- Email: [email protected]
Refining the Nodal Staging for Esophageal Squamous Cell Carcinoma Based on Lymph Node Stations
Refining the Nodal Staging for Esophageal Squamous Cell Carcinoma Based on Lymph Node Stations Jun Peng, MD, Wen-Ping Wang, MD, Ting Dong, MD, Jie Cai, MD, Peng-Zhi Ni, MD, and Long-Qi Chen, MD, PhD Department of Thoracic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China; and Department of Biostatistics, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
Background. The current N category of the American Joint Committee on Cancer (AJCC) staging system for esophageal carcinoma is controversial and inapplicable for precise counting. We tested the classifiers used in the AJCC staging system and proposed a modification to this system based on the number of metastatic lymph node (LN) stations to better represent the survival characteristics of esophageal squamous cell carcinoma (ESCC) in the Chinese population. Methods. Data from 1,351 patients with ESCC who underwent radical-intent surgical resection were reviewed. Univariate and multivariate analyses were performed to identify prognostic factors. The revised nodal categories are based on the number of metastatic LN stations. Results. There was no significant difference in overall survival between patients with N2 disease and those with N3 disease (p [ 0.103). Furthermore, according to the
seventh edition of the AJCC staging system, no significant difference was found between stage IIIB and IIIC (p [ 0.118). Based on a scatter plot, we revised the nodal classification into 4 categories: rN0 (no LN involvement), rN1 (1 station involved), rN2 (2–3 stations involved), and rN3 (‡ 4 stations involved). According to the revised nodal staging system, survival could easily be distinguished between patients in rN2 and rN3 (p [ 0.001) groups and also between patients with modified stage IIIB disease and modified stage IIIC disease (p [ 0.007). Conclusions. The nodal categories for ESCC should be based on the number of metastatic LN stations and be classified into the following 4 groups: N0 (no LN involvement), N1 (1 station involved), N2 (2–3 stations involved), and N3 (‡ 4 stations involved).
E
The new AJCC TNM staging system has been widely used to stratify patients and select treatment strategies. However, patients with ESCC constitute only 39.6% (1,834 of 4,627 cases) of the database used to elaborate the seventh AJCC staging system for esophageal cancer [7]. Because squamous cell carcinoma is the most common pathologic type of esophageal cancer in China, we believe that more data from Chinese patients are essential to validate the generalizability of the current staging system for ESCC [11, 12]. Furthermore, several studies from Asian countries that focused on ESCC had reported that the seventh edition of the AJCC staging system cannot satisfactorily distinguish among different risk groups of patients with resected ESCC, especially between the N2 and N3 subgroups [13–16]. The new N staging system is based on the number of metastatic LNs. However, the exact number of metastatic LNs is sometimes difficult to calculate when an enlarged LN is actually the coalescence of multiple positive LNs or when a single enlarged LN is broken into several pieces during lymphadenectomy. It is known that China is a country with a high burden of tuberculosis, and the LN infected by tuberculosis is more fragile and more calcified [16, 17], and this classification has neglected the
sophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases worldwide [1]. Surgical resection is still the cornerstone of treatment of ESCC, and the lymph node (LN) involvement status is one of the most important prognostic factors for patients with ESCC and resectable disease [2, 3]. Many studies have suggested that a node classification system based on the number of metastatic LNs rather than the presence or absence of LN involvement is a better predictor of outcomes [4–6]. The seventh edition of the American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) cancer staging system had acknowledged the importance of the number of involved LNs by introducing a numerically based classification of regional LN involvement and has provided 2 different staging systems for ESCC and esophageal adenocarcinoma [7]. The new staging system had been reported to result in better performance than the sixth edition [8–10]. Accepted for publication June 22, 2015. Address correspondence to Dr Chen, Department of Thoracic Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan 610041, China; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.06.081
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PENG ET AL REFINING THE NODAL STAGING FOR ESCC
extent of LN metastasis, which is also considered a significant prognostic factor [14, 16]. In this retrospective study, we present data from a large cohort of patients in China and test the nodal categories defined in the seventh edition of the AJCC system for staging ESCC. We then propose modified nodal categories based on the number of metastatic LN stations for staging ESCC to better discriminate the survival differences among groups.
Patients and Methods Patients This study was approved by the Ethics Committee of the West China Hospital of Sichuan University, which waived the requirement for written informed consent from individual patients owing to the retrospective nature of this study. The patients’ data for this study was collected from the esophageal carcinoma database of our hospital between August 2005 and September 2013. All the patients enrolled in the study met the following criteria: (1) they had pathologically confirmed thoracic ESCC; (2) at least 12 LNs were examined for a pathologic diagnosis; (3) no neoadjuvant therapy was given; (4) tumor-free resection margins were determined by microscopic examination of the surgical specimen (R0); (5) there was no distant metastasis (M0); (6) and complete information was available for stage grouping. For the upper thoracic ESCC, we usually conducted a 3-field lymphadenectomy, whereas for middle and lower ESCC, we usually conducted a 2-field lymphadenectomy. All the patients included in the current study were restaged according to the seventh edition of the AJCC Cancer Staging Manual.
Follow-Up All patients were followed up at 3-month intervals for the first 2 years, at 6-month intervals for the following 3 years, and then annually thereafter. Survival time was measured from the date of operation to the date of death or last follow-up. The last general follow-up of survivors was done at the end of November 2014.
Statistical Analysis Overall survival was computed using the Kaplan-Meier method, and the log-rank test was used to assess the survival differences between groups. Multivariate analysis for overall survival was performed using a stepwise Cox proportional hazard regression model. All statistical tests were 2-sided, and p values less than 0.05 were considered to be statistically significant. In the current study, the definition of each regional LN station was according to the seventh AJCC TNM staging system [18]. To determine the optimal cutoff points for the number of metastatic LN stations as a predictor of survival, the relationship between the number of metastatic LN stations and death from ESCC was investigated by using a scatter plot of the variable versus Martingale residuals from a Cox proportional hazards regression
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model, without the variable of interest. A best-fit line of the scatter was then applied to detect the optimal cutoff point [15, 19–22]. The goal of cancer staging is to group cancer characteristics for which patient survival decreases with increasing stages (monotonicity), greater differences in survival between different stages (discriminatory), and similar survival within the same stage (homogeneity) [7]. The likelihood ratio c2 test related to the Cox regression model was used for measuring homogeneity. Discriminatory ability and monotonicity of gradients were measured using the linear trend c2 test. In addition, discriminatory ability was quantified using Harrell’s c statistic. A value of 0.5 refers to random prediction, a value equal to 1 refers to perfect discrimination. The Akaike information criterion (AIC) within the Cox proportional hazard model was used to minimize potential bias in comparing different prognostic systems. The AIC was defined as: AIC ¼ 2 log maximum likelihood þ 2 (the number of parameters in the model). A smaller AIC value indicates a better model for predicting outcome [3, 23]. All statistical analyses were carried out using SPSS, version 16.0 (SPSS Inc, Chicago, IL) and SAS, version 8.2 (SAS Institute, Cary, NC).
Results Patient Characteristics In the current study, 1,351 patients who underwent esophagectomy were enrolled; the median age was 60 years (range, 31–85 years) (Table 1). The median number of examined LNs was 19 (range, 12–62). The median number of positive nodes was 2 (range 1–41). The median number of harvested LN stations was 7 (range, 1–13), and the median number of metastatic LN stations was 2 (range, 1–7). The percentage of patients with examined and positive nodes in each station are shown in Fig 1. The rate of LN metastasis was 50% (676 of 1,351 cases). The overall 5-year survival rate was 41.6%.
Cutoff Points Analysis for rN Staging To determine the optimal cutoff points for the number of metastatic LN stations, the Martingale residuals of the Cox model (sex, age, tumor location, surgical approaches, pathologic T categories, adjuvant therapy, and histologic differentiation) were calculated and then plotted against the number of metastatic LN stations. Based on a scatter plot, we classified the patients into 4 categories: rN0 (no LN involvement), rN1 (1 station involved), rN2 (2–3 stations involved), and rN3 ( 4 stations involved) (Fig 2).
Univariate and Multivariate Analyses of Prognostic Factors Table 1 presents the results of the univariate analyses for overall survival. The 30-day mortality rate was 1.2% for the entire cohort. The age, sex, histologic grade, T stage, AJCC N stage and rN stage were found to be significantly
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Table 1. Patient Characteristics and Results of Univariate Analysis for Prognosis (N ¼ 1,351)
Variable
No. of Patients (%)
Age (y) 60 685 (50.7) >60 666 (49.3) Sex Male 1,122 (83.0) Female 229 (17.0) Tumor location Upper 119 (8.8) Middle 866 (64.1) Lower 366 (27.1) Histologic grade Well (G1) 54 (4.0) Moderate (G2) 567 (42.0) Poor (G3) 730 (54.0) T stage Tis þ T1 187 (13.9) T2 225 (16.7) T3 726 (53.7) T4 213 (15.8) AJCC N stagea N0 675 (50.0) N1 386 (28.6) N2 218 (16.1) N3 72 (5.3) Revised N stageb rN0 675 (50.0) rN1 324 (24.0) rN2 289 (21.4) rN3 63 (4.7) Adjuvant therapy No 796 (58.9) Yes 555 (41.1) a
N2 versus N3, p ¼ 0.103.
b
Median Survival (mo)
5-Year Survival (%)
44.9 35.2
43.0 40.2
36.5 75.7
38.7 56.7
... 36.3 42.3
51.4 38.7 46.7
... 45.3 32.2
67.5 41.9 39.0
p Value 0.036
0.002
0.174
<0.001
<0.001 ... 75.7 31.7 22.1
74.5 57.7 35.4 22.9
... 30.0 21.5 17.6
61.0 30.1 13.4 17.4
... 35.2 22.0 15.8
61.0 31.6 15.6 8.3
<0.001
<0.001
0.417 37.8 44.3
42.9 38.1
rN2 versus rN3, p ¼ 0.001.
AJCC ¼ American Joint Committee on Cancer;
Fig 1. Percentage of patients with examined and positive nodes in each station.
and modified nodal categories are presented in Table 1. There was no survival difference between pathologic N2 and N3 stages (p ¼ 0.103) (Fig 3A). However, according to the modified nodal categories, survival could be discriminated between patients with pathologic rN2 and rN3 (p ¼ 0.001) (Fig 3B). The Kaplan-Meier curves of patients with ESCC based on the seventh edition AJCC and modified TNM staging systems are depicted in Figures 3C and 3D. Both systems show a relatively ordered monotonic distribution of survival. However, according to the seventh edition AJCC staging system, the Kaplan-Meier plot shows overlapping curves for stages IIIB and IIIC (p ¼ 0.118) (Fig 3C). When the modified staging system was used, the survival rate could easily be distinguished between patients with stage IIIB disease and those with stage IIIC disease (p ¼ 0.007) (Fig 3D; Table 3). Reclassifying nodal category by using the number of metastatic LN stations, the modified staging system showed improved homogeneity, monotonicity of gradients, and discriminatory ability, revealing an improved performance of the new staging system (Table 4).
G ¼ grade.
associated with prognosis. In the current study, the N and rN classifications were highly correlated (Spearman correlation coefficient ¼ 0.964; p < 0.001). Therefore 2 separate multivariate models, 1 with N and the other with rN, were constructed to avoid problems with the presence of multicollinearity. In multivariate analysis, age, sex, T stage, N stage, and rN stage were independent prognostic factors (Table 2).
Comparison of Seventh AJCC and Modified TNM Staging Systems The overall survival curves according to the N classifications of the seventh edition AJCC and modified nodal categories are shown in Figures 3A and 3B, respectively. The long-term survival data for the seventh edition AJCC
Comment The TNM staging system is essential for determining prognosis, guiding therapy, evaluating treatment protocols, and facilitating the exchange of information between different centers [24]. The seventh edition of the AJCC TNM staging system for esophageal cancer has been widely used to stratify patients and select treatment strategies. However, several studies have been published that doubt the reliability and generalizability of the current staging system. Gertler and colleagues [25] also found that for ESCC, the new TNM prognostic grouping was not significantly distinctive for stages IA versus IB, stages IIA versus IIB, stages IIIA versus IIIB, and stages IIIC versus IV. Several previous studies that focused on ESCC also reported the deficiencies of the seventh AJCC TNM
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PENG ET AL REFINING THE NODAL STAGING FOR ESCC
staging system. Yamasaki and associates [13] and Chen and coworkers [14] recently reported that the survival probability was not significantly different between the N2 and N3 categories according to the seventh AJCC TNM staging system. Yang and colleagues [15] used data from 2 centers and found that not only N2 versus N3 but also stage IIIB versus stage IIIC showed no significant difference in the survival of patients with ESCC. Furthermore, they modified the nodal categories into 4 categories of positive LNs: 0, 1, 2 to 3, and greater than or equal to 4. In the current study, we also found that not only N2 versus N3 but also stage IIIB versus stage IIIC showed no significant difference in the survival of patients with ESCC from our institution. Three reasons may lead to the aforementioned outcomes. First, although squamous cell carcinoma composes the vast majority of esophageal carcinoma cases, patients with ESCC constitute only 39.6% of the database used to elaborate the seventh edition of the AJCC staging system for esophageal cancer. However, adenocarcinoma and squamous cell carcinoma have different biological characteristics [26]. Approximately three quarters of all adenocarcinoma lesions are found in the distal esophagus, whereas squamous cell carcinoma is more frequent in the proximal to middle esophagus [1], and
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the tumor location had been reported to be related to LN metastasis [27, 28]. Second, the exact number of metastatic LNs is influenced by the operation of surgeon and pathologist. Veeramachaneni and associates [29] found that there is considerable room for surgeon and pathologist to improve the precision of pathologic staging. Third, the seventh edition of the AJCC nodal staging has neglected the extent of LNs metastasis, which is also a significant prognostic factor [14, 16, 30]. Furthermore, given the same number of involved LNs, the prognosis might differ between patients with metastatic LNs clustered in 1 station and those distributed to 2 or more stations [31]. To improve the performance of the TNM staging system in patients with ESCC, we revised the nodal categories based on the number of metastatic LN stations, which covered both the extent and number of LN metastases. Our large sample size provided sufficient power for detecting the relatively small survival differences between groups. We used Martingale residuals from a Cox proportional hazards regression model as a robust statistical approach to determine the optimal cutoff points for the number of metastatic LN stations, which allowed us to discriminate the survival differences between the groups. According to the revised N Table 2. Multivariate Cox Regression Analysis for the Prognosis of 1,351 Patients With ESCC
Fig 2. Scatter plot of number of metastatic lymph node (LN) stations on x-axis versus Martingale residuals for the 1,351 patients with esophageal squamous cell carcinoma (ESCC). Patients above horizontal line (zero) were at increased risk for death compared with expected risk from Cox proportional hazards regression model. Patients below the horizontal line (zero) were at decreased risk for death compared with expected risk. Curved line represents smoother scatter plot. Curved line crosses horizontal line at 1 metastatic LN station, indicating that this would be best cutoff point to predict death from esophageal carcinoma. Point at which curved line reaches platform is at 4 metastatic LN stations, indicating that this would be another cutoff point.
Prognostic Factor
Hazard Ratio
95% CI
p Value
Age (y) Sex Tumor location Upper Middle Lower Histologic grade Well (G1) Moderate (G2) Poor (G3) T stage Tis þT1 T2 T3 T4 AJCC N stage N0 N1 N2 N3 Revised N stage rN0 rN1 rN2 rN3 Adjuvant therapy
1.217 0.745
1.022–1.450 0.576–0.964
0.028 0.025
1 0.862 0.660
... 0.631–1.177 0.468–0.931
0.051 0.351 0.018
1 1.841 2.164
... 0.809–4.191 0.953–4.914
0.054 0.146 0.065
1 1.645 2.842 3.246
... 1.031–2.626 1.874–4.308 2.082–5.059
<0.001 0.037 <0.001 <0.001
1 1.894 2.490 3.045
... 1.522–2.356 1.954–3.173 2.151–4.310
<0.001 <0.001 <0.001 <0.001
1 1.825 2.394 3.634 0.932
... 1.451–2.294 1.904–3.010 2.524–5.232 0.864–1.006
<0.001 <0.001 <0.001 <0.001 0.071
AJCC ¼ American Joint Committee on Cancer; CI ¼ confidence interval; ESCC ¼ esophageal squamous cell carcinoma.
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staging system, the prognosis could easily be distinguished not only in N2 versus N3 but also in stage IIIB versus stage IIIC. A cancer staging system that is based on the accurate prediction of survival in patients with esophageal carcinoma helps clinicians plan optimal treatment. To improve the survival of patients with locoregional advanced esophageal carcinoma, multidisciplinary therapy comprising chemotherapy or radiotherapy (or both) in combination with radical esophagectomy has been developed. Fujiwara and coworkers [32] and other investigators have reported that neoadjuvant therapy may be beneficial for patients with clinical stage II/III ESCC
PENG ET AL REFINING THE NODAL STAGING FOR ESCC
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[32, 33]. Therefore it is crucial to estimate the clinical nodal stage for patients with ESCC. However, it remains difficult to clinically determine the precise number of metastatic LNs based on the currently available diagnostic systems [34]. According to our revised nodal staging system based on the number of metastatic LN stations, it is relatively easy to estimate the clinical nodal stage. Our study has some limitations. First, this is a single-center retrospective study, and our findings need to be validated with another data set. Second, some of the patients were lost to follow-up, which may result in a bias of our results. This limitation partly
Fig 3. (A) Overall survival by the nodal category of seventh American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system (N0 versus N1, N2, N3: p < 0.001; N1 versus N2: p ¼ 0.003; N1 versus N3: p ¼ 0.001; N2 versus N3: p ¼ 0.103). (B) Overall survival by revised nodal categories based on number of metastatic lymph node stations (rN0 versus rN1, rN2, rN3: p < 0.001; rN1 versus rN2: p ¼ 0.001; rN1 versus rN3: p < 0.001; rN2 versus rN3: p ¼ 0.001). (C) Overall survival by original seventh AJCC TNM staging system (overall log rank: p < 0.001; stage IIIA versus stage IIIB, p ¼ 0.021; stage IIIA versus stage IIIC, p < 0.001; stage IIIB versus stage IIIC, p ¼ 0.118). (D) Overall survival by the modified TNM staging system (overall log rank: p < 0.001; stage IIIA versus stage IIIB, p ¼ 0.040; stage IIIA versus stage IIIC, p < 0.001; stage IIIB versus stage IIIC, p ¼ 0.007).
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PENG ET AL REFINING THE NODAL STAGING FOR ESCC
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Table 3. Overall Survival According to the Seventh AJCC TNM Staging System and the Modified Staging System Classification
References
No. of Median 5-Year p Patients (%) Survival (mo) Survival (%) Value
Seventh AJCC TNMa Stage 0 þ Ia 52 Stage IB 107 Stage IIA 149 Stage IIB 391 Stage IIIA 324 Stage IIIB 160 Stage IIIC 168 Modified-TNMb Stage 0 þ Ia 52 Stage IB 107 Stage IIA 149 Stage IIB 386 Stage IIIA 291 Stage IIIB 206 Stage IIIC 160
Not reached Not reached Not reached 74.43 28.20 21.67 17.60
95.8 71.2 62.5 52.5 25.7 14.3 6.2
<0.001
Not reached Not reached Not reached 74.43 28.20 21.97 16.03
95.8 71.2 62.5 53.8 24.4 17.1 4.1
<0.001
a Stage IIIA versus IIIB, p ¼ 0.021; stage IIIA versus IIIC, p < 0.001; stage b IIIB versus IIIC, p ¼ 0.118. stage IIIA versus IIIB, p ¼ 0.040; stage IIIA versus IIIC, p < 0.001; stage IIIB versus IIIC, p ¼ 0.007.
AJCC ¼ American Joint Committee on Cancer; metastasis.
TNM ¼ tumor, node,
results from the retrospective nature of this study. Third, the number in some subgroups was small; therefore we could not give a more precise analysis for some subgroups. In conclusion, we suggest that the nodal categories for ESCC be based on the number of metastatic LN stations and be classified into the following 4 groups: N0 (no LN involvement), N1 (1 station involved), N2 (2–3 stations involved), and N3 ( 4 stations involved). However, more data from Chinese centers are essential to confirm our results.
Table 4. Changes in Homogeneity, Discriminatory Ability, and Monotonicity of Gradient Between the Seventh AJCC TNM Staging System and the Modified Staging System Homogeneity
Classification
Cox Likelihood Ratio c2
Seventh AJCC TNM staging system Modified TNM staging system a
Higher score ¼ better.
Discriminatory Ability Linear Monotonicity Trend Harrell’s 2 c AIC c-Statistic
170.33
139.122
178.26a
142.937a 0 .6691a
b
0.6652
6608.18 6600.249b
Lower score ¼ better.
AIC ¼ Akaike information criterion; AJCC ¼ American Joint Committee on Cancer; TNM ¼ tumor, node, metastasis.
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27. Li B, Chen H, Xiang J, et al. Pattern of lymphatic spread in thoracic esophageal squamous cell carcinoma: a singleinstitution experience. J Thorac Cardiovasc Surg 2012;144: 778–85; discussion 85–6. 28. 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;36:480–6. 29. Veeramachaneni NK, Zoole JB, Decker PA, Putnam JB Jr, Meyers BF. Lymph node analysis in esophageal resection: American College of Surgeons Oncology Group Z0060 Trial. Ann Thorac Surg 2008;86:418–21; discussion 21. 30. Feng J, Mao T, Chen WH, Fang WT. [Impact of number and extent of lymph node metastasis on prognosis of thoracic esophageal cancer]. Zhonghua Wei Chang Wai Ke za Zhi 2011;14:715–8. 31. Takeno S, Yamashita SI, Yamamoto S, et al. Number of metastasis-positive lymph node stations is a simple and reliable prognostic factor following surgery in patients with esophageal cancer. Exp Ther Med 2012;4:1087–91. 32. Fujiwara Y, Yoshikawa R, Kamikonya N, et al. Neoadjuvant chemoradiotherapy followed by esophagectomy vs. surgery alone in the treatment of resectable esophageal squamous cell carcinoma. Mol Clin Oncol 2013;1:773–9. 33. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012;19:68–74. 34. Akutsu Y, Matsubara H. The significance of lymph node status as a prognostic factor for esophageal cancer. Surg Today 2011;41:1190–5.
Background. The current N category of the American Joint Committee on Cancer (AJCC) staging system for esophageal carcinoma is controversial and inapplicable for precise counting. We tested the classifiers used in the AJCC staging system and proposed a modification to this system based on the number of metastatic lymph node (LN) stations to better represent the survival characteristics of esophageal squamous cell carcinoma (ESCC) in the Chinese population. Methods. Data from 1,351 patients with ESCC who underwent radical-intent surgical resection were reviewed. Univariate and multivariate analyses were performed to identify prognostic factors. The revised nodal categories are based on the number of metastatic LN stations. Results. There was no significant difference in overall survival between patients with N2 disease and those with N3 disease (p [ 0.103). Furthermore, according to the
seventh edition of the AJCC staging system, no significant difference was found between stage IIIB and IIIC (p [ 0.118). Based on a scatter plot, we revised the nodal classification into 4 categories: rN0 (no LN involvement), rN1 (1 station involved), rN2 (2–3 stations involved), and rN3 (‡ 4 stations involved). According to the revised nodal staging system, survival could easily be distinguished between patients in rN2 and rN3 (p [ 0.001) groups and also between patients with modified stage IIIB disease and modified stage IIIC disease (p [ 0.007). Conclusions. The nodal categories for ESCC should be based on the number of metastatic LN stations and be classified into the following 4 groups: N0 (no LN involvement), N1 (1 station involved), N2 (2–3 stations involved), and N3 (‡ 4 stations involved).
E
The new AJCC TNM staging system has been widely used to stratify patients and select treatment strategies. However, patients with ESCC constitute only 39.6% (1,834 of 4,627 cases) of the database used to elaborate the seventh AJCC staging system for esophageal cancer [7]. Because squamous cell carcinoma is the most common pathologic type of esophageal cancer in China, we believe that more data from Chinese patients are essential to validate the generalizability of the current staging system for ESCC [11, 12]. Furthermore, several studies from Asian countries that focused on ESCC had reported that the seventh edition of the AJCC staging system cannot satisfactorily distinguish among different risk groups of patients with resected ESCC, especially between the N2 and N3 subgroups [13–16]. The new N staging system is based on the number of metastatic LNs. However, the exact number of metastatic LNs is sometimes difficult to calculate when an enlarged LN is actually the coalescence of multiple positive LNs or when a single enlarged LN is broken into several pieces during lymphadenectomy. It is known that China is a country with a high burden of tuberculosis, and the LN infected by tuberculosis is more fragile and more calcified [16, 17], and this classification has neglected the
sophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases worldwide [1]. Surgical resection is still the cornerstone of treatment of ESCC, and the lymph node (LN) involvement status is one of the most important prognostic factors for patients with ESCC and resectable disease [2, 3]. Many studies have suggested that a node classification system based on the number of metastatic LNs rather than the presence or absence of LN involvement is a better predictor of outcomes [4–6]. The seventh edition of the American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) cancer staging system had acknowledged the importance of the number of involved LNs by introducing a numerically based classification of regional LN involvement and has provided 2 different staging systems for ESCC and esophageal adenocarcinoma [7]. The new staging system had been reported to result in better performance than the sixth edition [8–10]. Accepted for publication June 22, 2015. Address correspondence to Dr Chen, Department of Thoracic Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan 610041, China; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.06.081
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PENG ET AL REFINING THE NODAL STAGING FOR ESCC
extent of LN metastasis, which is also considered a significant prognostic factor [14, 16]. In this retrospective study, we present data from a large cohort of patients in China and test the nodal categories defined in the seventh edition of the AJCC system for staging ESCC. We then propose modified nodal categories based on the number of metastatic LN stations for staging ESCC to better discriminate the survival differences among groups.
Patients and Methods Patients This study was approved by the Ethics Committee of the West China Hospital of Sichuan University, which waived the requirement for written informed consent from individual patients owing to the retrospective nature of this study. The patients’ data for this study was collected from the esophageal carcinoma database of our hospital between August 2005 and September 2013. All the patients enrolled in the study met the following criteria: (1) they had pathologically confirmed thoracic ESCC; (2) at least 12 LNs were examined for a pathologic diagnosis; (3) no neoadjuvant therapy was given; (4) tumor-free resection margins were determined by microscopic examination of the surgical specimen (R0); (5) there was no distant metastasis (M0); (6) and complete information was available for stage grouping. For the upper thoracic ESCC, we usually conducted a 3-field lymphadenectomy, whereas for middle and lower ESCC, we usually conducted a 2-field lymphadenectomy. All the patients included in the current study were restaged according to the seventh edition of the AJCC Cancer Staging Manual.
Follow-Up All patients were followed up at 3-month intervals for the first 2 years, at 6-month intervals for the following 3 years, and then annually thereafter. Survival time was measured from the date of operation to the date of death or last follow-up. The last general follow-up of survivors was done at the end of November 2014.
Statistical Analysis Overall survival was computed using the Kaplan-Meier method, and the log-rank test was used to assess the survival differences between groups. Multivariate analysis for overall survival was performed using a stepwise Cox proportional hazard regression model. All statistical tests were 2-sided, and p values less than 0.05 were considered to be statistically significant. In the current study, the definition of each regional LN station was according to the seventh AJCC TNM staging system [18]. To determine the optimal cutoff points for the number of metastatic LN stations as a predictor of survival, the relationship between the number of metastatic LN stations and death from ESCC was investigated by using a scatter plot of the variable versus Martingale residuals from a Cox proportional hazards regression
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model, without the variable of interest. A best-fit line of the scatter was then applied to detect the optimal cutoff point [15, 19–22]. The goal of cancer staging is to group cancer characteristics for which patient survival decreases with increasing stages (monotonicity), greater differences in survival between different stages (discriminatory), and similar survival within the same stage (homogeneity) [7]. The likelihood ratio c2 test related to the Cox regression model was used for measuring homogeneity. Discriminatory ability and monotonicity of gradients were measured using the linear trend c2 test. In addition, discriminatory ability was quantified using Harrell’s c statistic. A value of 0.5 refers to random prediction, a value equal to 1 refers to perfect discrimination. The Akaike information criterion (AIC) within the Cox proportional hazard model was used to minimize potential bias in comparing different prognostic systems. The AIC was defined as: AIC ¼ 2 log maximum likelihood þ 2 (the number of parameters in the model). A smaller AIC value indicates a better model for predicting outcome [3, 23]. All statistical analyses were carried out using SPSS, version 16.0 (SPSS Inc, Chicago, IL) and SAS, version 8.2 (SAS Institute, Cary, NC).
Results Patient Characteristics In the current study, 1,351 patients who underwent esophagectomy were enrolled; the median age was 60 years (range, 31–85 years) (Table 1). The median number of examined LNs was 19 (range, 12–62). The median number of positive nodes was 2 (range 1–41). The median number of harvested LN stations was 7 (range, 1–13), and the median number of metastatic LN stations was 2 (range, 1–7). The percentage of patients with examined and positive nodes in each station are shown in Fig 1. The rate of LN metastasis was 50% (676 of 1,351 cases). The overall 5-year survival rate was 41.6%.
Cutoff Points Analysis for rN Staging To determine the optimal cutoff points for the number of metastatic LN stations, the Martingale residuals of the Cox model (sex, age, tumor location, surgical approaches, pathologic T categories, adjuvant therapy, and histologic differentiation) were calculated and then plotted against the number of metastatic LN stations. Based on a scatter plot, we classified the patients into 4 categories: rN0 (no LN involvement), rN1 (1 station involved), rN2 (2–3 stations involved), and rN3 ( 4 stations involved) (Fig 2).
Univariate and Multivariate Analyses of Prognostic Factors Table 1 presents the results of the univariate analyses for overall survival. The 30-day mortality rate was 1.2% for the entire cohort. The age, sex, histologic grade, T stage, AJCC N stage and rN stage were found to be significantly
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Table 1. Patient Characteristics and Results of Univariate Analysis for Prognosis (N ¼ 1,351)
Variable
No. of Patients (%)
Age (y) 60 685 (50.7) >60 666 (49.3) Sex Male 1,122 (83.0) Female 229 (17.0) Tumor location Upper 119 (8.8) Middle 866 (64.1) Lower 366 (27.1) Histologic grade Well (G1) 54 (4.0) Moderate (G2) 567 (42.0) Poor (G3) 730 (54.0) T stage Tis þ T1 187 (13.9) T2 225 (16.7) T3 726 (53.7) T4 213 (15.8) AJCC N stagea N0 675 (50.0) N1 386 (28.6) N2 218 (16.1) N3 72 (5.3) Revised N stageb rN0 675 (50.0) rN1 324 (24.0) rN2 289 (21.4) rN3 63 (4.7) Adjuvant therapy No 796 (58.9) Yes 555 (41.1) a
N2 versus N3, p ¼ 0.103.
b
Median Survival (mo)
5-Year Survival (%)
44.9 35.2
43.0 40.2
36.5 75.7
38.7 56.7
... 36.3 42.3
51.4 38.7 46.7
... 45.3 32.2
67.5 41.9 39.0
p Value 0.036
0.002
0.174
<0.001
<0.001 ... 75.7 31.7 22.1
74.5 57.7 35.4 22.9
... 30.0 21.5 17.6
61.0 30.1 13.4 17.4
... 35.2 22.0 15.8
61.0 31.6 15.6 8.3
<0.001
<0.001
0.417 37.8 44.3
42.9 38.1
rN2 versus rN3, p ¼ 0.001.
AJCC ¼ American Joint Committee on Cancer;
Fig 1. Percentage of patients with examined and positive nodes in each station.
and modified nodal categories are presented in Table 1. There was no survival difference between pathologic N2 and N3 stages (p ¼ 0.103) (Fig 3A). However, according to the modified nodal categories, survival could be discriminated between patients with pathologic rN2 and rN3 (p ¼ 0.001) (Fig 3B). The Kaplan-Meier curves of patients with ESCC based on the seventh edition AJCC and modified TNM staging systems are depicted in Figures 3C and 3D. Both systems show a relatively ordered monotonic distribution of survival. However, according to the seventh edition AJCC staging system, the Kaplan-Meier plot shows overlapping curves for stages IIIB and IIIC (p ¼ 0.118) (Fig 3C). When the modified staging system was used, the survival rate could easily be distinguished between patients with stage IIIB disease and those with stage IIIC disease (p ¼ 0.007) (Fig 3D; Table 3). Reclassifying nodal category by using the number of metastatic LN stations, the modified staging system showed improved homogeneity, monotonicity of gradients, and discriminatory ability, revealing an improved performance of the new staging system (Table 4).
G ¼ grade.
associated with prognosis. In the current study, the N and rN classifications were highly correlated (Spearman correlation coefficient ¼ 0.964; p < 0.001). Therefore 2 separate multivariate models, 1 with N and the other with rN, were constructed to avoid problems with the presence of multicollinearity. In multivariate analysis, age, sex, T stage, N stage, and rN stage were independent prognostic factors (Table 2).
Comparison of Seventh AJCC and Modified TNM Staging Systems The overall survival curves according to the N classifications of the seventh edition AJCC and modified nodal categories are shown in Figures 3A and 3B, respectively. The long-term survival data for the seventh edition AJCC
Comment The TNM staging system is essential for determining prognosis, guiding therapy, evaluating treatment protocols, and facilitating the exchange of information between different centers [24]. The seventh edition of the AJCC TNM staging system for esophageal cancer has been widely used to stratify patients and select treatment strategies. However, several studies have been published that doubt the reliability and generalizability of the current staging system. Gertler and colleagues [25] also found that for ESCC, the new TNM prognostic grouping was not significantly distinctive for stages IA versus IB, stages IIA versus IIB, stages IIIA versus IIIB, and stages IIIC versus IV. Several previous studies that focused on ESCC also reported the deficiencies of the seventh AJCC TNM
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PENG ET AL REFINING THE NODAL STAGING FOR ESCC
staging system. Yamasaki and associates [13] and Chen and coworkers [14] recently reported that the survival probability was not significantly different between the N2 and N3 categories according to the seventh AJCC TNM staging system. Yang and colleagues [15] used data from 2 centers and found that not only N2 versus N3 but also stage IIIB versus stage IIIC showed no significant difference in the survival of patients with ESCC. Furthermore, they modified the nodal categories into 4 categories of positive LNs: 0, 1, 2 to 3, and greater than or equal to 4. In the current study, we also found that not only N2 versus N3 but also stage IIIB versus stage IIIC showed no significant difference in the survival of patients with ESCC from our institution. Three reasons may lead to the aforementioned outcomes. First, although squamous cell carcinoma composes the vast majority of esophageal carcinoma cases, patients with ESCC constitute only 39.6% of the database used to elaborate the seventh edition of the AJCC staging system for esophageal cancer. However, adenocarcinoma and squamous cell carcinoma have different biological characteristics [26]. Approximately three quarters of all adenocarcinoma lesions are found in the distal esophagus, whereas squamous cell carcinoma is more frequent in the proximal to middle esophagus [1], and
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the tumor location had been reported to be related to LN metastasis [27, 28]. Second, the exact number of metastatic LNs is influenced by the operation of surgeon and pathologist. Veeramachaneni and associates [29] found that there is considerable room for surgeon and pathologist to improve the precision of pathologic staging. Third, the seventh edition of the AJCC nodal staging has neglected the extent of LNs metastasis, which is also a significant prognostic factor [14, 16, 30]. Furthermore, given the same number of involved LNs, the prognosis might differ between patients with metastatic LNs clustered in 1 station and those distributed to 2 or more stations [31]. To improve the performance of the TNM staging system in patients with ESCC, we revised the nodal categories based on the number of metastatic LN stations, which covered both the extent and number of LN metastases. Our large sample size provided sufficient power for detecting the relatively small survival differences between groups. We used Martingale residuals from a Cox proportional hazards regression model as a robust statistical approach to determine the optimal cutoff points for the number of metastatic LN stations, which allowed us to discriminate the survival differences between the groups. According to the revised N Table 2. Multivariate Cox Regression Analysis for the Prognosis of 1,351 Patients With ESCC
Fig 2. Scatter plot of number of metastatic lymph node (LN) stations on x-axis versus Martingale residuals for the 1,351 patients with esophageal squamous cell carcinoma (ESCC). Patients above horizontal line (zero) were at increased risk for death compared with expected risk from Cox proportional hazards regression model. Patients below the horizontal line (zero) were at decreased risk for death compared with expected risk. Curved line represents smoother scatter plot. Curved line crosses horizontal line at 1 metastatic LN station, indicating that this would be best cutoff point to predict death from esophageal carcinoma. Point at which curved line reaches platform is at 4 metastatic LN stations, indicating that this would be another cutoff point.
Prognostic Factor
Hazard Ratio
95% CI
p Value
Age (y) Sex Tumor location Upper Middle Lower Histologic grade Well (G1) Moderate (G2) Poor (G3) T stage Tis þT1 T2 T3 T4 AJCC N stage N0 N1 N2 N3 Revised N stage rN0 rN1 rN2 rN3 Adjuvant therapy
1.217 0.745
1.022–1.450 0.576–0.964
0.028 0.025
1 0.862 0.660
... 0.631–1.177 0.468–0.931
0.051 0.351 0.018
1 1.841 2.164
... 0.809–4.191 0.953–4.914
0.054 0.146 0.065
1 1.645 2.842 3.246
... 1.031–2.626 1.874–4.308 2.082–5.059
<0.001 0.037 <0.001 <0.001
1 1.894 2.490 3.045
... 1.522–2.356 1.954–3.173 2.151–4.310
<0.001 <0.001 <0.001 <0.001
1 1.825 2.394 3.634 0.932
... 1.451–2.294 1.904–3.010 2.524–5.232 0.864–1.006
<0.001 <0.001 <0.001 <0.001 0.071
AJCC ¼ American Joint Committee on Cancer; CI ¼ confidence interval; ESCC ¼ esophageal squamous cell carcinoma.
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staging system, the prognosis could easily be distinguished not only in N2 versus N3 but also in stage IIIB versus stage IIIC. A cancer staging system that is based on the accurate prediction of survival in patients with esophageal carcinoma helps clinicians plan optimal treatment. To improve the survival of patients with locoregional advanced esophageal carcinoma, multidisciplinary therapy comprising chemotherapy or radiotherapy (or both) in combination with radical esophagectomy has been developed. Fujiwara and coworkers [32] and other investigators have reported that neoadjuvant therapy may be beneficial for patients with clinical stage II/III ESCC
PENG ET AL REFINING THE NODAL STAGING FOR ESCC
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[32, 33]. Therefore it is crucial to estimate the clinical nodal stage for patients with ESCC. However, it remains difficult to clinically determine the precise number of metastatic LNs based on the currently available diagnostic systems [34]. According to our revised nodal staging system based on the number of metastatic LN stations, it is relatively easy to estimate the clinical nodal stage. Our study has some limitations. First, this is a single-center retrospective study, and our findings need to be validated with another data set. Second, some of the patients were lost to follow-up, which may result in a bias of our results. This limitation partly
Fig 3. (A) Overall survival by the nodal category of seventh American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system (N0 versus N1, N2, N3: p < 0.001; N1 versus N2: p ¼ 0.003; N1 versus N3: p ¼ 0.001; N2 versus N3: p ¼ 0.103). (B) Overall survival by revised nodal categories based on number of metastatic lymph node stations (rN0 versus rN1, rN2, rN3: p < 0.001; rN1 versus rN2: p ¼ 0.001; rN1 versus rN3: p < 0.001; rN2 versus rN3: p ¼ 0.001). (C) Overall survival by original seventh AJCC TNM staging system (overall log rank: p < 0.001; stage IIIA versus stage IIIB, p ¼ 0.021; stage IIIA versus stage IIIC, p < 0.001; stage IIIB versus stage IIIC, p ¼ 0.118). (D) Overall survival by the modified TNM staging system (overall log rank: p < 0.001; stage IIIA versus stage IIIB, p ¼ 0.040; stage IIIA versus stage IIIC, p < 0.001; stage IIIB versus stage IIIC, p ¼ 0.007).
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Table 3. Overall Survival According to the Seventh AJCC TNM Staging System and the Modified Staging System Classification
References
No. of Median 5-Year p Patients (%) Survival (mo) Survival (%) Value
Seventh AJCC TNMa Stage 0 þ Ia 52 Stage IB 107 Stage IIA 149 Stage IIB 391 Stage IIIA 324 Stage IIIB 160 Stage IIIC 168 Modified-TNMb Stage 0 þ Ia 52 Stage IB 107 Stage IIA 149 Stage IIB 386 Stage IIIA 291 Stage IIIB 206 Stage IIIC 160
Not reached Not reached Not reached 74.43 28.20 21.67 17.60
95.8 71.2 62.5 52.5 25.7 14.3 6.2
<0.001
Not reached Not reached Not reached 74.43 28.20 21.97 16.03
95.8 71.2 62.5 53.8 24.4 17.1 4.1
<0.001
a Stage IIIA versus IIIB, p ¼ 0.021; stage IIIA versus IIIC, p < 0.001; stage b IIIB versus IIIC, p ¼ 0.118. stage IIIA versus IIIB, p ¼ 0.040; stage IIIA versus IIIC, p < 0.001; stage IIIB versus IIIC, p ¼ 0.007.
AJCC ¼ American Joint Committee on Cancer; metastasis.
TNM ¼ tumor, node,
results from the retrospective nature of this study. Third, the number in some subgroups was small; therefore we could not give a more precise analysis for some subgroups. In conclusion, we suggest that the nodal categories for ESCC be based on the number of metastatic LN stations and be classified into the following 4 groups: N0 (no LN involvement), N1 (1 station involved), N2 (2–3 stations involved), and N3 ( 4 stations involved). However, more data from Chinese centers are essential to confirm our results.
Table 4. Changes in Homogeneity, Discriminatory Ability, and Monotonicity of Gradient Between the Seventh AJCC TNM Staging System and the Modified Staging System Homogeneity
Classification
Cox Likelihood Ratio c2
Seventh AJCC TNM staging system Modified TNM staging system a
Higher score ¼ better.
Discriminatory Ability Linear Monotonicity Trend Harrell’s 2 c AIC c-Statistic
170.33
139.122
178.26a
142.937a 0 .6691a
b
0.6652
6608.18 6600.249b
Lower score ¼ better.
AIC ¼ Akaike information criterion; AJCC ¼ American Joint Committee on Cancer; TNM ¼ tumor, node, metastasis.
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