Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer death in both females and males.1 More than 70% of gastric cancer cases occur in the developing world, with approximately 50% occurring in East Asia.2 Gastric cancer is less common in the United States, with an incidence of 12.3 cases in males and 6.0 cases in females per 100,000 per year and a disproportionately higher incidence in Asians.3 According to the Surveillance, Epidemiology, and End Results Program, approximately 26,370 new cases of stomach cancer were diagnosed in the United States in 2016, and an estimated 10,730 people died of this disease.4 Since the 1970s, the 5-year relative survival rate for gastric cancer in the United States has improved from 15% in 1975 to 29% in 2009.5 In contrast, in Japan and Korea, where screening programs have been implemented, the 5-year survival rate approaches 70%.6
RISK FACTORS AND CLASSIFICATION
A variety of risk factors have been linked to gastric cancer. Diets high in salt, salt-preserved foods, and/or processed meats have been associated with an increased risk for developing gastric cancer.7,8 Obesity and smoking have also been implicated in gastric cancer.9,10 Several studies have demonstrated a strong association between Helicobacter pylori and the development of gastric cancer.11–13 It is believed that H. pylori infection leads to chronic active gastritis, atrophic gastritis, and intestinal metaplasia. Interestingly, mass eradication of H. pylori has not been shown to reduce the risk for gastric cancer.14 Therefore, treatment of H. pylori should only be considered in patients with active peptic ulcer disease.15 Other risk factors include Epstein-Barr virus (EBV), prior gastric surgery, and radiation exposure.16–18 Family history of gastric cancer, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, and hereditary diffuse gastric cancer caused by mutations in the E-cadherin gene increase the risk.17
The anatomic distinction between gastric cancer and cancer of the gastroesophageal junction (GEJ) has been a topic of debate. The Siewert classification is the most widely used system and divides GEJ adenocarcinoma into 3 categories:20 type I tumor: adenocarcinoma of distal esophagus, located 1 cm to 5 cm above the GEJ; type II tumor: true carcinoma of gastric cardia, located within 1 cm above and 2 cm below the GEJ; type III tumor: subcardial gastric carcinoma, located 2 cm to 5 cm below the GEJ, and infiltrates esophagus from below.
The American Joint Committee on Cancer (AJCC) has updated the latest (7th) edition of TMN staging for stomach cancer to include tumors arising more than 5 cm distally of the GEJ or within 5 cm of the GEJ but without extension to the esophagus or GEJ.21
In the following sections, neoadjuvant and adjuvant therapy in gastric cancer are discussed using a case presentation to illustrate important concepts.
DIAGNOSIS AND STAGING
A 43-year old male with no significant past medical history presents with epigastric abdominal pain and heart burn for the past few weeks. He denies nausea, vomiting, melena, or hematochezia. His primary care physician (PCP) diagnoses him with gastroesophageal reflux disease (GERD) and initiates a trial of pantoprazole. Over the next 2 to 3 months, his symptoms do not improve and he has an associated 40-lb weight loss. Both social history and family history are noncontributory. Physical exam reveals epigastric tenderness without rebound or guarding. Laboratory evaluation reveals a hemoglobin of 12.6 g/dL with a mean corpuscular volume of 72 fL. A comprehensive chemistry profile is within normal limits. Given the constellation of presenting symptoms, especially the unintentional weight loss and the presence of microcytic anemia, his PCP suspects a malignant process and refers the patient to a gastroenterologist.
• What are the next appropriate steps for diagnosis?
The most common presenting symptoms of gastric cancer are weight loss and abdominal pain.22 Less commonly, patients exhibit nausea, anorexia, and dysphagia with proximal tumors. Melena is seen in only about 20% of patients. In Japan, where gastric cancer is more prevalent, mass screening programs allow for detection at an earlier stage, which partially accounts for the better survival rates seen in Asia as compared to the United States. Diagnostic work-up includes esophagogastroduodenoscopy (EGD) to assess Siewert category and to obtain a tissue sample for diagnosis. Full staging requires a complete blood count (CBC) with differential; comprehensive chemistry profile; computed tomography (CT) of chest/abdomen/pelvis with oral and intravenous contrast; endoscopic ultrasound (EUS) if no M1 disease is identified; positron emission tomography (PET)-CT if there is no evidence of M1 disease and if clinically indicated; and laparoscopy with cytology for clinical stage T1b or higher.23 Patients should be staged according to the TMN staging system (Table 1).