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Originally published as JCO Early Release 10.1200/JCO.2008.19.5982 on January 12 2009 © 2009 American Society of Clinical Oncology.
Transition in Biology and Philosophy in the Treatment of Gastroesophageal Junction AdenocarcinomaUniversity of North Carolina/Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 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%.1,2 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 Stein3 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.4 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 al1 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,2 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.5 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.6–11 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 pre- and 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 al12 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/m2) and leucovorin (500 mg/m2) as well as biweekly cisplatin (50 mg/m2). Arm B consisted of two courses of the same induction chemotherapy followed by 3 weeks of combined chemoradiotherapy with radiation delivered to 30 Gy in 15 fractions. Concurrent chemotherapy consisted of cisplatin (50 mg/m2 by 1-hour intravenous infusion) on days 1 and 8 and etoposide (80 mg/m2 by 1-hour intravenous infusion) on days 3 to 5. Surgery was performed 3 to 4 weeks later. There was good control for surgical techniques, and the patients were well balanced between treatment arms. Unfortunately, accrual to the trial was slow, resulting in early termination of the study. Analyses were performed with a median follow-up of almost 4 years, but the power to detect the postulated 10% survival advantage with the addition of radiation was low (40%). Nonetheless, the results of this trial demonstrate a strong trend toward a survival advantage favoring the addition of radiation therapy to the treatment regimen, with 3-year survival rates of 28% versus 47% (hazard ratio = 0.67; P = .07) favoring the radiation arm. The proportion of patients without local tumor progression at 3 years was 59.0% versus 76.5% (P = .06) in favor of the radiation arm. Pathologic complete response was seen in 2% versus 16% in favor of the radiation therapy arm. The design and conduct of this study were both of high quality, and the lack of adequate accrual is unfortunate. The patients were classified as well as possible for location of the tumor, and the study only included GE junction adenocarcinomas. These are not trivial issues, and this represents a large step forward in how studies of diseases in this anatomic region should be carried out. There was good definition of the surgery that was to be performed, improving the consistency of the operative procedures. The radiation therapy fields and delivery were well designed, but, as the authors acknowledge, the radiation dose was low at 30 Gy as compared with doses of 45 to 50 Gy in most clinical trials and generally accepted in clinical practice in esophageal and gastric malignancies. They intentionally used a lower dose to lessen operative morbidity and mortality; indeed, there was only a relatively small difference in operative mortality between the arms. One might hypothesize that a higher radiation dose could have provided even more benefit in terms of local control, as local failure occurred in 24% of patients receiving the adjuvant radiotherapy. With the results of this study, we as clinicians are left with many of the same uncertainties that we had before. However, this trial does provide additional support for the continued inclusion of neoadjuvant radiation therapy with concurrent chemotherapy in GE junction adenocarcinomas, both in practice and in clinical trials. All too often it is stated that local recurrence doesn't kill the patient—metastatic disease kills the patient. However, it is clearly true that a patient is not cured of their cancer when there is local recurrence, and salvage of local failure is rare. A critically important outcome of this study was the 41% local failure rate for patients who received neoadjuvant chemotherapy and surgery without radiation therapy. This is an exceedingly high rate of local failure, but is consistent with other data in the literature.13 Local control matters. Patients are not cured when their disease recurs locally, and local recurrence is often symptomatic. Local control in GE junction adenocarcinomas is poor when surgery and chemotherapy are the only treatment modalities. The data presented in the report by Stahl et al12 provide one more piece of information suggesting that radiation should continue to be a part of the management of patients with GE junction tumors. Hopefully, further studies using the strong design characteristics of this trial, and using newer therapeutic approaches, will allow us to further advance the management of this disease. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Joel E. Tepper Data analysis and interpretation: Joel E. Tepper, Bert O'Neil Manuscript writing: Joel E. Tepper, Bert O'Neil Final approval of manuscript: Joel E. Tepper, Bert O'Neil REFERENCES
1. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725–730, 2001. 2. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20, 2006. 3. Siewert JR, Stein HJ: Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 85:1457–1459, 1998.[CrossRef][Medline] 4. Pedrazzani C, de Manzoni G, Marrelli D, et al: Lymph node involvement in advanced gastroesophageal junction adenocarcinoma. J Thorac Cardiovasc Surg 134:378–385, 2007. 5. Krasna MJ, Tepper J: The role of multimodality therapy for esophageal cancer. Chest Surg Clin N Am 10:591–603, 2000.[Medline] 6. Urschel JD, Vasan H: A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 185:538–543, 2003.[CrossRef][Medline] 7. Urschel JD, Vasan H, Blewett CJ: A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 183:274–279, 2002.[CrossRef][Medline] 8. Malthaner RA, Wong RK, Rumble RB, et al: Neoadjuvant or adjuvant therapy for resectable esophageal cancer: A systematic review and meta-analysis. BMC Med 2:35; 2004.[CrossRef][Medline] 9. Kaklamanos IG, Walker GR, Ferry K, et al: Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: A meta-analysis of randomized clinical trials. Ann Surg Oncol 10:754–761, 2003.[CrossRef][Medline] 10. Fiorica F, Di Bona D, Schepis F, et al: Preoperative chemoradiotherapy for oesophageal cancer: A systematic review and meta-analysis. Gut 53:925–930, 2004. 11. Geh JI, Bond SJ, Bentzen SM, et al: Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: Evidence of a radiation and chemotherapy dose response. Radiother Oncol 78:236–244, 2006.[CrossRef][Medline] 12. Stahl M, Walz MK, Stuschke M, et al: Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 27:851–856, 2009. 13. Kelsen DP, Ginsberg R, Pajak TF, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979–1984, 1998.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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