Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. Preoperative radiotherapy for carcinoma of the esophagus. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone.
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.
                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 (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power.
                This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference. In a prospective multicenter study, 186 patients with squamous cell esophageal carcinoma, who after evaluation were considered suitable for surgery, were randomized to 4 treatment groups: Group 1, surgery alone; Group 2, pre-operative chemotherapy (cisplatin and bleomycin) and surgery; Group 3, pre-operative irradiation (35 Gy) and surgery; Group 4, pre-operative chemotherapy, radiotherapy, and surgery. Three-year survival was significantly higher in the pooled groups receiving radiotherapy as compared with the pooled groups not receiving radiotherapy. Comparison of the groups having pre-operative chemotherapy with those not having chemotherapy showed no significant difference in survival. Female patients had a significantly better survival than males. The results indicate that pre-operative irradiation had a beneficial effect on intermediate term survival, whereas the chemotherapy regime used did not influence survival. We update Radiation Therapy Oncology Group trial 8911 (USA Intergroup 113), a comparison of chemotherapy plus surgery versus surgery alone for patients with localized esophageal cancer. The relationship between resection type and between tumor response and outcome were also analyzed.
                The chemotherapy group received preoperative cisplatin plus fluorouracil. Outcome based on the type of resection (R0, R1, R2, or no resection) was evaluated. The main end point was overall survival. Disease-free survival, relapse pattern, the influence of postoperative treatment, and the relationship between response to preoperative chemotherapy and outcome were also evaluated.
                Two hundred sixteen patients received preoperative chemotherapy, 227 underwent immediate surgery. Fifty-nine percent of surgery only and 63% of chemotherapy plus surgery patients underwent R0 resections (P = .5137). Patients undergoing less than an R0 resection had an ominous prognosis; 32% of patients with R0 resections were alive and free of disease at 5 years, only 5% of patients undergoing an R1 resection survived for longer than 5 years. The median survival rates for patients with R1, R2, or no resections were not significantly different. While, as initially reported, there was no difference in overall survival for patients receiving perioperative chemotherapy compared with the surgery only group, patients with objective tumor regression after preoperative chemotherapy had improved survival.
                For patients with localized esophageal cancer, whether or not preoperative chemotherapy is administered, only an R0 resection results in substantial long-term survival. Even microscopically positive margins are an ominous prognostic factor. After a R1 resection, postoperative chemoradiotherapy therapy offers the possibility of long-term disease-free survival to a small percentage of patients. From 21 March to 22 June 1976, 124 patients with squamous cell carcinoma of the esophagus were randomized for inclusion in a prospective trial of preoperative irradiation. Fifteen patients were excluded because of inoperability. Sixty-seven patients were randomly selected to receive 4,000 rads of cobalt radiation for eight days prior to operation; 57 patients were operated upon without receiving radiation therapy. No significant differences were noted between the two groups with regard to age, sex, tumor site, experience of the surgeon, method of approach or surgical technique. Eight esophageal resections were performed upon 47 of the 62 irradiated patients and 33 of the 47 nonirradiated patients. Of the 62 irradiated patients, 14 died during operation, compared with 11 of the 47 nonirradiated patients, the difference between the two groups not being statistically significant. Irradiation was associated with a higher mortality for lesions in the mid third part of the esophagus, 11 of 29 versus four of 19, but again, the difference was not significant. In the irradiated patients, the five year actuarial postoperative survival rate was 9.5 versus 11.5 per cent for the nonirradiated patients. In conclusion, preoperative radiation therapy does not produce a statistically significant short term or long term benefit in the management of squamous cell carcinoma of the esophagus. OEO2 is a randomized, controlled trial of preoperative chemotherapy in patients undergoing radical surgery for esophageal cancer. Random assignment was to surgery alone (S) or to two cycles of combination cisplatin and fluorouracil before surgery (CS). Initial results reported in 2002 demonstrated an advantage for both disease-free and overall survival in the CS group. The analysis has now been updated after a median follow-up of 6 years.
                OEO2 recruited 802 patients, 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Survival by extent of resection is presented.
                There were 655 deaths, 335 for S and 320 for CS. The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P = .03) which in absolute terms is a 5-year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P < .001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%.
                Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care. Of 77 patients with potentially resectable squamous cell carcinoma of the esophagus who were asked to participate in a phase III trial of treatment with either immediate surgery (n = 24) or surgery plus preoperative chemotherapy (n = 22), only 46 agreed to randomization. A priori, 13 patients chose chemotherapy before surgery and 18 patients chose surgery only. The complete chemotherapy program consisted of three cycles with fluorouracil, 1 g/m2 per day for 5 days, and cisplatin, 20 mg/m2 per day for 5 days. The response rate to chemotherapy was 50% (17 of 34 patients). Side effects of therapy were higher than expected based on results of previous phase II studies. Two drug-related deaths were observed. The resectability rate for patients in the surgery only group was 79% (33 of 42 patients) compared with 70% (19 of 27 patients) for patients receiving chemotherapy. The postoperative rates of septic complications (41% [11 of 27 patients] vs 26% [11 of 42 patients]) and respiratory disorders (48% [13 of 27 patients] vs 31% [13 of 42 patients]) were higher for patients with preoperative chemotherapy than for those treated with surgery only. Surgery-related mortality was increased in the chemotherapy group (19% [five of 27 patients]) compared with the surgery only group (10% [four of 42 patients]). Patients responding to preoperative chemotherapy had prolonged survival (median, 13 months) compared with nonresponders (median, 5 months), but the median survival for the chemotherapy group and the surgery only group was identical (10 months). We conclude that the preoperative chemotherapy regime used in this multi-institutional trial neither influences resectability nor increases the overall survival of patients with localized esophageal cancer. However, preoperative chemotherapy is associated with considerable side effects and a high postoperative mortality rate. From June 1977 to May 1985, a prospective randomized clinical trial on pre-operative radiation for esophageal carcinoma was carried out in 206 patients. Lesions under 8 cm in length and patients younger than 65 years, at least on semi-liquid diet and not contra-indicated for surgery were randomized into a combined group (104 patients) or a surgery alone group (102 patients). Eight MV X ray units were used for the pre-operative radiation using A-P portals to deliver 4,000 cGy to the whole mediastinum and the left gastroepiploic lymphatic chain. Surgery was carried out after 2 to 4 week's rest. The immediate results of the combined group and the surgery alone group were: resection rate 93% and 85%, operative mortality 5% and 6%, intra-thoracic anastomotic leak 0% and 1%, positive pathology at the esophageal stump 0% and 2%, and lymph nodes metastasis 27% and 35% respectively. The 5-year survival rates of the combined group and the surgery alone group were 35% and 30%. We have noticed that those patients with lesions showing radiation reaction of grade III gave a 5-year survival of 50% (12/24). Because intra- and extra-thoracic lymphnode metastasis caused failures (41% and 34% of these two groups), increasing the preoperative tumor dose to 60 Gy or designing post-operative irradiation to cover the bilateral supraclavicular areas was necessary. The whole mediastinum and the left gastroepiploic lymphatics could further improve the results of surgery. Further studies are needed. This study investigated the role of preoperative chemotherapy in squamous cell cancer of the esophagus.
                A prospective randomized trial was undertaken in 147 patients: 74 received preoperative chemotherapy comprising cisplatin and 5-fluorouracil and 73 had surgical therapy alone. End points were cancer and therapy-related deaths.
                Sixty-six patients (89%) in the chemotherapy group underwent resection compared with 69 (95%) in the control group (p = not significant). Of the 60 patients who had resection after completing the chemotherapy program, 35 (58%) had a significant response, of whom four (6.7%) had a complete pathologic response. Postoperative mortality rates were 8.3% and 8.7% in the chemotherapy and control groups, respectively (p = not significant). Significant downstaging was evident with chemotherapy; curative resections were possible in 67% of these patients compared with 35% in the control group (p = 0.0003). T3 and T4 tumors were found in 67% and 91% of the chemotherapy and control groups, respectively (p = 0.0002). The respective figures for N1 disease were 70% and 88% (p = 0.009). An intent-to-treat analysis of survival showed no significant difference between the two groups. 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.
                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. Surgery is the standard treatment for patients with resectable esophageal carcinoma, but the long term prognosis of these patients is unsatisfactory. Some randomized trials of preoperative chemotherapy suggest that the prognosis of patients who respond may be improved.
                This randomized, controlled trial compared patients with clinically resectable esophageal epidermoid carcinoma who underwent surgery alone (Arm A) with those who received preoperative chemotherapy (Arm B). Overall survival and the prognostic impact of major response to chemotherapy were analyzed. Forty-eight patients were enrolled in each arm. Chemotherapy consisted of two or three cycles of cisplatin (100 mg/m2 on Day 1) and 5- fluorouracil (1000 mg/m2 per day continuous infusion on Days 1-5). In both study arms, transthoracic esophagectomy plus two-field lymphadenectomy was performed. The two groups were comparable in terms of patient characteristics.
                Forty-seven patients were evaluable in each arm. The curative resection rate was 74.4% (35 of 47 patients) in Arm A and 78.7% (37 of 47 patients) in Arm B. Treatment-related mortality was 4.2% in both arms. The response rate to preoperative chemotherapy was 40% (19 of 47 patients), including 6 patients (12.8%) who achieved a pathologic complete responses. Overall survival was not improved significantly. The 19 patients in Arm B who responded to chemotherapy and underwent curative resection had significantly better 3-year and 5-year survival rates (74% and 60%, respectively) compared with both nonresponders (24% and 12%, respectively; P = 0.0002) and patients in Arm A who underwent complete resection (46% and 26%, respectively; P = 0.01): Patients who achieved a pathologic complete response (P = 0.01), but not those who achieved a partial response (P = 0.2), had significantly improved survival.
                Patients with resectable esophageal carcinoma who underwent preoperative chemotherapy and obtained a pathologic complete response had a significantly improved long term survival. Major efforts should be undertaken to identify patients before neoadjuvant treatments who are likely to respond.
                Copyright 2001 American Cancer Society.
Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).