Esophageal cancer is a significant health hazard for

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1 Postoperative Radiotherapy Improved Survival of Poor Prognostic Squamous Cell Carcinoma Esophagus GENERAL THORACIC Junqiang Chen, MD, Ji Zhu, MD, Jianji Pan, MD, Kunshou Zhu, MD, Xiongwei Zheng, MD, Mingqiang Chen, MD, Jiezhong Wang, MD, and Zhongxing Liao, MD Departments of Radiation Oncology, Surgery, and Pathology, Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou, China; Department of Radiation Oncology, Fudan University Cancer Hospital, Shanghai, China; and Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas Background. The purpose of this study was identify prognostic factors and to investigate the association between postoperative radiotherapy and overall survival of thoracic esophageal squamous cell carcinoma patients. Methods. From January 1993 to March 2007, 1,715 patients underwent extended esophagectomy with threefield lymph node dissection with or without postoperative radiotherapy and were eligible for analysis. Patients were grouped to surgery only (n 1,277) and surgery plus postoperative radiotherapy (n 438). Radiation dose was 50 Gy in 25 fractions. Results. The overall survival rates at 1, 3, 5, and 10 years were 86.6%, 61.3%, 49.4%, and 36.1%, respectively. Univariate and multivariate analyses showed that age 60 years or more, male sex, tumor more than 5 cm long, poorly differentiated histology, T4 tumor, presence of a vascular cancer thrombus in the surgical specimen, lymph node positivity, 3 or more positive lymph nodes, and disease stage II or higher were negative prognostic factors for overall survival. Postoperative radiation therapy improved overall survival for patients with poor disease-related prognostic factors: positive nodal disease, 3 or more positive lymph nodes, stage III/IV, and large or deeply invading tumor. Postoperative radiation had no survival benefit for patients who did not have the poor disease-related prognostic factors. Conclusions. Postoperative radiotherapy is indicated for patients with poor disease-related prognostic factors. (Ann Thorac Surg 2010;90:435 42) 2010 by The Society of Thoracic Surgeons Accepted for publication April 1, Address correspondence to Dr Pan, Department of Radiation Oncology, Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, 91 Maluding, Fuma Rd, Fuzhou , China; panjianji@126.com. Esophageal cancer is a significant health hazard for humans. It is the eighth most common cancer worldwide, and especially in some areas of China, esophageal cancer is the fourth most common cause of death, occurs most often in the thorax, and is of squamous cell carcinoma histology in 95% of cases [1]. Because earlystage disease is usually asymptomatic, most of the patients treated present with locally advanced disease. Surgical resection remains the mainstay of treatment for locally advanced disease. However, the rates of local recurrence and distant metastasis are high after esophagectomy only [2 4]. Therefore, combined-modality treatments that include preoperative radiotherapy and chemotherapy are being used more often to improve the likelihood of complete resection, to reduce the rates of lymph node metastasis and local-regional recurrence, and to improve outcome after the surgery. However, whether postoperative radiotherapy affects treatment outcomes remains controversial [5 9]. Herein we report the experience on the effect of postoperative radiation for thoracic esophageal squamous cell carcinoma after radical esophagectomy with threefield lymphadenectomy at Fujian Province Cancer Hospital, a single institution located in a region in China in which this disease is endemic. We discuss the influence of the number of involved lymph nodes, pathologic disease stage, and other variables on the value of postoperative radiation, and we propose recommendations regarding the use of postoperative radiation for patients with locally advanced squamous cell carcinoma of the thoracic esophagus after surgery. Material and Methods Study Population From January 1993 to March 2007, 2,665 patients with thoracic esophageal squamous cell carcinoma were treated with surgery at Fujian Province Cancer Hospital, Fujian Medical University, Fuzhou, Fujian, China. Of these patients, 950 were excluded from this analysis for having received preoperative chemotherapy or radiation (306 cases), postoperative chemotherapy (159 cases), postoperative concurrent chemoradiation (173 cases), surgical procedures other than an extended esophagectomy with three-field lymphadenectomy that included removal of at least 15 nodes (237 cases), or for having had other malignancies before the diagnosis of esophageal cancer or having had disease of mixed histology (75 cases). The remaining 1,715 patients, all of whom under by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 GENERAL THORACIC 436 CHEN ET AL Ann Thorac Surg POSTOPERATIVE RADIOTHERAPY 2010;90: went extended esophagectomy with three-field lymph node dissection, which has been the standard surgical procedure for esophageal cancer at Fujian Cancer Hospital for the past 2 decades (and details of this operation have been described elsewhere [10]), were eligible for further analysis. Of those 1,715 patients, 1,277 had had surgery only and 438 patients had had surgery followed by postoperative radiotherapy. The procedure of this experiment has been verified by Ethics Committee of Fujian Province Cancer Hospital. The informed consents from all the patients have been obtained. Disease Staging and Classification The 2002 (sixth) edition of the International Union Against Cancer (UICC [Union Internationale Contre le Cancer]) TNM classification was used to determine the pathologic stage of the disease [11]. Postoperative Radiotherapy Postoperative radiation was begun 3 to 4 weeks after the surgery. For the 66 patients treated before January 1996, large T-shaped fields were used that encompassed the bilateral supraclavicular fossi, mediastinum, left gastric nodes, and the tumor bed. After January 1996, 372 patients were treated with modified T field. The upper border of both the large and modified T fields was at the top of the C6 vertebral body. The lower border of the large T field was at the T12 or L1 level, whereas the lower border of the modified T field covered the lower extension of the gross tumor identified on preoperative computed tomography (CT) images, plus a margin. The radiation fields used are illustrated in Figure 1. Radiation was given through anteroposterior fields first to 36 Gy at 2 Gy per fraction followed by parallel opposing oblique fields to 14 Gy to avoid the spinal cord. Six to eight mv photons was used to deliver the radiation to the mediastinum through anteroposterior and bilateral fields. Eighteen mv photons was used to irradiate the oblique fields. The radiation dose in all cases was prescribed to the isocenter. The bilateral supraclavicular fossi were treated with 12 MeV electrons. The total postoperative radiation dose to the tumor bed was 50 Gy in 25 daily fractions. Follow-Up Patients were instructed to return periodically for follow-up evaluations every 3 months for the first year, every 6 months for the next 2 years, then annually thereafter. Of our 1,715 patients, 879 (51%) returned for follow-up visits according to schedule, 666 (39%) returned but not according to schedule, and 170 (10%) never returned for follow-up. Survival status for patients who did not come at scheduled follow-up times was updated by means of telephone calls or letters every 6 months. Survival status for patients who could not be reached in this way was obtained through the Fujian bureau registration center system. For patients whose medical records at the Fujian Cancer Hospital indicated that they had died, we confirmed this information with the Fujian bureau registration center system. Statistical Analysis Data were analyzed using SPSS version 15 software (SPSS, Chicago, IL). Patients were grouped as surgery only and surgery plus postoperative radiation. The 2 test was used to compare differences between groups. Patients who were lost to follow-up were censored. Overall survival was determined as the time (in months) from the date of surgery to last follow-up or to March 1, 2009, for living patients or to the date of death. Overall survival rates were calculated using the Kaplan-Meier method, and differences between groups were compared using the log-rank test. A Cox proportional hazard regression model was used to perform univariate and multivariate analyses. Results The characteristics of the 1,715 patients analyzed are shown in Table 1. Survival For the entire study population, the overall survival rates at 1, 3, 5, and 10 years were 86.6%, 61.3%, 49.4%, and 36.1%, respectively. Five-year survival rates for patients with UICC stage I, stage IIA, stage IIB, stage III, stage IVA, and stage IVB were 83.8%, 70.8%, 52.1%, 41.1%, Fig 1. Radiation portals used in postoperative radiation therapy for patients with locally advanced thoracic squamous cell esophageal carcinoma. (A) Anteroposterior opposed 6-MV photon fields. (B) Parallel opposed oblique fields to spare the spinal cord. (C) Bilateral supraclavicular electron fields.

3 Ann Thorac Surg CHEN ET AL 2010;90: POSTOPERATIVE RADIOTHERAPY Table 1. Patient Characteristics Sorted by Treatment Group Variable No. of Patients (%) Surgery Only Surgery Radiation (n 1,277) (n 438) 2 Value 437 p Value GENERAL THORACIC Sex Male 882 (69.1) 342 (78.1) Female 395 (30.9) 96 (21.9) Age, years (59.0) 303 (69.2) (41.0) 135 (30.8) Tumor location Upper thorax 166 (13.0) 108 (24.7) Mid thorax 973 (76.2) 308 (70.3) Lower thorax 138 (10.8) 22 (5.0) Tumor length cm 760 (59.5) 222 (50.7) 5 cm 517 (40.5) 216 (49.3) Tumor differentiation Low (G1) 212 (16.6) 86 (19.6) Moderate (G2) 777 (60.8) 273 (62.3) High (G3-4) 288 (22.6) 79 (18.0) Margin status Negative 1250 (97.9) 425 (97.0) Positive 27 (2.1) 13 (3.0) Cancer thrombus Negative 1096 (85.8) 384 (87.7) Positive 181 (14.2) 54 (12.3) pt category T1 111 (8.7) 9 (2.1) T2 246 (19.3) 77 (17.6) T3 850 (66.6) 283 (64.6) T4 70 (5.5) 69 (15.8) No. positive lymph nodes (53.8) 83 (18.9) 1 to (24.0) 181 (41.3) 3 to (13.5) 109 (24.9) (8.7) 65 (14.8) Disease stage, UICC I 99 (7.8) 1 (0.2) IIA 571 (44.7) 61 (13.9) IIB 43 (3.4) 17 (3.9) III 252 (19.7) 105 (24.0) IVA 59 (4.6) 69 (15.8) IVB 253 (19.8) 185 (42.2) UICC Union Internationale Contre le Cancer. 31.2%, and 25.9%, respectively. In terms of type of treatment, 5-year survival rates were 51.5% for the surgery only group and 44.6% for the surgery plus postoperative radiation group. Postoperative radiotherapy was associated with a higher hazard ratio for overall survival (p 0.026, Fig 2A) if the entire population was included in the analysis, whereas postoperative radiation was associated with a statistically significant better overall survival for patients with positive nodal involvement (p 0.001; Fig 2B). Effect of Postoperative Radiation on Survival According to Disease Characteristics LYMPH NODE INVOLVEMENT. A total of 44,237 nodes had been removed from the 1,715 patients, with a mean of 25.8 nodes per patient (range, 15 to 73). The overall node

4 GENERAL THORACIC 438 CHEN ET AL Ann Thorac Surg POSTOPERATIVE RADIOTHERAPY 2010;90: Fig 2. Effect of postoperative radiation therapy on overall survival in (A) the entire study population of 1,715 patients or (B) 945 patients with positive nodal involvement after threefield esophagectomy alone (S alone) or followed by postoperative radiation (S R). Fig 3. Effect of postoperative radiation on overall survival in patients with (A) 0 to 2 lymph node involvement or (B) 3 or more lymph node involvement. Fig 4. Effect of postoperative radiation on overall survival in patients with (A) stage I/II disease (n 830) or (B) stage III or higher disease (n 885).

5 Ann Thorac Surg CHEN ET AL 2010;90: POSTOPERATIVE RADIOTHERAPY Table 2. Univariate Analysis of Factors Influencing Overall Survival Variable 5 Year Overall Survival Rate (%) Hazard Ratio (95% CI) p Value Sex Male (reference) Female ( ) Age, years (reference) ( ) Tumor location Lower thorax (reference) Mid thorax ( ) Upper thorax ( ) Tumor differentiation High (G1) (reference) Moderate (G2) ( ) Low (G3) ( ) Margin status Negative (reference) Positive ( ) Cancer thrombus Negative (reference) Positive ( ) Tumor length cm (reference) 5 cm ( ) pt category T (reference) T ( ) T ( ) T ( ) No. positive lymph nodes (reference) 1 to ( ) to ( ) ( ) Disease stage, UICC I (reference) IIA ( ) IIB ( ) III ( ) IVA ( ) IVB ( ) GENERAL THORACIC CI confidence interval; UICC Union Internationale Contre le Cancer. positivity rate was 7.9% (3,487 of 44,237 nodes), and 55.1% of patients (945 of 1,715) had lymphatic metastases. Postoperative radiation improved overall survival among patients with 3 or more involved lymph nodes: 5-year survival rates for those patients were 17.8% for the surgery only group and 25.2% for the surgery plus radiation group (p 0.001; Fig 3B). However, for patients with 0 to 2 involved lymph nodes, postoperative radiation did not affect the 5-year survival rate (61.7% for surgery only versus 58.0% for surgery plus radiation; p 0.16; Fig 3A). Thirty-eight of the patients with no lymph node involvement had pt4 tumors, and 21 of those 38 patients had postoperative radiation. Postoperative radiation also improved the 5-year survival rate for patients with node negative disease and pt4 tumors (33.8% for surgery only versus 72.4% for surgery plus radiation; p 0.045; data not shown). CLINICAL DISEASE STAGE. The effect of postoperative radiation on survival according to clinical disease stage is shown in Figure 4. For patients with stage III/IV disease,

6 GENERAL THORACIC 440 CHEN ET AL Ann Thorac Surg POSTOPERATIVE RADIOTHERAPY 2010;90: Table 3. Multivariate Analysis of Factors Influencing Overall Survival Variable All Patients Node-Negative Patients Node-Positive Patients HR (95% CI) p Value HR (95% CI) p Value HR (95% CI) p Value Sex ( ) ( ) ( ) Age ( ) ( ) ( ) Tumor location ( ) ( ) ( ) Tumor grade ( ) ( ) ( ) Margin status ( ) ( ) ( ) Cancer thrombus ( ) ( ) ( ) Tumor length ( ) ( ) ( ) No. of positive lymph nodes ( ) ( ) pt status ( ) ( ) ( ) Disease stage, UICC ( ) ( ) ( ) Treatment ( ) ( ) ( ) CI confidence interval; HR hazard ratio; UICC Union Internationale Contre le Cancer. the 5-year overall survival rates were 27.9% for the surgery only versus 37.2% for the surgery plus radiation subgroup (p 0.000; Fig 4B). For patients with stage I or II disease, the 5-year overall survival rates were 70.1% for the surgery only subgroup and 70.4% for the surgery plus radiation subgroup (p 0.977; Fig 4A). Univariate and Multivariate Analyses of Prognostic Variables The univariate analyses showed the following characteristics to be associated with poorer 5-year survival: age 60 years or older; male sex; tumor more than 5 cm long, of low or moderate histologic differentiation, and deeply invading (ie, pt2 to T4); the presence of a vascular cancer thrombus in the surgical specimen; lymph node positivity, higher numbers of positive lymph nodes, and disease stage of II or higher (Table 2). Multivariate analyses of the entire study group confirmed the significance of all of these variables except for tumor grade, and further showed that receipt of postoperative radiation was also associated with poorer 5-year overall survival rates (Table 3). For patients without lymph node metastases, only age 60 years or more and deep tumor invasion (pt T2) were associated with poorer 5-year overall survival rates (Table 3). For patients with lymph node metastases, male sex, deep tumor invasion (pt T2), the presence of a vascular thrombus in the surgical specimen, lymph node positivity, higher numbers of positive lymph nodes, higher disease stage, and no receipt of postoperative radiotherapy were associated with poorer 5-year overall survival rates (Table 3). Comment The results from the current study showed that older age; male sex; tumor more than 5 cm long, poorly differentiated histology, depth of invasion; presence of a vascular cancer thrombus in the surgical specimen; lymph node positivity and higher numbers of positive lymph nodes; and disease stage of II or higher were negative prognostic factors for overall survival of esophageal squamous cell carcinoma patients after extended esophagectomy with three-field lymphenectomy. Secondly, this study showed that postoperative radiotherapy improved overall survival among patients who had poor disease-related prognostic factors: three or more positive lymph nodes, advanced clinical stage III/IV, and large or deeply invading tumor. Furthermore, this study showed that postoperative radiation did not provide a survival benefit nor was it detrimental for patients who did not have the poor disease-related prognostic factors. Overall, the findings of this study suggest that it is essential to use proper patient selection criteria when making a therapy recommendation, the art of practicing medicine. During the past 2 decades, radical esophagectomy and three-field nodal dissection is the most common procedure, as it provides good exposure of the tumor bed and nodal basin and allows radical dissection of the lymph nodes in the neck, thorax, and upper abdomen, which not only provides critical information on pathologic tumor status and nodal involvement but also improves survival [12, 13]. However, even with such extensive surgery, 27% to 43% of patients will have recurrent disease in the nodal basin and distant metastases [2, 3, 14 17]. Local-regional recurrence rates are as high, ranging from 41.5% to 49% [2,3, 14 17], and the number of involved lymph nodes strongly correlates with the local-regional recurrence rate [14, 15, 18]. Kimura and associates [18] reported localregional recurrence rates of 17.6%, 48.5%, and 78.6% for patients with 0, 1 to 3, and more than 4 involved lymph nodes. Bhansali and associates [15] also reported similar local-regional recurrence rates of 23%, 33%, 48%, and 73% for patients with 0, 1, 2 to 4, and 5 or more involved lymph nodes. Baba and associates [14] also found localregional recurrence rates of 29%, 42%, and 71% among patients who had 0, 1 to 5, and more than 5 involved lymph nodes. These high rates of local-regional recurrence suggest that surgery by itself is not adequate for cure in such cases and that adjuvant therapy, given before or after surgery, is indicated.

7 Ann Thorac Surg CHEN ET AL 2010;90: POSTOPERATIVE RADIOTHERAPY Table 4. Surgery Versus Surgery Plus Postoperative Radiation Therapy for Esophageal Cancer Study [reference] Ténière et al [5] Fok et al [6] Zieren et al [7] Xiao et al [8, 9] Current study Study period 12/ /1985 7/ /1989 6/ /1991 9/ /1997 1/1993 3/2007 Treatment Surgery (n) 119 (73) a 65 ( ) 35 (23) 275 (132) 1277 (590) Surgery XRT (n) 102 (58) 65 ( ) 35 (24) 220 (148) 438 (355) Tumor histology SCC SCC, AdeCa SCC SCC SCC Surgical intent Radical 46% radical, 54% palliative Tumor location Mid lower Upper, mid, and lower thoracic and GEJ Radiation equipment 88% accelerator, 12% Co-60 Surgery to PORT interval PORT volume Bilateral supraclavicular Tumor bed only fossi, mediastinal, and left gastric (if involved) PORT dose 23.5% radical, 76.5% palliative Upper, mid, and lower thoracic Radical Upper, mid, and lower thoracic Radical (three-field) Upper, mid, and lower thoracic Unknown Accelerator Accelerator Accelerator 3 months 4 6 weeks 3 6 weeks 3 4 weeks 3 4 weeks 1.8 Gy/d 5 d/week, to Gy 3.5 Gy/d 3d/ week, to Gy Tumor bed, bilateral supraclavicular fossi for upper thoracic, left gastric if lower tumor 1.8 Gy/d 5d/ week, to 55 Gy Bilateral supraclavicular fossi, mediastinal, and left gastric 2 Gy/d 5 d/week, to Gy Tumor bed, bilateral supraclavicular fossi, upper & mid mediastinum (372 patients) plus peri-gej, left gastric (66 patients) 2 Gy/d 5 d/week, to Gy Median survival time (months) Surgery Surgery XRT Five-year overall survival Surgery (%) 17.6 (7) 37.1 (17.6) 51.5 (29.6) Surgery XRT 18.7 (7) 41.3 (34.1) 44.6 (38.0) (%) p Values b b 441 GENERAL THORACIC a Numbers in parentheses indicate the number of patients with lymph node involvement. b Lymph node involvement and stage III patients. AdeCA adenocarcinoma; d day; GEJ gastroesophageal junction; Gy/d Gray per day; SCC squamous cell carcinoma; Surgery XRT surgery plus postoperative radiation therapy. Postoperative radiotherapy has been attempted for patients with esophageal cancer with inconsistent results (Table 4). Xiao and associates [8] reported that all patients in the surgery only group died within 4 years after the treatment, whereas the 5-year overall survival rate was 19.3% in the group given postoperative radiation, a statistically significant improvement in outcome (p 0.034). Subgroup analyses of patients with 1 or 2 positive nodes showed 5-year survival rates of 43.4% with postoperative radiation and 22.6% without postoperative radiation [9]. The results from the present study showed that postoperative radiation was associated with a statistically significant improvement in survival, but only in those patients with 3 or more involved lymph nodes; no such association was found in patients with 1 or 2 involved lymph nodes (5-year survival rates: 50.7% with postoperative radiation and 41.2% with surgery only; p 0.070). Even though postoperative radiation conferred no survival benefit for patients with 0 to 2 involved lymph nodes in our study, it did confer a survival benefit for node negative patients with T4 disease or tumors longer than 5 cm. Interestingly, positive surgical margin was not associated with overall survival regardless of whether postoperative radiation was used or not. The number of involved lymph nodes has been well established as a prognostic factor for survival [9, 12, 19]. Tachibana and associates [12] reported that the 5-year survival rates in a study of 141 esophageal cancer patients who underwent esophagectomy and three-field nodal dissection were 65.5% for those with no positive nodes, 37.9% for those with 1 to 4 positive nodes, and 14% for those with 5 or more positive nodes (p 0.000). These rates are consistent with those of the present study: the 5-year survival rates in our study were 71.7% for patients with 0 positive nodes, 45% for those with 1 or 2 positive nodes, 25.8% for those with 3 to 5 positive nodes, and

8 GENERAL THORACIC 442 CHEN ET AL Ann Thorac Surg POSTOPERATIVE RADIOTHERAPY 2010;90: % for those with more than 5 positive nodes (p 0.000). In summary, the results of our study showed that extended esophagectomy with three-field lymphenectomy remains an effective treatment modality for thoracic esophageal squamous cell carcinoma with 50% 5-year survival, that the overall survival rates were influence by patient-, disease-, and treatment-related prognostic factors, and that postoperative radiotherapy improved survival in patients with poor disease-related prognostic factors. The results of this study provide rationale in establishing patient selection criteria for the design of future prospective randomized trials that aim at testing the effect of adjuvant therapies for esophageal squamous cell carcinoma after surgery. References 1. Mei G, Yi-dian Z, Hai-jun Y, et al. Analysis of clinicopathological characteristics for 5406 cases of esophageal neoplasm. Chin J Cancer Prev Treat 2008;15: Kato H, Tachimori Y, Watanabe H, et al. Recurrent esophageal carcinoma after esophagectomy with three-field lymph node dissection. J Surg Oncol 1996;61: Nakagawa S, Kanda T, Kosugi S, et al. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg 2004;198: Mariette C, Balon JM, Piessen G, et al. Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease. Cancer 2003;97: Ténière P, Hay J-M, Fingerhut A, et al. Postoperation radiation therapy dose not increase survival after curative resection for squamous carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial. French University Association for Surgical Research. Surg Gynecol Obstet 1991;173: Fok M, Sham JS, Choy D, et al. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 1993;113: Zieren HU, Muller JM, Jacobi CA, et al. Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus: a prospective randomized study. World J Surg 1995;19: Xiao ZF, Yang ZY, Liang J, et al. Value of radiotherapy after radical surgery for esophageal carcinoma: a report of 495 patients. Ann Thorac Surg 2003;75: Xiao ZF, Yang ZY, Miao YJ, et al. Influence of number of metastatic lymph nodes on survival of curative resected thoracic esophageal cancer patients and value of radiotherapy: report of 549 cases. Int J Radiat Oncol Biol Phys 2005;62: Chen J, Liu S, Pan J, et al. The pattern and prevalence of lymphatic spread in thoracic oesophageal squamous cell carcinoma. Eur J Cardiothorac Surg 2009;36: Sobin L, Wittekind C. TNM classification of malignant tumors. 6th edn. New York: Wiley-Liss, Tachibana M, Kinugasa S, Yoshimura H, et al. Clinical outcomes of extended esophagectomy with three-field lymph node dissection for esophageal squamous cell carcinoma. Am J Surg 2005;189: Fujita H, Sueyoshi S, Tanaka T, et al. Three-field dissection for squamous cell carcinoma in the thoracic esophagus. Ann Thorac Cardiovasc Surg 2002;8: Baba M, Aikou T, Yoshinaka H, et al. Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus. Ann Surg 1994;219: Bhansali MS, Fujita H, Kakegawa T, et al. Pattern of recurrence after extended radical esophagectomy with three-field lymph node dissection for squamous cell carcinoma in the thoracic esophagus. World J Surg 1997;21: Kyriazanos ID, Tachibana M, Shibakita M, et al. Pattern of recurrence after extended esophagectomy for squamous cell carcinoma of the esophagus. Hepatogastroenterology 2003; 50: Matsubara T, Ueda M, Takahashi T, et al. Localization of recurrent disease after extended lymph node dissection for carcinoma of the thoracic esophagus. J Am Coll Surg 1996; 182: Kimura H, Konishi K, Arakawa H, et al. Number of lymph node metastases influences survival in patients with thoracic esophageal carcinoma: therapeutic value of radiation treatment for recurrence. Dis Esophagus 1999;12: Shimada H, Okazumi S, Matsubara H, et al. Impact of the number and extent of positive lymph nodes in 200 patients with thoracic esophageal squamous cell carcinoma after three-field lymph node dissection. World J Surg 2006;30: