An Attempt at Validation of the Seventh Edition of the Classification by the International Union Against Cancer for Esophageal Carcinoma

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1 An Attempt at Validation of the Seventh Edition of the Classification by the International Union Against Cancer for Esophageal Carcinoma Matthias Reeh, MD, Michael F. Nentwich, MD, Katharina von Loga, MD, Julia Schade, Faik G. Uzunoglu, MD, Alexandra M. Koenig, MD, Maximilian Bockhorn, MD, Thomas Rosch, MD, Jakob R. Izbicki, MD, FACS, and Dean Bogoevski, MD Department of General, Visceral and Thoracic Surgery, Institute of Pathology, and Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany Background. The aim of our study was to investigate the ability of the Seventh edition of the classification by the International Union Against Cancer (UICC) to identify patients at higher risk and to predict the overall survival in patients with esophageal carcinoma. Methods. Demographic and clinical data of 605 patients, who underwent esophagectomy for esophageal carcinoma between 1992 and 2009, were analyzed. Tumor stage and grade were classified according to the sixth and seventh editions of the UICC classification. Results. Tumor depth (T), lymph node affection (N), and metastasis (M) status according to the seventh edition of the UICC classification showed significant differences in survival of each single status. Kaplan-Meier analysis of overall survival by the seventh edition of the UICC classification showed poor discrimination between stages Ib and IIa (p 0.098), stages IIIa and IIIb (p 0.672), and stages IIIc and IV (p 0.799). Further, the estimated median survival time between stages IIa and IIb was discordant. Conclusions. The seventh edition of the UICC TNM classification cannot satisfactorily distinguish among different risk groups of patients with resected esophageal carcinoma. The new subgroups do not unify the different TNM stages with similar survival. We strongly propose that the next revision of the UICC classification should reduce the stages to groups with similar survival, without defining complex subgroups. (Ann Thorac Surg 2012;93:890 6) 2012 by The Society of Thoracic Surgeons Accepted for publication Nov 14, Address correspondence to Dr Reeh, Department of General, Visceral and Thoracic Surgery, University Medical Centre of Hamburg- Eppendorf, Martinistrasse 52, Hamburg, Germany; Esophageal carcinoma is the sixth most common cause of cancer deaths worldwide [1]. The long-term (5 years overall) survival rate after curative resection is still below 15% [2]. The prognosis of locally advanced esophageal cancer is particularly worse. This makes it even more important to use an appropriate and sensitive classification system for accurate prediction of survival in patients with locally advanced esophageal carcinoma. Inasmuch as there have been no changes from the fifth to the sixth edition of the International Union Against Cancer (UICC) TNM staging systems for esophageal cancer, several studies have arrogated modifications in the classification systems [3 7]. A criticism has been that the staging system gives too much weight to the predictive impact of the primary tumor depth, whereas nodal status as a prognostic factor has been underestimated. Recent studies have postulated that the number of affected lymph nodes is the most important marker for predicting survival in patients with resected esophageal cancer [8 11]. A subdivision of nodal classification based on the number of involved lymph nodes has been suggested instead of classifying the N status only according to the presence or absence of involved lymph nodes. The new seventh edition of the UICC TNM staging system was released at the end of 2009 [12]. This new data-driven classification was constructed by the analyses of a database that included 4627 patients with esophageal carcinoma treated by surgical operation alone [13]. The aim of our study was to investigate the ability of the seventh edition of the UICC TNM classification to distinguish between patients at higher risk and to predict the overall survival in patients who underwent surgical resection for esophageal carcinoma. A second focus was to compare the sixth and seventh editions of the UICC TNM classification by reference to the same study population. Patients and Methods Patients The University-Hospital Hamburg-Eppendorf is a specialist reference center for the treatment of patients with esophageal carcinoma in Germany. A prospective database for all patients with surgically resectable esophageal carcinoma was established in 1992 at the Department for General, Visceral and Thoracic Surgery at the University Hospital Hamburg-Eppendorf, Germany. Only patients 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg REEH ET AL 2012;93: TH EDITION OF UICC CLASSIFICATION FOR ESOPHAGEAL CARCINOMA 891 without perioperative chemotherapy and histologically proven esophageal cancer were included in this study. The demographic, clinical, and operative and postoperative courses of each patient were collected. Informed consent was obtained from all patients before their inclusion in the prospective database. The study was approved by the Medical Ethical Committee of the chamber of physicians of Hamburg. Surgical procedures in patients with esophageal carcinomas encompassed either transhiatal (TH) or thoracoabdominal (TA) esophagectomy. The thoracoabdominal (Ivor Lewis) esophagectomies were performed by rightsided thoracotomy, median inverse T-shaped laparotomy, and left-sided cervicotomy for collar anastomosis until the middle of From the middle of 2003 onward, the anastomosis was done highly intrathoracically. A wide peritumoral resection was performed, including an en bloc subtotal esophageal resection with dissection of the right-sided paratracheal, aortopulmonary window, subcarinal, mediastinal, and paracardial lymph nodes. The azygos vein was also resected. An extensive lymphadenectomy of the upper abdominal compartment (D-II lymphadenectomy, including the paracardial nodes, the left gastric artery nodes along with the lymph nodes of the lesser curvature of the stomach, the celiac trunk, the common hepatic artery, and the splenic artery) was conducted. The transhiatal esophagectomies consisted of an inversed T-shaped laparotomy, followed by wide peritumoral dissection of the distal esophagus and abdominal lymph node dissection of the upper abdominal compartment (D-II lymphadenectomy), and a dissection of the lymph nodes of the posterior mediastinum extending as far as the main carina of the trachea. Above the tracheal bifurcation, the dissection was continued bluntly with the use of digital dissection and staying close to the esophageal wall. Follow-Up Postoperative follow-up was conducted in all patients at 3-month intervals for the first 2 years and at 6-month intervals thereafter, and included physical examination, plain chest radiography, abdominal ultrasonography, endoscopy, endosonography, computed tomography of the chest and abdomen along with positron emission tomography computed tomography after January 2006 in selected cases, studies of tumor markers (carcinoembryonic antigen and CA 199), and bone scanning. Recurrence was diagnosed if proved by biopsy or by unequivocal evidence of tumor masses (newly appearing metastases or local recurrence) with a tendency to grow during further follow-up, follow-up until death, or both. Events considered were death, local recurrence, and distant metastasis. When no events were recorded, the patients were censored at the last contact. The last general follow-up of survivors was done at the end of April Overall patient survival, defined as time from operation to death or last follow-up, was used as a measure of prognosis. Statistical Analysis We used the SPSS 17.0 for Windows for statistical analysis. Tumor stage and grade were classified according to the sixth and seventh editions of the TNM classification of the UICC. The major changes between the sixth and seventh editions of the UICC TNM staging classification are shown in Table 1. Table 1. TNM Definitions and Stage Groups by Sixth and Seventh Editions of the UICC Classification Sixth Edition Seventh Edition Tis Carcinoma in situ Tis Carcinoma in situ/high-grade dysplasia T1 Lamina propria or submucosa T1 Lamina propria or submucosa T1a Lamina propria or muscularis mucosae T1b Submucosa T2 Muscularis propria T2 Muscularis propria T3 Adventitia T3 Adventitia T4 Adjacent structures T4 Adjacent structures T4a Pleura, pericadium, diaphragm or adjacent peritoneum T4b Other adjacent structures, eg aorta, vertebral body, trachea N0 No regional lymph node metastasis N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1 1 to 2 regional lymph nodes (site dependent) N2 3 to 6 regional lymph nodes N3 6 regional lymph nodes Mx M status unknown M0 No distant metastasis M1 Distant metastasis M1 Distant metastasis M1a/b Distant metastasis site dependent TNM tumor, node, metastasis; UICC International Union Against Cancer.

3 892 REEH ET AL Ann Thorac Surg 7TH EDITION OF UICC CLASSIFICATION FOR ESOPHAGEAL CARCINOMA 2012;93:890 6 Associations between categoric variables at operation were assessed by the Fisher exact test. The Kaplan-Meier method was used to estimate the occurrence probability of an event (death, recurrence) [14]. Point and interval estimates for survival probabilities at 60 months were calculated. Differences between patient groups with respect to their survival were assessed by the use of log-rank tests, and the difference was considered to be statistically significant at p Apart from a patient s sex and age at the time of operation, those covariates with a p value 0.05 in univariate survival analysis (log-rank test) were entered into multivariate Cox proportionalhazards analysis to assess the independent influence of these covariates [15]. In this case, significance statements refer to p values of two-tailed tests with a p value Results Clinical Data Of the 614 patients who underwent esophagectomy between 1992 and 2009, 605 patients were available for follow-up (9 patients were lost to follow-up, mainly patients from abroad). The mean follow-up time was 26.2 months (median follow-up time, 14.6 months; IQR, 5.2 to 32 months). The median age was 62 years (range, 34 to 83 years) and 79.7% were men. The thoracoabdominal approach was used in 345 (57%) patients; whereas the transhiatal approach was used in 260 (43%) patients. The surgical morbidity rate was 26.6%, with an in-hospital mortality rate of 7.4%. Adenocarcinomas (n 309; 51.1%) and squamous cell carcinomas (n 296; 48.9%) were equally distributed. Patients with squamous cell carcinoma showed shorter median overall survival of 15.6 months in comparison with adenocarcinomas with 20.1 months (p 0.008). The vast majority of patients were staged as pt3 (n 275; 45.5%), followed by pt2 (n 155; 25.6%), and pt1 (n 135; 22.3%), whereas a locally advanced tumor stage (pt4) was found in 40 (6.6%) patients. The N status of all patients was calculated by the sixth and seventh editions of the UICC TNM classifications. The median number of surgically removed lymph nodes accounted for 20 lymph nodes (range, 0 to 100 lymph nodes), whereas the median number of affected lymph nodes was 4 (range, 1 to 80). According to the definition in the sixth edition, lymph node involvement was found in 59.7% of all cases (n 361). Analysis of N status by the classification of the seventh edition of the UICC showed a homogenous distribution of all patients (pn1 20.2%, pn2 21.5%, pn3 17.5%). In 97.5% of all cases (n 590) an M0 status was classified by the seventh edition of the UICC. According to the sixth edition, an M1a status was found in 15.5% of all cases (n 94), and M1b status was classified in 2.5% of all cases (n 15). The rate of complete surgical resection (R0) was achieved in 481 patients (79.5%). R0 status was reached in 80.6% of all patients who underwent TA and in 78.1% of all patients who underwent TH (p 0.750). Most of the carcinomas were located in the lower third of the esophagus (n 467; 77.2%) followed by the middle third (n 86; 14.2%) and the upper third (n 52; 8.6%). In the majority of patients, moderate histologic grading was identified (G2, 53.9%) followed by undifferentiated (G3, 44%). Survival Analysis Kaplan-Meier survival analysis with pairwise comparisons was performed for each T, N, and M status by the sixth and seventh editions of the UICC classification. The overall 5-year survival rate was 12.9%, with a median survival of 17.3 months (IQR to months). Classifications for T, N, and M status according to the seventh edition of the UICC showed significant differences in survival of each stage (Table 2). In contrast to a previously published study [16], the subdivision in a group of seven or more positive lymph nodes (pn3) seemed to be necessary because our data showed a significant difference of survival in patients with N2 and N3 status (p ) (Table 2). Pairwise comparison of the resection margins showed no significant difference between microscopically (R1) and macroscopically (R2) incomplete resections (p 0.068), whereas the survival of R0 patients was significantly better than that of R1 resected patients (p 0.001) and R2 patients (p 0.001). A further parameter that showed a significant impact on survival was tumor grading (G2 vs. G3, p 0.001). In regard to the primary tumor location (proximal vs. middle vs. distal third), no significant differences in survival were found (p 0.095). Kaplan-Meier analysis of overall survival by the seventh edition of the UICC classification showed poor discrimination between stages Ib and IIa (p 0.098), stages IIIa and IIIb (p 0.672), and stages IIIc and IV (p 0.799). Further on, the estimated median survival time between stages IIa and IIb did not decrease adequately (Fig 1). In contrast, Kaplan-Meier analysis according to the sixth edition of the UICC classification showed no significant differences of survival only between stages IIa and IIb (p 0.319) and between stages IVa and IVb (p 0.451) (Fig 2). Further on, in comparison with the seventh edition, no estimated median survival time decreased inadequately. A univariate Cox regression model was performed with the incorporation of age; sex; histology type; T, N, and M stage; resection margins; tumor grading; and primary tumor location. All parameters except age, sex, and tumor location were significant prognostic markers of survival in univariate Cox regression analysis (Table 3). The tumor depth (pt) and the lymph node affection (pn stage) remained independent prognostic factors of survival even in multivariate Cox regression analysis (Table 3). Comment The TNM staging classification is of immense importance in the planning, treatment decision, prognostication, and evaluation of treatment results in patients as well as in

4 Ann Thorac Surg REEH ET AL 2012;93: TH EDITION OF UICC CLASSIFICATION FOR ESOPHAGEAL CARCINOMA 893 Table 2. Demographic Parameters and Survival Analyses Variables n (%) 5-Year Survival (%) Median Survival, Months (CI 95%) p Value a Age, mean (range) (34 83) ( ) Sex F 123 (20.3) ( ) M 482 (79.7) ( ) Histology type AC 309 (51.1) ( ) SCC 296 (48.9) ( ) Seventh edition UICC pt (22.3) ( ) (25.6) ( ) (45.5) ( ) 4 40 (6.6) ( ) pn (40.8) ( ) (20.2) ( ) (21.5) ( ) (17.5) ( ) M M1 15 (2.5) ( ) Resection margin R0 481 (79.5) ( ) R1 91 (15.0) ( ) R2 33 (5.5) ( ) Surgical approach TA 345 (57.0) ( ) TH 260 (43.0) ( ) Location of primary tumor Upper third 52 (8.6) ( ) Middle third 86 (14.2) ( ) Lower third 467 (77.2) ( ) Grading G1 13 (2.1) ( ) G2 326 (53.9) ( ) G3 266 (44) ( ) a Log-rank test. AC adenocarcinoma; CI confidence interval; SCC squamous cell carcinoma; TA thoracoabdominal; TH transhiatal; UICC International Union Against Cancer. research. Therefore, the classification has to be accepted among the different professions of an oncologic center. The latest revision of the TNM classification (seventh edition) was awaited with big expectations and hope. It was expected to bring a new and better classification system of esophageal carcinomas and to stratify better the patients at higher risk for recurrence, as well as to distinguish among patients who need adjuvant chemo- (radio) therapy. The question that remains is whether this classification brought some improvement. Knowledge of cancer detection, treatment, and experience in staging has steadily increased and is a dynamic process, so that the UICC classification has had to be revised frequently. However, since the publication of the fifth edition of the UICC classification in 1997, there have been no changes in the classification of esophageal carcinoma. In the past decade, numerous studies have investigated the impact of the UICC TNM classification. All of them reported poor discrimination of survival by this classification system and postulated fundamental modifications in the TNM classification system [3 9]. The main modifications of the new TNM classification were performed in the N and M status. Studies postulated a poor quality in predicting survival by using the N classification of the sixth edition, which differentiated only between the presence (N1) and absence (N0) of involved lymph nodes. However, within the groups of patients with positive lymph nodes, survival was not homogeneous. Therefore, recently published studies have suggested potentially new N classifications that

5 894 REEH ET AL Ann Thorac Surg 7TH EDITION OF UICC CLASSIFICATION FOR ESOPHAGEAL CARCINOMA 2012;93:890 6 Fig 1. Kaplan-Meier survival curves for patients defined by seventh edition of the International Union Against Cancer classification. (CI confidence interval.) were defined by the number of affected lymph nodes [3 5, 7 8]. Independently of the defined number of subgroups and the cutoff definitions, all studies predicted more precisely the overall survival of patients after esophagectomy in comparison with the sixth edition. Because of these findings, a new subclassification of N status was defined in the seventh edition [12, 13]. In our study, the number of affected lymph nodes of all patients with any T status and any M status defined by the seventh edition was monotonic and distinctive, in contrast to a recent study by Hsu and colleagues, which reported similar survival in patients with N2 and N3 disease [16]. They postulated the N3 status to be unnecessary in tumor staging and survival prediction. We could not reinforce these findings. In our study population, 130 patients had three to six affected lymph nodes (N2), and nearly the same number (106 patients) had more than six affected lymph nodes (N3). The median survival time was significantly different: 13.9 months in the N2 group in comparison with 5.9 months in the N3-group (P ). Our data confirm the findings of other authors that the number of involved nodes is an independent predictor of survival in esophageal tumors [3 5, 7, 8, 17]. After 13 years without modifications in the TNM classification for esophageal carcinoma, the UICC improved the old and inadequate N classification of the Fig 2. Kaplan-Meier survival curves for patients defined by sixth edition of the International Union Against Cancer classification. (CI confidence interval.)

6 Ann Thorac Surg REEH ET AL 2012;93: TH EDITION OF UICC CLASSIFICATION FOR ESOPHAGEAL CARCINOMA 895 Table 3. Univariate and Multivariate Survival Analysis Results Variables HR p 95% CI Univariate variables Age Sex Histology type a T a N a M a Resection margin a Grading a Location Multivariate variables Histology type T a N a M Resection margin Grading a Significant results with p CI confidence interval; HR hazard ratio; TNM tumor, node, metastasis. sixth edition by defining three different N groups by the number of affected lymph nodes (N1 to N3). However, another modification of crucial importance the demand for the minimal number of lymph nodes removed has not been changed in the new UICC classification. The seventh edition still demands only six lymph nodes for the proper nodal classification of esophageal carcinoma. It is confusing, because in order to be classified as pn3 a patient must have at least seven affected lymph nodes. This lymph node yield is also unusually low compared with the UICC recommendations for colorectal (12 lymph nodes), gastric (15 lymph nodes), and pancreatic (10 lymph nodes) carcinoma and is even in contrast with the actual pn classification (pn3 with more than six affected lymph nodes). The extent of lymph node dissection during surgical resection for esophageal carcinoma is still controversial [3, 18 26]. Until now no consensus has existed regarding the minimal number of lymph nodes required for nodal staging. Our study group investigated the impact of different lymph node yields in 2008 [8]. The data results suggested that extensive nodal sampling ( 19 lymph nodes) improves adequate nodal staging in esophageal carcinoma. Further on, lower rates of local recurrence are achieved by en bloc resection with extensive lymphadenectomy, as has been shown by previous investigations by our group [27 30]. The UICC stage groupings combine multiple variables of the TNM classification into a defined number of groups with monotonic and distinctive survival. Since the beginning, stage groupings have followed a linear pattern of increasing T, N, and M status. Even the new UICC classification (seventh edition) tried only slightly to change this old-fashioned pattern. However, esophageal carcinoma does not grow and spread like this simple linear progression. It is well known that a patient with a tumor of low T stage and high N stage can have the same poor prognosis as a patient with distant metastases. Therefore, a grouping by homogenous and distinctive survival is required, as has been postulated by several authors [3, 5, 7, 8, 31]. Our results in the Kaplan-Meier survival analyses showed no distinctive survival between several UICC groups of the seventh edition. The goal of stage grouping is to unify different TNM stages into a small and adequate number that allows accurate and precise prediction of survival and the identification of patients who will profit from adjuvant therapy. Unfortunately, the new UICC classification has a trend toward making stage groupings more complex by defining subgroups. These definitions are far too complex and confusing, and, as shown by our analysis of our own patient population, they did not improve the prediction for overall survival of patients. The original purpose of stage grouping is defeated by these trends. It has to be mentioned that this study has some limitations, which must be considered in the interpretation of these results. This was a retrospective, singlecenter analysis. The number of patients was far too low to compete against the database on which the new edition of the UICC classification was created. However, we described 605 patients who underwent surgical procedures in a highly standardized manner by a German esophageal center. The aim of this study was not to present another proposal for a new TNM classification but to present an attempt at validating the seventh edition of the UICC classification for esophageal carcinoma. In conclusion, our data suggest that the seventh edition of the UICC classification does not exactly predict survival in patients with resected esophageal carcinoma (in some stages, prediction is worse than in the sixth edition). A threshold of six lymph nodes for nodal staging of esophageal carcinoma as currently demanded by the UICC is still insufficient. The new edition has a trend to a more complex and confusing classification. 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