Prospective evaluation of preoperative chemotherapy in resectable squamous cell carcinoma of the thoracic esophagus. Chemotherapy followed by surgery compared with surgery alone for localized 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. 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. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. 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. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. 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 prospective study was performed to clarify the surgical outcome of patients with esophageal carcinoma who would benefit from induction chemotherapy followed by surgery. Of 55 eligible patients, 42 (76.3%) agreed to randomization with either chemotherapy followed by surgery (n = 21) or surgery alone (n = 21). The other 13 refused. The chemotherapy consisted of cisplatin, 5-fluorouracil and leucovorin. All 55 patients underwent esophagectomy with two- or three-field resection, including two (3.6%) hospital mortalities. Of the 21 patients receiving chemotherapy, the response rate was 33.3% after the first course and 60% after the second course. A complete response was not obtained. Responders to the first course showed a prolonged survival, however time to treatment failure did not differ between patients treated with chemotherapy followed by surgery or surgery alone. This chemotherapy offered a worse surgical outcome for patients with pretreatment diagnosis of T3. Multivariate analysis identified a partial response to the first course of chemotherapy to be a favorable prognostic indicator. Preoperative chemotherapy does not give a survival benefit over surgery alone for patients with advanced tumor (T3). Initial response to the first dose of chemotherapy is deemed to be a prognostic factor for patients with less advanced tumor (T1/T2). We performed a multi-institutional randomized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer.
                Preoperative chemotherapy for patients randomly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil. Surgery was performed two to four weeks after the completion of the third cycle; patients also received two additional cycles of chemotherapy after the operation. Patients randomly assigned to the immediate-surgery group underwent the same surgical procedure. The main end point was overall survival.
                Of the 440 eligible patients with adequate data , 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery. After a median possible study time of 55.4 months, there were no significant differences between the two groups in median survival: 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who underwent immediate surgery (P=0.53). At one year, the survival rate was 59 percent for those who received chemotherapy and 60 percent for those who had surgery alone; at two years, survival was 35 percent and 37 percent, respectively. The toxic effects of chemotherapy were tolerable, and the addition of chemotherapy did not appear to increase the morbidity or mortality associated with surgery. There were no differences in survival between patients with squamous-cell carcinoma and those with adenocarcinoma. Weight loss was a significant predictor of poor outcome (P=0.03). With the addition of chemotherapy, there was no change in the rate of recurrence at locoregional or distant sites.
                Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus. 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. 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. 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. 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. 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. A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer.
                We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival.
                ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001).
                In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).
                Copyright 2006 Massachusetts Medical Society. 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.
In summary, preoperative chemotherapy plus surgery may offer a survival advantage compared to surgery alone for resectable thoracic esophageal cancer, but the evidence is inconclusive. There is some evidence of toxicity and preoperative mortality associated with chemotherapy.