Primary Location of GEJ Tumors Affects Treatment

Treatment approaches are being refined by the primary location of gastroesophageal junction (GEJ) tumors, said Stephen C. Yang, MD, during the 5th Annual School of Gastrointestinal Oncology^™ (SOGO^®) meeting.

“The site does matter because it influences therapy,” said Yang, associate vice chair for faculty development, and professor of surgery and medical oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland. “A multidisciplinary approach remains necessary for all of these tumors. It not only involves the esophageal group but also the gastric group at our institution.”

But Yang said there has been confusion about whether junction tumors should be treated as esophageal or gastric cancer. The confusion, he said, could be related to the fact that there are several ways to classify these tumors.

Classifying a Tumor: Gastric or Esophageal

The most commonly used classification for assessing and planning treatment of GEJ tumors is the Siewert classification, which has been used since the 1980s.¹ Type I is similar to esophageal cancers by epidemiology and histology and type III is similar to distal gastric tumors with intestinal and diffuse histologic types and no association with reflux, Yang said. Type I GEJ tumors are 1 to 5 centimeters above the GEJ with type III starting 2 cm below the junction. Type II tumors begin 1 cm above the junction to 2 cm below the junction (Table^1,2).

Less commonly used systems, Yang said, are the Union for International Cancer Control and Nishi’s Japanese Classification of Esophageal Cancer.

Yang noted in his presentation that the National Comprehensive Cancer Network had adopted the Siewert classification. The guidelines describe Siewert types I and II tumors as being esophageal and suggests clinicians follow recommendations for esophageal cancer. Siewert type III tumors are described as gastric cancer.²

Yang suggested clinicians consider the molecular and genomic classifications, especially for gastroesophageal adenocarcinoma, which is the primary histologic cell type in GEJ tumors. He pointed to a recent study³ in Cancer Discovery that found similarities between adenocarcinomas of the stomach and esophagus and their definitive distinction from squamous cell carcinomas of the esophagus. The authors suggest that a “single-target, single-drug” rationale has proved too simplistic for GEJ adenocarcinoma because of the genomic instability and heterogeneity of this disease.

“The gastroesophageal junction tumors are [characterized by] mostly chromosomal instability but also share other genomic characteristics similar to gastric cancer but are still primarily associated with esophageal cancer,” Yang said. “A small component has genomic stable types that have microsatellite instability and also a small percentage are associated with the Epstein-Barr virus.”

Yang said the variability of GEJ tumors has made treatment challenging. Controversies for GEJ tumors include the following: how best to stage these tumors, should induction or radiation be added to the regimen, what is the best surgical approach, and whether to add adjuvant therapies and under which situations.

Table. Siewert Classification of Gastroesophageal Junction Tumors^{1, 2}

“No trials have specifically addressed this for true type II GEJ tumors,” he said. Yang said that the histology of the stomach away from the tumor may be the key to determining which classification these borderline tumors fall under. It’s important to determine if the rest of the mucosa is healthy, noted Yang. If there is atrophy of the mucosa, the presence of Helicobacter pylori, or the patient has a history of reflux, it likely that the tumor is primarily gastric cancer. On the other hand, if the mucosa is healthy and there is H pylori, it is most likely esophageal.

Treatment Approaches

Another controversy, Yang said, is the surgical approach and whether surgery should take more of the esophagus or more of the stomach. He cited a 2015 study, a retrospective analysis of 266 patients with surgically resectable GEJ adenocarcinomas from 2003 to 2013.4 The analysis reported that a positive circumferential resection margin was more common with gastrectomy (29%) versus esophagectomy (11%; P = .025). Further, no significant differences in mortality, morbidity, or disease recurrence were found.

Yang said another question that remains is whether to use induction or adjuvant radiation. A retrospective data analysis from the Surveillance, Epidemiology, and End Results registry database showed that adjuvant radiation therapy was associated with a survival benefit as compared with neoadjuvant radiation therapy for the treatment of patients with type II GEJ cancer.⁵

A total of 1497 patients with resectable GEJ cancer were identified, with 746 receiving adjuvant radiation therapy and 751 receiving neoadjuvant radiation therapy.

Adjuvant radiation had a significantly lower death risk (HR, 0.84; 95% CI, 0.73-0.97; P = .0168) as well as a significantly lower disease-specific death risk (HR, 0.84; 95% CI, 0.72-0.97; P = .0211).⁵

“The individualized surgical approach remains critical not only preoperatively but also intraoperatively for decision making,” Yang said.

References:

1. Curtis N, Noble F, Bailey I, Kelly JJ, Byrne JP, Underwood TJ. The relevance of the Siewert classification in the era of multimodal therapy for adenocarcinoma of the gastro-oesophageal junction. J Surg Oncol. 2013;109(3):202-207. doi:10.1002/jso.23484
2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Esophageal and esophagogastric junction cancers (version 1.2020). Accessed April 20, 2020. https:// www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
3. Nagaraja A, Kikuchi O, Bass A. Genomics and targeted therapies in gastroesophageal adenocarcinoma. Cancer Discov. 2019;9(12):1656-1672. doi:10.1158/2159-8290.CD-19-0487
4. Parry K, Haverkamp L, Bruijnen R, et al. Surgical treatment of adenocarcinomas of the gastro-esophageal junction. Ann Surg Oncol. 2015;22(2):597-603. doi:10.1245/s10434-014-4047-1
5. Miccio J, Oladeru O, Yang J. et al. Neoadjuvant vs. adjuvant treatment of Siewert type II gastroesophageal junction cancer: an analysis of data from the surveillance, epidemiology, and end results (SEER) registry. J Gastrointest Oncol. 2016;7(3):403- 410. doi:10.21037/jgo.2015.10.06