According to the Surveillance, Epidemiology and End Results database, in 2017 there were 28,000 new cases of gastric cancer, accounting for 1.8% of all malignancies in the United States, and an estimated 10,960 gastric cancer–related deaths.1 Worldwide, gastric cancer is the fifth most common malignancy and the third most common cause of death from any cancer.2 The incidence of gastric cancer varies significantly by geographic region, with countries in Eastern Asia (China, Japan), Eastern Europe, and Central and South America accounting for 50% of all new cases.3 Although the incidence of gastric cancer has declined in recent years, this decrease has not been observed consistently across all nations.2 In particular, the incidence of gastric cancers arising from the cardia has been increasing, which is perhaps due to a higher prevalence of obesity in Western societies.4
In this article, we review key aspects of management of metastatic gastric cancer, including selection of first- and second-line therapy, and discuss targeted agents and upcoming clinical trials.
EPIDEMIOLOGY AND RISK FACTORS
Chronic infection with Helicobacter pylori, a gram-negative bacterium, is a strong etiological factor for the development of gastric cancer, contributing to up to 70% of cases.2 The pathogen can colonize the gastric mucosa, leading to chronic inflammation. Although most patients remain asymptomatic, 1% to 3% develop gastric cancer and another 0.1% develop mucosa-associated lymphoid tissue lymphoma.5 H. pylori infection is more commonly associated with cancer of the gastric body than with cancer of the gastroesophageal junction (GEJ). The increased burden of gastric cancer in countries in Eastern Asia, Latin America, and Eastern Europe has been correlated to the prevalence of chronic H. pylori infection in these areas.
Carcinogenesis secondary to H. pylori infection may occur via several mechanisms. First, H. pylori can release virulence factors, such as cytotoxin-associated gene A, vacuolating cytotoxin, and outer membrane proteins, into the cytosol of host cells, leading to changes in patterns of cell proliferation and apoptosis.6 These virulence factors can modulate the host immune system, attenuating it to promote dysplasia. In addition, continued recognition of these factors by the immune system leads to a persistent inflammatory response, with the release of cytokines such as interleukin (IL) -1β, IL-6, and IL-8. This leads to chronic mucosal damage, further promoting dysplasia with eventual transformation into adenocarcinoma.7 In Japan and Korea, where screening for H. pylori infection is routinely performed, there have been improvements in overall survival (OS) rates for gastric cancer, with 5-year OS rates of 70%.8 The International Agency for Research on Cancer recommends further research into population-based screening and treatment programs for patients with chronic H. pylori infection. However, despite this recommendation, optimal screening strategies are not clearly defined.9
Other risk factors for the development of gastric cancer include chronic gastroesophageal reflux disease; smoking; alcohol use; exposure to radiation; diets high in fats, salt, and smoked items and low in fruits and vegetables; obesity; and exposure to chemotherapeutic agents such as procarbazine.10 Another pathogen suspected, but not proven, to be associated with increased risk for gastric cancer is the Epstein-Barr virus, a human herpesvirus found in 80% of all gastric carcinomas with lymphoid features.11 In addition, whether the use of medications such as statins and nonsteroidal anti-inflammatory drugs confers a decreased risk of gastric cancers remains unclear.10
A 55-year-old Caucasian man with a history of type 2 diabetes mellitus presents to the gastrointestinal (GI) clinic with a 6-month history of dysphagia. The dysphagia is worsened with ingestion of solids, particularly towards the end of the day. He states that the food often gets “stuck in the middle of the chest.” The patient denies any nausea or emesis but notes that he has a poor appetite. He reports having worsening mid-epigastric abdominal pain that is non-radiating, dull in character, and 6/10 in intensity. He also reports a 10-lb weight loss over the past 2 months. He has no previous history of reflux, chest pain, dyspnea, or cough. Review of systems is otherwise benign. Physical exam is within normal limits.
• Which tests should be conducted when gastric cancer is suspected?