Global Perspectives on Surveillance, Risk Factors, and Early Gastric Cancer Management

Global Perspectives on Surveillance, Risk Factors, and Early Gastric Cancer Management

Several presentations delivered on January 18 offered a look at how different regions identify and manage early gastric cancer (GC) around the world.

The European Perspective

As explained by Alexander G. Meining, MD, of the Ulm University, in Germany, current estimates predict that 16 of every 100,000 individuals develop GC each year in the European Union. However, the incidence varies considerably across individual countries both within and outside the European Union, with the highest rates observed in parts of Eastern Europe and Portugal and the lowest rates observed in Northern Europe and parts of Western Europe. Trends over time illustrate that the GC incidence across Europe has dropped by 2.1% per year, on average, in tandem with sharp reductions in the prevalence of Helicobacter pylori (H. pylori). In accord, the incidence of noncardia GC has steadily decreased, whereas the incidence of cardia GC has held relatively steady.

In contrast with colorectal cancer (CRC), no official screening programs for GC exist in any European country, even for high-risk populations. However, Dr. Meining explained that in many European countries, patients complaining of dyspepsia usually undergo prompt upper endoscopy, and the procedure is also often carried out in patients undergoing colonoscopy for CRC screening. As such, many early gastric lesions are detected by chance, thereby improving survival outcomes.

Endoscopic resection is recommended for early GC lesions that are well differentiated, nonulcerated, clearly confined to the mucosa, and that have a very low risk of lymph node metastasis. Endoscopic submucosal dissection is favored over endoscopic mucosal resection for most superficial GC lesions and should ideally be performed by experienced endoscopists. In reality, however, many European regions have poor access to state-of-the-art upper endoscopy and lack trained endoscopists, leading to poor adherence to published guidelines.

The South American Perspective

Dr. Paola Montenegro speaks during General Session 2.
South America, like many other less developed regions, carries one of the greatest GC burdens in the world. It features a very high GC incidence and very high mortality rates. In fact, Latin America has one of the highest mortality-to-incidence ratios worldwide, well exceeding 0.8, explained presenter Paola Montenegro, MD, of the Instituto Nacional de Enfermedades Neoplásicas, in Peru.

As in other regions, noncardia GC predominates among both men and women in South America. However, HER2-positive GC is less common in South America compared with other regions of the world.

The risk factors for GC in South America are largely similar to those recognized globally and include H. pylori infection, smoking, alcohol use, high consumption of red meat or processed meat, excessive salt intake, and carriage of IL1RN*2. However, heavy use of chili pepper also poses a moderate risk for GC.

Although the incidence of GC in Latin America has declined over time because of reductions in H. pylori infections, reduced smoking, and improvements in food preservation and diet, Dr. Montenegro thinks that additional significant declines are unlikely given the high prevalence of H. pylori in young people. The estimated pooled prevalence of H. pylori across Latin America currently stands at 64%. This high rate of H. pylori exposure is strongly driven by factors associated with poverty, such as overcrowded housing and homes with earth floors.

Dr. Montenegro thinks the large mortality burden from GC in South America is tied to the fact that patients present with more advanced stages of disease—only about 16% of cases are diagnosed with stage I disease—in tandem with poor access to cancer care. The large population of indigenous peoples in South America face great disparities in health care due to language barriers and location constraints since many of these individuals live in remote or rural areas. In the end, this means that only 79% of patients with GC in South America receive treatment, as compared with 88% of patients in Europe and 92% in Asia-Pacific.

The Asian Perspective

Dr. Seiichiro Abe speaks during General Session 2.
Although the incidence of GC is markedly higher in Asia compared with other global regions, the GC mortality rate is quite low. Seiichiro Abe, MD, of the National Cancer Center Hospital, in Japan, explained that the primary reason for this is early disease detection.

Both South Korea and Japan have national screening programs. South Korea’s screening program has been in place since 1999 and invites all people over age 40 to undergo either upper gastrointestinal (GI) series or esophagogastroduodenoscopy every other year. The participation rate in this program currently exceeds 40%. Population-based analysis of the program showed that the screening efforts have reduced the overall odds of GC mortality by 21%, largely driven by the effectiveness of upper GI endoscopy for identifying early disease.

In addition to screening, Japan also uses primary prevention to decrease the incidence of GC. A 1-week course of treatment required for H. pylori eradication is covered for all individuals by the Japanese health insurance system, and this therapy has become a routine standard of care for the general population. 

When it comes to GC detection, Dr. Abe explained that Asia uses GI endoscopy as a multifunctional modality to carefully and systematically observe the stomach in order to identify lesions, confirm histology, and guide targeted biopsy of suspicious lesions. Current practice is to systematically observe the stomach by taking quadrant images at the antrum, lower, and middle gastric body, along with several images in retroflection. Asian countries also rely on advanced imaging technologies such as chromoendoscopy with indigo carmine and image-enhanced endoscopy to identify very early-stage disease.

When early GC is identified, endoscopic submucosal dissection is widely accepted as a standard of care for disease resection, particularly in Japan. This procedure provides favorable short- and long-term outcomes in Asian patients undergoing curative endoscopic resection, often yielding results comparable to surgery. 

The North American Perspective

Margaret Gulley, MD, of the University of North Carolina at Chapel Hill, focused her talk on how to leverage the Epstein-Barr virus (EBV) to better classify, treat, and monitor GC. “It’s important to focus on the 10% of GCs that are EBV-related because the biology is different in this group, and therefore there are some treatment strategies we should consider,” she said.

As Dr. Gulley explained, EBV-associated GC represents a distinct class of gastric adenocarcinomas with a prominent CD8 T-cell infiltrate that has essentially been rendered inactive by myriad virus-driven strategies. To capitalize on the presence of the cytotoxic T cells within the tumor, it seems reasonable to leverage immunotherapy approaches. For example, use of PD-1 or PD-L1 inhibitors might liberate T cells within the tumor to attack EBV-infected cells. Other strategies that may work particularly well in EBV-positive GCs include methods to upregulate viral antigen presentation by driving cell lysis and preventing virus-associated cell survival with use of targeted therapies.

Because EBV-positive disease represents a distinct molecular subtype of gastric adenocarcinoma, this opens the door for genomic assays to aid in disease management. Dr. Gulley described a 67-gene solid tumor mutation panel that, in addition to assessing for mutations and copy number variants, also has the ability to quantify three cancer-causing pathogens: EBV, H. pylori, and HPV.

“This kind of gene panel where we can combine pathogens and human gene variants in the same test will be very useful in these pathogen-related cancers like GC,” she said.

Dr. Gulley also discussed a noninvasive blood-based test that quantifies mutations, gene copy number variants, and viral load within the cell-free DNA in plasma to gain insight into tumor changes, making it useful and practical for periodic monitoring. For individuals with a known cancer genotype, this plasma mutation panel can be used to track tumor burden in response to therapy, monitor clonal evolution, detect drug-resistant mutations, and identify very early relapse based on serial blood plasma specimens.

Evaluation of Extensive Intraoperative Peritoneal Lavage

To add more depth to the session, Daishi Morimoto, MD, of Nagoya University Graduate School of Medicine, in Japan, presented data from a study evaluating a strategy for preventing GC recurrence following surgery (Abstract 1).

A small randomized trial previously showed that extensive intraoperative peritoneal lavage (EIPL), in addition to standard treatment, reduced the rate of peritoneal recurrence by about 50% among patients with advanced GC by physically removing free-floating cancer cells within the peritoneum.

“This is too good to be believed, but it’s a very important issue. We couldn’t just ignore it,” Dr. Morimoto said. As such, he and his colleagues designed a multicenter randomized phase III trial to confirm the benefit of EIPL. Although EIPL for advanced GC was found to be safe, the primary endpoint of disease-free survival (DFS) was not met.

The analysis focused on 295 patients with T3/T4 gastric adenocarcinoma who were scheduled to undergo total or distal gastrectomy. After confirming that these individuals had resectable disease, the group assigned to EIPL underwent peritoneal lavage with 1 L of saline at least 10 times before the abdomen was closed, whereas the control group underwent 1 lavage with up to 3 L of saline just one time. Thereafter, patients received standard case based on disease stage.

No differences between arms in the incidence of postoperative complications occurred.

The benefit of EIPL seen in the small randomized trial could not be replicated. The DFS rates for the EIPL and control groups at 3 years were 63.9% and 59.7%, respectively, and at 5 years were 58.0% and 51.9%, respectively (hazard ratio [HR] 0.82, 95% CI [0.57, 1.16]; p = 0.25). A comparison of the EIPL and non-EIPL arms identified no differences for overall survival (3 years: 75.0% vs. 73.7%; 5 years: 62.5% vs. 57.1%; HR 0.91, 95% CI [0.60, 1.37]; p = 0.65) or peritoneal recurrence-free survival (3 years: 72.3% vs. 69.7%; 5 years: 59.3% vs. 59.2%; HR 0.92, 95% CI [0.62, 1.36]; p = 0.68).

Exploratory subgroup analyses suggest that EIPL may offer benefit to patients with grade 2 or greater intra-abdominal surgical site infection postsurgery (5-year DFS for EIPL vs. non-EIPL: 68.6% vs. 47.4%; p = 0.10). However, this remains to be confirmed.

– Kara Nyberg, PhD