Chemosensitized Radiation for
Cancer of the Esophagus

Authors: Richard Whittington, MD
Affiliations: University of Pennsylvania Cancer Center
Posting Date - February 9, 1996

Last Revision Date: Sunday, 14-Feb-1999 13:59:52 EST
Copyright © 1994-1999, The Trustees of the University of Pennsylvania

Carcinoma of the esophagus actually represents two different diseases. Squamous carcinoma and adenocarcinoma typically present in different locations and have different natural histories and patterns of spread. For squamous carcinomas, the major question of the last decade has been whether chemotherapy with radiation is better than radiation alone. The answer is yes.

Older series demonstrated that the risk of mediastinal recurrence following high-dose radiation ranged from 40% to 70%. In the early 1980s, there were several phase II trials using combined chemotherapy and radiation to reduce both local and distant recurrence. The agents used most frequently were 5-FU, mitomycin and cisplatin, although some reports included vinca alkaloids and bleomycin. These early studies showed it was possible to achieve rapid responses. There was also a suggestion that both local control and survival were improved, although it was argued that this was a reflection of patient selection in phase II protocols. 

Subsequently, there were two large randomized trials for patients with localized esophageal carcinoma (primarily squamous) that compared chemotherapy plus radiation to radiation alone. The first trial, directed by the Radiation Therapy Oncology Group (RTOG), randomized patients to receive four monthly cycles of chemotherapy, consisting of a 96-hour infusion of 5-FU and a single 75mg/m2 dose of cisplatin. These patients also received 50 Gy radiation therapy concurrently with the first two cycles of chemotherapy. The toxicity was substantial, and only half the patients received the full four courses of chemotherapy. The control group received 64 Gy radiation therapy alone. Mature analyses of these data demonstrated that, compared with radiation alone, the addition of chemotherapy to the lower dose of radiation improved the local control (56% vs. 35%) and two-year survival (38% vs. 10%). Both local and distant failures were reduced, suggesting that chemotherapy affected both mediastinal tumors, as well as distant micrometastases. 

Another trial, directed by the Eastern Cooperative Oncology Group (ECOG), randomized patients to chemotherapy with a 96-hour infusion of 5-FU and a single 10 mg/m2 dose of mitomycin-C plus radiation vs. radiation alone. These patients also were allowed to undergo surgical resection after 40 Gy. If no resection was performed, radiation was continued to a dose of 60 to 66 Gy. Preliminary results showed that, in the combined modality arm, a higher percentage of patients achieved resectability, and both resected and unresected patients had a superior survival rate, with a doubling in the median survival. 

Current efforts seek to determine whether neoadjuvant chemotherapy improves the results of chemosensitized radiation, and also to determine the optimal dose of radiation. There are rare instances in oncology in which the dose of radiation may be reduced by the addition of chemotherapy, but the RTOG trial suggests that the lower dose of radiation with chemotherapy may produce superior local control compared with higher doses of radiation alone. 

Adenocarcinomas of the esophagus were rarely diagnosed 20 years ago, but for reasons that are not clear, they currently constitute more than half of the esophageal tumors in many institutions. Because of a long-standing interest in Barrett's esophagus and adenocarcinomas arising in Barrett's esophagus, the University of Pennsylvania Cancer Center has investigated a number of treatment programs in adenocarcinomas of the esophagus. The initial treatment recommended was surgery or radiation alone. Subsequently, patients were treated with high-dose radiation therapy and chemotherapy, without surgery. Both of these approaches were associated with a very high mediastinal recurrence rate. Later, patients were treated with surgery and postoperative radiation. While this sharply reduced the local recurrence rate, survival was not improved as much as hoped because of a high risk of distant metastases. Surgery with postoperative chemotherapy was also used, but the mediastinal recurrence rate rose nearly to the level seen in patients treated with surgery alone, although these recurrences were apparently delayed. Most recently, patients were treated with surgery, followed by combined radiation therapy and chemotherapy, with a significant improvement in two-year survival and a low mediastinal recurrence rate (see Table 1).

It appears from this experience that, in adenocarcinomas of the esophagus, all three treatment modalities complement each other. Surgery is the only effective therapy for controlling the intraluminal component of the tumor, because the dose of radiation is limited by the sensitivity of the surrounding structures. Because the esophagus is anatomically similar to the rectum in that it has a muscular wall with no serosa, these tumors frequently invade through the wall with a high risk of microscopic residual tumor at the radial margin. This leads to a high risk of recurrence in the surgical bed, which may be reduced by the addition of adjuvant radiation. Even when the mediastinal tumor is controlled, there is still a high risk of distant recurrence. Because these recurrences tend to occur late, the two-year survival is not long enough to demonstrate a benefit to adjuvant chemotherapy. But at four years, there appears to be a benefit to adjuvant chemotherapy, with a survival of 8% with surgery and radiation therapy compared with 25% with surgery + radiation + chemotherapy. Our current research efforts, including UPCC 1291, are directed at optimizing the sequence and intensity of these modalities.

Dr. Whittington is an Associate Professor of Radiation Oncology and a noted expert in the use of radiation therapy in the treatment of gastrointestinal and genitourinary cancers, particularly in combination with other treatment modalities.  Dr. Whittington can be reached at 215-662-6515.