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© 2001 American Society for Clinical Oncology Randomized Trial of Preoperative Chemoradiation Versus Surgery Alone in Patients With Locoregional Esophageal CarcinomaFrom the University of Michigan Medical Center, Ann Arbor, MI. Address reprint requests to Susan G. Urba, MD, University of Michigan Medical Center, 1500 E Medical Center Dr, 1366 Cancer Center, Ann Arbor, MI 48109; email surba{at}umich.edu
PURPOSE: 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. MATERIALS AND METHODS: 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 (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. CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.
PATIENTS WITH local-regional esophageal carcinoma have a poor 3-year survival when treated with surgery alone. This fact has prompted many investigators to explore preoperative chemoradiation approaches in an effort to improve survival. Between 1985 and 1987, the University of Michigan conducted a pilot study of intensive preoperative chemotherapy consisting of cisplatin, fluorouracil, and vinblastine administered concurrently with 45 Gy of radiation for 43 patients with locoregional disease.1,2 The results were promising. Median survival was 29 months, compared with a median survival of 12 months for 100 historical controls treated with surgery alone at the same institution. In fact, median survival for the 10 patients who were complete histologic responders after the chemoradiation was 70 months. Based on these data, we decided to conduct a randomized trial comparing this piloted regimen to surgery alone for patients with local-regional esophageal carcinoma. This was a single-institution trial conducted at the University of Michigan.
Eligibility Criteria Patients had histologically confirmed squamous cell carcinoma, adenocarcinoma, or mixed adenosquamous carcinoma of the esophagus or the gastroesophageal junction. No prior treatment was allowed. Disease was limited to the esophagus and regional lymph nodes as defined by the American Joint Committee on Cancer tumor-node-metastasis staging classification.3 Although celiac nodes are not considered regional lymph nodes, patients with enlarged celiac nodes were allowed into the protocol because this area was included in the radiation port, and celiac nodes may be resected at surgery. Patients with documented distant metastases or endoscopically demonstrated invasion of the tracheobronchial tree were excluded. Patients were required to have a Karnofsky performance status of 60% or greater. Age limit was 75 years or younger, and creatinine clearance had to be at least 50 mL/min. The WBC count had to be greater than 3,500/mm3, and the platelet count had to be greater than 100,000/mm3. No previous malignancy was allowed other than surgically cured basal cell carcinoma of the skin or carcinoma-in-situ of the cervix.
Staging Procedures
Treatment Plan Patients were randomized to arm I (transhiatal esophagectomy) or to arm II (preoperative chemoradiation followed by transhiatal esophagectomy).
Arm I: Transhiatal Esophagectomy For localized tumors of the gastric cardia, the stomach was divided in such a fashion as to maintain a 4- to 6-cm margin beyond gross palpable tumor. For tumors of the cervicothoracic esophagus, concomitant laryngopharyngectomy and permanent tracheostomy were required. Alimentary continuity after transhiatal esophagectomy was restored using either the stomach or a colon interposition anastomosed to the pharynx. At the time of surgery, if the patient had an intrathoracic esophageal tumor that could not be resected safely using the transhiatal approach, a thoracotomy and transthoracic esophagectomy was carried out. Regardless of the method of esophagectomy (transhiatal without thoracotomy or transthoracic), a cervical esophageal anastomosis was performed whenever possible to minimize potential postoperative morbidity from an anastomotic leak. Postoperative radiotherapy was not used for patients with positive nodes, but was applied for positive margins of resection.
Arm II: Preoperative Chemotherapy and Radiation Followed by Esophagectomy Dose modifications were made for toxicity, using the Southwest Oncology Group toxicity criteria. If granulocytes dropped below 1,000/mm3 and/or platelets dropped below 50,000/mm3, all chemotherapy was held. The chemotherapy was restarted when granulocytes had recovered to 1,000/mm3 or greater and when platelets had recovered to 50,000/mm3 or greater. If grade 2/3 stomatitis occurred, the fluorouracil and vinblastine were held until the toxicity resolved. If grade 2/3 diarrhea occurred, the fluorouracil was held until the toxicity resolved, and stools were also cultured for Clostridium difficile toxin. Renal toxicity was assessed by a repeat of the creatinine clearance before day 17, when the cisplatin was scheduled to be restarted. If the creatinine clearance was 50 mL/min or greater, a full dose of cisplatin was given. If the clearance was 40 to 49 mL/min, 15 mg/m2/d was given on days 17 through 21. If the clearance was less than 40 mL/min, no further cisplatin was given. Radiation. Patients were simulated to encompass the tumor volume with 5-cm cephalo-caudad margins and 2-cm radial margins. To maintain stability and reduce motion, all patients were immobilized in Alpha cradles (KGF Enterprise Inc, Chesterfield, MI). Patients were CT-simulated and scanned in the treatment position. The tumor and targets were identified and outlined using UM-plan/Scandaplan (University of Michigan, Ann Arbor, MI) three-dimensional treatment planning. Beam arrangements targeted the tumor and involved nodes and aimed to reduce normal tissue exposure and restricted spinal cord doses to no more than 36 Gy. Uninvolved nodal regions were not included in treatment fields. Daily fractions of 1.5 Gy were given twice a day, on days 1 through 5, 8 through 12, and 15 through 19, to a total dose of 45 Gy. Surgery. Transhiatal esophagectomy was performed on approximately day 42, after a 3-week rest after completion of the chemoradiation. The details of the surgery are described above (see Arm I: Transhiatal Esophagectomy).
Statistical Design
Patient Characteristics Between January 1989 and July 1994, 217 patients were evaluated for enrollment in this protocol. One hundred patients were eligible and enrolled in the study. One hundred seventeen did not enroll for the following reasons: 73 patients refused, 10 had medical contraindications, 18 patients’ tumor pathology review did not fit the criteria of the protocol, six had already had some treatment for the tumor, four patients had two or more cancers, and six were disqualified for other miscellaneous reasons. The cutoff date for data included in this analysis was March 1999. Of the 100 patients enrolled, 50 were randomized to arm I, and 50 were randomized to arm II. Patient characteristics are listed in Table 1. The potential prognostic factors for survival were well balanced between the randomized groups.
Table 2 lists the doses of the proposed radiation and chemotherapy tolerated by the patients on arm II of the study. One hundred percent of the planned dose of preoperative radiation was delivered to the majority of the patients. Chemotherapy dose reductions were required for each of the three agents in approximately one third of the patients.
Toxicity Forty-nine patients in arm II are assessable for toxicity of chemoradiation, summarized in Table 3. The one patient who was not assessable was enrolled in the study and randomized to arm II, but before treatment was started, metastatic disease was diagnosed on the radiation-planning CT scan. He therefore never received any of the protocol chemotherapy.
Seventy-eight percent of patients experienced grade 3/4 granulocytopenia, and one half of these developed neutropenic fever. Thirty-one percent had grade 3/4 thrombocytopenia. Sixteen percent received RBC transfusions, and 63% required feeding tubes to maintain nutrition before surgery because of radiation esophagitis. No patient required parenteral nutrition.
Surgical Results
Arm I. All 50 patients on the surgical arm of the study underwent esophagectomy. Forty-five patients had gross total resection of disease. Five patients had palliative resections: two patients had unresectable residual disease at the cervical margin, one had tumor adherent to the pericardium, one had tumor invasion into the carina, and one had omental metastases discovered at surgery. One patient had microscopic positive margins in the surgical specimen and received postoperative radiation. There were two perioperative deaths. One resulted from a postoperative pneumonia, and the other was caused by a cervical anastomotic leak that led to sepsis and death in the postoperative setting. Four patients developed an anastomotic leak that eventually healed with local wound care. One patient developed a major wound dehiscence that required re-operation; the cervical margin was also involved with cancer, and she died a few months later of metastatic disease. Arm II. Forty-seven of the 50 patients randomized to arm II underwent esophagectomy. Three patients were not operated on for the following reasons: metastases were discovered in one patient on the radiation-planning CT scan and so protocol therapy ceased, and the other two patients received the preoperative chemotherapy and radiation, but metastases were discovered on preoperative CT scan. Forty-five patients underwent gross total resection of disease. Two patients had liver metastases discovered at surgery and were never rendered disease-free. There was one perioperative death resulting from ischemic bowel. One patient had a microscopic positive margin in the surgical specimen and received postoperative radiation. Seven patients developed an anastomotic leak that eventually healed with local wound care. At the time of esophagectomy after chemoradiation, 14 (28%) of the 50 patients had no residual cancer in the resected esophagus (T0N0).
Survival Data Overall survival was measured from the date of randomization to either the date of death or the date of last patient contact at which the patient was alive. Survival was estimated by the method of Kaplan and Meier and compared between groups using the log-rank test. The association for several factors with survival was simultaneously evaluated using Cox’s proportional hazards regression analysis. There was no difference in median survival, which was 17.6 months in arm I and 16.9 months in arm II (Table 5). Although the survival rate at 3 years was somewhat longer for those randomly assigned to the multimodality arm (30%) than to the surgery-alone arm (16%), this difference was not significant (P = .15). The univariate hazards ratio is 0.73 (95% confidence interval, 0.48 to 1.12). The survival curves are shown in Fig 1.
The univariate, or unadjusted, association of several patient and disease characteristics with overall survival is summarized in Table 6. Tumors larger than 5 cm and age greater than 70 years were predictors of shorter survival. Lymph node involvement by CT scan criteria, histology, and tumor site were not significant predictors.
Multivariate analysis was performed to determine the association of five possible prognostic factors and treatment with survival (Table 7). All 100 patients were included in the analysis. No interaction was discovered between any of the patient factors and treatment. Tumors more than 5 cm, squamous cell histology, and age more than 70 years are independently associated with shorter survival after adjusting for the other factors in the model. This difference between squamous cell and adenocarcinoma histology has not been noted in any previous trial, to our knowledge. Patients randomized to the multimodality arm have a 31% lower risk of death from any cause over the study (P = .09) after adjusting for the other prognostic factors. Although this is not statistically significant, this suggests a possible trend to the benefit of multimodality therapy, but the sample size was too small to detect a more subtle survival difference.
Survival by pathologic response. Patients treated on the multimodality arm were assessed for pathologic response at the time of surgery. Twenty-eight percent of patients were histologic complete responders. There was a significant association between survival and pathologic response, with patients who achieved a complete response (T0N0) having longer survival. Patients with complete histologic response had a median survival duration and 1-year and 3-year survival rates of 49.7 months, 86%, and 64% respectively, whereas patients with residual disease in the resected specimen had a median survival duration and 1-year and 3-year survival rates of 12 months, 52%, and 19% respectively (P = .01). The survival curves are shown in Fig 2.
Disease-free survival. For those patients who were never rendered free of disease by surgery (five patients on each arm of the study) a disease-free survival of zero was assigned. This explains the Kaplan-Meier plot starting at 90% at time 0, rather than at 100%. There were nine patients (three patients in arm I and six patients in arm II) who died without recurrence and who are censored at the time of death. The duration of disease-free survival did not differ between the randomized treatment groups. Cancer recurred or was never eliminated in 43 patients in arm I and in 36 patients in arm II. At 3 years, disease-free survival was 16% in arm I and 28% in arm II (P = .16). These survival curves are shown in Fig 3.
Patterns of relapse. The pattern of first relapse was compared between patients treated in each arm using the exact  2 test. In addition to the five patients in each arm who were never disease-free, there were two patients in the multimodality arm excluded from this analysis because of unknown site of relapse. A higher occurrence of local-regional disease as a component of first failure was observed in arm I (42%, 19 of 45) compared with arm II (19%, eight of 43) (P = .02). However, the proportion of patients with distant disease at the time of first recurrence was almost the same in each arm: arm I, 60% (27 of 45) versus arm II, 65% (28 of 43) (P > .66). Cause-specific survival. Two deaths in arm I and four deaths in arm II were not due to cancer or its treatment. In the cause-specific analysis, these patients are censored at the time of death from another cause. The estimated 3-year cause-specific survival rate is not significantly different between treatment arms: 16% for patients in arm I and 30% for patients in arm II (P = .13).
This randomized trial comparing multimodality therapy consisting of intensive preoperative chemoradiation versus surgery alone did not demonstrate a statistically significant survival difference between treatment arms. The prior pilot trial conducted at the University of Michigan suggested that median survival for patients treated with this same therapy could be more than doubled to 29 months in comparison with 12 months for historic controls treated with surgery alone.1,2 Therefore, the statistical design assumed that a doubling of median survival was possible, and so the study was powered to detect this large difference between the treatment groups, with at least 80% power, and so a relatively small sample size of 100 patients was needed. Thus this trial did not have the ability to assess more subtle survival differences. Patient characteristics were fairly similar, although there was a greater percentage of patients with adenocarcinoma in the current trial (75%) compared with the pilot study (49%). However, these patients were evenly stratified in arm I and arm II. Patients in the current trial who were treated with surgery alone had a median survival of 17.6 months, which was better than the 12-month median survival of the historic controls that had served as the comparison group for the pilot study. The staging of these patients, operative techniques, and postoperative support have improved over the years. Therefore, surgically treated patients have a better survival today in comparison with those undergoing that same treatment years ago. However, the patients treated with combined-modality therapy in arm II had a poorer median survival than those patients in the pilot study, even though they were also being treated with the more recent surgical techniques. This would suggest that the chemoradiation was simply not as effective as the pilot study had suggested, or that there was an unrecognized difference between the patient groups in the two trials. Accurate staging of disease at the time of diagnosis is essential to assure balanced randomization of patients between study arms. At the time this study was designed, endoscopic ultrasound, thoracoscopy, and laparoscopy were not part of standard staging evaluation at our institution. Since that time, more data have been reported, suggesting a possible role for these procedures in the staging of patients with esophageal cancer.4-8 The largest amount of data has been reported for endoscopic ultrasound, and many institutions, including the University of Michigan, are beginning to develop expertise in this procedure. Some of these techniques will enhance future trials. In our study, there was a marked survival advantage for patients who achieved a histologic complete response as a result of the preoperative treatment. This benefit has been previously noted in other reported trials of preoperative chemoradiation.9-11 Therefore, strategies aimed at increasing the complete response rate are needed to impact on overall survival. One strategy is the use of more effective drug combinations, and numerous phase II trials are currently ongoing to test new regimens that often include a taxane in the chemotherapy design. The site of first recurrence in our trial included distant metastases in approximately 60% of patients in both arms, and this further emphasizes the need for tolerable, systemic adjuvant therapies. The appropriateness of a transhiatal esophagectomy without thoracotomy in patients with carcinoma has engendered some controversy among those who believe that aggressive mediastinal lymphadenectomy has important therapeutic benefits in the treatment of esophageal cancer. They also argue that inability to perform a complete mediastinal lymph node dissection in patients undergoing transhiatal esophagectomy results in inadequate staging of these tumors. The University of Michigan General Thoracic Surgery Service has used transhiatal esophagectomy and a cervical esophagogastric anastomosis for benign and malignant disease since its initial 1978 report.12 Our cumulative experience with 1,085 patients undergoing transhiatal esophagectomy includes a hospital mortality rate of 4%, relatively low postoperative morbidity, and actuarial survival of patients with cancer equal to or exceeding that reported after more traditional methods of transthoracic esophageal resection.13 The overall actuarial survival rate in our patients has been 67% at 1 year, 47% at 2 years, and 27% at 5 years. In 217 cancer patients who have had preoperative chemoradiation at our institution or elsewhere before transhiatal esophagectomy, the 2-year survival rate was 29% and the 5-year survival rate was 20%. Forty-nine patients (23%) were complete responders (T0N0 tumors), and in this subset of patients, the 1-year actuarial survival rate was 86% and the 5-year survival rate was 48%. At the time of transhiatal esophagectomy, we continue to sample accessible celiac axis, perigastric, periesophageal, subcarinal, and cervical lymph nodes for the purpose of staging. We find little, if any, evidence that the completeness of the lymphadenectomy in patients undergoing an esophagectomy for cancer determines survival in the majority of these patients. Four other randomized trials of preoperative chemoradiation have been reported, and only one of these demonstrated survival benefit to combined-modality therapy. Walsh et al14 randomized 113 patients with adenocarcinoma of the esophagus to receive either surgery alone or preoperative chemoradiation. The chemotherapy consisted of two courses of cisplatin and fluorouracil given in weeks 1 and 6, and radiation was administered in 15 fractions over a 3-week period to a total of 40 Gy. Only one of the cycles of chemotherapy was actually given concurrently with the radiation. The combined-modality therapy provided a significant improvement in median survival (16 v 11 months; P = .01) and in 3-year survival (32% v 6%; P = .01) compared with surgery alone. It is noteworthy that the results of the combined-modality arm of the Walsh trial and the one we are reporting are very similar (3-year survival rates of 32% and 30%, respectively); the differences are in outcomes with surgery alone (6% and 16%, respectively). The 6% survival rate is somewhat lower than would be expected from the experience of recent studies in the United States. Kelsen et al15 recently reported a randomized trial of preoperative chemotherapy versus surgery alone, and the 3-year survival rate for patients treated in the control arm in that trial was 26%. The European Organization for Research and Treatment of Cancer enrolled 282 patients with squamous cell cancer in a study that compared surgery alone with preoperative chemoradiation.16 The combined therapy consisted of two 1-week courses of cisplatin and radiation, separated by a 2-week break, to a total dose of 37 Gy. There was no survival difference between groups. Median survival was 18.6 months in both arms, and the 3-year survival rate was 35% in the surgical arm and 37% in the combined-modality arm. The excellent result in the surgical arm may reflect the fact that the patient population was limited to those with earlier stage disease (stage I and II). Interestingly, there was a significant difference in the proportion of deaths that were attributed to esophageal cancer between the two groups (86% of patients in the surgical arm v 67% of patients who received the combined treatment; P = .002). But there was also a difference in postoperative mortality between the arms (5% of patients in the surgical arm and 17% of patients in the combined-modality arm; P = .012), which accounts for no overall difference in survival. However, the group of patients treated preoperatively had longer disease-free survival, a longer interval free of local disease, and a higher frequency of curative resection. The last two randomized trials of chemoradiation delivered the chemotherapy and radiation sequentially rather than concurrently. Nygaard et al17 conducted the Second Scandinavian Trial in esophageal cancer. It was a four-arm trial in which 187 patients were treated with surgery alone, preoperative chemotherapy, preoperative radiotherapy, or preoperative chemotherapy followed by radiation and then surgery. The chemoradiation arm used cisplatin and bleomycin, and when it was compared with the surgical arm, there was no difference in median or long-term survival. Another sequential trial was conducted in France by LePrise et al18 for 86 patients with squamous cell carcinoma. The radiation dose was only 20 Gy, which is less than one half of current standards, and it was sandwiched between two courses of cisplatin and fluorouracil. No survival difference was noted between arms at 1, 2, or 3 years. These trials using preoperative chemoradiation are listed in Table 8.
An Intergroup trial was opened to compare surgery with preoperative chemoradiation, but it was recently closed because of poor accrual. The data from the three randomized trials using chemoradiation for squamous cell carcinoma did not demonstrate survival benefit, and the percentage of patients with this histology in future trials will be quite small because of the dramatically increasing incidence of adenocarcinoma. For patients with adenocarcinoma, the data are conflicting. The Irish trial showed a survival advantage for preoperative chemoradiation, yet our trial, with 75% of patients with adenocarcinoma, did not show a statistically significant advantage. Five randomized trials of preoperative chemotherapy without radiation have been conducted. Four of these trials have shown no benefit to the chemotherapy.15,17,19,20 The only trial to suggest survival benefit was reported in abstract form from the Netherlands at a median follow-up of 15 months, and so more mature data are awaited.21 At this time, there is no role for preoperative chemotherapy as part of standard care for patients with esophageal cancer outside of an investigational setting. In conclusion, the randomized trial from the University of Michigan comparing preoperative chemoradiation with surgery alone did not demonstrate a significant difference in survival between arms. However, in the multivariate analysis, the comparison of the effect of treatment arms on survival had a P value of .09, which raises the possibility that there may be a mild trend for benefit of multimodality therapy, but this study was statistically powered to detect a relatively large difference in survival. Thus a more subtle survival difference could not be detected. It is reasonable to continue to use surgery as a standard of care for patients with esophageal carcinoma, as well as to continue investigation of potentially more effective chemoradiation regimens for these patients.
Supported by the University of Michigan Comprehensive Cancer Center Core Grant no. (P30) CA-46592.
1. Forastiere AA, Orringer MB, Perez-Tamayo C, et al: Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer of the esophagus. J Clin Oncol 8: 119-127, 1990
2.
Forastiere AA, Orringer MB, Perez-Tamayo C, et al: Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: Final report. J Clin Oncol 11: 1118-1123, 1993 3. Esophagus, in Fleming ID, et al (eds): AJCC Cancer Staging Handbook, ed 5. Philadelphia, PA, J.B. Lippincott, 1998, pp 65-69 4. Koch J, Halvorsen RA: Staging of esophageal cancer: Computed tomography, magnetic resonance imaging, and endoscopic ultrasound. Semin Roentgen 24: 364-372, 1994 5. Rice TW, Boyce GA, Sivak MV, et al: Esophageal carcinoma: Esophageal ultrasound assessment of preoperative chemotherapy. Ann Thorac Surg 53: 972-977, 1992[Abstract] 6. Chak A, Canto M, Gerdes H, et al: Prognosis of esophageal cancers preoperatively staged to be locally invasive (T4) by endoscopic ultrasound (EUS): A multicenter retrospective cohort study. Gastroenterol Endo 42: 501-506, 1995 7. O’Brien MG, Fitzgerald EF, Lee G, et al: A prospective comparison of laparoscopy and imaging in the staging of esophagogastric cancer before surgery. Am J Gastroenterol 90: 2191-2194, 1995[Medline]
8.
Krasna MJ: Advances in staging of esophageal carcinoma. Chest 113: 107S-111S, 1998
9.
Stahl M, Wilke H, Fink U, et al: Combined preoperative chemotherapy and radiotherapy in patients with locally advanced esophageal cancer: Interim analysis of a phase II trial. J Clin Oncol 14: 829-837, 1996
10.
Ganem G, Dubray B, Raoul Y, et al: Concomitant chemoradiotherapy followed, where feasible, by surgery for cancer of the esophagus. J Clin Oncol 15: 701-711, 1997 11. Forastiere AA, Heitmiller RF, Lee DJ, et al: Intensive chemoradiation followed by esophagectomy for squamous cell and adenocarcinoma of the esophagus. Cancer J Sci Am 3: 144-152, 1997[Medline] 12. Orringer MB, Sloan H: Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg 76: 643-654, 1978[Abstract] 13. Orringer MB, Marshall B, Iannettoni MD: Transhiatal esophagectomy: Clinical experience and refinements. Ann Surg 230: 392-400, 1999[Medline]
14.
Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335: 462-467, 1996
15.
Kelsen DP, Ginsberg R, Pajak TF, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339: 1979-1984, 1998
16.
Bossett JF, Gignoux M, Triboulet JP, et al: Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. N Engl J Med 337: 161-167, 1997 17. Nygaard K, Hagen S Hansen HS, et al: Preoperative radiotherapy prolongs survival in operable esophageal carcinoma: A randomized, multicenter study of preoperative radiotherapy and chemotherapy—The second Scandinavian trial in esophageal cancer. World J Surg 16: 1104-1109, 1992[Medline] 18. LePrise E, Etienne PL, Meunier B, et al: A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 73: 1779-1784, 1994[Medline] 19. Roth JA, Pass HU, Flanagan MM, et al: Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 96: 242-248, 1988[Abstract] 20. Schlag P: Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus: Chirurgische Arbeitgemeinschaft fur Onkologie Der Deutschen Gesellschaft fur Chirurgie Study Group. Chirurg 63: 709-714, 1992[Medline] 21. Kok TC, von Lanschot J, Siersema PD, et al: Neoadjuvant chemotherapy in operable esophageal squamous cell cancer: Final report of a phase III multicenter randomized controlled trial. Proc Am Soc Clin Oncol 16: 277, 1997 (abstr 984) Submitted February 1, 2000; accepted July 17, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
