Carcinoma of the Esophagus: Is Biology Screaming in My Deaf Ears? (2005)

Carcinoma of the esophagus is rampant in many parts of the world, accounting for up to 600,000 new cases per year. In the West, adenocarcinoma has been on the rise. There are obvious associations with increased body mass, gastroesophageal reflux, and smoking, whereas the role of over-the-counter acid suppressants remains uncertain. Progression of Barrett’s metaplasia to adenocarcinoma adds another intriguing twist to the formula. Although adenocarcinoma still predominantly afflicts white men, recently a similar trend has been observed in black men, and adenocarcinoma seems to be increasing in white women as well. Increasingly, the gastroesophageal junction is involved with adenocarcinoma of the esophagus or proximal stomach, posing special intellectual and practical challenges. Lifestyle, especially when it includes tobacco and alcohol abuse associated with poor nutrition, has been linked to squamous cell carcinoma in the West. Adenocarcinoma has intrigued us initially by primarily afflicting white men, but it may turn out to be a lifestyle-related cancer after all. Localized esophageal cancer is a virulent malignancy and is often diagnosed when patients have enlarged regional lymph nodes and a deeply penetrated primary. Despite many efforts to improve treatment, there has been little change in the 5-year overall survival (OS) rates, which have remained under 20% for decades. The morbidity associated with therapy delivers a devastating blow to the patient’s quality of life, particularly if an extensive resection is performed. Off-protocol preoperative chemoradiotherapy is popularly prescribed in academic and nonacademic centers, without convincing data to justify its use. One popular argument for this practice is that preoperative chemoradiotherapy provides a window of opportunity for the appearance of metastasis before surgery; another argument is that it often serves as a stress test before surgery for the group of patients harboring significant comorbid conditions. After stating these arguments, it is clear that the value of preoperative approaches in the treatment of carcinoma of the esophagus remains questionable and needs to be resolved. It is also clear that patients who achieve a pathologic complete response (pCR) after preoperative therapy survive longer than those who do not. One question is are these patients living longer because they achieved a pCR because of preoperative therapy or would they have done just as well if they had no preoperative therapy? How can we possibly answer this conundrum, knowing that, to date, none of the well-conducted randomized trials (there are not many) of preoperative chemoradiotherapy has succeeded in prolonging OS? Are we increasing the fraction of patients who achieve a pCR (and is their survival also being prolonged) as a result of preoperative therapy? Maybe, but the number of these additional pCR patients is too small to influence trial results. Can we learn more by unraveling some of the mysteries of the clinical biology of localized esophageal cancer? The following report certainly provides a basis for it. In this issue of the Journal of Clinical Oncology, Berger et al present their data on 171 patients with localized carcinoma of the esophagus who were seen over a 9-year period. It turned out to be a favorable population, with the majority of patients ( 65%) having a node-negative clinical stage (IIB or less). Of these patients, 131 underwent chemoradiotherapy followed by surgical resection. Cisplatinfluorouracil–based chemotherapy was used, and the median radiation dose was 45 Gy. The median follow-up time at this review was rather short, just 14 months. The authors correlated pathologic response with OS and disease-free survival. A pCR was observed in 42 (32%) of the 131 patients, and some degree of response was observed in an additional 10%. The 5-year OS rate for the entire cohort was 26%, and the median survival time was 33 months. For patients who achieved a pCR, however, the 5-year OS rate was 48%, and the median survival time was 50 months. Ten percent of the patients who had some pathologic response did better than JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 19 JULY 1 2005