Nonoperative Therapy for Esophageal Cancer

Bruce D. Minsky, MD
Vice Chairman, Department of Radiation Oncology
Memorial Sloan-Kettering Cancer Center

Based on the positive results from the Radiation Therapy Oncology Group (RTOG) 85-01 trial,^1-3 the conventional nonsurgical treatment for esophageal carcinoma is combined-modality therapy. In the combined-modality–therapy arm of that trial, patients received four cycles of 5-fluorouracil (5-FU;1,000 mg/m²/24 hr x 4 days) and cisplatin (75 mg/m², day 1). Radiation therapy (50 Gy at 2 Gy/day) was given concurrently with day 1 of chemotherapy.

A significant improvement occurred in median survival (14 months vs 9 months), and 5-year survival (27% vs 0%, P <.0001) with combined-modality therapy vs irradiation (64 Gy) alone.^{2 Furthermore, a clear plateau in the survival curve was noted; with a minimum follow-up of 5 years, the 8-year survival rate was 22%.3 Histology did not significantly influence the results; 21% of patients with squamous cell carcinomas (n = 107) were alive at 5 years compared with 13% of patients with adenocarcinoma (n = 23; P value was not significant). The incidence of local failure as the first site of failure (local persistence + recurrence) was also decreased in the combined-modality arm (45% vs 65%). Although survival was increased, the 45% local failure rate was suboptimal. Therefore, new approaches, such as intensification of the radiation dose, and the use of newer chemotherapeutic agents were developed.}

The replacement trial to RTOG 85-01 was INT 0123 (RTOG 94-05).⁴ A total of 236 patients with clinical stage T1-4 N0-1 M0 squamous cell carcinomas (85% of cases) or adenocarcinomas (15% of cases) were entered into this trial to test a nonoperative approach. Following stratification by weight loss, primary tumor size, and histology, these patients were randomized to receive combined-modality therapy consisting of four monthly cycles of 5-FU (1,000 mg/m²/24 hr x 4 days) and cisplatin (75 mg/m², bolus day 1), with concurrent irradiation (50.4 Gy) versus the same chemotherapy with a higher dose of irradiation (64.8 Gy).⁴ Among the 216 eligible patients, no significant difference was recorded in median survival (12.9 months vs 17.6 months), 2-year survival (29% vs 38% of cases), or local/regional failure and/or local persistence (59% vs 52% of cases) between the high-dose and standard-dose arms. However, the 2-year local control, median survival, 2-year survival, and treatment-related death rate in the standard-dose arm were all similar to the combined-modality arm of RTOG 85-01, thereby confirming that nonoperative combined-modality therapy is effective in the treatment of esophageal cancer.

Two prior RTOG phase II trials also examined the role of increasing the radiation dose. The Intergroup INT 0122 (RTOG 90-12) trial enrolled 45 patients with squamous cell carcinoma who were treated with 3 cycles of neoadjuvant 5-FU, cisplatin followed by concurrent 5-FU, cisplatin, and 64.8 Gy. The local failure rate was 39%, median survival 20 months, and the 3-year survival was 30%. Likewise, the RTOG 92-07 trial used a 15-20 Gy brachytherapy boost following treatment with 5-FU, cisplatin, and 50 Gy in 49 eligible patients with squamous cell carcinoma or adenocarcinoma. In this trial, a total local failure rate of 63% was reported (37% local failure plus 26% local persistence), a median survival of 11 months, a 2-year survival of 31%, and a treatment-related death rate of 10%.⁵ The crude fistula rate was 12% and the cumulative yearly incidence was 17.5%/year. The INT 0122, RTOG 92-07, or the INT 0123 trials have not shown a local control or survival advantage compared with RTOG 85-01. Therefore, the standard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy remains 50.4 Gy.

The most widely used systemic agent in the treatment of esophageal cancer is 5-FU. New chemotherapeutic agents exist in both development and practice for esophageal cancer. These agents have been used as a component in both preoperative and nonoperative combined-modality therapy treatment programs. Taxol-based regimens have been associated with encouraging response rates in patients with advanced disease, and its incorporation into preoperative combined-modality regimens has shown encouraging results.^6-13 As with combined modality regimens in other gastrointestinal cancers, development of the ideal regimens and schedules remains an active area of clinical investigation.

Published October 2000