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From the Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Correspondence: Address correspondence to: Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, 1515 Holcombe Blvd., Box 426, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; Fax: 713-745-1163; E-mail: jajani{at}mdanderson.org
Squamous cell carcinoma is endemic in certain regions of the world. Its incidence keeps declining in the West, where adenocarcinoma is the most preponderant histology. A number of studies suggest that, stage per stage, natural history is similar for both histologies. However, certain stark differences are worth pondering. Patients with squamous cell carcinoma of the esophagus in the West have some typical characteristics (these patients often smoke and drink heavily, and their nutritional status is suboptimal) compared with those with adenocarcinoma (these patients have a long-term history of reflux, are often obese, and are usually Caucasian males with Barrett metaplasia). The molecular biology of these two histologies is also different. Adenocarcinoma usually tends to localize in the distal esophagus and at the gastroesophageal junction, whereas squamous cell carcinoma tends to localize in the upper half of the esophagus. There is another twist to these descriptions; squamous cell carcinoma in the endemic areas may be different than squamous cell carcinoma of the West mainly because of the prevailing carcinogens in those regions. Thus, the patients in China and Iran do not necessarily smoke heavily or abuse alcohol but develop cancers because of an exposure to other carcinogens and certain nutritional deficiencies.
Localized squamous cell carcinoma of the esophagus is a challenge. A great deal of literature exists with a variety of strategies. Surgery alone has resulted in dismal outcome with only 60% of patients achieving an R0 resection and 20% to 25% of patients achieving a 5-year survivorship after an R0 resection. Nevertheless, surgery remains the standard for T1–3, any N, and M0 patients, particularly in the endemic areas and many countries other than in North America. Postoperative therapy of resected squamous cell carcinoma is of no value.
There are two important issues to discuss: preoperative therapy and definitive nonsurgical therapy. It has been clearly demonstrated that definitive chemoradiotherapy of squamous cell carcinoma can result in a 5-year survivorship of 25% with acceptable morbidity.1,2 This study performed by the US Intergroup has established a new standard in North America. This option of nonoperative therapy must be made available to all patients with local-regional squamous cell carcinoma. It consists of definitive chemotherapy (5-fluorouracil and cisplatin) and radiotherapy (50.4 Gy). The other option of course is surgery; however, the higher the tumor in the esophagus, the higher the morbidity of surgery, and thus, the lower the quality of life for the patient. Because the long-term results of definitive chemoradiotherapy appear to be the same as that for surgery, these two options are often entertained in the United States.3 However, this is not the case globally, for example, in Germany and Japan definitive chemoradiotherapy is not considered a comparable option with surgery.
Where do we stand with preoperative therapy for patients with potentially resectable squamous cell carcinoma of the esophagus? In the article published in this issue of the Annals of Surgical Oncology, Chan et al.4 discuss this very issue in detail. Over a period of 6+ years, the authors treated 83 patients with squamous cell carcinoma of the esophagus. All patients were considered eligible for surgery and received one of two schedules of 5-fluorouracil and cisplatin followed by a surgical intervention. The outcome of these patients was compared with 76 historical patients who were treated with only surgical resection. The authors compared the overall and median survival times and concluded that the overall and median survival times in the preoperative chemotherapy group and the historical control group are statistically insignificant. Therefore, preoperative chemotherapy does not benefit patients.
We should all be instantly struck by the methodology of clinical investigation used in this article. Comparison with historical control is outdated because of its retrospective nature, built in patient selection, and inability to keep pace with the changing medical/surgical technology. The current study also lacks more precise clinical staging. In that respect, the conclusions derived from the current article cannot withstand rigorous scrutiny. However, such comparisons (similar to the technique of meta-analysis) can be hypothesis generating but do not set new treatment standards. Nevertheless, Chan et al. did arrive at the same conclusions as did the large US Intergroup trial.5 The Intergroup study of more than 440 patients, conducted in many North American institutions, was a prospectively randomized phase III study comparing 3 cycles of preoperative 5-fluorouracil plus cisplatin (and 2 cycles postoperatively) plus surgery to surgery alone. The median survival time for patients in both groups was approximately 18 months, therefore, it was concluded that the addition of preoperative chemotherapy does not benefit patients with potentially resectable carcinoma of the esophagus. The Medical Research Council trial6 randomized 802 patients to 2 cycles of preoperative chemotherapy with 5-fluorouracil and cisplatin followed by surgery or surgery alone. This trial has a number of clinical methodology problems, however, at a short median follow-up time of 2 years, there is a 3.5-month survival advantage (16.8 months vs. 13.3 months) for the group treated with preoperative chemotherapy. The median survival of the control group is a bit less than expected, and whether the advantage in survival time would prevail with a longer follow-up is uncertain. At this time, however, I am skeptical that we have a new standard.
The other area of significant investigation has been the use of preoperative concurrent chemotherapy and radiotherapy. This research area is worth pursuing, however, despite an increase in pathologic complete response rate from chemoradiotherapy, there is no demonstrable benefit in overall survival time.3 Thus, I agree with the conclusions reached by Chan et al.4 that preoperative therapy of patients with potentially resectable carcinoma of the esophagus should not be a standard and should remain in the investigational domain.
Future efforts should concentrate on exploiting this ideal translational research model. The esophageal tumor tissue being accessible, new strategies should now be developed to better understand the biology and individualized therapy of patients with this cancer.
Received for publication May 24, 2002. Accepted for publication June 20, 2002.
REFERENCES
This article has been cited by other articles:
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  H. Takeuchi, S. Ozawa, N. Ando, Y. Kitagawa, M. Ueda, and M. Kitajima Cell-Cycle Regulators and the Ki-67 Labeling Index Can Predict the Response to Chemoradiotherapy and the Survival of Patients With Locally Advanced Squamous Cell Carcinoma of the Esophagus Ann. Surg. Oncol., August 1, 2003; 10(7): 792 - 800. [Abstract] [Full Text] [PDF]
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