Gastric cancer is one of the world’s leading causes of morbidity and mortality from malignant disease. An estimated 1 million cases of gastric cancer occurred globally in 2012, making it the fifth most common malignancy in the world, after lung, breast, colorectal, and prostate cancers. More than 70% of gastric cancer cases occur in the developing world, and approximately 50% occur in East Asia. Gastric cancer is less common in the United States, with the incidence of gastric cancer among males and females in the United States at 12.3 and 6.0 per 100,000/year, respectively; however, there is a disproportionally higher incidence in Asians.
Guidelines for esophageal cancer screening and surveillance of Barrett’s esophagus exist; however, guidelines for gastric cancer screening and surveillance of gastric intestinal metaplasia (IM) are lacking Since the 1970s there have been notable improvements in the 5-year relative survival rates for gastric cancer in the United States, from 15% in 1975 to 29% in 2009.6 However, these low survival rates suggest that most cases (over 65%) are still diagnosed at an advanced stage. The overall 5-year relative survival rate is about 20% in most parts of the world, but in Japan and Korea 5-year survival rates above 70% for stage I and II gastric cancer have been reported. A multicenter retrospective study of 2191 patients with gastric cancer undergoing surgical resection showed that early gastric cancer (EGC) comprised approximately 20% of all surgically resected cancers in North America compared with 50% of resected cancers in Japan. Although these differences can be explained by multiple factors, one of the most plausible reasons is the implementation of a screening program for the detection of EGC in Japan and Korea. Identification of risk factors involved in carcinogenesis and interventions to address these risk factors may reduce the incidence of gastric cancer. Reducing gastric cancer mortality also requires early identification of patients who are at high risk for gastric cancer and management strategies to slow or prevent the progression of gastric cancer. It is likely to be more cost-effective to detect and treat early-stage gastric cancer with endoscopic resection rather than surgical resection. Detection of early cancer also means that one does not need chemotherapy and radiotherapy as an adjunct, thereby reducing significant morbidity and cost.
Gastric cancer is a multifactorial disease involving both genetic and environmental risk factors. Its risk factors differ depending on whether cancers arise in the proximal region or in the distal region. Advanced age, male sex, smoking, and family history are common risk factors for both proximal and distal cancers. In terms of race/ethnicity, whites tend to develop cardia cancer, whereas Hispanics and Asians tend to develop distal cancer. Helicobacter pylori infection and dietary factors, such as high intake of salt, increase the risk of distal cancer. On the other hand, obesity and GERD are mainly associated with cancers arising from the proximal region.
The incidence of gastric cancer increases with age. Approximately, 70% of cases were diagnosed in individuals aged 55 to 84. Compared with women, men have a higher risk of both proximal and distal gastric cancer. The reason for this difference is unclear, but environmental or occupational exposures may play a role. Men have historically tended to smoke more than women, whereas estrogens may protect against the development of gastric cancer. Delayed menopause and increased fertility may lower the risk of gastric cancer.
There is significant variability in the gastric cancer incidence among races. The incidence of gastric cancer among whites is approximately half that of Asians/Pacific Islanders, African Americans, and Hispanics for both men and women. Among Asian American subgroups, Korean and Japanese Americans have an especially high incidence rate. In a study evaluating the effect of immigration on the incidence of gastric cancer among Japanese in Hawaii, first-generation participants had high rates of gastric cancer; however, after 2 generations, gastric cancer rates among Japanese Americans had decreased to a level that was similar to those of Americans of European ancestry.
Helicobacter pylori bacterial infection triggers a series of inflammatory reactions, which are considered an important cause of chronic gastritis. Progression from chronic gastritis to gastric atrophy and IM is an early step of mucosal changes in the stomach leading to dysplasia and ultimately cancer. H pylori have been classified as a World Health Organization Class I carcinogen since 1994 because several studies have demonstrated an association between H pylori infection and the development of gastric cancer, Gastric cancer develops in approximately 1% of H pylori-infected subjects; conversely, more than 90% of patients with gastric cancer have had current or past H pylori infection.
Hereditary diffuse gastric cancer is a rare, autosomal dominant, genetic syndrome characterized by the early onset of diffuse gastric adenocarcinoma (ie, before age 40), an increased risk of lobular breast cancer, and signet-ring cell colorectal cancer, and a poor prognosis. Gastric cancer risk is also increased in patients with Lynch syndrome, with affected individuals carrying a 10% lifetime risk. Other hereditary syndromes such as hereditary breast and ovarian cancer, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jeghers, and juvenile polyposis are also associated with an increased risk for gastric cancer. Atrophic gastritis and intestinal metaplasia AG and IM are considered precursor conditions of gastric cancer, and both are strongly associated with H pylori infection.
Other factors such as cigarette smoking, alcohol, obesity, low fruit/vegetable consumption, and high salt intake have also been investigated. Their effects appear to be modest compared with the risk factors discussed.
Screening can be performed in the general population (mass screening) or only for individuals identified to have an increased risk for developing gastric cancer. Although the effectiveness of mass screening for gastric cancer still remains controversial, it has been undertaken in Korea and Japan, where there is a high incidence of the disease. On the other hand, in countries with a low incidence of gastric cancer, such as the United States, mass screening would not be cost-effective, and only individuals identified to be at high risk for gastric cancer should be considered for screening. Abundant evidence shows that H pylori infection, family history of gastric cancer, and Atrophic Gastritis/Intestinal Metaplasia are associated with an increased risk of gastric cancer, and therefore individuals with these risk factors could be considered high risk. Because of the low incidence of gastric cancer in the United States, endoscopic screening is not currently recommended. Because endoscopic resection techniques such as endoscopic submucosal dissection are becoming increasingly available in the United States, many EGCs can be endoscopically resected without the need for surgery. Given these developments, a change in our approach to managing individuals at high risk for developing gastric cancer is needed. Because a high-risk patient population exists and endoscopic screening can further risk-stratify patients, the establishment of a screening and surveillance protocol for high-risk individuals is warranted.
The new national guidelines in Japan now recommend that screening be started at age 50. A study evaluating the cost-effectiveness of screening the general population for upper GI (UGI) cancers including EGC in the United States by performing an upper endoscopy at the time of screening colonoscopy showed that the incremental cost-effectiveness ratio for this intervention was $95,559 per quality-adjusted life-year saved; this is comparable with published incremental cost-effectiveness ratios for other cancer screening interventions that are commonly performed in the United States. Therefore, a screening program targeting a smaller high-risk population should be substantially more cost-effective.
Screening for gastric cancer generally involves 4 methods: Upper Gastrointestinal series, serum pepsinogen (PG) testing, H pylori serology, and endoscopy. Endoscopy is the only method available for direct visual examination of the gastric mucosa, and it allows for biopsy sampling so that histologic evaluation can be performed. Endoscopy is the criterion standard test for diagnosing gastric cancer because of its high detection rate. In Japan and Korea, endoscopy has become the primary method for gastric cancer screening given its superior test characteristics, availability, and affordability. However, the use of endoscopy for gastric cancer screening in the United States does have several potential limitations, such as the need for additionally trained endoscopists to meet the increased demand, potential adverse events of endoscopy, patient acceptance, and cost.
Data from Japan and Korea support the effectiveness of screening for gastric cancer in high-risk populations. Screening every 2 years decreased the incidence of gastric cancer and endoscopic resection could be applied to more patients who underwent EGD screening within 2 years. A European review article proposed that annual endoscopic surveillance would appear justified in all patients with Intestinal Metaplasia of incomplete type. The 2015 American Society for Gastrointestinal Endoscopy guidelines suggests that surveillance endoscopy be performed in patients with gastric intestinal metaplasia who are at an increased risk of gastric cancer because of ethnic background or family history and that surveillance interval should be individualized.
Recently, in Singapore, a new blood test is being performed to screen individuals for gastric cancer. This is a miRNA-based biomarker (Gastroclear) that stratifies individuals into low, medium and high risks of having or subsequently developing gastric cancer. This test can be used to determine initial screening and subsequent surveillance endoscopies and intervals. It has been shown to have higher sensitivity compared to other tests for screening gastric cancer and seems to have great potential after further validation.
In conclusion, Comprehensive guidelines for gastric cancer screening and surveillance of high-risk individuals are warranted. The optimal gastric cancer prevention program will combine risk stratification for screening and surveillance for high-risk groups. Because race, H pylori infection, family history of gastric cancer, and Atrophic Gastritis/Intestinal Metaplasia are significant risk factors for gastric cancer, the initial approach should be to identify individuals with these risk factors, it would be reasonable to begin screening individuals who are at high risk for developing gastric cancer and then to perform surveillance endoscopy at 1- or 2-year intervals if IM is identified on screening endoscopy or if the patient has a family history of gastric cancer. Gastric cancer screening in the appropriate population will likely lead to an increase in the detection of EGCs, which may improve the likelihood of being able to intervene with endoscopic therapy, such as endoscopic submucosal dissection, and reduce mortality from gastric cancer.
Dr. Jaideep Raj Rao is the senior consultant surgeon at JR surgery at Mount Elizabeth Novena Hospital, Singapore. He’s a specialist in minimally invasive and robotic surgery, bariatric and metabolic surgery, as well as gastrointestinal surgery, oncology surgery, and hernia and complex abdominal wall reconstruction.