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From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021
Correspondence: Address correspondence to: David P. Kelsen, MD, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY; Fax; 646-422-2017; E-mail: kelsend{at}mskcc.org
Esophageal and gastroesophageal junction tumors remain serious medical problems in the western world. On a global basis, esophageal cancer is among the more common of malignancies, with a total of approximately 400,000 cases each year.1 Although a substantial percentage of patients whose condition is newly diagnosed already have incurable disease, usually caused by distant metastasis, approximately 50% of patients, after careful staging, will have disease that appears to be limited to the local or regional area. Over the past 15 years, the treatment options for local or regional esophagus cancer have been extensively explored. These options include surgical resection without additional therapy, chemoradiation without surgery, chemoradiotherapy followed by surgery, or chemotherapy and then surgery. The review by Iyer et al.2 in this issue of Annals of Surgical Oncology conveys the pros and cons for each of these treatment options.
Surgical resection has been the mainstay of therapy with curative intent. Previously, esophagectomy was associated with significant mortality rates, up to 15%, and high postoperative morbidity. Recent data, however, indicate that esophageal resections at high volume cancer centers, by surgeons performing such procedures frequently, demonstrate a significantly improved surgical mortality rate of 2% to 3%.3 The best operation for esophagus cancer is still not clear: the major options are a transhiatal approach or a transthoracic esophagectomy. A recent study compared these two approaches for esophagus cancer in a random assignment trial of 220 patients.4 This study demonstrated a significant reduction in surgical morbidity with the transhiatal approach as compared with transthoracic resections (27% vs. 57%, P < .001). The 5-year survival rate was 29% with a transhiatal resection and 39% with the extended resection. The study was not powered to assess relatively small differences in survival. Although improvements in staging, including a more widespread use of positron-emission tomography (PET) or computed tomography (CT), allow better selection of patients who might yet be cured by local or regional therapy, the best operation to perform for this disease currently is unclear. What is reasonably clear is that surgery alone, even in the best hands, results in cure for only a fourth to a third of all patients who have surgery.
The second approach to local or regional disease is the use of radiation therapy plus concurrent systemic chemotherapy. Many trials have been performed over the past 15 years to evaluate this approach. Most random assignment trials have used a cisplatin-based and fluorouracil-based chemotherapy combination. Perhaps the most well known of these studies is that of Herskovic et al.5 (RTOG-8501) who reported on the short-term and long-term results of a random assignment trial comparing radiation alone at a dose of 6400 cGy to a lower dose of 5040 cGy with concurrent cisplatin and fluorouracil chemotherapy.6 This study was closed early, at an interim analysis, because of a significant survival advantage observed in patients randomized to receive chemoradiation. The trial demonstrated long-term survival for some patients receiving chemoradiation alone (not given preoperatively).5,6 Significant toxicity was seen, however, with 50% of patients developing at least one grade III toxicity. Although treatment-related mortality in this study was low, other trials using similar techniques have reported that up to 3% to 6% of patients receiving chemoradiation die as a result of treatment. More recent studies, which have further tried to increase the radiation dose with cisplatin-fluorouracil chemotherapy, have not been associated with improved outcome.7
Because both approaches (surgery alone or chemoradiation therapy without operation) result in long-term, disease-free survival in a third or fewer patients, considerable interest exists in combining all three modalities. The rationale is that chemoradiation therapy given initially will increase the likelihood of an R0 surgical resection. This maximizes the chances for cure because patients with even positive microscopical margins are highly likely to have recurrence. As Iyer et al. point out, however, three moderately large random assignment trials recently have been reported that have investigated the use of chemoradiation therapy followed by operation in comparison with surgery alone or in comparison with completing chemoradiation therapy without operation. All of these are currently available in abstract form only.8–10 Two of these random assignment studies compared chemoradiation with chemoradiation followed by surgery.8,10 In the study by Bedenne et al.,8 only patients responding to therapy were randomized to either complete chemoradiation or to proceed to surgery, presumably selecting the group most likely to have benefit from the tri-modal approach.8 These studies failed to demonstrate a survival advantage with the addition of surgery, although local control may have been improved.8,10 The third recently reported random assignment trial compared chemoradiation followed by surgery with surgery alone.9 This study also failed to demonstrate an improvement with the tri-modal approach.
The fourth approach recently examined in three large random assignment studies was chemotherapy before surgical resection, after surgical resection, or both.11–13 In two studies, one in which five cycles of cisplatin and fluorouracil were administered (three cycles before resection and two following resection)12 and the other in which two cycles of cisplatin and fluorouracil were administered following resection,13 no benefit was seen to the addition of chemotherapy. In the third study, however, in which two cycles of the same chemotherapy were administered before surgery,11 a significant benefit to the addition of chemotherapy was observed. Although subtle differences in trial design make these studies difficult to compare, data for chemotherapy administered around the time of an operation for esophagus cancer remain inconclusive.
Notably, all of these studies used cisplatin and fluorouracil chemotherapy as the cytotoxic therapy, either alone or in combination with radiation. What should we learn from these trials? It seems reasonably clear that a conventional chemotherapy regimen of cisplatin-fluorouracil with radiation is associated with real but modest benefit. Further, improvements in outcome with minor dose or schedule changes using this regimen are unlikely. Assuming that the final reports of the recent randomized studies noted above are the same as those reported in the abstracts, if the systemic regimen chosen is cisplatin-fluorouracil, no currently available data support a routine operation after chemoradiation therapy.
One possible approach would be to offer an immediate operation to fit patients with distal third esophageal and gastroesophageal junction esophageal cancers. For squamous cell carcinomas in patients having an R0 resection, no additional therapy would be recommended. For patients with adenocarcinoma having an R0 resection but who are at high risk for local failure (T3 or greater or lymph node-positive disease), postoperative chemoradiation using radiation therapy fields and treatment plans as reported by MacDonald et al.14 for Intergroup 116 would be a conventional approach. On the other hand, patients with mid-third or particularly upper-third esophageal cancers, in whom the risks of operation and the likelihood of an R0 resection are less, might best be treated by chemoradiation without planned surgery. The role of an operation in patients who have persistent localized disease after completion of chemoradiation remains investigational and is currently under study.
Additional studies are urgently needed to improve on these results. Although it is encouraging that at least a few patients can be cured with reasonably tolerable therapy, most patients with this disease will still have recurrence. The issue is particularly pressing because of the rapid increase in the incidence of adenocarcinoma of the distal esophagus, gastroesophageal junction, and proximal stomach, which has been noted by many investigators. These are frequently fit patients who are in the most productive period of their lives. Improved therapy will probably depend on the development of better systemic agents and on customizing therapy using these cytotoxic and biological agents. For example, taxane-based and irinotecan-based systemic regimens have been developed during the past 3 to 5 years. Phase I and some phase II studies have now been completed identifying tolerable doses and schedules. Initial efficacy data are preliminary, although the survival outcome reported in several single institutional trials is encouraging. The rapid development of new agents in gastrointestinal oncology is particularly exciting. In colorectal cancer, recent studies have demonstrated that the use of bevacizumab plus chemotherapy offers a substantial survival advantage to chemotherapy alone.15 For patients with progressive disease, a second antibody, cetuximab, when given with chemotherapy has improved response rates as well. These and other similar agents in combination with chemotherapy are now undergoing their initial studies in esophageal cancer. Lastly the development of molecular profiles will aid in choosing patients who are highly likely to respond, or highly unlikely to respond, to a given agent before beginning therapy.
A second strategy toward customizing treatment is the use of imaging with PET or CT. A PET or CT done early in the treatment plan, within 2 weeks of starting therapy, may allow the identification of patients who are not benefiting from a given systemic regimen or chemoradiation therapy regimen and allow either early surgical intervention or switch to alternative chemotherapeutic agents.16
The development of new agents and new techniques of identifying the appropriate patients to treat with these agents is an exciting time in gastrointestinal oncology. When combined with improved surgery by experienced surgeons at high volume centers and the use of better radiation therapy planning, we have at least the hope that we will substantially improve the outcome for our patients with esophageal cancer in the near term.
Received for publication April 2, 2004. Accepted for publication May 19, 2004.
REFERENCES
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  H. S. Vats, T. K. Banerjee, J. Resnick, and Q. Khan Esophageal Adenocarcinoma Arising from Barrett's Dysplasia: A Case Report of Double Occurrence and Prolonged Survival after Chemotherapy. Clin. Med. Res., September 1, 2006; 4(3): 184 - 188. [Abstract] [Full Text] [PDF]
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