Pathologic Lymph Node Ratio Is a Predictor of Survival in Esophageal Cancer

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1 ORIGINAL ARTICLES: SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. Pathologic Lymph Node Ratio Is a Predictor of Survival in Esophageal Cancer Castigliano M. Bhamidipati, DO, MS, George J. Stukenborg, PhD, Christopher J. Thomas, MPA, Christine L. Lau, MD, Benjamin D. Kozower, MD, MPH, and David R. Jones, MD Division of Thoracic and Cardiovascular Surgery, Department of Surgery, and Division of Patient Outcomes, Policy and Population Research, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia Background. A ratio between pathologic and examined lymph nodes may have predictive relevance in esophageal cancer. We sought to determine the prognostic value of lymph node ratio (LNR) compared with TNM and N stage using the seventh edition American Joint Commission on Cancer and International Union Against Cancer criteria. Methods. We abstracted data from 347 consecutive patients undergoing esophagectomy for esophageal cancer between 1999 and 2010 at our institution. Patients were stratified into surgery alone or induction therapy followed by surgery. Kaplan-Meier and Cox proportional hazard models estimated the survival function using LNR as a continuous variable or categorized into 0, more than 0.0 to less than 0.1, 0.1 to less than 0.2, 0.2 to less than 0.3, and 0.3 or greater. The influence of LNR on survival was assessed by the Wald 2 statistic and survival plots. Results. A total of 173 patients (49.9%) underwent induction therapy. The pathologic complete response rate was 55 of 173 (32%). The median number of examined nodes in surgery alone was 14 (interquartile range, 8 to 21), and induction was 12 (interquartile range, 7 to 17). Patients with nodal disease (n 137) had a median LNR of 0.2 with equivalent survival regardless of induction therapy. Examination of LNR as a continuous variable demonstrated that LNR is an independent predictor of survival in both groups. After categorization, LNR contributed more toward estimating survival than pn stage in both groups. Conclusions. Lymph node ratio is an independent predictor of survival in patients undergoing esophagectomy for esophageal cancer. The LNR makes a greater contribution in estimating overall survival than pn stage, regardless of the utilization of induction therapy. (Ann Thorac Surg 2012;94: ) 2012 by The Society of Thoracic Surgeons Esophageal cancer is the seventh leading cause of cancer mortality worldwide [1]. In the United States, an estimated 14,500 deaths are anticipated this year from the disease based on data provided by the National Center for Health Statistics [2]. In 2009, the American Joint Commission on Cancer (AJCC) and International Union Against Cancer (UICC) performed a significant revision of the TNM staging system for esophageal cancer [3]. Among the most notable changes were an appreciation for tumor histologies as distinct pathologic entities, and as such, staging criteria reflect these differences [3, 4]. Thus, the current system provides a better separation of adenocarcinoma and squamous cell cancer Accepted for publication March 21, Presented at the Fifty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9 12, Address correspondence to Dr Jones, Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia School of Medicine, PO Box , Charlottesville, VA ; djones@ virginia.edu. (SCC) histologies at initial diagnosis, but is based on pathologic TNM data from patients who did not undergo induction therapy [3, 4]. A second important modification of the new staging system is the acknowledgment of the importance of nodal disease and tumor differentiation. Specifically, the seventh edition of the AJCC/UICC staging system for esophageal cancer now stratifies nodal disease into N1, N2, and N3 subcategories based on the number of regional histologically positive nodes. Prior iterations of the staging system only permitted binary classification of nodal disease (ie, present or absent). Interestingly, for patients who have undergone induction therapy before surgery, the reliability, accuracy, and prognostic potential of the nodal burden using the new nodal staging toward independently estimating survival are unknown. The importance of removing or sampling an adequate number of lymph nodes (LN) in esophageal cancer for survival and for accurate staging has been the focus of several studies [5 9]. In an analysis of the recent World by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc

2 1644 BHAMIDIPATI ET AL Ann Thorac Surg LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 2012;94: wide Esophageal Cancer Collaboration, Rice and colleagues [3] reported that as the number of positive nodes increases, survival decreases, although there is a dependence on T stage. This interplay of T stage and node positivity was the basis for the subclassification of stages II and III in the new seventh edition of the staging system. Insufficient LN retrieval could potentially result in inadequate staging, whereas improving staging accuracy may occur with increased nodal examination [5, 6, 10]. As such, accurate cancer staging, particularly nodal staging, is not only the basis for recommending initial treatment strategies, but is important for prognosis as well. There is an increasing appreciation that the number of histologically positive lymph nodes removed compared with the total number of lymph nodes resected may have clinical relevance [11 18]. This lymph node ratio (LNR) has been shown to independently predict survival among resected gastric cancer patients [12]. Similar reports, using the new TNM classification, for both colon and advanced stage rectal cancer patients found that LNR was more predictive of disease-free survival than the commonly accepted pathologic characteristics [19 21]. The potential relevance of LNR to overall survival of esophageal cancer patients undergoing resection with or without induction therapy has not been well studied. In addition, the utility of LNR in predicting survival after the adoption of the new seventh edition AJCC/UICC TNM staging system is unknown. Finally, it is also unknown whether the LNR may have an improved ability to predict survival compared with the absolute number of positive nodes as stratified by the new staging criteria. The purpose of this study was to determine the utility of LNR to independently predict survival in patients with esophageal cancer who were undergoing surgery with or without induction therapy, using the current seventh edition AJCC/UICC TNM staging system. Patients and Methods Patients and Analysis Groups A retrospective analysis of a prospectively maintained General Thoracic Surgery Database at the University of Virginia (UVA-GTSD) from 1999 through 2010 was performed. The UVA-GTSD is maintained by the division of thoracic and cardiovascular surgery and includes all data fields contained within The Society of Thoracic Surgery (STS) General Thoracic Surgery Database in addition to other important clinicopathologic variables. Institutionalspecific data were also obtained from the UVA Health System Clinical Data Repository (CDR). The CDR is maintained by the division of clinical informatics, department of public health sciences, and contains patient level information that is managed through the UVA Health System. The CDR collects data and links the UVA-GTSD related information at our institution based on variables defined by the STS national database. Cases where data were missing completely at random were not excluded Table 1. Patient and Tumor Characteristics Stratified by Treatment Cohort Patient and Tumor Characteristics Surgery (n 174) Induction (n 173) p Value Age 67 (11) 59 (9) Male/female 149/25 141/ Surgical approach Thoracotomy 149 (86) 172 (99) Nonthoracotomy 23 (13) 1 (1) Other 2 (1)... Comorbidity present 126 (72) 132 (76) 0.41 EUS FNA 151 (87) 155 (90) 0.58 Tumor histology 0.98 Adenocarcinoma 148 (85) 147 (85) Squamous cell 26 (15) 26 (15) carcinoma Histologic grade Pathologic complete (32) response Well differentiated, G1 25 (14) 15 (9) Moderately 68 (39) 37 (21) differentiated, G2 Poorly differentiated, G3 81 (47) 66 (38) Pathologic tumor stage Tis... 2 (1) 1 69 (40) 20 (12) 2 50 (29) 27 (16) 3 53 (31) 68 (39) 4 2 (1) 2 (1) Pathologic N stage N0 105 (60) 108 (62) N1 33 (19) 44 (25) N2 16 (9) 15 (9) N3 20 (12) 6 (4) Pathologic M stage 0.99 M0 172 (99) 171 (99) M1 2 (1) 2 (1) Pathologic TNM stage a IA 40 (23) 12 (7) IB 29 (17) 7 (4) IIA 9 (5) 9 (5) IIB 41 (24) 44 (25) IIIA 22 (13) 30 (17) IIIB 12 (7) 9 (5) IIIC 19 (11) 5 (3) IV 2 (1) 2 (1) Deceased 65 (37) 71 (41) 0.48 Death due to EC 33 (51) 46 (65) 0.10 Positive margin 12 (7) 12 (7) 0.99 Lymph nodes examined 15 (9) 13 (9) 0.04 a Based on the American Joint Commission on Cancer/International Union Against Cancer, seventh edition, staging system for esophageal cancer. Data shown as n (%) or mean (SD) as appropriate. EC esophageal cancer; EUS esophageal ultrasonography; FNA fine-needle aspiration.

3 Ann Thorac Surg BHAMIDIPATI ET AL 2012;94: LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 1645 from analysis; however, variables with large missing data ( 10%) underwent case-wise deletion. The Human Investigations Committee at UVA approved this study (HSR 16010). We abstracted data from 347 patients who underwent elective esophagectomy for adenocarcinoma or SCC. Thoracic surgeons certified by the American Board of Thoracic Surgery performed all operations. A dedicated group of surgical pathologists reviewed all esophageal cancer specimens using a protocol previously agreed upon by the surgeons. In general, for all transthoracic approaches, an en bloc esophagectomy was performed with all celiac, hepatic, and mediastinal nodes included in one specimen. Pathology reports were restaged using the seventh edition AJCC/UICC TNM criteria. Postoperatively. patients were followed at 3 weeks by the thoracic surgeon, and then again at 3 to 4 weeks after surgery to remove the jejunostomy feeding tube once soft diet was tolerated. Subsequent to this visit, patients were followed semiannually for 2 years and then annually thereafter by contrast-enhanced computed tomography. All visits were completed in concert with the referring oncologist. The total number of LN and the number of positive LN sampled were determined, and LNR was subsequently computed. Patients were stratified into two treatment cohorts: surgery alone or induction therapy followed by surgery. Two independent investigators (C.M.B. and C.J.T.) abstracted data from clinical records to enrich internal validity and consistency. Statistical Analysis The study population of 347 esophageal cancer patients who received either radiation followed by surgery or surgery only were determined by propensity score analysis to control for potential allocation to treatment bias in the comparison of survival outcomes by type of treatment. Multivariable logistic regression analysis was used to estimate the probability that a patient would receive surgery with or without neoadjuvant therapy. The multivariable logistic regression model included 9 covariates identified a priori as indicators of therapy choice by the surgeons making these decisions in practice. The covariates included Zubrod score, clinical stage, congestive heart failure, coronary artery disease, cardiovascular disease, pulmonary disease, home oxygen use, creatinine, and patient age. Zubrod scores and clinical stage values were grouped to facilitate the matching process. Measuring the proportion of variability explained, and the accuracy of the discrimination between patients by type of treatment received assessed the adequacy of the prediction equation. Each patient who received surgery only was matched to a patient who received neoadjuvant treatment with the closest estimated probability of allocation to surgery only. The adequacy of the matching process was assessed by evaluating the balance achieved between groups for each covariate included in the prediction equation. The primary outcome of interest was to examine the predictive ability of LNR on overall survival. The statistical significance of differences in proportions for categorical variables was evaluated by the Pearson 2 or Fisher s exact test where appropriate (p 0.05). The statistical significance of differences in mean values for continuous variables was assessed using single factor analysis of variance or general linear models (p 0.05). The distribution of LNs sampled and the subsequent LN positivity among the surgery alone and induction therapy groups were examined by histograms. Based on the continuous variable, LNR was categorized by deciles into 0, more than 0.0 to less than 0.1, 0.1 to less than 0.2, 0.2 to less than 0.3, and 0.3 or greater. We developed the LNR intervals based on our data to pro- Fig 1. Histograms of the sampled and positive lymph nodes among surgery and induction cohorts. (A) Sampled lymph nodes among surgery cohort; (B) Positive lymph nodes among surgery cohort; (C) Sampled lymph nodes among induction cohort; (D) Positive lymph nodes among induction cohort.

4 1646 BHAMIDIPATI ET AL Ann Thorac Surg LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 2012;94: Table 2. Lymph Node Ratio Correlates With Pathologic Nodal Stage Pathologic N Stage a Surgery Induction N N N N a p less than Data shown as mean SD. vide clinically relevant LNR strata while probing to identify the subset of LNR with the greatest predictive potential. Categorization of continuous data assumes that the relationship between the predictor and the response is flat within intervals, which is less reasonable than the usual linearity assumption. The need for dummy variables and multiple intervals leads to less power and imprecision. Nevertheless, as categorization is putatively more clinically useful, we examined LNR as both variable types. Kaplan-Meier plots were developed to represent the unadjusted relationship between the probability of survival and years of follow-up for patients by categorized LNR. The log rank test examined association with the probability of survival. Separate Cox proportional hazard models estimated the survival function in surgery and induction groups. Pathologic covariates such as T, N, and M stage, tumor type, surgical procedure, and number of positive LN resected were selected a priori based on the established literature. The relationship between survival and LNR were assessed by calculating the relative hazard ratios as a function of death after adjustment of these pathologic covariates. While there was no specific threshold for the number of LN removed during an operation to be included in our analysis, the effect of LNR on the relative hazard of death was estimated with reference to LNR being 0.0 (ie, no positive LN were sampled). The relative contribution in estimating the survival hazard made by each covariate was assessed using the Wald 2 test statistic minus the predictor s degrees of freedom. Survival plots derived from the Cox proportional hazard models among node-positive patients estimating the 5-year probability of survival by LNR stratum were computed. Data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC) and SPSS 20 (IBM, Chicago, IL). Results Patient and Tumor Characteristics We analyzed a composite of 347 patients, of which 174 patients underwent surgery alone and 173 patients received induction therapy before surgery (Table 1). Of patients receiving induction therapy, the overwhelming majority had chemoradiotherapy. There were 44 patients in the surgery alone group (25%), and 23 patients in the induction therapy group (13%) who received adjuvant therapy. These patients were not excluded from analyses to enable a comprehensive examination of the objective of this study. Pretreatment esophageal ultrasonography with or without fine-needle aspiration was used in the staging of esophageal cancer in 87% to 90% of patients. Adenocarcinoma was the most common tumor histology (85%). An Ivor-Lewis approach for esophagectomy was the preferred procedure for recipients in both cohorts. Most patients had poorly differentiated tumors in both groups, although there were more G1 or welldifferentiated tumors in the surgery only group. The R1 resection rate for patients in both groups was 7%. This compares favorably with the R1 resection rate of 11% reported for 4,627 patients by the Worldwide Esophageal Cancer Collaboration [3]. The average number of examined nodes was 15 9in surgery alone patients, and 13 9 in patients receiving induction therapy (Fig 1). For patients undergoing an Ivor-Lewis resection (299 of 347, 86%), the average number of nodes resected was This correlates nicely with the median number of 15 nodes resected using this approach in 396 patients in the multinational study by Peyre and colleagues [22]. Table 3. Cox Proportional Hazard Regression Models Estimating Survival Function Surgery Induction Proportional Hazard Models df 2 p Value 2 p Value Model 1 Number lymph nodes positive Pathologic tumor stage Pathologic N stage Lymph node ratio (continuous) Model 2 Number lymph nodes positive Pathologic tumor stage Pathologic N stage Lymph node ratio (category) df degrees of freedom; 2 Wald chi-square statistic.

5 Ann Thorac Surg BHAMIDIPATI ET AL 2012;94: LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 1647 We next created a general linear model to ascertain whether the LNR correlated with the pathologic nodal stage (pn stage). The mean LNR in the surgery alone group (0.13) and induction group (0.11) was similar. Differences in mean LNR stratified by the pn stage were highly statistically different in both the surgery and the induction groups (Table 2). These data support the conventional understanding of nodal staging and disease burden where linear increases in mean LNR correlated agreeably with an increase in pn stage. Lymph Node Ratio Predicts Survival in Both Surgery and Induction Groups The multivariable logistic regression model developed to predict allocation to treatment achieved an adequate level of statistical performance. The model accounted for 56% of the overall variation in treatment category. The model also adequately discriminated between patients in different treatment categories, correctly identifying 88% of the patients allocated to surgery only. Clinical stage groups and patient age were the two most important predictors of treatment. Balance in the matched population was achieved for clinical stage group and age, but not for other covariates included in the prediction equation. After adjustment of the known pathologic characteristics of esophageal cancer, LNR measured continuously was an independent predictor of survival in both the surgery group (p 0.001) and the induction group (p 0.004). The number of positive LN was not independently associated with survival in either group. Categorized LNR did not independently influence survival in the surgery cohort (p 0.41) or induction therapy cohort (p 0.16). Importantly, LNR measured continuously made a greater contribution in estimating overall survival than pn stage or the absolute number of positive LN in both cohorts (Table 3). Additionally, when LNR was categorized into deciles, the relative contribution toward estimating survival was greater than the number of positive LN in both cohorts. To further examine the contribution of LNR to survival, Kaplan-Meier curves were generated to demonstrate the survival probability by categorized LNR in both groups (Fig 2). Descriptively, these plots suggest that categorized LNR has an inverse relationship with the probability of survival in the surgery only and the induction groups. Empirically, we also show that as LNR increased, the probability of survival decreased in both treatment strategies. Lymph Node Ratio Influences Relative Hazard of Death To identify a clinically usable stratum of LNR, and to examine the qualitative association between increasing LNR and the survival hazard, Cox proportional hazard ratios were calculated. Increasing LNR strata among surgery only recipients increased the relative hazard of death (Table 4). Similarly, incremental increases in the estimated hazard of death as LNR strata increased were also noted among induction patients. Our data Fig 2. Kaplan-Meier curves estimating the probability of survival by treatment group: (A) surgery; (B) induction. (CI confidence interval; LNR lymph node ratio.) suggest that, in both the surgery only cohort and induction cohort, there is a threefold change in the survival hazard ratio of death when LNR is 0.3 or greater in comparison with a LNR that is between more than 0.0 and less than 0.1. As would be expected, a complete pathologic response after induction therapy significantly reduced the risk of death (hazard ratio 0.08, 95% confidence interval: 0.08 to 0.13). Cox proportional hazard model derived survival plots for node-positive patients were examined by LNR interval, and these data suggested a clear separation in the probability of survival over time (Fig 3). Among

6 1648 BHAMIDIPATI ET AL Ann Thorac Surg LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 2012;94: Table 4. Relative Adjusted Hazard Ratios of Survival by Categorized Lymph Node Ratio Surgery Induction Covariate n HR (95% CI) n HR (95% CI) Pathologic tumor stage 1 69 Reference 20 Reference ( ) ( ) ( ) ( ) ( ) ( ) PCR ( ) Pathologic N stage N0 104 Reference 108 Reference N ( ) ( ) N ( ) ( ) N ( ) ( ) Lymph node ratio (category) Reference 97 Reference 0.0 to ( ) ( ) 0.1 to ( ) ( ) 0.2 to ( ) ( ) ( ) ( ) CI confidence interval; HR hazard ratio; PCR pathologic complete response. surgery patients, the probability of survival at 5 years reduced by more than 20% when LNR was 0.2 or greater (p 0.001). In the induction cohort, the probability of 5-year survival reduced precipitously with relative increases in LNR intervals (p 0.001). Collectively, these data show that LNR significantly influences the relative hazard of death. Comment The current study demonstrates that LNR is an independent predictor of survival in patients undergoing surgery for esophageal cancer with or without induction therapy. Furthermore, using the new seventh edition of the AJCC/ UICC staging criteria, pn stage was not an independent predictor of survival in either the surgery only or induction therapy groups. In addition, the absolute number of histologically positive LN was not an independent predictor of survival in either cohort. Finally, the relative contribution of LNR to predicting overall survival was greater than pn stage among patients undergoing treatment for esophageal cancer. In support of our findings regarding the correlation of LNR to survival, Hsu and coworkers [6] published their series of 488 patients and confirmed that metastatic LNR more than 0.2 independently increased survival hazard (hazard ratio 2.2, 95% confidence interval: 1.7 to 2.9) [6] In contrast to our study, the Hsu study had 94% SCC histology, excluded all patients receiving induction therapy, and used the sixth edition AJCC/UICC staging criteria [6]. Using the sixth edition AJCC/UICC staging criteria, Mariette and colleagues [23] showed that among patients who underwent esophagectomy, when LNR was more than 0.2, survival was 22%. After covariate adjustments, the number of LN metastases more than 4 and LNR more than 0.2 were the only predictors of poor prognosis. Interestingly, ptnm stage, an established predictor, was not independently indicative of survival (adjusted odds ratio 1.0, 95% confidence interval: 0.9 to 1.1) [23]. Finally, in a small cohort of 266 patients, Tachibana and associates [24] described 2-year and 5-year survival of patients with metastatic LNR of 0.1 or greater to be 15% and 5%, respectively. These researchers included only SCC histology, had no induction therapy patients, and used the fifth edition AJCC/UICC staging criteria. Similar to those reports, we also found that among our surgery only patients when node-positive disease was present, a threshold LNR of 0.2 or greater significantly lowered probability of survival (Fig 2). Our study also demonstrates that increasing LNR independently increases the survival hazard for both groups. In addition, the number of LN examined in the current study was similar across groups, and patients with nodepositive disease (n 137) with a median LNR of 0.2 had equivalent survival regardless of induction therapy. In addition to the number of histologically positive nodes removed, there is evidence that a more complete lymphadenectomy may offer a survival advantage [25].In a multivariable analysis of 2,303 highly selected patients (no induction or adjuvant therapy and no celiac nodal disease), the overall number of LN resected was an independent predictor of survival. Cox regression modeling in that study suggested a threshold of 23 to 29 nodes resected provided the best predictive outcome [25]. We examined the number of nodes resected as a continuous variable and found no predictive value in the surgery only or induction therapy groups. This difference of our study from that study may be related to patient selection,

7 Ann Thorac Surg BHAMIDIPATI ET AL 2012;94: LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 1649 Fig 3. Survival plots by lymph node ratio groups in both treatments: (A) surgery; (B) induction. the smaller sample size of our study, or more likely the high number of en bloc esophagectomies (37%) where the median number of LN removed was 30, and 66% of these patients had 23 or more nodes removed [25]. Furthermore, in that study, only 22% of patients had 23 or more nodes removed during an Ivor-Lewis esophagectomy, comparable to our 17% of patients having 23 or more nodes removed for the same procedure. In contrast to the important work by Rice and colleagues [3], who eloquently showed that the number of cancer positive LN was an independent predictor of survival in esophageal cancer surgery recipients, our data were unable to reach a similar conclusion. This discrepancy likely has several explanations. Foremost, the Rice study [3] examined more than 4,600 patients who underwent surgery alone for esophageal cancer, compared with our surgical cohort of 174 patients. Thus, it is possible that our study is underpowered, and as such failed to make a similar observation as the Rice study. In addition, their work examined patients who underwent surgery for adenocarcinoma, SCC, and undifferentiated cancer of the esophagus or esophagogastric junction [3], whereas we analyzed patients with adenocarcinoma or SCC only. Finally, while the Rice analysis [3] included regional positive LN metastases in their calculations, our work did not stratify the number of cancer positive LN by region. Limitations of our study include the retrospective analysis that has an inherent selection bias. Although the UVA-GTSD is carefully populated and screened for errors, the potential for miscoding is possible. Another potential limitation is that given regional referral patterns, the specific chemoradiotherapy regimens for all patients are not standardized. In addition, the potential of an unmeasured confounder may remain, which is inherent to the constraints of the UVA-GTSD database. We incorporated an undefined category into the LNR groups in our analyses to marginalize these effects. Finally, the effect of LNR on survival for patients with SCC cannot be accurately assessed, given that 85% of patients in our series had adenocarcinoma histology. Similarly, as the majority of our patients had an Ivor-Lewis esophagectomy, our findings may not be applicable to other resection strategies such as en bloc resection with threefield lymphadenectomy where more lymph nodes are removed [22]. Lastly, the independent contributions of the numerator and the denominator toward the computation of LNR may impact the interpretation of these data. That is to say, although there is no minimum number of nodes necessary to make a LNR accurate, adequate sampling is crucial in determining the LNR computation. To this end, we provide histograms used to examine the distribution and potential skew in these data, which suggest no obvious bias. In summary, the current study demonstrates that LNR is an independent predictor of survival in esophagectomy recipients regardless of whether the patient has surgery alone or induction therapy. Moreover, we found that LNR is more informative toward predicting survival than node positivity alone. We also found that neither the absolute number of positive LN nor the nodal staging criteria of the seventh edition AJCC/UICC TNM criteria were independent predictors of survival. Further studies, likely multiinstitutional, are needed to examine the utility of LNR as a predictor of survival for patients undergoing surgery for esophageal cancer. References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61: Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin 2010;60: Rice TW, Rusch VW, Ishwaran H, Blackstone EH. Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer cancer staging manuals. Cancer 2010;116: Rice TW, Blackstone EH, Rusch VW. A cancer staging primer: esophagus and esophagogastric junction. J Thorac Cardiovasc Surg 2010;139: Kelty CJ, Kennedy CW, Falk GL. Ratio of metastatic lymph nodes to total number of nodes resected is prognostic for survival in esophageal carcinoma. J Thorac Oncol 2010;5:

8 1650 BHAMIDIPATI ET AL Ann Thorac Surg LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 2012;94: Hsu WH, Hsu PK, Hsieh CC, Huang CS, Wu YC. The metastatic lymph node number and ratio are independent prognostic factors in esophageal cancer. J Gastrointest Surg 2009;13: Kayani B, Zacharakis E, Ahmed K, Hanna GB. Lymph node metastases and prognosis in oesophageal carcinoma a systematic review. Eur J Surg Oncol 2011;37: Saha S, Dehn TC. Ratio of invaded to removed lymph nodes as a prognostic factor in adenocarcinoma of the distal esophagus and esophagogastric junction. Dis Esophagus 2001;14: Roder JD, Busch R, Stein HJ, Fink U, Siewert JR. Ratio of invaded to removed lymph nodes as a predictor of survival in squamous cell carcinoma of the oesophagus. Br J Surg 1994;81: Fujita H, Kakegawa T, Yamana H, et al. Mortality and morbidity rates, postoperative course, quality of life, and prognosis after extended radical lymphadenectomy for esophageal cancer. 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Esophageal cancer with distant lymph node metastasis: prognostic significance of metastatic lymph node ratio. J Clin Gastroenterol 2000;31: Peyre CG, Hagen JA, DeMeester SR, et al. Predicting systemic disease in patients with esophageal cancer after esophagectomy: a multinational study on the significance of the number of involved lymph nodes. Ann Surg 2008;248: DISCUSSION DR ARJUN PENNATHUR (Pittsburgh, PA): That is a great presentation. I have a couple of questions. The new staging system takes into account the number of positive nodes and you say that the new staging system showed a significant difference survival in your study. On the other hand, you also said the number of positive nodes did not make a difference in survival in your cohort. In the new staging system, the N status is classified N1, N2 and N3 based on the number of positive nodes, but you state that the number of involved nodes do not make a difference in survival. Can you clarify? The second question has to do with the positive lymph node ratio. From your presentation, it seemed like lymph node ratio ranged from 0 to somewhere around a ratio of 0.1 to 3. So why was the lymph node ratio 0? Was not a single lymph node resected in these cases? DR BHAMIDIPATI: I will answer the second question first and then maybe it will address the first part. When we looked at the mean lymph node ratio, as I showed in the data, among surgical patients, the lymph node ratio average was about 15 while in the induction patients it was 13. When we looked at the median number of resected lymph nodes across the entire series from 1999 to 2010, in our surgical group, 14 nodes were resected, and in the induction group, 13 or so were resected; and there were several cases where resections were in the low to mid-40 range. DR PENNATHUR: That s fine, I understand that, but what is the range of the lymph node count in the resected specimen? How can the ratio of positive lymph nodes to total lymph nodes examined among node positive patients be 0 unless you have 0 nodes resected and 0 nodes examined? DR BHAMIDIPATI: So if there are 0 positive lymph nodes, then the numerator is 0, and so that computation had to be basically called 0. DR PENNATHUR: So this is just not an analysis of node positive (N1) patients. So in your analysis, you also included the N0 patients when you look at the ratios? Is this correct? DR BHAMIDIPATI: Yes, it includes our whole consecutive experience.

9 Ann Thorac Surg BHAMIDIPATI ET AL 2012;94: LNR PREDICTS ESOPHAGEAL CANCER SURVIVAL 1651 DR PENNATHUR: And in your analysis, the number of positive nodes did not make a difference in your cohort? DR BHAMIDIPATI: Not in our surgery or induction groups. The number of positive lymph nodes did not independently predict survival. We were a little surprised at that too. DR PENNATHUR: Perhaps this is related to number of nodes removed, So in your cohort, it appears that the pathologic N staging by the new staging system did not make any difference? DR BHAMIDIPATI: Not according to our series and the way our current analyses was conducted, but this will require further review. DR JOSHUA ROBERT SONETT (New York, NY): So how do you explain that compared with the huge database that created the AJCC staging? DR BHAMIDIPATI: Well, at our institution, I can speak for the operations being performed by board-certified thoracic surgeons who have done this operation across the entire series, and the staging done by pathologists, and is performed in agreement with the surgeons. I understand that our work in comparison to the more than 4,500 patients who were analyzed in the study that eventually led to the new AJCC staging criteria has discrepancies. DR PENNATHUR: This is an excellent group of thoracic surgeons, by the way, and the question here is with regard to the analysis. In terms of analysis, perhaps you should look a little more carefully before you say that the lymph node ratio makes a difference; but the number of positive lymph nodes did not make a difference. Perhaps this is related to the number of lymph nodes removed and examined. This is something you can reanalyze carefully. DR BHAMIDIPATI: Thank you for that suggestion. Yes, we will certainly go back and look at that in future work. DR SETH D. FORCE (Atlanta, GA): That was a great talk. The impression I have from that last question is that, as we talked about before, when I look at the data you presented, they showed that number of lymph nodes did not predict what the ratio was. To me that means that the number of lymph nodes removed is probably important, right? Again, if you remove 1 node and it is positive, then the ratio is important, but if you remove 20, it may have been that only 2 out of 20 were positive. So did you go back and look to see if your analysis holds true only if a certain number of lymph nodes were removed? Did you find that you had to remove a certain number of lymph nodes for your analysis to be true? DR BHAMIDIPATI: Thank you for your comments. Yes, we can look at that. We haven t done the analyses in that specific way. But that is a great suggestion and we can go back and do that, it is certainly possible. DR DANIEL L. MILLER (Atlanta, GA): The question I have is, let s say you remove a total of 10 lymph nodes. You have 3 nodes that are positive and they re all next to the left gastric artery. Then in a different scenario, you also have a total of 3 lymph nodes positive but 1 is at the left gastric artery, 1 paraesophageal, and 1 subcarinal. There should be a survival difference above and below the diaphragm if there are multiple nodes? You need to go back and look at that and see where the positive lymph nodes were located. The ratio would be the same in each patient, but I am sure the survival would be worst in the patient with lymph nodes positive in multiple stations. DR BHAMIDIPATI: That s a great comment and thank you for mentioning that. In the current methodology including the way our data are captured, we don t have anatomic or regional nodal basin information, but that is easily determined by going back and looking at the actual pathology report and then trying to sort out where the regional differentiation occurred. That could be done, and probably would add more value to our work in the future. DR MILLER: Definitely. DR BHAMIDIPATI: Sure, yes, thank you again.