Transition in biology and philosophy in the treatment of gastroesophageal junction adenocarcinoma.

The goal of defining the optimal treatment for adenocarcinomas of the gastroesophageal (GE) junction has been elusive for a number of reasons. Perhaps the most important is that the clinical trials that have been carried out for tumors of this site have been divided between those aimed at treating gastric cancer and those aimed at treating esophageal cancer. No randomized study until now has treated GE junction tumors as a separate entity. There is a clear spectrum of tumors that arise in the esophagus, the GE junction, and the stomach from the stand points of epidemiology, genetics, patterns of spread, and prognosis. Trials designed primarily for gastric cancer have included patients with GE junction tumors, but generally, the percentage of patients with GE junction tumors has been low, in the range of approximately 20%. Trials of esophageal cancer have included larger percentages of patients with GE junction tumors, but several (particularly older studies) have also included patients with squamous cell carcinomas. In addition, there is information to suggest that all adenocarcinomas of the GE junction are not the same disease, leading investigators such as Siewert and Stein to develop a classification system to divide GE junction tumors into three categories depending on the location of the tumor in the esophagus and stomach. In fact, the Siewert classification has significant surgical implications, given the differing pattern of nodal spread between type I and type III tumors, in particular. Even using this classification system, however, it is often quite difficult to distinguish between tumor types such as a Siewert type II tumor from a type I or type III tumor, as many of these tumors are large and cross type boundaries. One questions, therefore, whether the “lumping” of these diseases in clinical trials only muddies what may be true clinical differences among them? Certainly tumors of the gastric body have a unique epidemiology among the GE entities. Gastric cancers are decreasing in incidence, whereas tumors of the GE junction are increasing. Gastric tumors are associated with Helicobacter pylori infection, chronic gastritis, and low acid production, whereas GE junction tumors are, if anything, associated with high acid production and are inversely associated with H pylori. Squamous esophageal cancers, with their strong association with high alcohol intake and tobacco use, are also distinctly different from GE junction tumors, which tend to be associated with obesity and gastric reflux disease. Despite these problems of classification, significant advances in clinical care have been made over the past two decades. Although surgery remains the mainstay of therapy, two major trials have affected the management of GE junction cancers. The first was the Southwest Oncology Group trial reported in 2001 by Macdonald et al demonstrating the advantage of surgery plus postoperative combined radiation therapy and chemotherapy in patients who primarily had gastric cancers. Interestingly, much of the advantage in tumor control seemed to be due to a decrease in local-regional failure, suggesting that radiation therapy was a major component of the therapy. The second study, by Cunningham et al, the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial, demonstrated the survival benefit associated with preoperative and postoperative epirubicin, cisplatin, and fluorouracil chemotherapy, also primarily in patients with gastric cancer. The success of the MAGIC trial has raised questions regarding whether radiotherapy is a necessary component for cure of gastric and GE junction cancers. There have also been many studies testing preoperative radiation therapy and chemotherapy in esophageal cancer, usually involving both squamous and adenocarcinomas. The results from these studies have been mixed, resulting in further confusion. Because individual randomized studies have not been definitive, multiple meta-analyses have been performed and have generally shown that trimodality therapy is superior to surgery alone. Such analyses, however, do not adequately separate out the potential advantage of each adjuvant modality, nor have they distinguished GE junction adenocarcinomas from other esophageal cancers. The present state of knowledge leaves some patients with localized GE junction cancers treated with surgery alone, some with chemotherapy preand postoperatively, and some with trimodality therapy either preoperatively or postoperatively, depending mostly on the biases of the treating team of physicians. In this issue of Journal of Clinical Oncology, Stahl et al report additional information that provides some guidance regarding proper management, but unfortunately, these data are not so clear that they define standard of care. This was the first attempt at a randomized study limited exclusively to patients with Siewert types I to III adenocarcinomas of the GE junction. Patients were randomly assigned either to preoperative chemotherapy or preoperative chemotherapy plus chemoradiotherapy. The chemotherapy arm (arm A) consisted of 2.5 courses of the cisplatin, leucovorin, and fluorouracil (PLF) regimen, a 6-week schedule of weekly fluorouracil (2 g/m) and leucovorin (500 mg/m) as well as biweekly cisplatin (50 mg/m). Arm B consisted of two courses of the same induction chemotherapy followed by 3 weeks of combined chemoradiotherapy with radiation JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 6 FEBRUARY 2