By Susan G. Urba, Mark B. Orringer, Andrew Turrisi, Mark Iannettoni, Arlene Forastiere, Myla Strawderman

From the University of Michigan Medical Center, Ann Arbor, MI. Journal of Clinical Oncology, Vol 19, Issue 2 (January), 2001: 305-313

A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone. One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m²/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m²/d on days 1 through 21, and vinblastine 1 mg/m²/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42.

RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II . This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

N Engl J Med 1996 Aug 15;335(7):462-7

A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.

Walsh. Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 (fluorouracil, 15 mg per kilogram of body weight daily for five days, and cisplatin, 75 mg per square meter of body-surface area on day 7) and a course of radiotherapy (40 Gy, administered in 15 fractions over a three-week period, beginning concurrently with the first course of chemotherapy), followed by surgery. The patients assigned to surgery had no preoperative therapy. The median survival of patients assigned to multimodal therapy was 16 months, as compared with 11 months for those assigned to surgery alone (P=0.01). At one, two, and three years, 52, 37, and 32 percent, respectively, of patients assigned to multimodal therapy were alive, as compared with 44, 26, and 6 percent of those assigned to surgery, with the survival advantage favoring multimodal therapy reaching significance at three years (P=0.01).

Cancer 80:1011-20, 1997

Use of Concurrent Chemotherapy, Accelerated Fractionation Radiation, and Surgery for Patients with Esophageal Carcinoma

Adelstein. Patients received 2 induction courses with 4-day continuous intravenous infusions of cisplatin (20 mg/m²/day) and 5-fluorouracil (1000 mg/m²/day) beginning on Day 1 and Day 21, concurrent with a split course of accelerated fractionation radiation (1.5 grays [Gy] twice daily, to a total dose of 45 Gy). All patients were subsequently referred for surgical resection. A single, identical postoperative course of chemotherapy and 24 Gy accelerated fractionation radiation was planned for patients with residual tumor at surgery. Seventy-four patients were entered on this study; Sixty-seven patients (93%) underwent surgery, and 65 (90%) were found to have resectable tumors. Twelve of these patients (18%) died perioperatively, and 18 (27%) had no residual pathologic evidence of disease. 4-year projected recurrence free and overall survival rates were 49% and 44%, respectively.

Int J Radiat Oncol Biol Phys 1995 Jun 15;32(3):753-61

Management of adenocarcinoma of the esophagus with chemoradiation alone or chemoradiation followed by esophagectomy: results of sequential nonrandomized phase II studies.

Algan. The incidence of adenocarcinoma of the esophagus is increasing, but the optimal treatment for this disease is unknown. 11 patients (median age 66) were treated with concurrent chemotherapy [mitomycin C, and 5-fluorouracil (5-FU)] and radiotherapy to a median dose of 60 Gy (CRT group). From September 1987 to June 1992, 24 patients (median age 65) were treated with the same regimen of chemoradiation followed by planned esophagectomy (CRT+PE group). Of these, 12 patients (median age 62) actually underwent esophagectomy (CRT+E subgroup). RESULTS: The median overall survival was 19 months for the CRT group and 15 months for the CRT+PE group. For the CRT+E subgroup, the median overall survival was 33 months. The 3-year actuarial overall survival for the CRT and the CRT+PE groups were 36 and 28% (p = 0.949). The subset of patients treated with chemoradiation followed by esophagectomy had a 3-year actuarial overall survival of 33% (p = 0.274). Treatment-related mortality was 0 out of 11 in the CRT group and 2 out of 24 in the CRT+PE group. Dysphagia relief was similar in the CRT group vs. the CRT+E subgroup; however, a greater percentage of patients treated with chemoradiation alone had normal long-term swallowing function when compared to those patients also undergoing esophagectomy (100% vs. 73%). CONCLUSION: High-dose chemoradiation alone appears to provide similar survival and relief of dysphagia compared with high-dose chemoradiation followed by esophagectomy for patients with potentially resectable esophageal adenocarcinoma.

N Engl J Med 1997 Jul 17;337(3):161-7

Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus.

Bosset. We conducted a multicenter, randomized trial to compare preoperative chemoradiotherapy followed by surgery with surgery alone in patients with stage I and II squamous-cell cancer of the esophagus. The preoperative combined therapy consisted of two one-week courses; each involved radiotherapy, in a dose of 18.5 Gy delivered in five fractions of 3.7 Gy each, and 80 mg of cisplatin per square meter of body-surface area, administered 0 to 2 days before the first day of radiotherapy. The surgical plan included one-stage en bloc esophagectomy and proximal gastrectomy by the abdominal and right thoracic routes, to be performed immediately after randomization in the group assigned to surgery alone and two to four weeks after the completion of preoperative chemoradiotherapy in the group assigned to combined therapy. RESULTS: A total of 297 patients entered the study; 11 were found to be ineligible, and 4 were lost to follow-up. Of the remaining 282, 139 were assigned to surgery alone and 143 to combined therapy. After a median follow-up of 55.2 months, no significant difference in overall survival was observed; the median survival was 18.6 months for both groups. As compared with the group treated with surgery alone, the group treated preoperatively had longer disease-free survival, a longer interval free of local disease, a lower rate of cancer-related deaths, and a higher frequency of curative resection. However, there were more postoperative deaths in the group treated preoperatively with chemoradiotherapy.

Am J Clin Oncol 1997 Feb;20(1):11-5

Integration of surgery in multimodality therapy for esophageal cancer.

Ebie. While adding chemotherapy to radiation for the treatment of esophageal cancers has been shown to be beneficial, surgery usually follows treatment or is omitted. Twenty-five patients with esophageal cancer were treated in a phase I pilot protocol consisting of initial esophagectomy with gastroesophagostomy and subsequent combined chemotherapy and radiation. Chemotherapy consisted of cisplatin given on day 1 and 5-fluorouracil (FU) on days 1-5 by continuous infusion. Radiation therapy was administered in varying fractionation schedules of once or twice daily concomitantly with the chemotherapy. Treatment was repeated every other week for two to four cycles. Disease-free survival was 58 and 30% at 1 and 2 years, respectively. Survival was 58 and 32% at 1 and 2 years, respectively (median survival, 19 months). The local control rate and survival were better than those in our historical experience with cisplatin and 5-FU chemotherapy and radiation given prior to surgery.

Cancer 1998 Nov 1;83(9):1908-16

High dose chemoradiotherapy followed by esophagectomy for adenocarcinoma of the esophagus and gastroesophageal junction: results of a phase II study of the Eastern Cooperative Oncology Group.

Keller. Radiotherapy was administered in daily 2-gray (Gy) fractions 5 days a week until a total of 60 Gy was reached. 5-fluorouracil (5-FU) was infused continuously at a dose of 1000 mg/m2/day for 96 hours on Days 2-5 and 28-31. On Day 2, a 10 mg/m2 bolus of mitomycin was injected intravenously. Esophagectomy was performed 4-8 weeks following completion of the radiotherapy. Overall median survival was 16.6 months, 1-year survival 57%, and 2-year survival 27%. Survival was significantly worse for patients with circumferential cancers (median, 18.1 months vs. 8.3 months; P <0.05). CONCLUSION: High dose radiation therapy with concurrent 5-FU and mitomycin may be administered to patients with esophageal adenocarcinoma with acceptable morbidity. However, in a cooperative group setting, esophagogastrectomy following intensive chemoradiotherapy is associated with excessive morbidity and mortality. Circumferential tumor growth is a significant adverse prognostic factor.

J Thorac Cardiovasc Surg 1997 Aug;114(2):210-7

Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial.

Law. A prospective randomized trial was undertaken in 147 patients: 74 received preoperative chemotherapy comprising cisplatin and 5-fluorouracil and 73 had surgical therapy alone. Median survivals were 16.8 and 13 months, respectively (p = 0.17). Of those who completed the chemotherapy and resection, responders fared better than control patients. Median survivals were 42.2 months and 13.8 months, respectively (p = 0.003). Median survival (8.3 months) was worse for nonresponders than for control patients (p = 0.03). The recurrence pattern suggested a significant reduction in locoregional disease with chemotherapy. CONCLUSIONS: Preoperative chemotherapy was safe and resulted in significant downstaging and an increased likelihood of curative resection. Survival was not better than that in the surgery-alone group, but responders did fare better than nonresponders.