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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1160-1168 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.7118 Chemoradiation Followed by Surgery Compared With Chemoradiation Alone in Squamous Cancer of the Esophagus: FFCD 9102
From the University Hospital Le Bocage; Anticancer Center Georges-François Leclerc, Dijon; University Hospital Charles-Nicolle, Rouen; University Hospital Robert-Debré, Reims; University Hospital Claude-Huriez, Lille; Anticancer Center Alexis Vautrin, Vandoeuvre; University Hospital Hôtel-Dieu, Clermont-Ferrand; University Hospital Dupuytren, Limoges; Université de la Méditerranée, Marseille; and Clinique Sainte-Marie, Chalon, France Address reprint requests to Laurent Bedenne, MD, Fédération Francophone de Cancérologie Digestive, Faculté de Médecine, BP 87900, 21079 Dijon-Cedex, France; e-mail: lbedenne{at}u-bourgogne.fr
Purpose: Uncontrolled studies suggest that chemoradiation has similar efficacy as surgery for esophageal cancer. Therefore, a randomized trial was carried out to compare, in responders only, chemoradiation alone with chemoradiation followed by surgery in patients with locally advanced tumors. Patients and Methods: Eligible patients had operable T3N0-1M0 thoracic esophageal cancer. Patients received two cycles of fluorouracil (FU) and cisplatin (days 1 to 5 and 22 to 26) and either conventional (46 Gy in 4.5 weeks) or split-course (15 Gy, days 1 to 5 and 22 to 26) concomitant radiotherapy. Patients with response and no contraindication to either treatment were randomly assigned to surgery (arm A) or continuation of chemoradiation (arm B; three cycles of FU/cisplatin and either conventional [20 Gy] or split-course [15 Gy] radiotherapy). Chemoradiation was considered equivalent to surgery if the difference in 2-year survival rate was less than 10%. Results: Of 444 eligible patients, 259 were randomly assigned; 230 patients (88.8%) had epidermoid cancer, and 29 (11.2%) had glandular carcinoma. Two-year survival rate was 34% in arm A versus 40% in arm B (hazard ratio for arm B v arm A = 0.90; adjusted P = .44). Median survival time was 17.7 months in arm A compared with 19.3 months in arm B. Two-year local control rate was 66.4% in arm A compared with 57.0% in arm B, and stents were less required in the surgery arm (5% in arm A v 32% in arm B; P < .001). The 3-month mortality rate was 9.3% in arm A compared with 0.8% in arm B (P = .002). Cumulative hospital stay was 68 days in arm A compared with 52 days in arm B (P = .02). Conclusion: Our data suggest that, in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation.
Until now, surgery has been the mainstay of curative treatment in patients with thoracic esophageal cancer.1 However, after preoperative chemoradiation, 18% to 25% of the tumors are sterilized.2,3 With chemoradiation alone, a median survival time of 11 to 22 months was observed,4-6 and the 5-year survival rate reached 27% with chemoradiation in a randomized study,7 which is similar to the rate after surgery.1 Furthermore, nonrandomized studies in patients treated with chemoradiation found similar survival rates with or without additional surgery.8,9 The Fédération Francophone de Cancérologie Digestive (FFCD) was thus prompted to carry out a randomized trial comparing chemoradiation alone with chemoradiation followed by surgery in patients with esophageal cancer. The aim was to demonstrate the equivalence of the overall survival after chemoradiation alone or chemoradiation followed by surgery in patients responding to initial chemoradiation.
Eligibility Criteria Inclusion criteria were resectable T3N0-1M0 (International Union Against Cancer criteria, 1987)10 epidermoid or adenocarcinoma of the thoracic esophagus and clinical and biologic eligibility for surgery or chemoradiation. Exclusion criteria were tumor within 18 cm from the dental ridge or infiltrating the gastric cardia, tracheobronchial involvement, visceral metastases or supraclavicular nodes, weight loss more than 15%, symptomatic coronary heart disease, cirrhosis Child-Pugh B or C, and respiratory insufficiency.
Staging was based on computed tomography (CT). T3 tumors were defined by a diameter
Design and Random Assignment
Treatment Radiotherapy. Radiotherapy included the macroscopic tumor and lymph nodes, with a 3-cm proximal and distal margin and a 2-cm radial margin. The use of three or four fields and daily treatment of all fields were required. Initially, the following two techniques were allowed, according to the initial choice of the investigator for all of his or her included patients: split-course or conventional radiotherapy (Fig 1). Split-course radiotherapy was delivered in daily fractions of 3 Gy, including two sequences (days 1 to 5 and 22 to 26; 30 Gy) before random assignment and one sequence (days 43 to 47; 15 Gy) after random assignment in arm B (total, 45 Gy). Each sequence was separated by a 2-week rest period. Conventional radiotherapy was delivered in 5 daily fractions per week of 2 Gy during the 4.5 weeks before random assignment (46 Gy) and the 2 weeks after random assignment (20 Gy), for a total of 66 Gy. Beginning January 1999, an amendment based on the results of a randomized study permitted only conventional radiotherapy.13 Chemotherapy. Two cycles of chemotherapy were delivered before random assignment, starting on days 1 and 22, and three cycles were administered after random assignment in arm B, starting on days 43, 64, and 92. Fluorouracil (FU) 800 mg/m2 daily was administered as a continuous intravenous (IV) infusion (days 1 to 5). Cisplatin 15 mg/m2 (days 1 to 5) was delivered during a 1-hour IV infusion, preceded and followed by a 2-hour IV infusion of normal saline 1 L. If serum creatinine was more than 15 mg/L, chemotherapy was delayed for up to 2 weeks. If serum creatinine remained elevated, cisplatin was discontinued. In cases of angina-like pain or cerebral ischemia during FU infusion, FU was discontinued. Surgery. Surgery was to be performed between days 50 and 60 in arm A (Fig 1). No type of surgery was recommended. The pathology assessment indicated whether the resection was curative and whether there was no residual tumor, microscopic remnants, or a macroscopic tumor.
Follow-Up
End Points
Statistical Analysis Quality of life was compared between the two arms by analysis of variance. Its longitudinal changes were compared with a general mixed model analysis of variance for repeated measurements.16 The following variables were assessed as potential prognostic factors with respect to overall survival in univariate and multivariate (Cox model) analyses: center accrual size, sex, age, length and diameter of the tumor, presence of enlarged (> 1 cm) lymph nodes on CT scan, weight loss, dysphagia, histology, differentiation, and response to the pre–random assignment treatment (partial or complete).
Role of the Funding Sources
Patients From February 1993 until December 2000, 444 of 451 registered patients were eligible for the study. Reasons for ineligibility are outlined in Figure 2. Among the 259 responding patients who were randomly assigned (57%), 129 were assigned to surgery (arm A), and 130 were assigned to chemoradiation (arm B). The cutoff date was June 30, 2001. Median follow-up time was 47.4 months. Four patients were lost to follow-up after a median of 15 months. There was no significant difference between treatment groups (Table 1). The reasons for patients not receiving random assignment are detailed in Figure 2. Of eight deaths that occurred before random assignment, seven (1.6%) were possibly related to chemoradiation (three febrile aplasias, one septic shock, two bleedings caused by tumor necrosis, and one acute cardiac insufficiency).
Compliance With the Allocated Arm The compliance rates were significantly different (85% in arm A and 97% in arm B; P = .001; Fig 2). In arm A, 16 patients received chemoradiation (10 patients refused surgery, three were inoperable after random assignment, and three were explored without resection), and three patients received no treatment. In arm B, one patient underwent surgery (patient demand), and three patients had no treatment (two patients refused, and the cause was unknown in one patient).
Treatment Characteristics
Toxicity of Chemoradiation and Therapeutic Mortality in the Randomly Assigned Patients Before random assignment, the maximal toxicity was grade 3 in 51 (20%) of 259 patients and grade 4 in two (1%) of 259 patients. After random assignment, the maximal toxicity reached grade 3 in 36 (25%) of 142 patients and grade 4 in eight (6%) of 142 patients (Table 3).
During the first 3 months after registration, 12 patients (9%) died in arm A and one patient (1%) died in arm B (P = .002). Deaths in arm A were consecutive to surgical complications (n = 6), progressive disease (n = 3), or other causes (n = 3), and the death in arm B was related to herpetic encephalopathy. Six-month mortality rates were 16% in arm A (eight additional patients: surgical complication, n = 4; progressive disease, n = 3; and other, n = 1) and 6% in arm B (seven additional patients: progressive disease, n = 3; and other, n = 4; P = .015).
Survival
Length of Hospital Stay Length of hospital stay was known during the whole follow-up period in 220 patients (85%; 112 patients in arm A and 108 in arm B), unknown for only one period of follow-up in 32 patients (12%; 15 patients in arm A and 17 in arm B), and totally unknown for seven patients (3%; two patients in arm A and five in arm B). The figures listed in Table 4 relate the cumulative hospital stay. During the therapeutic period (ie, before the first follow-up report), the mean hospital stay was 38.6 days (SE = 2.60 days) in the surgery arm and 24.7 days (SE = 1.25 days) in the chemoradiation arm (P < .0001).
Dysphagia and Palliative Procedures
Type of First Failure
Quality of Life
Our results suggest that chemoradiation alone and chemoradiation followed by surgery are equivalent in terms of survival and quality of life in responders. Results were given from the start of treatment and not from random assignment because, although the differences were nearly the same, the results from the start of treatment better reflected overall survival. Indeed, the treatment administered before random assignment lasted for more than 1 month. Our study results are consistent with the results from the study by Stahl et al,17 in which 172 patients with epidermoid esophageal cancer were randomly assigned to either chemoradiation with surgery or chemoradiation without surgery. Median survival time was 16.4 months with surgery compared with 14.9 months without surgery, and 2-year survival rates were 39.9% and 35.4%, respectively (test for equivalence with  = –0.15, P = .007). As in our study, freedom from local progression was longer in the surgery group versus the no surgery group (at 2 years, 64.3% v 40.7%, respectively; HR = 2.1; 95% CI, 1.3 to 3.5; P = .003). If the patients responding to induction chemotherapy were considered, 3-year survival rates were 58% and 55% in the surgery and no surgery groups, respectively.17 In the FFCD 9102 study, random assignment was not performed at registration to test the efficacy and tolerance of chemoradiation and, hence, avoid cross over or continuation of an inefficient therapy. A smaller than expected percentage of patients was randomly assigned (57% instead of 75%). The rates of 71% and 87% for complete clinical response, which we based our calculations on, were drawn from phase II studies that included tumors that were not always locally advanced.4,6 Moreover,14 patients refusing surgery and 10 patients not fit for surgery were not randomly assigned. Thus, 24 more patients were eligible for chemoradiation (ie, 64%). A significant difference in therapeutic mortality was observed, and one could consider that chemoradiation increased the postoperative mortality rate, hence undercutting the benefit of surgery. However, a significantly higher operative mortality rate was reported only in two randomized studies comparing preoperative chemoradiation with surgery alone (9% v 4%, respectively, for Walsh et al18; 12% v 4%, respectively for Bosset et al19). In the latter study, the high dose per fraction (3.7 Gy) was probably responsible. In contrast, Le Prise et al,20 Urba et al,21 and Burmeister et al22 observed similar mortality rates in both the chemoradiation and surgery arms (9% v 7%, 2% v 4%, and 5% v 6%, respectively). Conversely, the benefit of chemoradiation may have been undercut in the first period of the trial by split-course chemoradiation, which was later demonstrated to be inferior to conventional protraction in a randomized study.13 The dose of 66 Gy used in our trial seems excessive considering the conclusion of the INT 0123 study that a dose of 64.8 Gy is not superior to 50.4 Gy.23 However, our study design was different and permitted the delivery of three cycles of concomitant chemoradiation instead of two cycles, as in the INT 0123 trial. Regarding adjuvant chemotherapy, although previous studies were negative,24 the Medical Research Council OE 02 trial concluded that two preoperative cycles of FU plus cisplatin resulted in a better survival than surgery alone without increasing operative mortality.25 This raises the question of which of the following is the optimal preoperative treatment: chemotherapy or chemoradiation. Actually, several trials testing preoperative chemoradiation versus surgery showed a trend favoring chemoradiation,20-22,26 and in a recent series, preoperative chemoradiation was predictive of R0 resection, which was a positive prognostic factor.27 Meta-analyses suggest that preoperative chemoradiation improves 3-year survival and decreases locoregional recurrence rate, although no such beneficial effects are observed after preoperative chemotherapy.28-30 However, it is difficult to conclude about the best neoadjuvant treatment because another meta-analysis demonstrated opposite results concerning 2-year survival.31 In our study, no specific type of surgery was proposed, and this could have produced heterogeneity. However, 94% of the patients had transthoracic esophagectomies, and 4% had transhiatal operation. Moreover, randomized studies or meta-analyses have not demonstrated the superiority of one technique.1,32 In this study, chemoradiation alone prevented 46% of the patients from having high-grade dysphagia until death, compared with previously reported rates of 60% to 67%.14 Nevertheless, dysphagia was better improved after surgery (63% mild or absent before death). In conclusion, this study suggests that therapeutic strategies with or without surgery result in similar survival rates for locally advanced thoracic esophageal cancer patients responding to chemoradiation. This study applies especially to patients with epidermoid tumors, who represented almost 90% of the patients, although no difference with adenocarcinomas was observed in multivariate analysis. However, chemoradiation alone entailed fewer early deaths and a shorter hospital stay but more locoregional relapses. Because clinical prognostic factors do not help in choosing between both strategies, further studies comparing surgery and chemoradiation should search for new predictive factors and evaluate new tools to detect early responders. Positron emission tomography scan was reported to discriminate responders from nonresponders as early as 14 days after starting chemoradiation and should be re-evaluated in future studies.33
The authors indicated no potential conflicts of interest.
Conception and design: Laurent Bedenne, Patrick Arveux, Christine Binquet Provision of study materials or patients: Laurent Bedenne, Pierre Michel, Olivier Bouché, Christophe Mariette, Thierry Conroy, Denis Pezet, Bernard Roullet, Jean-François Seitz, Jean-Philippe Herr, Bernard Paillot Collection and assembly of data: Laurent Bedenne, Patrick Arveux, Franck Bonnetain, Christine Binquet Data analysis and interpretation: Laurent Bedenne, Chantal Milan, Franck Bonnetain, Christine Binquet Manuscript writing: Laurent Bedenne, Chantal Milan, Thierry Conroy, Christine Binquet Final approval of manuscript: Pierre Michel, Olivier Bouché, Christophe Mariette, Thierry Conroy, Denis Pezet, Bernard Roullet, Jean-François Seitz, Jean-Philippe Herr, Bernard Paillot, Patrick Arveux, Franck Bonnetain
In addition to the authors, the following investigators participated in the Fédération Francophone de Cancérologie Digestive 9102 trial (principal investigators in each center are in bold type;  indicates deceased): J. Butel, P. Desselle, J.C. Brice, Abbeville Hospital; B. Tissot, Agen Hospital; A. Votte-Lambert, J.P. Joly, Amiens University Hospital; P. Burtin, J.P. Arnaud, Angers University Hospital; P. Cellier, Angers Anticancer Center; F. Estermann, Annemasse Hospital; B. Chauvet, Ste Catherine Institute Avignon; E. Maringe, Beaune Hospital; F. Ozanne, Beauvais Hospital; F. Varlet, Béthune Private Hospital Ambroise Paré; Y. Becouarn, A. Avril, Bordeaux Anticancer Center Bergonié; P. Rougier, B. Nordlinger, Boulogne-Billancourt University Hospital Ambroise Paré; M. Vincendet, Boulogne Sur Mer Private Hospital; J. Charneau, Boulogne Sur Mer Hospital; D. Pillon, Bourg En Bresse Hospital; N. Stremsdoerfer, M. Pelletier, Bourgoin-Jallieu Hospital; M.C. Clavero-Fabri, Bligny Hospital (Briis Sous Forges); B. Leduc, Brive Hospital; P. Segol, L.P. Argouach, A. Roussel, J. Maurel, R. Salame, Caen University Hospital; J. Lacourt, P. Janoray, O. Ruget, Chalon Sur Saône Private Hospital Ste Marie; D. Baudet-Klepping, Chalon Sur Saône Hospital; G. Dupont, Chaumont Private Hospital; G. Bommelaer, Clermont-Ferrand University Hospital; P. Ruszniewski, P. Hammel, Beaujon University Hospital, Clichy; S. Chaussade, B. Dousset, Cochin University Hospital; B. Denis, J.D. Wagner, E. Tamby, T. Petit, A.M. Weiss, Colmar Hospital Pasteur; J.C. Barbare, Compiègne Hospital; J.L. Jouve, J.M. Phelip, P. Senesse, C. Michiels, Dijon University Hospital; P. Maingon, B. Coudert, J. Fraisse, Dijon Anticancer Center Georges-François Leclerc; L. Gasnault, J.H. Gstach, B. Guichard, Dunkerque Hospital; M. Howaizi, Eaubonne Hospital; A.M. Queuniet, Elbeuf Hospital; P. Geoffroy, C. Picot, Epernay Private Hospital; J. Fournet, M. Mousseau, Grenoble University Hospital; C. Stampfli, P. Michel-Langlet, Laval Hospital; J. Doll, Le Chesnay University Hospital A Mignot; S. Durand, Le Havre Hospital; C. Buffet, Le Kremlin Bicêtre University Hospital; J.P. Triboulet, P. Quandalle, F. Denimal, M. Hebbar, Lille University Hospital; X. Mirabel, Lille Anticancer Center Oscar Lambret; G. Lledo, Lyon Private Hospital St Jean; M. Giovannini, Marseille Anticancer Center Paoli-Calmettes; P. Souillac, Meaux Hospital; M. Untereiner, Metz Private Hospital Claude-Bernard–Metz Hospital; E. Leroy-Terquem, Meulan Hospital; H. Lacroix, Nantes University Hospital; E. Francois, Nice Anticancer Center Antoine-Lacassagne; J.P. Lagasse, N. Breteau, Orléans Hospital; J.L. Legoux, Pessac University Hospital; J.C. Etienne, Poissy Hospital; J.F. Delattre, D. Lubrano, N. Levy-Chazal, J.P. Palot, Reims University Hospital; S. Nasca, L. Demange, T.D. Nguyen, Reims Anticancer Center Jean Godinot; S. Seng, Rouen Anticancer Center H Becquerel; P. Teniere, Rouen University Hospital; P. Thevenet, H. Le Brise, J. Fleury, Saint-Malo Hospital; J. Kammerer, H. Cosme, Sens Hospital; P. Novello, Saint Denis Anticancer Center René-Huguenin; J.P. Avignon, P. Parisot, C. Berton, J.C. Legueul, G. Aunis, St Jean de Braye Private Hospital; D. Vetter, Strasbourg University Hospital; C. Platini, Thionville Hospital; L. Cals, Toulon Hospital; D. Rouhier, B. Robin, T. Champetier, A. Cartalat, Valence Private Hospital Pasteur/Générale/Polyclinique; C. Marchal, F. Guillemin, Vandoeuvre Anticancer Center Alexis Vautrin; M. Flamenbaum, D. Cassan, Vichy Hospital; M. Ducreux, Villejuif Anticancer Center Gustave-Roussy.
We thank Cécile Girault and Fadil Masskouri for the management of the data and Jacqueline Appel for the typing of the manuscript. Special thanks to J.-F. Bosset, MD, who had a major role in the writing of the radiotherapy part of the protocol; to the members of the Independent Data Monitoring Committee, Marc Gignoux, MD, Michel Amouretti, MD, and Marc Buyse, MD, PhD; and to Richard Medeiros, Rouen University Hospital medical editor, for his valuable advice in editing the manuscript.
Supported by grants from the Ligue Nationale Contre le Cancer, the Fonds de Recherche de la Société Nationale Française de Gastroentérologie, the Programme Hospitalier pour la Recherche Clinique, and the Association pour la Recherche Contre le Cancer. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL, and the 27th Annual Journées Francophones de Pathologie Digestive, March 31-April 2, 2003, Paris, France. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Wurtz A, Chastanet P: Epidermoid carcinomas of the thoracic esophagus: Which tomodensitometric classification? Gastroenterol Clin Biol 12:921-925, 1988[Medline] 12. Miller A, Hogestraeten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 13. Jacob J, Seitz J, Langlois C, et al: Definitive concurrent chemoradiation therapy in squamous cell carcinoma of the esophagus: Preliminary results of a French randomized trial comparing standard versus split-course irradiation (FNCLCC-FFCD 9305). Proc Am Soc Clin Oncol 18:270a, 1999 (abstr 1035) 14. Coia L, Soffen E, Schultheiss T, et al: Swallowing function in patients with esophageal cancer treated with concurrent radiation and chemotherapy. Cancer 71:281-286, 1993[CrossRef][Medline] 15. Spitzer WO, Dobson AJ, Hall J, et al: Measuring the quality of life of cancer patients: A concise QL-index for use by physicians. J Chronic Dis 34:585-597, 1981[CrossRef][Medline] 16. Bonnetain F, Bedenne L, Michel P, et al: Definitive results of a comparative longitudinal quality of life study using the Spitzer QOL index in the randomized multicentric phase II trial FFCD 9102 (radiochemotherapy followed by surgery versus radiochemotherapy alone in patients with locally advanced esophageal cancer). Proc Am Soc Clin Oncol 22:250, 2003 (abstr 1002) 17. Stahl M, Stuschke M, Lehmann N, et al: Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23:2310-2317, 2005 18. Walsh T, Noonan N, Hollywood D, et al: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462-467, 1996 19. Bosset J, Gignoux M, Triboulet J, et al: Chemotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. N Engl J Med 337:161-167, 1997 20. Le Prise E, Etienne P, 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[CrossRef][Medline] 21. Urba S, Orringer M, Turrisi A, et al: Randomized trial of preoperative chemoradiation versus surgery alone in patient with locoregional esophageal carcinoma. J Clin Oncol 19:305-313, 2001 22. Burmeister B, Smithers B, Fitzgerald L, et al: A randomized phase III trial of preoperative chemoradiation followed by surgery versus surgery alone for localized resectable cancer of the esophagus. Proc Am Soc Clin Oncol 21:130a, 2002 (abstr 518) 23. Minsky B, Pajak T, Ginsberg R, et al: INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: High-dose versus standard-dose radiation therapy. J Clin Oncol 20:1167-1174, 2002 24. Kelsen D, Ginsberg R, Pajak T, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979-1984, 1998 25. Medical Research Council Oesophageal Cancer Working Group: Surgical resection with or without chemotherapy in oesophageal cancer: A randomized controlled trial. Lancet 359:1727-1733, 2002[CrossRef][Medline] 26. Apinop C, Puttisak P, Preecha N: A prospective study of combined therapy in esophageal cancer. Hepatogastroenterology 41:391-393, 1994[Medline] 27. Hofstetter W, Swisher S, Correa A, et al: Treatment outcomes of resected esophageal cancer. Ann Surg 236:376-385, 2002[CrossRef][Medline] 28. Urschel J, Vasan H: A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 185:538-543, 2003[CrossRef][Medline] 29. Urschel J, Vasan H, Blewett C: A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 183:274-279, 2002[CrossRef][Medline] 30. Fiorica F, Di Bona D, Schepis F, et al: Preoperative chemoradiotherapy for oesophageal cancer: A systematic review and meta-analysis. Gut 53:925-930, 2004 31. Kaklamanos I, Walker G, Ferry C, et al: Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: A meta-analysis of randomized clinical trials. Ann Surg Oncol 10:754-761, 2003 32. Hulscher J, van Sandick J, deBoer A, et al: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1662-1669, 2002 33. Wieder H, Brücher B, Zimmerman F, et al: Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 22:900-908, 2004 Submitted October 24, 2005; accepted October 11, 2006. Related Editorial
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ABSTRACT
INTRODUCTION
3 cm, without invasion of adjacent structures.
2 or Fisher's exact tests for categoric variables. The probability of survival was estimated using the Kaplan-Meier method. Data were analyzed according to the intent-to-treat principle as well as per protocol (ie, taking into account the treatment actually received). Survival was calculated from the date of registration to the most recent follow-up or death. Results are presented with 95% CIs. The accrual was slower than expected, and according to an amendment approved by the ethics committee, an interim analysis was performed on the first 200 patients (of 259 randomly assigned patients at that time) who had a follow-up of more than 1 year, and the data were examined in November of 2000 by the Independent Data Monitoring Committee. The discontinuation of the study was advised; the analysis favored the nonsurgical arm, and the committee concluded that there was no possibility of rejecting the hypothesis of equivalence with the planned number of patients. 
