Esophagogastric Junction and Gastric Adenocarcinoma: Current Challenges and Future Directions

Both esophageal cancer (EC) and stomach cancer are aggressive malignancies with contrasting risk factors, histologies, and molecular characteristics-yet for the most part comparable therapeutic approaches. EC accounts for close to 482,300 new cases and 406,800 deaths yearly, making it the sixth leading cause of cancer-related death worldwide, while stomach cancer affects close to 989,600 patients and results in 738,000 deaths yearly.[1] Both cancers occur predominantly in males but seem to be more prominent in different regions of the world, with stomach cancer having a higher incidence in Eastern Europe, Asia, and South America, and EC being more common in southern and eastern Africa and in central Asia.[1] In the United States, close to 17,460 cases of EC are diagnosed yearly, with 15,070 deaths annually, whereas stomach cancer affects 21,230 and results in 10,540 deaths annually.[2] An increasing number of cases of both diseases are attributable to a rapidly increasing incidence of cancers of the esophagogastric junction (EGJ) and gastric cardia. In EC, the evolution in the management of locoregional disease, as well as recent changes introduced to staging, have led to only very modest changes in the 5-year survival rate, which still does not exceed 19%.[4]

Given the heterogeneity and the lower incidence observed in the Western world, trying to define the optimal multimodal management has been challenging. The rapidly rising incidence of EGJ and gastric cardia cancers-which is increasing by close to 6-fold yearly-has made these among the fastest-growing malignancies in the United States.[3,4] This rapid increase is thought to be mainly a result of evolving risk factors, such as a lower incidence of Helicobacter pylori infection, as well as the increased predominance of obesity and gastroesophageal reflux in Western nations.[4] Despite this, multimodality trials of the past decade have failed to focus on this particular site, and EGJ tumors have accounted for not more than 20% of enrolled patients in most studies.[5,6] This and other factors have resulted in there being a variety of accepted standards of practice, which differ depending on the institution, personal preferences of the treating surgical and medical specialists, and geographic region of practice. It is also clear that multimodal therapy has had a positive impact on survival in patients with gastric and esophageal cancers, yet there is no consensus as to the best multimodal approach for EGJ tumors.

Systemic therapy alone added to surgery has been advocated.[5] On the other hand, chemoradiotherapy has been widely adopted in the United States based on an Intergroup trial.[6]

In his review and analysis, Dr. Sandler outlines the risk factors and anatomic features of EGJ and gastric adenocarcinomas and offers a detailed overview and update on the surgical and multimodal therapeutic approaches employed in these diseases.[7] The review is comprehensive and encompasses the major clinical findings as well as an analysis of the etiologies and molecular characteristics. It would have been preferable, however, if the discussion had included a greater focus on EGJ and gastric cardia cancers, given the increasing incidence of these diseases and their impact on overall patient outcomes in the Western world.

One challenge in incorporating EGJ tumors into clinical trials may be its anatomic heterogeneity. An EGJ tumor that is within 5 cm of the EGJ (Siewert type III) is considered as EC, whereas a tumor of the same location that does not extend to the esophagus or that is beyond 5 cm from the EGJ is treated as a gastric cancer.[8] There is also a lack of precision in definitions of the anatomic landmarks of the gastric cardia, with distal margins remaining particularly poorly defined. Despite the fact that Siewert type II carcinoma seems to differ from type III,[9] several experts have recently advocated classifying these two diseases as a single type, based on the apparent lack of difference observed in a single-institution report.[10] Such a change, however, will require further validation on a larger scale and needs to include patients from Western countries. It would be of service to investigators and patients alike in the meantime to devote a discussion to EGJ and gastric cardia tumors within the context of a comprehensive analysis of gastric or esophageal cancer. Future multimodal trials also ought to focus more on this anatomic site, so as to better understand the clinical behavior of EGJ tumors, and to better decipher the main etiologies behind the staggering increase in their incidence.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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