Application of the 8th AJCC TNM Staging System in Patients with Esophageal Squamous Cell Carcinoma

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1 Accepted Manuscript Application of the 8th AJCC TNM Staging System in Patients with Esophageal Squamous Cell Carcinoma Po-Kuei Hsu, MD, PhD, Hui-Shan Chen, PhD, Chia-Chuan Liu, MD, Shiao-Chi Wu, PhD PII: S (18) DOI: /j.athoracsur Reference: ATS To appear in: The Annals of Thoracic Surgery Received Date: 30 August 2017 Revised Date: 13 December 2017 Accepted Date: 23 December 2017 Please cite this article as: Hsu PK, Chen HS, Liu CC, Wu SC, Application of the 8th AJCC TNM Staging System in Patients with Esophageal Squamous Cell Carcinoma, The Annals of Thoracic Surgery (2018), doi: /j.athoracsur This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Application of the 8th AJCC TNM Staging System in Patients with Esophageal Squamous Cell Carcinoma Running title: Esophageal cancer staging Po-Kuei Hsu, MD, PhD 1, Hui-Shan Chen, PhD 2, Chia-Chuan Liu, MD 3, Shiao-Chi Wu, PhD 4 1 Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan 2 Department of Health Care Administration, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan 3 Division of Thoracic Surgery, Department of Surgery, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan 4 Institute of Health and Welfare Policy, National Yang-Ming University, Taipei, Taiwan Word count: 2684 Correspondence to: Po-Kuei Hsu, MD, PhD Division of Thoracic Surgery, Department of Surgery, Taipei-Veterans General Hospital No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan hsupokuei@yahoo.com.tw

3 Abstract Background. The 8 th edition of the American Joint Committee on Cancer Tumor-Node-Metastasis staging system separates classifications for the clinical (c), pathologic (p), and postneoadjuvant pathologic (yp) stages. We aimed to evaluate its application in patients with esophageal squamous cell carcinoma (ESCC). Methods. Patient data were obtained from the Taiwan Cancer Registry database. Patients who underwent esophagectomy for cstage I-III ESCC were included for survival analysis. Results. Data of 3399, 1805, and 1594 patients were included for c, p, and yp staging, respectively. The 3-year overall survival (OS) rates for cstage I, II, and III were 67.4%, 46.7%, and 38.4%, respectively. The 3-year OS rates for pstage I, II, III, and IV were 70.7%, 49.8%, 30.8%, and 10.6%, respectively. The 3-year OS rates for ypstage I, II, III, and IV were 59.4%, 37.8%, 27.6%, and 3.7%, respectively. Survival curve analysis demonstrated a robust discriminatory capability and monotonicity of gradients of the new system. However, ypstage I was observed in a heterogeneous group of patients with substantial survival differences. Meanwhile, patients in the ypt0n0 stage had a 5-year OS rate of 52.1%, which was equivalent to that of patients with pstage I (54.5%). The 5-year OS rate of patients in the yptis-2n0 stage was 39.1%, which was equivalent to that of patients in pstage II (40.1%). Conclusions. The present study serves as an external validation of the newly released staging system in the prognostication of patients with ESCC and suggests subgrouping of the ypstage I into ypt0n0 and non-ypt0n0 in the future. Keywords: AJCC TNM staging system, esophageal cancer, squamous cell carcinoma, survival

4 Esophageal cancer is among the most common causes of cancer-related death worldwide. In 2012, approximately 455,800 new esophageal cancer cases and 400,200 deaths due to esophageal cancer were recorded worldwide [1]. Characterized by dismal prognosis and a high frequency of disease recurrence, multimodality therapy has been the primary treatment approach. To facilitate patient stratification and treatment protocol decisions, classification and staging is of paramount importance. Moreover, accurate staging enables better prognostication and serves as a common language that allows for comparisons among institutions throughout the world. The 8 th edition of the American Joint Committee on Cancer Tumor-Node-Metastasis (AJCC TNM) staging system for cancer of the esophagus and esophagogastric junction is based on the Worldwide Esophageal Cancer Collaboration (WECC) database, which includes information on 22,654 patients from 33 institutions in six continents [2-4]. The random forest-based machine-learning analysis produced data-driven stage groups, which were reviewed by the AJCC Upper GI Task Force to form the final consensus stage groups. Among the major changes in the 8 th edition includes separate classifications for the clinical (ctnm), pathologic (ptnm), and postneoadjuvant pathologic (yptnm) stage groups [5-7]. Thus far, the newly released staging system has not been externally validated in a separate independent cohort. Therefore, in this study, we aimed to evaluate its application in patients who underwent esophagectomy for esophageal squamous cell carcinoma (ESCC) through an analysis of the Taiwan Cancer Registry (TCR) database, which is among the high-quality cancer registries in Asia and is an essential foundation in academic research and cancer control policy in Taiwan [8]. Patients and Methods Data were acquired as described previously [9, 10]. In brief, patient data were obtained

5 from the Taiwan Cancer Registry database, which is a national population-based database organized by the Health Promotion Administration, Ministry of Health and Welfare (MOHW) of Taiwan. Confidentiality was ensured by the Health and Welfare Data Science Center, MOHW, Taiwan, which encrypted individual identifiers to protect privacy before releasing information to investigators for research purposes. Hospitals with greater than a 50-bed capacity that provide outpatient and hospitalized cancer care are recruited to participate in the survey; they report all newly diagnosed cases of malignant neoplasms to the registry. Detailed clinical information including sex, date of birth, date of hospitalization, date of diagnosis, date of treatments, stage information, surgical method, surgical margin, treatment modality, radiation dose, and survival status was recorded. Individual patient-level data were linked with the National Register of Deaths Database to confirm the survival status and the date of death. In the present study, patients diagnosed with squamous cell carcinoma following the International Classification of Diseases for Oncology (ICD-O-3) site codes (C15.0 C15.5, C15.8, and C15.9) and morphology codes ( , and 8083) from 2008 through 2014 were identified and reclassified according to the 8 th edition of the AJCC TNM staging system [11]. Patients undergoing esophagectomy for cstage I III thoracic ESCC were included, whereas those with cervical tumors or incomplete clinicopathological information, which precluded ctnm, ptnm, or yptnm determination, were excluded. This study was approved by the Institutional Review Board of the Taipei-Veterans General Hospital. Statistical Analysis The rate of overall survival (OS) was calculated as the period between the date of initial treatment and the date of death. Patients who survived to the end of the follow-up period

6 (December 31, 2015) were censored. Survival curves were plotted using the Kaplan Meier method. All statistical calculations were performed using Statistical Analysis System (version 9.3; SAS Institute, Inc., Cary, NC) and Statistical Product and Service Solutions (version 20; SPSS Inc., Chicago, IL). Results The demographic data of the 3399 patients included in this study are shown in Table 1. The mean follow-up time was 28.2 (95% confidence interval [CI]: ) months. The OS rate was 92.5%, 77.1%, 45.3%, and 35.4% at 6 months and 1, 3, and 5 years, respectively. A total of 489, 1123, and 1787 patients had cstage I, II, and III with a 3-year OS rate of 67.4%, 46.7%, and 38.4%, respectively. Although the survival rate according to cstage groups was monotonically decreasing with increasing cstage, the difference was less distinctive between cstage II and III (cstage I vs. II: p < 0.001; II vs. III: p < 0.001, Figure 1A). A total of 1805 patients received upfront esophagectomy without any neoadjuvant treatments (upfront surgery group), while 1594 patients received neoadjuvant chemoradiation before surgical resection (neoadjuvant treatment group). The distribution of p(yp)t and p(yp)n categories for each ct and cn category is shown in Table 2. In the upfront surgery group, 293 of the 1805 patients (16.3%) had T category understaged clinically (pt > ct) and 340 (18.8%) were clinically overstaged (pt < ct). In the neoadjuvant treatment group, T category downstaging (ypt < ct) was noted in 992 of the 1594 (62.2%) patients, and 516 patients (32.4%) had no pathologic residual primary tumor (ypt0). With regard to N category, 438 (24.3%) and 375 (20.1%) patients were clinically understaged (pn > cn) and overstaged (pn < cn), respectively, in the upfront surgery group. Meanwhile, in the neoadjuvant treatment group, the N category was

7 downstaged in 1029 (64.6%) patients (ypn < cn), and 1073 (67.3%) patients had no pathologic lymph node involvement (ypn0). Overall, the pathologic complete response (ypt0n0) rate was 27.7% (441/1594) in our cohort. In the upfront surgery group, the 3-year OS rates were 70.7%, 49.8%, 30.8%, and 10.6% in patients with pstage I, II, III, and IV tumors. The rate of survival was significantly different in any two stages (p < 0.001). In the neoadjuvant treatment group, the 3-year OS rates were 59.4%, 37.8%, 27.6%, and 3.7% in patients with ypstage I, II, III, and IV tumors (Figure 1B). The rate of survival was also significantly different in any two stages (p < 0.001), except for ypstage II vs. III, which had a p value of Compared with cstage groups, both pstage and ypstage groups had greater differences in survival among patients in different stages, which means better discriminatory capability in pstage and ypstage groups. As for the differences between pstage and ypstage groups, the survival rate was generally worse in the ypstage groups compared with the corresponding pstage groups, particularly in the early stage groups. We further separated the ypstage I into pathologic complete response (ypt0n0) and non-pathologic complete response (ypstage I, non-ypt0n0, which includes yptis-2n0) subgroups (Figure 2). The 1, 3, and 5-year OS rates were 88.1%, 66.4%, and 52.1% in ypt0n0, while they were 81.0%, 50.8%, and 39.1% in the non-pathological complete response. In the survival curve plot, the curve of ypt0n0 was similar to that of pstage I, whereas the curve of non-ypt0n0 ypstage I was similar to that of pstage II, indicating a substantial difference in survival among patients within the ypstage I. To compare the new (8 th edition) and old (7 th edition) staging system, a survival curve analysis according to the 7 th edition of the AJCC TNM staging system was performed (Figure 3). In patients who underwent upfront esophagectomy, the discriminatory capability of the old

8 edition between stage III and IV was poor. Meanwhile, a good discriminatory capability and monotonicity of gradients were noted from ypstage I to IV in the ypstage. However, the ypt0n0 and ypt0n+ were in orphan status, highlighting the importance of the 8 th edition AJCC TNM staging system. Comment While the 7 th edition staging system for cancer of the esophagus and esophagogastric junction was based on a database of 4,627 esophagectomy patients from 13 institutions, the newly released staging system is based on a new expanded WECC database that collected information from 33 institutions spanning 6 continents [2-4, 12]. The information of 8156, 5631, and 2045 patients formed the basis for construction of the clinical, pathologic, and postneoadjuvant pathologic staging system, respectively, for ESCC [2-4]. In contrast, the TCR database, which is among the high-quality cancer registries in Asia, is an excellent tool for external validation of the TNM staging system. In the present study, 3399 patients who underwent esophagectomy for cstage I III ESCC were included. In total, data of 3399, 1805, and 1594 patients were used for evaluation of the performance of the clinical, pathological, and postneoadjuvant pathologic staging system in prognostication. The comparison between the WECC and TCR database is shown in Table 3. Compared to the clinical staging data of ESCC in the WECC database [2-4], more than one-third of patient data in the WECC database were collected before the year The protocol for diagnosis and treatment might be significantly different from current practice. Demographically, the percentage of female patients (6% vs. 30%) and those with well differentiated tumors (2.5% vs. 9.2%) in our cohort were low. In both the WECC and TCR databases, ESCCs were located predominantly in the middle and lower

9 esophagus. The distributions of ct and cn categories are similar between the two databases, except that the ct4 and cn3 are classified as cstage IV, and are thus excluded from the current analysis. The R0 resection rate was 89.6% in the cohort, which is similar to that in the WECC database (93% in the pathologic group and 91% in the neoadjuvant pathologic group). In patients who had upfront esophagectomy, 33.9%, 16.3%, 43.7%, and 3.3% had pt1, pt2, pt3, and pt4 stage, respectively, in the TCR database compared to the 15%, 19%, 54%, and 11% in the WECC database. The pn0 rates were similar in the two databases (58% vs. 57%). The relatively high percentage of pt3/4 category in the WECC database may be because neoadjuvant treatments are not popular in institutions that contributed pathologic staging data. In the WECC database, 65% of pathologic staging data for ESCC are from Asia, whereas only 20% of postneoadjuvant pathologic staging data are from Asia. Given that neoadjuvant chemotherapy or chemoradiation has become a standard treatment for ESCC in many Asia countries, such as Japan [13] and Taiwan, we encourage the WECC to include data from more Asia institutions in their database. The neoadjuvant treatments before esophagectomy in the WECC database were chemoradiotherapy (67%), chemotherapy (22%), and radiotherapy (10%) [7], whereas more than 95% of neoadjuvant treatments in the TCR database were chemoradiotherapy. The effect of neoadjuvant treatment on prognostication was mainly attributed to chemoradiotherapy, which is the current recommended treatment protocol for ESCC. With regard to stage distribution, 32.3% had ypt0 and 67.3% had ypn0 in the TCR database, which is comparable to that in the WECC database (ypt0, 30% and ypn0, 65%). In the survival curve analysis, our findings were similar with those from the WECC database. Survival according to pstage group remains the most significant discriminatory factor between different groups and the monotonicity of gradients. This means that patients in the

10 earlier stages have longer survival than those in the later stages. Survival according to the cstage has poor discriminatory ability, particularly between cstage II and III. Survival curves are compressed from above and below, with worse survival of those in the early stages and better survival of those in the later stages compared with the corresponding pstage groups [5]. The clinical staging in both WECC database and our cohort had shortcoming of frequent understaging and overstaging, owing to the fact that clinical categories were typically determined via imaging and histologic examination of biopsy specimens, which were performed with limited resolution. With regard to ypstage groups, the survival curves are generally depressed from above, with greater survival differences between pstage I/II and ypstage I/II than that between pstage III/IV and ypstage III/IV [7]. An interesting observation in our cohort is that ypstage I was a heterogeneous group consisting of patients with substantial survival differences. Although ypt0-2 cancers had similar survival for each N category in the WECC database and ypt0-2n0m0 cancers comprised ypstage I [4], we found that ypt0n0, i.e. pathologic complete response, was a unique subgroup with excellent survival. The 5-year OS rate of yp0n0 was 52.1%, which was equivalent to that of pstage I (54.5%), whereas the survival of yptis-2n0 (5-year OS rate: 39.1%) was equivalent to that of pstage II (40.1%). Our findings are compatible with reports that pathologic response is the major determinant of survival in patients after neoadjuvant treatments and that the pathologic complete response is associated with enhanced outcome, with a 5-year survival rate of approximately 52% 55% [14-17]. However, the interval between neoadjuvant chemoradiotherapy and surgery affects the probability of pathologically complete response [18, 19]. We suggest that the future edition of the staging system should specifically define the stage group of ypt0n0, for example, subgrouping stage I into Ia (ypt0n0 only) and Ib, and that the

11 optimal timing for ypt and N categories should be determined. This study has some limitations. First, we only included patients who underwent surgical resection. The cstage aid not only in prognostication before treatment but also in deciding the treatment strategy (for example, upfront esophagectomy or neoadjuvant strategy). Moreover, the cstage is the only applicable prognostication model in patients who cannot undergo surgery. However, the applicability of the 8 th edition of the AJCC TNM staging system in these patients was not evaluated in this study. Second, the follow-up time in this cohort was short. However, the prognosis of ESCC is extremely poor, and 44.8% of the included patients had died at the end of Moreover, the median follow-up time was 1.7 years in this study compared to the 1.6 years in the WECC database. Therefore, we consider our data as a proper external validation for the new staging system. Third, the survival rate of patients with pstage 0 tumors was similar to that of patients with pstage I. However, the number is small. Because patients who received endoscopic treatments for clinical TisN0 tumors were not included, the survival rate of patients with pstage 0 in the present study should be carefully interpreted. In addition, the effect of adjuvant therapy on survival and its impact on prognostication in the new staging system were not fully evaluated. Analysis based on the WECC database showed that the addition of adjuvant therapy was not associated with better survival in the non risk-adjusted model [6, 20]. However, many confounding factors are present, e.g., age, comorbidity, and postoperative performance status, when the impact of adjuvant treatment on survival is evaluated retrospectively. Direct outcome comparison between patients with or without adjuvant treatments is not fair because only patients with more advanced disease stage and those who were presumed to have worse outcome would receive adjuvant treatments. A retrospective study in a propensity score-matched cohort has demonstrated the survival benefit of adjuvant chemoradiotherapy [9]. However, the

12 survival benefit may not be the same across all stages, and patients in the late stage still have worse prognosis compared to those in the early stage despite that the use of adjuvant treatments potentially enhances the survival compared to surgery alone in patients with the same stage of disease. Therefore, the impact of adjuvant therapy on the new staging system is complicated and beyond the scope of current study. Lastly, although the TCR database has standardized definitions of terminology, coding, reporting, and corrigendum procedures to ensure the completeness and accuracy of cancer registration data [8], studies based on TCR database has limitations that are inherent to retrospective studies based on nationwide database, including the variability of clinical staging, neoadjuvant treatment protocols, surgical techniques, and pathologic examinations. However, as positron emission tomography/computed tomography (PET/CT) is covered by the Taiwan National Health Insurance system, almost all patients with a diagnosis of esophageal cancer receive PET/CT as a staging workup. Moreover, the most popular neoadjuvant chemotherapy protocols are cisplatin/5-fluorouracil (5-FU)-based chemotherapy, which is the only regimen reimbursed by the Taiwan National Health Insurance system, and carboplatin/paclitaxel-based chemotherapy, which is supported by the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial. In summary, the TCR database provides a resource for external validation of the 8 th edition of the AJCC TNM staging system for cancers of the esophagus and esophagogastric junction. The new cstage, pstage, and ypstage groups demonstrate robust discriminatory capability between groups, and the rate of survival is monotonically decreasing with increasing stage. The results of our analysis also indicate the ypstage I stage should be subgroup based on ypt0n0 to improve the homogeneity within stage groups.

13 References 1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, CA Cancer J Clin 2015;65: Rice TW, Apperson-Hansen C, DiPaola LM, Semple ME, Lerut TE, Orringer MB, et al. Worldwide Esophageal Cancer Collaboration: Clinical staging data. Dis Esophagus 2016;29: Rice TW, Chen LQ, Hofstetter WL, Smithers BM, Rusch VW, Wijnhoven BP, et al. Worldwide Esophageal Cancer Collaboration: pathologic staging data. Dis Esophagus 2016;29: Rice TW, Lerut TE, Orringer MB, Chen LQ, Hofstetter WL, Smithers BM, et al. Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data. Dis Esophagus 2016;29: Rice TW, Ishwaran H, Blackstone EH, Hofstetter WL, Kelsen DP, Apperson-Hansen C. Worldwide Esophageal Cancer Collaboration Investigators. Recommendations for clinical staging (ctnm) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus 2016;29: Rice TW, Ishwaran H, Hofstetter WL, Kelsen DP, Apperson-Hansen C, Blackstone EH. Worldwide Esophageal Cancer Collaboration Investigators. Recommendations for pathologic staging (ptnm) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus 2016;29: Rice TW, Ishwaran H, Kelsen DP, Hofstetter WL, Apperson-Hansen C, Blackstone EH. Worldwide Esophageal Cancer Collaboration Investigators. Recommendations for neoadjuvant pathologic staging (yptnm) of cancer of the esophagus and esophagogastric

14 junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus 2016;29: Chiang CJ, You SL, Chen CJ, Yang YW, Lo WC, Lai MS. Quality assessment and improvement of nationwide cancer registration system in Taiwan: a review. Jpn J Clin Oncol 2015;45: Hwang JY, Chen HS, Hsu PK, Chao YK, Wang BY, Huang CS, et al. A propensity - matched analysis comparing survival after esophagectomy followed by adjuvant chemoradiation to surgery alone for esophageal squamous cell carcinoma. Ann Surg 2016;264: Hsu PK, Chen HS, Liu CC, Huang CS, Hsieh CC, Hsu HS, et al. Pre- versus postoperative chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg 2017;154: Rice TW, Ishwaran H, Ferguson MK, Blackstone EH, Goldstraw P. Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol 2017;12: Rice TW, Rusch VW, Apperson-Hansen C, Allen MS, Chen LQ, Hunter JG, et al. Worldwide Esophageal Cancer Collaboration. Dis Esophagus 2009;22: Matsuda S, Takeuchi H, Kawakubo H, Ando N, Kitagawa Y. Current advancement in multidisciplinary treatment for resectable cstage II/III esophageal squamous cell carcinoma in Japan. Ann Thorac Cardiovasc Surg 2016;22: Meredith KL, Weber JM, Turaga KK, Siegel EM, McLoughlin J, Hoffe S, et al. Pathologic response after neoadjuvant therapy is the major determinant of survival in patients with esophageal cancer. Ann Surg Oncol 2010;17: Meguid RA, Hooker CM, Taylor JT, Kleinberg LR, Cattaneo SM 2nd, Sussman MS, et al.

15 Recurrence after neoadjuvant chemoradiation and surgery for esophageal cancer: does the pattern of recurrence differ for patients with complete response and those with partial or no response? J Thorac Cardiovasc Surg 2009;138: Donahue JM, Nichols FC, Li Z, Schomas DA, Allen MS, Cassivi SD, et al. Complete pathologic response after neoadjuvant chemoradiotherapy for esophageal cancer is associated with enhanced survival. Ann Thorac Surg 2009;87: Vallböhmer D, Hölscher AH, DeMeester S, DeMeester T, Salo J, Peters J, et al. A multicenter study of survival after neoadjuvant radiotherapy/chemotherapy and esophagectomy for ypt0n0m0r0 esophageal cancer. Ann Surg 2010;252: Shapiro J, van Hagen P, Lingsma HF, Wijnhoven BP, Biermann K, ten Kate FJ, et al. Prolonged time to surgery after neoadjuvant chemoradiotherapy increases histopathological response without affecting survival in patients with esophageal or junctional cancer. Ann Surg 2014;260: Shaikh T, Ruth K, Scott WJ, Burtness BA, Cohen SJ, Konski AA. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg 2015;99: Rice TW, Patil DT, Blackstone EH. 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice. Ann Cardiothorac Surg 2017;6:

16 Table 1. Patient demographics Number % Age (yrs, mean ± SD) 55.2 ± 9.4 Sex Male Female Tumor length (cm, mean ± SD) 4.5 ± 2.5 Tumor location Upper Middle Lower Unknown Tumor differentiation Well Moderate Poor Unknown Clinical stage I II III Resection margin Negative Positive Unknown Neoadjuvant treatment No Yes SD: standard deviation

17 Table 2. Distribution of p (yp)t and p (yp)n categories for each ct and cn category Upfront surgery Neoadjuvant treatment ct pt ypt is/ Total 0 is/ Total Total cn pn ypn Total Total Total

18 Table 3. Comparison between Worldwide Esophageal Cancer Collaboration (WECC) and Taiwan Cancer Registry (TCR) databases WECC TCR c stage Number Decades (%) Before Continent (%) Asia Outside Asia 50 0 Age (yrs ± SD) 61 ± ± 9 Sex (%) Female 30 6 Tumor location (%) Upper Middle Lower Tumor differentiation (%) Well 9 3 Moderate Poor ct (%) ct1/ ct3/ cn (%) cn p stage Number Continent (%) Asia Outside Asia 35 0 pt (%) ptis/1/ pt3/ pn (%) pn Adjuvant therapy (%) Chemoradiotherapy 7 29 Chemotherapy 11 8 Radiotherapy 5 7 yp stage Number Continent (%) Asia

19 Outside Asia 80 0 Neoadjuvant therapy (%) Chemoradiotherapy Chemotherapy 22 3 Radiotherapy 10 1 ypt (%) ypt yptis/1/ ypt3/ ypn (%) ypn SD: standard deviation; c stage: clinical stage; p stage: pathologic stage; yp stage: postneoadjuvant pathologic stage

20 Figure Legends Figure 1. Survival curves according to (A) clinical stages (blue: stage I; red: stage II; green: stage III) and (B) pathologic stages (grey: stage 0; thick blue: stage I; thick red: stage II; thick green: stage III; thick tan: stage IV) and postneoadjuvant pathologic stages (thin blue: stage I; thin red: stage II; thin green: stage III; thin tan: stage IV). Figure 2. The ypstage I was separated into ypt0n0 (gray) and ypstage I, non-ypt0n0 (black) subgroups. The survival curve of the former is similar to that of pstage I (blue), whereas the survival curve of the latter is similar to that of pstage II (red). Figure 3. Survival curves according to the 7 th AJCC TNM staging system (A) in patients after upfront esophagectomy (gray: stage 0; blue: stage I; red: stage II; green: stage III; yellow: stage IV) and (B) in patients after neoadjuvant treatments and esophagectomy (gray: stage 0; blue: stage I; red: stage II; green: stage III; yellow: stage IV; light purple: ypt0n0; dark purple: ypt0n+).

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