred strain, in which initial colonization of the antrum by bacteria later spreads to the body or corpus, leading to severe chronic inflammation and increases in apoptosis (programmed cell death) and proliferation. The alterations in cellular turnover are associated with a loss of parietal and chief cells (atrophy), intestinal metaplasia, and dysplasia, followed by invasive gastric adenocarcinoma in mice 14 to 22 months after infection.^38,39 Genetic manipulation of the C57BL/6-susceptible murine strain has facilitated detailed study and has thus led to a deeper understanding of genetic factors that promote murine gastric cancer, and in particular, the role of the adaptive immune response. For example, gastric Helicobacter infection in mice deficient in lymphocytes, including mice with recombinase-activating gene (RAG) deficiency, severe combined immunodeficiency, or T cell deficiency, does not result in tissue damage, cell lineage alterations, or the metaplasia-dysplasia-carcinoma sequence.^40,41 Infection in B cell–deficient mice (which retain a normal T cell response) results in severe atrophy and metaplasia identical to that seen in infected wild-type mice.⁴¹ Taken together these studies underscore the crucial role of CD4⁺ T lymphocytes in orchestrating gastric neoplasia.

How do CD4⁺ T lymphocytes contribute to gastric cancer progression? Susceptible mouse strains, such as C57BL/6, mount a strong helper T cell type 1 (Th1) interferon-γ (IFN-γ), interleukin-12 (IL-12) type of immune response, whereas resistant strains, such as the BALB/c, have an opposite Th2 response (IL-4, IL-5).^39,42,43 A Th2 response is associated with protection from mucosal damage despite the inability to eliminate bacterial colonization and in fact is often associated with higher bacterial colonization rates. Mouse strains such as the C3H, which has a mixed Th1/Th2 cytokine profile, show intermediate disease, suggesting that cytokines within an immune response interact to form a continuum of disease rather than discrete disease states. More recently, Th17 cells, which express IL-17, have been shown to be an important component of H. pylori–induced gastritis.

Although the composite immune milieu most likely dictates disease manifestations, studies are beginning to define the role of individual cytokines in the predisposition to disease. This is best illustrated in the IFN-γ knockout mice, in which a lack of IFN-γ protects infected mice from atrophy.^39,43 On the other hand, mice lacking IL-10, a cytokine that acts to dampen an immune response, develop severe atrophic gastritis in response to infection.^39–43 More recently, genetic murine models have illustrated the importance of the IL-6–IL-11 family of cytokines in the development of gastric cancer.⁴⁴

Manipulation of the immune response within wild-type strains confirms the central role of the Th1/Th2 response in producing disease. For example, infection with the intestinal helminth Heligmosomoides polygyrus skews the immune response toward Th2 polarization and protects the C57BL/6 host from Helicobacter-induced atrophy and metaplasia.⁴⁵ This mouse model mimics both the parasitic infection status and the paradoxical low gastric cancer–high H. pylori infection rates seen in areas of Africa, potentially explaining this apparent inconsistency. These observations in mice led to human studies in Africa and Latin America that confirmed that geographic regions with low gastric cancer rates had much higher Th2 relative to Th1 immune responses to H. pylori.^46,47 In general, the increased Th2-type responses were found in areas where serum immunoglobulin E (IgE) levels were high and the prevalence of intestinal parasitism by helminths is greater than 50%. These findings further stress the importance of the host response to infection and suggest the possibility that manipulation of the genetically predetermined host cytokine profile in response to environmental challenges may lessen or exacerbate the disease process.

There is a great deal of genetic diversity between strains of H. pylori owing to point mutations, insertions, deletions, and base-pair substitutions within its genome. Several strains may infect a single individual, and existing strains can undergo mutations and change over time.^48,49 Despite this genetic diversity, several genes are recognized as risk factors for gastric carcinoma, including the cag pathogenicity island, the vacA gene, and the babA2 gene.

The H. pylori genome is 1.65 million base pairs and codes for approximately 1500 genes, two thirds of which have been assigned biological roles.⁵⁰ The function of the remaining one third of the genome remains obscure. Factors that contribute to carcinogenesis include those that enable the bacteria to effectively colonize the gastric mucosa, those that incite a more aggressive host immune response, and those that affect host cell-growth signaling pathways.

Motility toward epithelial cells of the stomach is a vital feature of H. pylori survival tactics. This function is ensured by several factors, including spiraling movement (FlaA and FlaB proteins), which are designed to navigate the thick gastric mucus and through efficient modifications of the extracellular matrix and mucus layer, thus decreasing viscosity and allowing bacterial penetration.^51,52 In addition, H. pylori expresses a variety of genes that contribute to buffering of stomach acid in order to maintain a relatively neutral pH. This includes a urease gene cluster, consisting of seven genes, of which UreA/UreB complex (comprising the urease enzyme) codes for 10% of the protein of H. pylori and is vital for its survival.

A significant proportion (e.g., ≈20%) of H. pylori organisms can be found adherent to the surface of gastric mucous cells. Occasionally H. pylori can also be found intracellularly, particularly in preneoplastic and neoplastic lesions.⁵³ Adhesion of the bacteria to the epithelial layer is facilitated by a large family of 32 related outer-membrane proteins (Hop proteins) that include the adhesins. One of the best-characterized adhesins is BabA, which is encoded by the strain-specific gene babA2, a member of a highly conserved family of outer membrane proteins. BabA binds to the fucosylated Lewis B blood group antigen on gastric epithelial cells and forms a scaffold apparatus that allows bacterial proteins to enter host epithelial cells. Bacterial strains that possess the babA2 gene adhere more tightly to epithelial cells, promote a more aggressive phenotype, and are associated with a higher incidence of gastric adenocarcinoma.⁵⁴

The cag pathogenicity island is approximately 40 kb and contains 31 genes. The terminal gene of this island, cagA, is often used as a marker for the entire cag locus. Compared with cagA-negative (cag−) strains, cag-positive (cagA+) strains are associated with more severe inflammation, higher degrees of atrophic changes, and a greater chance of progressing to gastric adenocarcinoma.^55–58 The estimated risk has ranged from an odds ratio of 2 to as high as 28.4.²³ However, many of the genes adjacent to cagA code for a type 4 secretion system (TFSS), often viewed as a molecule needle that injects bacterial proteins (such as CagA) into host cells. The remarkable finding that CagA is injected into host cells, where it is phosphorylated by Src and c-Abl kinases, has raised the possibility that CagA could directly promote growth, migration, and transformation. Indeed, transgenic expression of H. pylori CagA induces gastrointestinal (GI) and hematopoietic neoplasms in mice.⁵⁹ Other genes within the pathogenicity island are also believed to be important for disease (cagE or picB, cagG, cagH, cagI, cagL, cagM) because they appear to be required for in vitro epithelial cell cytokine release, although they do not seem to have as great an effect on immune cell cytokine activation as cagA.^60–62 These findings may explain the attenuated inflammatory response and lower cancer risk with cagA− strains in vivo.^63–66

All strains of H. pylori carry the vacA gene, which codes for a pore-forming vacuolating toxin, but expression of vacA differs according to allelic variation. Approximately 50% of H. pylori strains express the vacA protein, which has been shown to be a very powerful inhibitor of T cell activation in vitro.⁶⁷ Although vacA and cagA map to different loci within the H. pylori genome, the vacA protein is commonly expressed in cagA+ strains. There are various forms of vacA, and the s1m1 strains are highly toxigenic. Other bacterial virulence factors, such as cagE, may play a role in the modulation of apoptosis and the host inflammatory response, thereby contributing to disease manifestations. Indeed, “virulent strains” (cagA+, cagE+, and VacA+ s1m1) appear to be more potent inducers of proinflammatory mediators than “nonvirulent strains” (cagA−, cagE−, and VacA−), possibly explaining the higher association of cagA+ strains with gastric cancer.⁶⁸

DIETARY FACTORS

Numerous dietary factors have been implicated as risk factors for gastric cancer. The decline in gastric cancer rates has coincided with the widespread use of refrigeration and the concomitant higher intake of fresh fruits and vegetables and lower intake of pickled and salted foods. Use of refrigeration for more than 10 to 20 years has been associated with a decreased risk of gastric cancer.^17,69 Lower temperatures reduce the rate of bacterial, fungal, and other contaminants of fresh food, as well as the bacterial formation of nitrites. Additionally, high intake of highly preserved foods may be associated with increased gastric cancer risk,⁷⁰ likely because of higher contents of salt, nitrates, and polycyclic aromatic amines.⁷¹

Much attention has been given to the effects of high nitrate intake. When nitrates are reduced to nitrite by bacteria or macrophages, they can react with other nitrogenated substances to form N-nitroso compounds that are known mitogens and carcinogens.^72,73 In rats, N-nitroso compounds have been shown to cause gastric cancer.⁷⁴ However studies trying to link N-nitroso exposure to gastric cancer risk have been inconclusive, perhaps reflecting the fact that nitrate intake does not necessarily correlate with nitrosation levels.^75,76 A Swedish cohort study found a nearly two-fold increased risk of gastric cancer associated with high dietary nitrate intake.⁷⁰ However, separate large cohort studies from Europe did not demonstrate an association between nitrate intake and risk of gastric cancer.^77,78

Another factor implicated in the development of gastric cancer is a diet high in salt (pickled foods, soy sauce, dried and salted fish and meat). High salt intake has been associated with higher rates of atrophic gastritis in humans and animals in the setting of Helicobacter infection⁷⁹ and increases the mutagenicity of nitrosated food in animal models.¹⁷ High salt diets are associated with a roughly two-fold increased risk of gastric cancer.^80,81 Cohort and case-control studies have also found an increased risk of gastric cancer associated with processed meat intake.^70,82 Possible mechanisms include higher bacterial loads, up-regulation of H. pylori cagA expression, and increased cell proliferation and p21 expression.^79,83,84

Epidemiologic studies have had inconsistent findings with regard to fruit and vegetable consumption and risk of gastric cancer. A cohort study from Japan found significantly decreased risks of gastric cancer associated with increased vegetable and fruit intake.⁸⁵ A Swedish cohort study demonstrated a reduced risk of gastric cancer associated with high vegetable intake, but no association was seen with amount of fruit consumption.⁸⁶ A large cohort study of nearly 500,000 adults in the United States and a separate nested case-control study from Europe failed to find an association between fruit and vegetable intake and gastric cancer risk.^87,88

Other foods or dietary factors that have been implicated as potential risk factors for gastric cancer are high intake of fried food, foods high in fat, high intake of red meat, and aflatoxins.^82,89–91 Diets with a high intake of fresh fish and antioxidants may be protective.^90,92–94 However, there are insufficient data to make definitive conclusions regarding these factors.

CIGARETTE SMOKING

Tobacco has long been established as a carcinogen, and numerous epidemiologic studies have demonstrated an association between cigarette smoking and risk of gastric cancer.⁹⁵ Several large cohort studies from Europe and Asia have reported a significantly increased risk of gastric cancer among smokers.^96–98 A meta-analysis found that compared with never smokers, current smokers had a 1.5-fold increased risk of gastric cancer for the cardia as well as noncardia region.⁹⁹ The authors also reported an increased association with greater amounts of smoking.

Moist snuff is a smokeless tobacco product promoted as an alternative to cigarettes and has reportedly reduced levels of carcinogenic nitrosamines. However, results of a Swedish cohort study demonstrated a 1.4-fold increased risk of noncardia gastric cancer among regular snuff users.¹⁰⁰ Snuff exposure also increases the rate of gastric carcinogenesis in H. pylori–infected mice.¹⁰¹

ALCOHOL

Multiple cohort and case-control studies from the United States and Europe have found no significant association between alcohol consumption and cardia or noncardia gastric cancer.^98,102,103 A separate population-based case-control study in the United States also found no association between any alcohol use and risk of either cardia or noncardia gastric cancer, although a reduced risk was reported with wine consumption (cardia, odds ratio [OR] 0.6; 95% confidence interval [CI]: 0.5 to 0.9; noncardia, OR 0.7; 95% CI: 0.5 to 0.9).¹⁰⁴

OBESITY

Obesity is a recognized risk factor for numerous gastrointestinal malignancies.¹⁰⁵ Increased body mass index (BMI) appears to be associated with a mild to moderate increased risk of gastric cardia cancer but not for noncardia gastric cancer.^106–110 Results of the National Institutes of Health–American Association of Retired Persons (NIH-AARP) Diet and Health Cohort Study demonstrated that marked obesity (BMI = 35 kg/m²) was associated with a significantly increased risk of gastric cardia cancer (hazard ratio, 2.46) but not with noncardia gastric cancer.¹⁰⁶ A separate cohort study from the Netherlands also found an increased risk of cardia cancer with increasing BMI.¹⁰⁷

INHERITED PREDISPOSITION

As is true for most malignancies, genetic and environmental factors play important roles in the pathogenesis of gastric cancer. Generally, intestinal-type gastric cancer is considered to be largely due to environmental causes (i.e., H. pylori infection), whereas diffuse gastric cancer is considered a primarily genetic malignancy. In the case of intestinal-type gastric cancer, however, assigning relative values to environmental and genetic contributions is complex, given that the major environmental factor, H. pylori, also tends to exhibit familial clustering.

Overall, 10% of cases of gastric cancer appear to exhibit familial clustering,¹¹¹ and family history is likely an independent risk factor for the disease even after controlling for H. pylori status.^112,113 In a cohort study of relatives of patients with gastric cancer, siblings had a two-fold increased risk of gastric cancer, adjusted for H. pylori infection.¹¹⁴ In a case-control study from Japan, a positive family history was associated with a significantly increased odds of gastric cancer in women (OR, 5.1), but not in men.¹¹⁵ A study from Scandinavia showed that having a twin with gastric cancer conferred a markedly higher risk for the disease (hazard ratios, 9.9 for monozygotic twins and 6.6 for dizygotic twins), leading the researchers to calculate that heritable factors accounted for 28% of gastric cancers, compared with 10% for shared environmental factors and 62% for nonshared environmental factors.¹¹⁶

Some of the familial clustering seen with intestinal-type gastric cancer may be related to genetic factors that play a role in the host immune response to H. pylori infection. Data from South Korea indicate that individuals with a family history of gastric cancer more frequently have H. pylori infection as well as associated atrophic gastritis or intestinal metaplasia.¹¹⁷ In a case-control study from Scotland, relatives of patients with gastric cancer had a higher prevalence of atrophy and hypochlorhydria, but a similar prevalence of H. pylori infection, compared with controls.¹¹⁸ The greater prevalence of atrophy was confined to those patients with H. pylori infection, suggesting the possibility these individuals were perhaps exhibiting a more vigorous immune response to H. pylori. In a number of model systems, the development of gastric atrophy has been linked to a strong Th1 immune response.^43,45,119 Thus, it was postulated that candidate disease-susceptibility genes for gastric atrophy and cancer might be genes that participate in the innate and adaptive immune responses to H. pylori infection. Inflammation is modulated by an array of pro- and anti-inflammatory cytokines, and several genetic polymorphisms have been described that influence cytokine response.

IL-1β is an important proinflammatory cytokine and a powerful inhibitor of acid secretion. Thus, the initial report in this area described in the setting of H. pylori infection an association between proinflammatory IL-1 gene cluster polymorphisms (IL-1B encoding IL-1β, and IL-1RN encoding its naturally occurring receptor antagonist, IL-1RA) and neoplastic progression. Individuals with the IL-1β-31*C or -511*T and IL-1RN*2/*2 genotypes were shown in the study to be at higher risk for development of H. pylori–dependent hypochlorhydria and gastric cancer.¹²⁰ The increased risk of progression to cancer with these genotypes was in the two- to three-fold range compared with noninflammatory genotypes. The initial report was confirmed in other studies.^121–125 Subsequently, Hwang and colleagues¹²⁶ demonstrated that carriers of the IL-1β-511T/T genotype or the IL-1RN*2 allele had higher mucosal IL-1β levels than noncarriers, and they also confirmed the association between the -511T/T genotype and severe gastric inflammation and atrophy. The importance of IL-1β in carcinogenesis has now been demonstrated in a transgenic study, in which stomach-specific expression of human IL-1β in transgenic mice led to spontaneous gastric inflammation and cancer that correlated with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach.¹²⁷

Additional associations with gastric cancer risk have been reported for genetic polymorphisms in tumor necrosis factor-α (TNF-α) and IL-10. Proinflammatory genotypes of TNF-α and IL-10 each were associated with a two-fold higher risk of noncardia gastric cancer. When combined with proinflammatory genotypes of IL-1β and IL-1RN, patients with three or four high-risk genotypes showed a 27-fold greater risk of gastric cancer.¹²⁸ Additional studies have shown that polymorphisms of the TLR4 gene also increase the risk of gastric cancer. Carriers of the TLR4+896G polymorphism had an 11-fold increased risk of hypochlorhydria, and significantly more severe gastric atrophy and inflammation.¹²⁹ Accumulated evidence suggests that the genetic predisposition to gastric cancer may be largely determined by the TLR and cytokine responses to chronic Helicobacter infection.

The best described form of hereditary gastric cancer is the diffuse gastric cancer that is seen in the presence of a germline mutation in the gene CDH1, which encodes the cell adhesion molecule E-cadherin. A large New Zealand kindred was found to have a germline mutation in the E-cadherin gene, and similar mutations have been reported in several additional kindreds, all with diffuse-type gastric cancer.^130–133 The age of onset of gastric cancer in individuals with CDH1 mutations is less than 40 years but can be highly variable, and the estimated lifetime risk of gastric cancer is close to 70%.^134,135 Germline CDH1 mutations are also associated with familial lobular breast cancer.^136,137

A small part of the familial clustering of gastric cancer can be attributed to other cancer syndromes (see Chapter 122). Patients with familial adenomatous polyposis (FAP) have a prevalence of gastric adenomas ranging from 35% to 100%, and their risk of gastric cancer is close to 10-fold higher than that of the general population.¹³⁸ These cancers frequently arise from fundic gland polyps and develop at an early age.^139,140 Patients with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have an approximately 11% risk of developing gastric cancer, predominantly of the intestinal type, with a mean age at diagnosis of 56 years.¹⁴¹ Patients with juvenile polyposis also have a 12% to 20% incidence of gastric cancer.^142,143

CHRONIC ATROPHIC GASTRITIS

Chronic atrophic gastritis, which is defined as the loss of specialized glandular tissue in its appropriate region of the stomach, is an established early morphologic change that occurs along the sequence toward the development of gastric cancer.^16,183 The presence of atrophic gastritis has an annual incidence of progression to gastric cancer of approximately 0.5% to 1%.^184–187 The extent of atrophic gastritis within the stomach correlates with risk of progression to cancer.^188–190

There are two forms of atrophic gastritis. The more common is multifocal atrophic gastritis (MAG), which is associated with H. pylori infection and more likely to be associated with metaplasia. The presence of H. pylori infection is associated with an approximately 10-fold increased risk of atrophic gastritis.¹⁹¹ There is considerable regional variation in the prevalence of atrophic gastritis in H. pylori–infected individuals, with a roughly 3-fold increase in Asian compared with Western countries.^191,192 The second form of atrophic gastritis, corporal atrophic gastritis, is associated with antiparietal cell and intrinsic factor antibodies. This form of atrophy is confined to the body and fundus. Corporal atrophic gastritis is associated with pernicious anemia and an increased gastric cancer risk, albeit not as high as that seen with H. pylori–induced multifocal atrophic gastritis, owing most likely to a lesser degree of inflammation.^185,193

Mechanisms underlying the increased risk of gastric cancer in the setting of gastric atrophy may be related to low acid output (achlorhydria), which predisposes to gastric bacterial overgrowth (with non-Helicobacter organisms), greater formation of N-nitroso compounds, and diminished ascorbate secretion into the gastric lumen.¹⁹⁴ Additionally, serum gastrin levels are increased in response to the reduced acid output. Gastrin is a known growth factor for gastric mucosal cells, and sustained elevations of serum gastrin may contribute to abnormal growth and increased risk of neoplastic progression.^195,196

INTESTINAL METAPLASIA

Intestinal metaplasia (IM) can be subdivided into three categories, as classified by Jass and Filipe and as discussed in Chapter 51.¹⁹⁷ Type I is the complete form of IM, containing Paneth cells, goblet cells that secrete sialomucins, and absorptive epithelium with well-defined brush borders. Type I metaplasia does not raise the risk of gastric cancer. Type II or incomplete metaplasia contains few absorptive cells, few columnar intermediate cells, and goblet cells that express sialomucins. Type III is intermediate between type I and type II and contains properties of both.¹⁹⁸ It is estimated that the presence of type II or III IM is associated with a 20-fold increased risk of gastric cancer. Early gastric cancer develops in 42% of patients with type III IM within five years of follow-up, suggesting that IM represents a precursor lesion for the intestinal form of gastric cancer.¹⁹⁹ However, whether cancer arises from areas of IM or whether IM simply represents a marker for higher gastric cancer risk remains unclear. As is the case with atrophic gastritis, the prevalence of IM in H. pylori–infected individuals is higher in Asia (≈40%) as compared with the West.^191,192

DYSPLASIA

Histologic assessment of gastric dysplasia and adenocarcinoma is based on the 2000 Vienna classification (Table 54-4).²⁰⁰ The prevalence of gastric dysplasia ranges from as low as 0.5% in low-risk areas²⁰¹ to 20% in high-risk areas.²⁰² Prospective studies have shown that low-grade dysplasia may regress in up to 60% of cases, whereas it progresses to high-grade dysplasia in 10% to 20% of cases (Fig. 54-4).^203–205 High-grade dysplasia rarely regresses, and is associated with an annual incidence of progression to gastric cancer of 2% to 6%.^205–207 In a prospective cohort study from the Netherlands, the presence of high-grade dysplasia was associated with a markedly increased risk of progression to cancer (adjusted hazard ratio, 40.1).²⁰⁶ High-grade dysplasia is often associated with synchronous cancer and can be uni- or multifocal.²⁰⁸

Table 54-4 Padova International Classification System for Gastric Dysplasia

Adapted from Rugge M, Correa P, Dixon M, et al. Gastric dysplasia: The Padova International Classification. Am J Surg Pathol 2000; 24:167.

Figure 54-4. Histopathology of gastric dysplasia. Left, Low-grade dysplasia is characterized by a proliferation of neoplastic epithelial cells with nuclear pseudostratification and hyperchromasia in the absence of architectural changes. Right, High-grade dysplasia has more severe cytologic abnormalities with abnormal architectural features, including irregular fused or cribriform glands and papillae.

GASTRIC POLYPS

The prevalence of gastric polyps in the general population is approximately 0.8% to 2.4%.^209,210 Gastric polyps consist predominantly of fundic gland polyps (≈50%), hyperplastic polyps (≈40%), and adenomatous polyps (≈10%).^210,211 The clinical course of fundic gland polyps is generally benign, and they are detected with increasing frequency in the era of proton pump inhibitor (PPI) use. In a series of 599 consecutive patients who underwent upper endoscopy, use of PPIs for 5 years or longer was associated with a significantly increased risk of fundic gland polyps (hazard ratio, 3.8).²¹² The rate of malignant transformation of fundic gland polyps is generally quite low (≈1%) and confined to polyps larger than 1 cm.²¹³ One notable exception to the benign nature of fundic gland polyps is in patients with FAP. In this group the prevalence of fundic gland polyps ranges from 51% to 88%, with dysplasia present in more than 40% of cases.^139,140

Hyperplastic polyps are almost always benign lesions. The rare hyperplastic polyps that undergo malignant transformation often contain areas of intestinal metaplasia or dysplasia and typically form a well-differentiated intestinal-type cancer.²¹³

In contrast to fundic gland and hyperplastic polyps, gastric adenomas undergo malignant transformation at a high rate. Gastric adenomas that were followed by serial endoscopy with biopsy were documented to progress to dysplasia and then to carcinoma in situ, which developed within 4 years of follow-up in approximately 11% of cases.²¹⁴ Endoscopic biopsy of gastric polyps to find dysplasia or carcinoma is associated with significant sampling error.²¹⁵ Therefore, it is suggested that all adenomas (and other polyps larger than 1 cm or those causing symptoms such as occult bleeding) be removed by endoscopic polypectomy. Decisions regarding surveillance intervals should be made on an individual basis.

PREVIOUS GASTRECTOMY

It has been reported by several groups that gastric surgery for benign conditions can predispose patients to a higher risk of gastric cancer, beginning 20 years after the surgery.^216–219 The risk is greatest for those who underwent surgery before the age of 50 years, perhaps reflecting the long lag period necessary between the operation and the development of cancer.²¹⁷ The cancers tend to occur at or near the surgical anastomosis on the gastric side; only rarely do they reside on the intestinal side of the anastomosis.²²⁰

Numerous theories have been proposed to explain the increased propensity for cancer to form at the surgical anastomosis site. They include hypochlorhydria resulting in gastric bacterial overgrowth, with increased production of nitrites, chronic enterogastric reflux of bile salts and pancreatic enzymes, which are potent gastric irritants, and atrophy of the remaining fundic mucosa secondary to low levels of antral hormones such as gastrin.^17,221,222 The Billroth II operation predisposes to the development of cancer at a four-fold higher rate than a Billroth I procedure, suggesting that bile reflux may be a significant predisposing factor.²¹⁷ H. pylori and associated intestinal metaplasia are found less frequently in postgastrectomy gastric cancers as compared to distal gastric cancers in the nonoperative stomach.²²³ It is unclear whether screening for gastric cancer in this population of patients in areas of low cancer incidence would be cost effective. With the advent of H. pylori eradication therapy as well as PPIs, the number of gastric resections for peptic ulcer disease has decreased dramatically, significantly reducing the effect of the postgastrectomy state as a risk factor for gastric cancer.

PEPTIC ULCER DISEASE

Large epidemiologic studies have demonstrated a consistently increased risk of gastric cancer in patients with a history of a gastric ulcer. In a cohort study of nearly 58,000 adults from Sweden who were followed for an average of nine years, a history of gastric ulcer was associated with a significant 1.8-fold increased risk of gastric cancer.²²⁴ Interestingly, a history of duodenal ulcer was associated with a significant 40% decreased risk of gastric cancer. A separate case control study of more than 90,000 U.S. veterans found a similarly increased risk of noncardia gastric cancer (but not cardia cancer) in patients with a history of gastric ulcer, and a corresponding decreased risk in those with a history of duodenal ulcer.²²⁵ The reasons for these disparate cancer risks are not entirely clear.

MÉNÉTRIER’S DISEASE (see Chapter 51)

In a review of case reports, 15% of patients with Ménétrier’s disease had associated gastric cancer,²²⁶ including several cases that documented a progression from dysplasia to cancer.^227,228 Because of the rarity of Ménétrier’s disease, it has been difficult to study its relationship with gastric cancer in any controlled fashion, and no recommendations regarding endoscopic surveillance can be made.

SCREENING AND SURVEILLANCE

The majority of the literature regarding screening for gastric cancer comes from east Asia, where the prevalence of this disease is among the highest in the world.²²⁹ Since 1960, the Japanese have been performing mass screening, using upper GI barium studies followed by endoscopy if any suspicious lesions are found. Japanese researchers have reported a sensitivity of 66% to 90% and a specificity of 77% to 90% for this screening approach.²³⁰ Not surprisingly, studies from Japan have also shown that use of screening leads to a diagnosis of gastric cancer at earlier stages, with one study reporting that more than 50% of cases detected by screening were diagnosed as stage I.²³¹ (Staging of gastric cancer is discussed later.) Long-term follow-up data from the Japanese Public Health Center cohort of more than 42,000 adults showed that subjects who underwent screening had a nearly 50% reduced risk of death from gastric cancer.²³² A separate cohort study of 87,000 adults from Japan found a 25% to 35% risk reduction in death from gastric cancer among those who participated in gastric cancer screening.²³³ However, similar risk reductions were seen for death from all causes, casting a level of uncertainty on the true magnitude of benefit associated with screening with respect to preventing death from gastric cancer.

The serum pepsinogen (PG) test is increasingly used to screen for patients at highest risk for having preneoplastic gastric lesions.²³⁴ As discussed in Chapter 49, the stomach produces two types of pepsinogen: PGI and PGII. In the presence of atrophic gastritis, production of PGI from oxyntic glands is reduced, whereas PGII production remains relatively constant. Therefore, low serum pepsinogen I levels (<70 mg/L) and a serum pepsinogen I/II ratio less than 3 are useful for the identification of patients with atrophic gastritis.²²⁹ A prospective cohort study found that patients with low serum PGI concentrations had a significantly elevated risk of gastric cancer.²³⁵

Screening for gastric cancer with upper endoscopy is likely cost-effective in moderate- to high-risk populations, such as older Asian men.²³⁶ However, in populations with a lower incidence of gastric cancer, screening is less likely to have the same degree of benefit.

PREVENTION

Given the lethal nature of gastric cancer and its link to chronic infection and inflammation, much attention has been paid to the possibility of “chemoprevention” of gastric neoplastic lesions. The approach most studied has been H. pylori eradication, but consideration also has been given to supplementation with antioxidants, nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2 antagonists. In this section, we first summarize the literature regarding possible beneficial effects of H. pylori eradication and then consider other strategies.

ENDOSCOPY

Esophagogastroduodenoscopy (EGD) is currently the procedure of choice for the diagnosis of gastric cancer (Fig. 54-5A). When a nonhealing gastric ulcer is found, at least six to eight biopsy specimens from the edge and base of the ulcer are recommended.²⁹⁸ As discussed in Chapter 13, the American Gastroenterological Association has recommended that an upper endoscopy be performed in patients who are older than 55 years with new-onset dyspepsia and in patients younger than 55 years who have “alarm” symptoms (weight loss, recurrent vomiting, dysphagia, evidence of bleeding, anemia).²⁹⁹ Dyspeptic patients in whom an empirical trial of proton pump inhibitors and eradication of H. pylori do not relieve symptoms should undergo prompt endoscopic evaluation as well. The basis for these recommendations is the low incidence of gastric cancer in individuals younger than 55 years. The yield of upper endoscopy for the detection of gastric cancer in patients with occult bleeding and a normal colonoscopy will vary based on the patient’s baseline risk of gastric cancer. Extensive involvement by the diffuse type of gastric cancer can manifest as a rigid and thickened stomach, also known as linitis plastica.

Figure 54-5. Endoscopic examples of gastric cancer. A, Ulcerated gastric adenocarcinoma mass lesion. B, Chromoendoscopic view of a superficial depressed gastric cancer, highlighted with indigo carmine (arrow).

(From Toyoda H, Tanaka K, Hamada Y, et al. Endoscopic diagnosis of hypopharyngeal, esophageal and gastric neoplasm. Dig Endosc 2006; 18:S41-3.)

In Japan and other areas of high gastric cancer prevalence, chromoendoscopy, magnification endoscopy, and narrow band imaging are used alone or in combination as aids in the detection of early gastric cancer (see Fig. 54-5B). Distinct irregular mucosal surface and vascular patterns have been found to correlate with the presence of dysplasia and carcinoma.³⁰⁰ There are also ongoing investigations into the utility of newer techniques such as autofluorescence and confocal microendoscopy for the diagnosis of early gastric neoplasia.^301,302

A classification system has been developed for early gastric cancer based on endoscopic appearance,³⁰³ the purpose of which is to assess early lesions for risk of submucosal invasion as well as risk of lymph node spread (Fig. 54-6). The three types include superficial polypoid (type 0-I), superficial flat/depressed (types 0-IIa to 0-IIc), and superficial excavated (type 0-III) lesions. The most commonly observed subtype is 0-IIc, the nonpolypoid depressed lesion.³⁰³ This classification system is used most often in Japan, where endoscopic mucosal resection and submucosal dissection are frequently performed for early gastric neoplasia.

Figure 54-6. Schematic representation of the major variants of type 0 neoplastic lesions of the stomach: polypoid (Ip and Is), nonpolypoid (IIa, IIb, and IIc), nonpolypoid and excavated (III).

(From The Paris endoscopic classification of superficial neoplastic lesion: Esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003; 58:S3-43.)

UPPER GASTROINTESTINAL SERIES

Upper GI series has been largely replaced by upper endoscopy as the initial test of choice for the diagnosis of gastric cancer. Barium studies have been reported to have 60% to 70% sensitivity and 90% specificity for the detection of advanced gastric cancer.³⁰⁴

COMPUTED TOMOGRAPHY GASTROGRAPHY

Computed tomography (CT) colonography has gained significant attention for its potential role as a screening modality for colon polyps and colon cancer (see Chapter 123). CT gastrography has also been studied for the diagnosis of early gastric cancer. In a study of 39 patients from South Korea with early gastric cancer, CT gastrography had a sensitivity of 73% to 76% and good interobserver reliability (R = 0.84).³⁰⁵ Only small studies have been performed thus far using this imaging modality, and CT gastrography cannot yet be recommended for screening outside of the research setting.

SERUM MARKERS

To date no reliable serum marker has been identified with sufficient sensitivity and specificity for the diagnosis of gastric cancer. Low serum pepsinogen I levels, low ratios of serum pepsinogen I to pepsinogen II, and hypergastrinemia have been reported in patients with atrophic gastritis and intestinal metaplasia, but the utility for the detection of gastric cancer has been mixed.^306,307 In a screening study of 17,000 Japanese men, a positive pepsinogen test (defined as a serum pepsinogen I <50 µg/L and a pepsinogen I/II <3), in combination with upper GI series, identified gastric cancer in 0.28% of subjects (≈1 in 350), and 88% of these were early gastric cancers.³⁰⁸ Additionally, 89% of the cancers identified by the pepsinogen test alone were early gastric cancers. The major limitation of this test is the low specificity for the diagnosis of gastric cancer.³⁰⁹

Serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 have been extensively studied for the diagnosis of gastric cancer. The sensitivities of these markers is quite low for early gastric cancer,³¹⁰ and elevated levels are levels also seen in other epithelial malignancies. These tumor markers are frequently elevated in recurrent gastric cancer, especially in patients who had elevated levels prior to surgical resection.³¹¹ More recent studies have identified, among others, transforming growth factor-β1, CA 72-4, tumor M2-pyruvate kinase, hepatocyte growth factor, and others as potential markers for the diagnosis of gastric cancer.^312–315 However, larger studies are required to determine their clinical utility.

METHODS OF STAGING

Accurate staging in gastric cancer is important for treatment decisions. Endoscopic ultrasound (EUS) is the best-studied modality for the staging of gastric cancer and remains the test of choice. However, improvements in image quality for both CT and magnetic resonance imaging (MRI) make these studies potential alternatives to EUS.

Endoscopic Ultrasonography

EUS allows the visualization of the five layers of the gastric wall. The superficial gastric mucosa is represented by an echogenic first layer, and the deeper mucosa by a hypoechogenic second layer; the submucosa is represented by an echogenic third layer, the muscularis propria as a hypoechogenic fourth layer, and the serosa as an echogenic fifth layer.³²² Studies of the ability of EUS to determine T stage have reported an accuracy rate of 67% to 92%, with accuracy of determination of serosal involvement ranging from 78% to 100%.³²³ EUS is particularly useful for staging early gastric cancer, which can be potentially resected endoscopically (Fig. 54-8). In a study of 295 patients with early gastric cancer, high-frequency EUS was found to have 90% accuracy for differentiating between mucosal and submucosal tumor invasion.³²⁴

Figure 54-8. Staging of gastric cancer using EUS. A, Endoscopic image showing a 25-mm protruding mass on the posterior wall of the antrum. Biopsy of the mass revealed an adenocarcinoma. B, EUS image of the lesion, showing the hypoechoic mucosal mass (arrow) with an intact submucosal layer, indicating that the lesion is an early (T₁) gastric cancer. EUS, endoscopic ultrasonography.

(From Kim JH, Song KS, Youn YH, et al. Clinicopathologic factors influence accurate endosonographic assessment for early gastric cancer. Gastrointest Endosc 2007; 66:901-8.)

In terms of N staging, the rate of detection of perigastric lymph nodes with EUS is comparable to staging with CT, with a diagnostic accuracy ranging from 50% to 80%.^325–329 A particular difficulty with N staging lies in the fact that many small lymph nodes can also harbor metastases, and thus understaging can occur. One study of 1253 lymph nodes in 31 patients with gastric cancer found that 55% of lymph nodes containing tumor were smaller than 5mm.³³⁰

EUS also has the ability to identify and biopsy submucosal lesions, such as gastric lymphomas and stromal tumors (discussed later and in Chapters 29 and 31). These lesions typically involve thickening of the submucosa and muscularis propria and may appear as gastric fold thickening on barium studies or endoscopy.

SURGICAL THERAPY

Surgical resection remains the primary curative treatment for gastric cancer. In addition, surgical resection often provides the most effective palliation of symptoms, particularly those of obstruction. In some cases, surgery is required for diagnosis, as in cases of nonhealing gastric ulcers with negative biopsy results or in cases with persistent pyloric outlet obstruction suggesting an antral carcinoma. Surgery should be attempted in most cases of gastric cancer. However, in the presence of extensive involvement of diffuse-type cancer (or linitis plastica), bulky metastatic disease, retroperitoneal invasion, or peritoneal carcinomatosis, or if the patient has severe comorbid illnesses, the prognosis may be sufficiently poor to make the value of resection questionable.

Surgery, and laparoscopy in particular, can be useful in the staging of cancer. Laparoscopy can help identify primary tumor resectability, peritoneal deposits, and appropriate candidates for neoadjuvant therapy. Laparoscopic peritoneal lavage has been used to detect occult intraperitoneal free cancer cells. A positive peritoneal lavage correlates significantly with eventual development of overt peritoneal metastases.³³⁷

In general, total gastrectomy is performed for proximal gastric tumors and diffuse gastric cancer, and partial gastrectomy is reserved for tumors in the distal stomach. Large, randomized multicenter trials performed in France and Italy compared subtotal with total gastrectomy for adenocarcinoma of the antrum and found no differences in five-year survival rates or operative mortality.^338,339 Some centers have argued for performing a complete splenectomy with gastrectomy. However, several retrospective and prospective studies found that concurrent splenectomy increased morbidity and had either no effect on or worsened survival.^340,341

The extent of lymphadenectomy accompanying the gastrectomy has been a subject of debate for many years. The Japanese advocate a more extensive lymph node dissection (D2 resection) than their Western counterparts (D1 resection) and have higher published survival rates. A D2 resection entails resection of the nodes of the celiac axis and the hepatoduodenal ligament in addition to the perigastric lymph nodes taken in a D1 procedure. The differences in reported survival rates may reflect the fact that the Japanese have a much higher incidence of early gastric cancer, and the more extensive lymph node dissection performed in Japan may find more positive lymph nodes, making survival rates of Japanese patients with N0 staging appear to be higher than those of their potentially understaged Western counterparts. A large prospective multicenter Dutch study of more than 1000 patients reported no significant difference in five-year survival, with higher rates of postoperative death and complications for D2 lymphadenectomy than for the more conservative D1 lymphadenectomy.³⁴² A British prospective study of 400 patients likewise showed no benefit from more extensive surgery; five-year survival rates were 35% for D1 resection and 33% for D2 resection.³⁴⁰ At present, data are insufficient to support extended lymph node resection in centers outside Japan. To prevent understaging, the current recommendation is a minimum D1 lymphadenectomy with removal of at least 15 nodes.³⁴³

ENDOSCOPIC MUCOSAL RESECTION AND SUBMUCOSAL DISSECTION

Advances in endoscopic techniques have permitted endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) to be used as curative therapies for select early gastric cancers (EGCs). This technique has been used widely for intestinal-type cancers in Japan, where studies have shown that only 3.5% of patients with EGCs smaller than 2 to 3 cm have lymph node involvement, making these lesions amenable to local therapy. Lesions larger than 4.5 cm have a greater than 50% chance of spread into the submucosa, are associated with “positive” nodes, and are therefore less likely to be endoscopically resectable.³⁴⁴

The following criteria have been suggested for choosing to perform EMR in gastric cancer: (1) the cancer is located in the mucosa and the lymph nodes are not involved, as indicated by EUS; (2) the maximum size of the tumor is less than 2 cm when the lesion is slightly elevated (type IIa) and less than 1 cm when the tumor is flat or slightly depressed (type IIb or IIc, respectively) without an ulcer scar (see Fig. 54-6); (3) there is no evidence of multiple gastric cancers or simultaneous abdominal cancers; and (4) the cancer is of the intestinal type.³⁴⁵

It is generally not possible to remove lesions larger than 1.5 to 2 cm en bloc by EMR. Endoscopic submucosal dissection is a technique developed in Japan and permits en bloc resection of larger early gastric cancers. With ESD, submucosal saline injection is performed, followed by the use of endoscopic electrosurgical knives to resect the entire tumor (Fig. 54-9).³⁴⁶ In addition to an R0 resection, ESD allows for more precise histopathologic assessment of depth of invasion and lymphovascular involvement, and permits appropriate assessment for risk of lymph node metastasis. If the preprocedure evaluation does not reveal regional lymph node involvement, much larger superficial lesions can be resected. Because experience with this technique has increased, en bloc resection rates are now reported to be greater than 90%, with local recurrence rates less than 3%.³⁴⁶ Due to the large size of some of the lesions being resected, the risk of perforation is relatively high (2% to 6%).^347,348 However, perforations recognized early can generally be treated with closure using endoscopic clipping.³⁴⁶

Figure 54-9. Endoscopic submucosal dissection for early gastric cancer (EGC). A, Conventional endoscopic view showing an EGC type 0-Ip at the angularis. B, Endoscopic view after indigo carmine spraying to enhance the lesion margin. C, Normal tissue surrounding the lesion marked with a needle knife. D, A circumferential cut around the marking dots made with an insulated-tip electrosurgical knife. E, Base after submucosal dissection of lesion, performed en bloc. F, The specimen stretched and pinned on a wood plate before immersion in formalin.

(From Lee IL, Wu CS, Tung SY, et al. Endoscopic submucosal dissection for early gastric cancers: Experience from a new endoscopic center in Taiwan. J Clin Gastroenterol 2008; 42:42-7.)

No randomized clinical trials have yet been performed comparing surgery to endoscopic resection for early gastric cancer.

CHEMOTHERAPY

In Western countries, approximately 75% of patients with gastric cancer have disease that has spread to the perigastric lymph nodes or have distant metastases at the time of diagnosis.³²² In such patients who have undergone potentially curative resection, recurrence rates are high. Unfortunately, gastric cancer appears to be fairly resistant to conventional chemotherapy. Numerous clinical trials have been performed evaluating the role of adjuvant chemotherapy following attempted curative resection for gastric cancer.³⁴⁹ The majority of the studies were inconclusive, but a series of meta-analyses of these trials suggested a 15% to 20% reduction in the risk of death in patients who received adjuvant chemotherapy.^350,351 More recent randomized trials of cisplatin- or epirubicin-based adjuvant chemotherapy have largely failed to show a benefit.^352,353

Neoadjuvant chemotherapy, on the other hand, does appear to benefit patients with resectable disease. In the United Kingdom MAGIC trial, 503 patients with gastric, gastroesophageal junction, or distal esophageal cancer were randomly assigned to undergo surgery alone or surgery with neoadjuvant epirubicin, cisplatin, and 5-fluorouracil (5-FU). Compared with surgery alone, the neoadjuvant group had significantly improved five-year survival (36% vs. 23%), progression-free survival (hazard ratio, 0.66), and overall survival (hazard ratio, 0.75).³⁵⁴ As a result, preoperative chemotherapy is now considered an acceptable treatment option for gastric cancer.

CHEMORADIATION

Combined chemoradiation after surgical resection appears to be effective at improving progression-free and overall survival in gastric cancer. The Intergroup Trial 0116 randomized 603 patients with gastric or gastroesophageal junction cancer to undergo surgery alone or surgery followed by 5-FU, leucovorin, and radiation therapy. Subjects in the surgery-alone group had shorter median survival time (27 months vs. 36 months) and worse overall- and relapse-free survivals (hazard ratios, 1.35 and 1.52, respectively).³⁵⁵ Following publication of the results of this study, adjuvant chemoradiation became the standard of care in the United States, although the optimal chemotherapy regimen is not yet clear. Early studies of the use of neoadjuvant chemoradiation have also shown promising results.³⁵⁶

INTRAPERITONEAL CHEMOTHERAPY

Because systemic chemotherapy is ineffective for peritoneal metastasis, intraperitoneal (IP) chemotherapy can be considered in patients whose tumors are resected for cure but have a high likelihood of microscopic residual disease. In a randomized trial of 248 patients with gastric cancer, postoperative hyperthermic IP chemotherapy was associated with improved overall survival compared with surgery alone.³⁵⁷ The treatment benefits were most pronounced in patients with stage III and IV disease, serosal invasion, and lymph node metastases. Although a second clinical trial reported similar results,³⁵⁸ other studies have failed to demonstrate a benefit of hyperthermic IP chemotherapy.^359,360 A meta-analysis of studies of IP chemotherapy for patients with resectable gastric cancer reported a significantly reduced risk of death in patients who received hyperthermic IP chemotherapy (hazard ratio, 0.6).³⁶¹ At present, the use of hyperthermic IP chemotherapy should be confined to patients enrolled in clinical trials, especially in Western countries.

UNRESECTABLE DISEASE

Unfortunately, up to one third of patients with gastric cancer will have unresectable disease at the time of diagnosis.²⁹² Chemotherapy for locally advanced gastric cancer without distant metastases can result in shrinking of the tumor to the point at which successful curative resection is possible.^362,363 Even when curative surgery is not possible, chemotherapy has been shown both to improve survival as well as quality of life compared to best supportive care in this group of patients.³⁶⁴ Several randomized clinical trials have demonstrated efficacy of multidrug cisplatin-based regimens.^365,366 A newer clinical trial using the EOX regimen (epirubicin, oxaliplatin, and capecitabine) was found to be noninferior to cisplatin-based regimens, and had a median survival of 11.2 months.³⁶⁷ The benefit of the EOX regimen is the substitution of oxaliplatin and capecitabine for cisplatin and 5-FU, respectively, resulting in greater convenience, ease of administration, and potentially fewer side effects.

Patients with advanced gastric cancer of the distal antrum or pylorus are at risk for developing gastric outlet obstruction. Traditionally, surgical gastrojejunostomy was performed for relief of symptoms and to allow continued enteral nutrition. With the advent of endoscopic stents, duodenal stenting across the obstructing tumor has emerged as a nonsurgical alternative for palliation. The results of a literature review of studies evaluating gastrojejunostomy and stenting found no differences between rate of technical success (96% to 100%), early and late complications, and persistent symptoms.³⁶⁸ Recurrent obstructive symptoms were more common with stenting. Both gastrojejunostomy and endoscopic stenting are acceptable options for the relief of malignant gastric outlet obstruction. The decision should be based on the individual clinical scenario as well as the availability of appropriate surgical or endoscopic expertise.