Gastric cancer--an enigmatic and heterogeneous disease.

GASTRIC CANCER IS A COMPLEX AND ENIGMATIC disorder noted for marked global variations in etiology, incidence, natural course, and management. Many factors likely lead to and discriminate among biologically and clinically relevant gastric cancer subsets: antecedent tumorigenic conditions (Helicobacter pylori gastritis, CDH1 mutation, and other chronic gastric disorders), location of the primary tumor (proximal or distal), subtypes of adenocarcinoma (diffuse, intestinal, or mixed), ethnicity of the afflicted population (differing levels of susceptibility and aggressiveness of the tumors), and a predictive biomarker (ERBB2). In essence, gastric cancer is a heterogeneous condition that represents several diseases. Additional complexities are introduced by the prevailing therapeutic approaches that differ across the globe, including types and extent of resection, including endoscopic approaches, laparoscopic approaches, or open gastrectomy with varying extents of lymph nodal dissection, and types of adjunctive strategies, including perioperative chemotherapy, postoperative chemotherapy, and postoperative chemoradiation. In endemic areas, particularly in Japan, Korea, and China, localized gastric cancer (clinical stage T1a) is often treated by primary surgery that includes more extensive lymph nodal dissection, referred to as D2 dissection when level 2 lymph nodes are removed. However, in nonendemic areas, such as the United States, the extent of lymph node dissection is often suboptimal (referred to as D0 or D1 dissection). Are the outcomes in Asian patients different because of differences in tumor biology and patient genetics, differing therapeutic strategies, or both? Although adjunctive therapeutic strategies vary by region, each strategy has improved the cure rates compared with surgery alone by approximately 10%, and therefore, adjunctive therapies should be offered to all high-risk gastric cancer patients. In the West, most high-risk patients often receive postoperative chemoradiation or preoperative and postoperative chemotherapy, whereas in Japan, such patients receive adjuvant S-1 chemotherapy following a D2 dissection. The Japanese adjuvant strategy with S-1 appears appropriate for patients with gastric cancer in China and Korea because these tumors are biologically similar and the extent of surgery is similar. Whether the level 1 evidence established in Asia can be applied to Western patients is a quandary. Similarly, Asian gastric cancer experts have reservations regarding the level 1 evidence established in the West, primarily due to concerns related to suboptimal results and the extent of surgery. In this issue of JAMA, the GASTRIC (Global Advanced/ Adjuvant Stomach Tumor Research International Collaboration) Group reports findings from a patient-level metaanalysis of postoperative chemotherapy adjuvant trials. The investigators examined primary patient data from 60% of patients from randomized trials completed over a 30-year period to examine the role of adjuvant chemotherapy following gastric cancer resection. Collective analyses for overall survival and disease-free survival suggest a statistically significant benefit for patients who received chemotherapy after surgery compared with those who were only observed after surgery (hazard ratio, 0.82). The authors also analyzed data by region and type of chemotherapy (single agent vs combination), but the results were not consistent. This could be due to subgroups with small numbers of patients or other differences (eg, tumor biology combined with therapy variables). However, the authors suggest that singleagent adjuvant chemotherapy is justified as a control group (presumably for a future randomized trial). A number of caveats to their analysis and conclusions should be considered. Meta-analyses are considered hypothesis generating and are not performed to test a hypothesis or establish a standard of care. Moreover, the exploratory results reported by the GASTRIC group have the limitations inherent in post hoc subgroup analyses. The authors included trials conducted from the 1970s; trials that were underpowered; trials with flawed designs (some without stratifications or with unrealistic expectations); trials with various chemotherapy agents and combi-

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