- Email: [email protected]
Extent of Lymphadenectomy Is Associated With Improved Overall Survival After Esophagectomy With or Without Induction Therapy
Extent of Lymphadenectomy Is Associated With Improved Overall Survival After Esophagectomy With or Without Induction Therapy Pamela Samson, MD, MPHS, Varun Puri, MD, MSci, Stephen Broderick, MD, G. Alexander Patterson, MD, Bryan Meyers, MD, MPH, and Traves Crabtree, MD Division of Cardiothoracic Surgery, Washington University in St. Louis, St. Louis, Missouri; St. Luke’s Hospital, Division of Cardiothoracic Surgery, Chesterfield, Missouri; and Division of Cardiothoracic Surgery, Southern Illinois University College of Medicine, Springfield, Illinois
Background. National Comprehensive Cancer Network (NCCN) guidelines recommend sampling 15 or more lymph nodes during esophagectomy. The proportion of patients meeting this guideline is unknown, as is its influence on overall survival (OS). Methods. Univariate analysis and logistic regression were performed to identify variables associated with sampling 15 or more lymph nodes among patients undergoing esophagectomy in the National Cancer Data Base (NCDB). The NCCN guideline was evaluated in Cox proportional hazards modeling, along with alternative lymph node thresholds. Positive to examined node (PEN) ratios were calculated, and OS was compared using Kaplan-Meier analysis. Results. From 2006 to 2012, only 6,961 of 18,777 (37.1%) patients undergoing esophagectomy had sampling of 15 or more lymph nodes. Variables associated with sampling 15 or more lymph nodes included income greater than or equal to $38,000, procedure performed in an academic facility, and increasing clinical T and N stages. Induction therapy was associated with a decreased likelihood of 15 or more lymph nodes being sampled. The
largest decrease in mortality hazard in patients undergoing upfront esophagectomy was detected when 25 lymph nodes or more were sampled (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.67–0.89; p < 0.001), whereas for patients undergoing induction therapy, sampling of 10 or 15 or more lymph nodes was associated with optimal survival benefit (HR, 0.81; 95% CI, 0.74–0.90; p < 0.001). PEN ratios of 0 to 0.10 were associated with maximum survival benefit among all patients undergoing esophagectomy. For patients with a PEN ratio of 0, increases in OS were detected with higher lymph node sampling (85.3 months for sampling of 20 or more lymph nodes versus 52.0 months for sampling 1–9 lymph nodes; p < 0.001). Conclusions. For patients undergoing upfront esophagectomy, there may be an increased survival benefit for examining 20 to 25 lymph nodes, which is higher than current recommendations. However, only a minority of patients are meeting current guidelines.
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(NCCN) recommends that patients receiving upfront esophagectomy (operative treatment before systemic therapy or radiation therapy) have at least 15 lymph nodes sampled [6]. The guidelines further state that although the ideal number of lymph nodes sampled after induction therapy is currently unknown, a similar extent of sampling is recommended [6]. Using the National Cancer Data Base (NCDB), our goal was to evaluate perioperative characteristics and long-term survival outcomes of patients who underwent sampling of 15 or more lymph nodes. We hypothesized that the optimal number of lymph nodes obtained may be different for patients undergoing upfront esophagectomy and patients receiving induction therapy, and we used cut-point analysis to investigate the relationship between lymph node number and overall survival (OS) in both patient populations. Finally, we investigated the influence of the positive to examined
or the approximately 17,000 individuals diagnosed with esophageal cancer per year, surgical resection, with multimodality therapy for locally advanced cases, offers the best chance of long-term survival [1]. However, both institutional and national databases have documented that clinical N0 status rarely correlates with pathologic staging in patients undergoing upfront esophagectomy, even with the use of preoperative endoscopic ultrasonography and positron emission tomography [2–5]. Currently, the National Comprehensive Cancer Network Accepted for publication Aug 5, 2016. Presented at the Fifty-second Annual Meeting of The Society of Thoracic Surgeons, Phoenix, AZ, Jan 23–27, 2016. Address correspondence to Dr Crabtree, Division of Cardiothoracic Surgery, Southern Illinois University College of Medicine, 701 N First St, Rm D252, PO Box 19679, Springfield, IL 62794-9679; email: tcrabtree53@ siumed.edu.
Ó 2016 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2016;-:-–-) Ó 2016 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2016.08.010
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node (PEN) ratio on OS for all patients undergoing esophagectomy.
Patients and Methods The NCDB Participant User File (PUF) for esophageal cancer was reviewed to identify patients undergoing esophagectomy from 2006 to 2012. The NCDB is a joint program of the American College of Surgeons Commission on Cancer and the American Cancer Society and records approximately 70% of malignancies in the United States [7]. The PUF reports deidentified patient and treatment center information and was deemed exempt from institutional review board review. Patient, tumor, and treatment variable definitions are detailed on the NCDB PUF data dictionary website (http://ncdbpuf.facs. org/node/259). Patients undergoing esophagectomy were categorized as receiving either upfront esophagectomy or induction therapy followed by esophagectomy. Exclusion criteria for this analysis included clinical M1 disease and patients with a tumor size recorded as 30 cm or larger for likelihood of miscoding. Patients recorded as having no lymph nodes sampled were denied N0 status and recoded as unknown pathologic N stage and unknown positive lymph node number. Descriptive statistics of continuous variables were expressed as mean SD. Independent sample t tests were used to compare normally distributed continuous variables. c2 tests were used to compare categorical variables. Backward stepwise multivariate logistic regression was used to identify variables independently associated with obtaining 15 or more lymph nodes. Variables with a p value of less than 0.05 on univariate analysis were chosen for model entry. Cox proportional hazards modeling identified variables independently associated with mortality. Variables entered into the model included patient characteristics (age, sex, race, education, income, insurance status, Charlson/Deyo score, facility type), tumor data (histologic type, pathologic T and N stages, margin status), and postoperative variables (30-day readmission status and inpatient length of stay). In the upfront esophagectomy model, adjuvant therapy status was also included. The number of examined lymph nodes was included, and repeated models were run with alternative dichotomization categories: less than or greater than or equal to 5, 10, 15, 20, 25, 30, and 35 lymph nodes. With each iteration, the Wald c2 statistic, hazard ratio (HR), 95% confidence interval (CI), and p value were recorded as a measure of the variable’s relative influence and significance in the model. This method of cut-point analysis has been previously described in esophageal lymph node cut-point threshold analysis [8]. The PEN ratio was calculated by dividing the total number of positive lymph nodes by the number of lymph nodes examined for each patient. Patients with zero examined lymph nodes recorded were excluded from this analysis. Patients with a PEN ratio of 0 were selected for subgroup survival analysis based on their number of
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lymph nodes examined (1–9, 10–19, or 20 or more lymph nodes sampled). OS in patients undergoing esophagectomy was analyzed using Kaplan-Meier analysis and the log-rank test. All statistical analyses were performed using IBM SPSS Statistics, version 22.0 (SPSS Inc, Chicago, IL). p values of less than 0.05 were considered statistically significant.
Results From 2006 to 2012, 18,777 patients underwent esophagectomy with complete nodal information reported, 11,816 (62.9%) of whom had 0 to 14 lymph nodes sampled, and 6,961 (37.1%) of whom had sampling of 15 or more lymph nodes (Table 1). The rate of obtaining 15 or more lymph nodes increased from 2006 to 2012 (from 31% to 45% for upfront esophagectomy cases and from 25% to 44% for induction therapy cases. For community centers, the rate of sampling 15 or more lymph nodes increased from 22.4% in 2006 to 36.8% in 2012. For academic centers, this rate increased from 33.4% in 2006 to 49.5% in 2012. Patients undergoing sampling of 15 or more lymph nodes were less likely to have received induction therapy (55.1% versus 58.1%; p < 0.001). Of the 10,997 patients receiving induction therapy, 10,126 (92.1%) received chemoradiation, whereas 871 (7.9%) received chemotherapy alone. Variables associated with an increased likelihood of 15 or more lymph nodes being sampled included higher-income zip code ($38,000; odds ratio [OR], 1.18; 95% CI, 1.08–1.29; p < 0.001), performance in an academic center (OR, 1.26; 95% CI, 1.17–1.36; p < 0.001), increasing clinical T stage (reference, T0/Tis: T1, OR, 1.51; 95% CI, 1.18–1.94; p ¼ 0.001; T2: OR, 1.79; 95% CI, 1.39–2.31; p < 0.001; T3: OR, 1.81; 95% CI, 1.41– 2.34; p < 0.001), and increasing clinical N stage (reference, N0: N1: OR, 1.13; 95% CI, 1.04–1.23; p ¼ 0.003; N2: OR, 1.49; 95% CI, 1.24–1.79; p < 0.001; N3: OR, 2.04; 95% CI, 1.38–3.01; p < 0.001). Only induction therapy was associated with a decreased likelihood of obtaining 15 or more lymph nodes (OR, 0.70; 95% CI, 0.65–0.76; p < 0.001). Patients undergoing esophagectomy who underwent sampling of 15 or more lymph nodes experienced greater improved median OS than did those who had less than 15 lymph nodes sampled (42.0 months 1.44 versus 37.1 0.76, respectively; p < 0.001). However, on subgroup analysis, although improved OS was detected for patients undergoing induction therapy with the NCCN guideline (35.9 months 1.3 versus 32.4 0.70; p < 0.001), there was no difference detected for patients undergoing upfront esophagectomy (51.1 months 2.7 versus 48.0 1.8; p ¼ 0.26) (Fig 1). The results of the upfront esophagectomy Cox proportional hazard model are shown in Table 2. The NCCN guideline of sampling 15 or more lymph nodes was evaluated in the first model and was seen to be associated with a significant reduction in mortality (HR, 0.90; 95% CI, 0.82–0.98; p ¼ 0.02). This is likely because of the fact that the Cox model adjusts for other covariates influencing mortality, whereas the Kaplan-Meier analysis does not.
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Table 1. Univariate Analysis of Patients Who Had 15 or More Lymph Nodes Sampled Variable Age Male sex White race Income $38,000 Distance from treatment center <21% of population in patient’s zip code without high school diploma Private insurance Metropolitan county Academic center Facility esophagectomy cases/y Charlson/Deyo Score 0 1 2 Clinical T stage 0, in situ 1 2 3 4 X Clinical N status 0 1 2 3 X Induction therapy Pathologic tumor size (mm) R0 resection 30-d mortality 90-d mortality 30-d readmission Positive nodes Length of inpatient stay (d)
0–14 Lymph Nodes Examined (n ¼ 11,816 [62.9%])
15 Lymph Nodes Examined (n ¼ 6,961 [37.1%])
p Value
63.0 10.0 9,760 (82.6%) 10,900 (93.3%) 9,650 (83.7%) 42.9 120.8 9,891 (85.7%)
63.0 10.1 5,815 (83.5%) 6,429 (93.5%) 5,872 (86.2%) 62.9 174.6 5,965 (87.5%)
0.68 0.10 0.51 <0.001 <0.001 0.001
5,405 (46.5%) 9,086 (80.4%) 5,725 (48.6%) 8.6 11.6
3,386 (49.4%) 5,433 (81.3%) 4,342 (62.4%) 13.3 14.4
0.001 0.23 <0.001 <0.001
8,511 (72.0%) 2,603 (22.0%) 702 (5.9%)
5,112 (73.4%) 1,462 (21.0%) 387 (5.6%)
0.11
249 1,860 1,837 4,472 284 3,114
110 1,192 1,219 2,929 126 1,385
(2.1%) (15.7%) (15.5%) (37.8%) (2.4%) (26.4%)
5,272 (44.6%) 3,726 (31.5%) 310 (2.6%) 52 (0.4%) 2,449 (20.7%) 6,658 (58.1%) 36.8 25.1 986 (8.7%) 447 (4.4%) 972 (9.6%) 915 (8.1%) 0.87 1.77 14.0 13.1
To investigate the variance in outcomes depending on the number of lymph nodes examined, repeated iterations of the model were performed based on less than or greater than or equal to 5, 10, 20, 25, 30, and 35 lymph nodes sampled. The results of this analysis are shown in Table 3. The relative influence of lymph nodes examined on survival increased in the models with 20 or more lymph nodes sampled or 25 or more lymph nodes obtained (as demonstrated by concordant increases in the Wald c2 statistic and decreases in the HR). On repeated KaplanMeier analysis, a significant difference in median OS was detected at the threshold of 25 lymph nodes examined (55.4 months 4.6 versus 48.0 1.6; p ¼ 0.04) (Fig 2). The results of the Cox proportional hazard model for patients undergoing induction therapy and the examined lymph node cut-point analysis are listed in Tables 4 and 5. In this model, 10 or more lymph nodes or 15 lymph or
(1.6%) (17.1%) (17.5%) (42.1%) (1.8%) (19.9%)
<0.001
3,087 (44.3%) 2,447 (35.2%) 264 (3.8%) 62 (0.9%) 1,099 (15.8%) 3,753 (55.1%) 39.4 26.0 520 (7.6%) 214 (3.7%) 442 (7.7%) 531 (7.9%) 1.93 3.96 14.0 13.0
<0.001
<0.001 <0.001 0.008 0.04 <0.001 0.68 <0.001 0.90
more lymph nodes examined was associated with the greatest relative weight in the model when compared with other nodal dichotomization values, as well as the greatest reduction in overall mortality hazard. For each patient, a PEN ratio was calculated and categorized into 0 to 0.10, 0.11 to 0.20, 0.21 to 0.30, and 0.31 to 1.0. For both patients undergoing upfront esophagectomy and patients receiving induction therapy, with each incremental increase in the PEN ratio category, a decrease in median OS was detected (Fig 3). For patients undergoing upfront esophagectomy, a PEN ratio of 0 to 0.10 resulted in a median OS of 85.3 months (SE not reached), a PEN ratio of 0.11 to 0.20 resulted in a median OS of 27.7 1.8 months, a PEN ratio of 0.21 to 0.30 resulted in a median OS of 17.9 1.7 months, and a PEN ratio of 0.31 to 1.0 resulted in a median OS of 13.5 0.6 months (p < 0.001). For patients undergoing induction therapy, a
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Fig 1. (A) Although no difference in overall survival (OS) was detected in patients who had 15 lymph nodes examined when undergoing upfront esophagectomy, a significant difference was seen for (B) patients who received induction therapy at this threshold. (LN ¼ lymph node; NCCN ¼ National Comprehensive Cancer Network.)
similar trend was seen: for median OS, a PEN ratio of 0 to 0.1 resulted in an OS of 42.3 1.3 months, a PEN ratio of 0.11 to 0.20 resulted in an OS of 25.3 1.25 months, a PEN ratio of 0.21 to 0.30 resulted in an OS of 22.7 1.3 months, and a PEN ratio of 0.31 to 1.0 resulted in an OS of 17.9 0.6 months (p < 0.001).
Finally, for patients with a PEN ratio of 0 (indicating 0 positive nodes, with a range of 1–90 lymph nodes examined), we investigated the effect of an increasing number of lymph nodes examined in pathologically node-negative patients. For patients with pathologic N0 stage, categories of analysis included 1 to 9, 10 to 19, and
Table 2. Cox Proportional Hazards Model Evaluating Variables Independently Associated With Mortality for Patients Undergoing Upfront Esophagectomy Variable Age (per y increase) Academic cancer center Charlson/Deyo score (reference: 0) 1 2 Pathologic T stage (reference: 0) T1 T2 T3 T4 Pathologic N stage (reference: 0) N1 N2 N3 Inpatient length of stay (per d) 30-d readmission Pathologic tumor size (per mm) Positive surgical margins Adenocarcinoma histologic type 15 lymph nodes sampled Received adjuvant chemotherapy CI ¼ confidence interval.
Wald c2
Hazard Ratio (95% CI)
p Value
37.7 6.2 11.6
1.02 (1.01–1.02) 0.89 (0.82–0.98)
<0.001 0.01
1.13 (1.02–1.26) 1.25 (1.07–1.45)
0.02 0.004
204.3 1.05 1.72 2.71 3.45
(0.67–1.67) (1.08–2.74) (1.71–4.31) (2.06–5.77)
0.82 0.02 <0.001 <0.001
1.82 1.86 2.61 1.01 1.17 1.01 1.76 0.85 0.90 0.67
(1.63–2.03) (1.40–2.46) (1.93–3.53) (1.01–1.02) (1.03–1.34) (1.00–1.01) (1.56–2.00) (0.76–0.94) (0.82–0.98) (0.60–0.75)
<0.001 <0.001 <0.001 <0.001 0.02 <0.001 <0.001 0.002 0.02 <0.001
130.4
97.5 5.4 33.6 79.0 9.2 5.4 45.2
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Table 3. Variation in Wald c2 and Hazard Ratio at Different Lymph Node Thresholds Examined for Patients Undergoing Upfront Esophagectomy Number of Nodes Sampled 5 10 15 20 25 30 35
Wald c2 5.5 8.3 5.4 16.0 10.9 2.7 2.5
Hazard Ratio (95% CI) 0.85 0.87 0.90 0.80 0.79 0.86 0.82
(0.74–0.97) (0.79–0.96) (0.82–0.98) (0.72–0.89) (0.69–0.91) (0.72–1.03) (0.64–1.05)
p Value 0.02 0.004 0.02 <0.001 0.001 0.10 0.11
With each iteration, covariate hazard ratios and significance in the model were checked. There were no significant changes in other covariates that were independently associated with mortality hazard in the overall model. CI ¼ confidence interval.
20 lymph nodes or more examined based on the findings of our previous Cox proportional hazards model analysis. Indeed, even for patients with pathologic N0 disease, there was a significant improvement in OS with an increasing number of nodes sampled (Fig 4). Specifically, for 1 to 9 lymph nodes examined, the median OS was 52.0 2.1 months, for 10 to 19 lymph nodes sampled, the median OS was 66.8 2.8 months, and for 20 or more lymph nodes sampled, OS was 85.3 months (p < 0.001).
Comment NCCN guidelines recommend sampling at least 15 lymph nodes at the time of esophagectomy. This analysis found
Fig 2. Kaplan-Meier curve comparing patients undergoing upfront esophagectomy who had less than or greater than 25 lymph nodes sampled demonstrates a significant difference in survival. (LN ¼ lymph node.)
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that although the rate of meeting this measure increased steadily from 2006 to 2012 (from 31% to 45% for upfront esophagectomy cases and from 25% to 44% for induction therapy cases), the majority of esophagectomies are not undergoing this extent of nodal sampling. Furthermore, our analysis found that although examining 15 or more lymph nodes was independently associated with a lower overall mortality hazard, further improvements in survival were seen for patients undergoing upfront esophagectomy when greater than 20 or 25 lymph nodes were sampled. Even for node-negative patients, sampling an increased number of nodes resulted in improved median OS, likely because of increased staging accuracy. To our knowledge, this is the first study to examine the relationship between number of lymph nodes examined and survival for esophageal cancer patients using the NCDB. This description and analysis of almost 19,000 esophagectomies is 1 of the largest to date investigating examined lymph node thresholds. Our findings that examining an increased number of lymph nodes may be associated with further survival improvements are similar to studies that used other national and international databases. One such analysis, with almost 5,000 patients undergoing esophagectomy from 1998 through 2005, found that patients who underwent sampling of 30 or more lymph nodes had the longest OS, independent of other variables [9]. An international collaborative study of 2,300 patients undergoing esophagectomy (60% adenocarcinoma histologic type) found improvement in survival with a cutoff value of 23 lymph nodes sampled [8]. However, 2 other studies (1 a 14-year institutional experience and the other a nationwide analysis in Sweden) failed to demonstrate a survival difference among patients undergoing esophagectomy who had more than 20 nodes or more than 16 nodes examined, respectively [10, 11]. Like our analysis, other groups have analyzed optimum examined lymph node count separately in patients receiving upfront operations versus those receiving induction therapy. An institutional review at Cornell with more than 260 patients undergoing upfront esophagectomy found a mortality reduction for patients who received a lymphadenectomy for any of the highest 3 quartiles (34% decrease for patients with 17–25 nodes, 48% decrease for patients with 26–40 nodes, and 49% decrease for patients with 40 or more nodes examined) when compared with the lowest quartile (16 lymph nodes sampled) [12]. A study of the Worldwide Esophageal Cancer Collaboration (WECC) database found that optimal lymphadenectomy varied according to pathologic T stage: 10/12 nodes for pT1, 15/22 nodes for pT2, and 31/42 nodes for pT3/T4 for adenocarcinomas/squamous cell carcinomas, respectively, receiving upfront esophagectomy [13]. When these pathologic T-stage cut points were applied to the same WECC database for 135 patients receiving induction therapy, improved OS was again detected [14]. Even for patients with persistent nodal disease, those who received lymphadenectomy consistent with the WECC cut points still had significant improvement in 3-year OS [14]. An institutional analysis at
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Table 4. Cox Proportional Hazards Model Evaluating Variables Independently Associated With Mortality for Patients Who Received Induction Therapy Variable Age (per y increase) Income $38,000 Academic cancer center Pathologic T stage (reference: 0) T1 T2 T3 T4 Pathologic N stage (reference: 0) N1 N2 N3 Inpatient length of stay (per d) 30-d readmission Positive surgical margins 15 lymph nodes sampled
Wald c2
Hazard Ratio (95% CI)
p Value
50.5 31.2 6.3 34.0
1.02 (1.01–1.02) 0.69 (0.61–0.79) 0.88 (0.80–0.97)
<0.001 <0.001 0.012
0.99 1.05 1.35 1.78
(0.82–1.19) (0.89–1.25) (1.15–1.57) (1.25–2.54)
0.90 0.56 <0.001 0.001
1.67 1.81 3.47 1.02 1.49 1.63 0.81
(1.50–1.85) (1.43–2.31) (2.47–4.87) (1.01–1.02) (1.26–1.76) (1.39–1.91) (0.74–0.90)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
124.3
115.7 21.5 35.1 16.1
CI ¼ confidence interval.
Duke University found that there was no threshold number of examined lymph nodes for patients receiving induction therapy with pathologic T1/T2 tumors, whereas for pathologic T3/T4 tumors, significant improvements in survival were detected with 7 or more lymph nodes examined [15]. However, given the low correlation between clinical and pathologic staging, it could be challenging to replicate these survival benefits prospectively. PEN ratio has also gained attention as a prognostic indicator for survival, not only for esophageal cancer but also for colonic and gastric cancers [16, 17]. One institutional database found that a ratio of 0.20 or less had greater prognostic significance than the conventional staging system at the time (sixth edition of the UICC TNM classification) [18]. Another institutional analysis found that the PEN ratio was predictive of survival independent of the number of lymph nodes sampled and Table 5. Variation in Wald c2 and Hazard Ratio at Different Examined Lymph Node Thresholds for Patients Who Received Induction Therapy No. of Nodes Sampled
Wald c2
5 10 15 20 25 30
4.5 20.3 16.1 12.2 4.5 0.5
Hazard Ratio (95% CI) 0.87 0.80 0.81 0.80 0.84 0.93
(0.76–0.99) (0.72–0.88) (0.74–0.90) (0.71–0.91) (0.72–0.99) (0.75–1.15)
p Value 0.03 <0.001 <0.001 <0.001 0.03 0.50
With each iteration, covariate hazard ratios and significance in the model were checked. There were no significant changes in other covariates that were independently associated with mortality hazard in the overall model. CI ¼ confidence interval.
has recommended clinical calculation of this value, in addition to traditional TNM staging, to examine probabilities of patient survival [19]. That finding can be illustrated by the following example: Although a patient with 2 of 4 positive lymph nodes would be classified as stage N2, and a patient with 12 of 24 positive lymph nodes would be classified as stage N3, both patients have a PEN ratio of 0.5. It is likely that the patient with N2 disease with only 4 lymph nodes sampled was actually understaged; however, the PEN ratio of 0.5 groups him with other patients with significant positive nodal burden. However, the increased accuracy of staging with an increased number of lymph nodes sampled still likely has a role to play here: If an increasing number of negative lymph nodes are found, even in a patient with 1 to 2 positive lymph nodes, it increases the confidence that the patient’s disease truly is stage N1, rather than stage N2 or N3. This logic is likely why we see significant survival improvements among patients with pathologic N0 disease who have an increasing number of lymph nodes examined; this has also been documented by other investigators [20]. With our NCDB analysis, as well as the works from other institutional and national databases cited previously, there is a strong case for increased nodal sampling at the time of esophagectomy being associated with improved survival, most likely by more accurate staging or nodal disease clearance, or both. Our study found that variables independently associated with having at least met the NCCN guidelines of 15 or more lymph nodes examined included increasing clinical T stage and N stage (perhaps increasing the surgeon’s suspicion for pathologic nodal disease) and patients from higher-income zip codes (possibly reflecting referral patterns to specialists). Additionally, patients receiving care at academic centers or high-volume cancer centers were more likely to meet
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Fig 3. Kaplan-Meier curves by positive to examined node (PEN) ratio for (A) patients undergoing upfront esophagectomy and (B) patients receiving induction therapy.
this minimum number, which may also be associated with the presence of a general thoracic surgeon or a surgeon with oncologic training. Finally, induction therapy was also independently associated with a decreased likelihood of obtaining at least 15 lymph nodes, possibly because of more difficult dissection conditions (for the surgeon) or identification of nodes (by the pathologist). There are limitations to our analysis. Although we were able to confirm that patients meeting the NCCN guideline
Fig 4. Kaplan-Meier curve for patients undergoing esophagectomy with a positive to examined node (PEN) ratio of 0 by examined lymph node number. (LN ¼ lymph node.)
of sampling 15 or more lymph nodes actually had improved 30- and 90-day mortality (although this may be confounded by unmeasured variables accounting for the patient’s ability to tolerate a more extensive lymphadenectomy or a surgeon’s case volume), and there was no difference in 30-day readmission or length of stay, we were not able to capture more granular complications that may be associated with extended lymphadenectomy, such as anastomotic leak or vocal cord injury [21]. Furthermore, surgical approach (open versus minimally invasive) was not reported for approximately 60% of patients and therefore was not analyzed. There also is no available variable for surgical technique (Ivor-Lewis versus transhiatal esophagectomy or 2-field versus 3-field lymphadenectomy). From our own experience, we chose to focus on ranges of lymph node value dichotomization rather than an absolute cut point number of lymph nodes. We know that lymph node counts can be significantly lower when they are delivered to the pathology department as an en bloc specimen versus in labeled packets [22] and that there may be variability between how many nodes the surgeon believes they have sampled and what is ultimately reported by the pathology department. In lung cancer, interventions such as a lymph node collection kit with prelabeled stations has been shown to increase lymph node yield as well as the proportion of patients diagnosed with positive lymph nodes [23]. We also acknowledge that there are a variety of statistical approaches that could have been used in this analysis, each with their respective benefits and limitations [8–11]. Although we chose an analysis method similar to that of Peyre and colleagues [8], we recognize that alternative approaches may have given slightly different thresholds. Finally, we were not able to examine disease-free survival
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as part of this analysis. This would certainly be helpful in further investigating if survival benefits result from accurate staging allocation or the possible increased clearance of microscopic disease burden at the time of operation resulting in decreased recurrence rates, or both. In conclusion, our analysis suggests that although the NCCN guideline of sampling 15 or more lymph nodes is associated with an optimal benefit for patients who undergo induction therapy, a higher number of sampled lymph nodes was associated with further improvements in survival for patients undergoing upfront esophagectomy. This was also true for patients whose disease was ultimately node negative, likely because of more accurate stage allocation. Although the NCDB allows us to probe national trends in lymph node retrieval, it should serve as a starting point to investigate institutional practices and comparisons regarding surgical approach and technique, with end points of both disease-free survival and OS. Pamela Samson, MD, MPHS, has received grant support through NIH Cardiothoracic Surgery T32 HL07776. Varun Puri, MD, MSci, has received grant funding through NIH K07CA178120 and K12CA167540-02. The NCDB is not responsible for the analytic methodology used in this study, and the conclusions drawn are solely those of the authors.
References 1. Surveillance, Epidemiology, and End Results Program, SEER statistical fact sheets: esophageal cancer. Available at http:// seer.cancer.gov/statfacts/html/esoph.html. Accessed January 15, 2016. 2. Crabtree TD, Yacoub WN, Puri V, et al. Endoscopic ultrasound for early stage esophageal adenocarcinoma: implications for staging and survival. Ann Thorac Surg 2011;91:1509–16. 3. Stiles BM, Mirza F, Coppolino A, et al. Clinical T2-T3N0M0 esophageal cancer: the risk of node positive disease. Ann Thorac Surg 2011;92:491–8. 4. Crabtree TD, Kosinski AS, Puri V, et al. Evaluation of the reliability of clinical staging of T2N0 esophageal cancer: a review of the Society of Thoracic Surgeons Database. Ann Thorac Surg 2013;96:382–90. 5. Dubecz A, Kern M, Solymosi N, et al. Predictors of lymph node metastasis in surgically resected T1 esophageal cancer. Ann Thorac Surg 2015;99:1879–86. 6. National Comprehensive Cancer Network (NCCN) guidelines: esophageal and esophagogastric junction cancers, version 3, 2015. Available at http://www.nccn.org/professionals/ physician_gls/pdf/esophageal.pdf. Accessed January 15, 2015. 7. American College of Surgeons, National Cancer Database. Available at https://www.facs.org/quality-programs/cancer/ ncdb. Accessed January 15, 2016.
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8. Peyre CG, Hagen JA, DeMeester SR, et al. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg 2008;248:549–56. 9. Groth SS, Virnig BA, Whitson BA, et al. Determination of the minimum number of lymph nodes to examine to maximize survival in patients with esophageal carcinoma: data from the Surveillance Epidemiology and End Results database. J Thorac Cardiovasc Surg 2010;139:612–20. 10. Lagergren J, Mattsson F, Zylstra J, et al. Extent of lymphadenectomy and prognosis after esophageal cancer surgery. JAMA Surg 2015;151:32–9. 11. van der Schaaf M, Johar A, Wijnhoven B, et al. Extent of lymph node removal during esophageal cancer surgery and survival. J Natl Cancer Inst 2015;107:djv043. 12. Altorki NK, Zhou XK, Stiles B, et al. Total number of resected lymph nodes predicts survival in esophageal cancer. Ann Surg 2008;248:221–6. 13. Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg 2010;251:46–50. 14. Stiles BM, Nasar A, Mirza FA, et al. Worldwide Oesophageal Cancer Collaboration guidelines for lymphadenectomy predict survival following neoadjuvant therapy. Eur J Cardiothorac Surg 2012;42:659–64. 15. Hanna JM, Erhunmwunsee L, Berry M, et al. The prognostic importance of the number of dissected lymph nodes after induction chemoradiotherapy for esophageal cancer. Ann Thorac Surg 2015;99:265–9. 16. Tong LL, Gao P, Song YX, et al. Can lymph node ratio take the place of pN categories in the UICC/AJCC TNM classification system for colorectal cancer? Ann Surg Oncol 2011;18: 2453–60. 17. Zhang BY, Yuan J, Cui ZS, et al. Evaluation of the prognostic value of metastatic lymph node ratio for gastric cancer. Am J Surg 2014;207:555–65. 18. Mariette C, Piessen G, Briez N, Triboulet JP. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg 2008;247: 365–71. 19. Tan Z, Ma G, Yang H, Zhang L. Can lymph node ratio replace pn categories in the tumor–node–metastasis classification system for esophageal cancer? J Thorac Oncol 2014;9: 1214–21. 20. Greenstein AJ, Litle VR, Swanson SJ, et al. Effect of the number of lymph nodes sampled on postoperative survival of lymph-node negative esophageal cancer. Cancer 2008;112: 1239–46. 21. Ma GW, Situ DR, Ma QL, et al. Three-field vs two-field lymph node dissection for esophageal cancer: a metaanalysis. World J Gastroenterol 2014;20:18022–30. 22. Veeramachaneni NK, Zoole JB, Decker PA, et al. Lymph node analysis in esophageal resection: American College of Surgeons Oncology Group Z0060 trial. Ann Thorac Surg 2008;86:418–21. 23. Osarogiagbon RU, Ramirez RA, Wang CG, et al. Dual intervention to improve pathologic staging of resectable lung cancer. Ann Thorac Surg 2013;96:1975–81.
DISCUSSION DR PAUL SCHIPPER (Portland, OR): Traves, I think that the quanta of a lymph node is actually kind of a nebulous thing to define, and I’m going to push that just a bit. If you had somebody who did a lymph node dissection of just the left gastric and got 15 nodes there, would you consider that an adequate dissection, or is it the fact that if you want to get greater lymph node counts, you have to go into other lymph node stations in order to do that because there are only so many nodes per
station and what you are really looking at with lymph node count is a surrogate of how many stations that that surgeon went into, they went a little further afield? The other thing I noticed with your talk is that with the induction therapy, there was a greater count of lymph nodes if they did not have it versus if they did, and maybe with induction therapy those lymph nodes just all got stuck together and it was in fact the same number of stations dissected, same operation; it’s just that the
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pathologist found 15 stuck nodes or 25 very discrete nonstuck nodes. DR CRABTREE: Paul, that is a great observation. We don’t have data from the database on what nodal stations were taken. That would be a great subsequent analysis instead of the total lymph node count. The issue of the pathologist is a confounding variable, but generally one would think that that would be a consistent variable at your institution. I think from a quality perspective, it is still reasonable to consider the total lymph node count as long as you are consistent in the process that you are doing. That is a great point. I don’t have adequate data on whether it was a 2-field or a 3-field lymphadenectomy. All I have is the total lymph node count. There was a great paper by Dr Watson’s group that was presented here last year that actually in the induction therapy patients tried to focus on looking at the actual pathology or treatment effect of the treated lymph nodes in those patients. That is something I cannot get to in the database but also a factor in what you described. DR STEVEN R. DEMEESTER (Los Angeles, CA): Traves, great job. Congratulations on reinforcing what a lot of papers are demonstrating, the benefit of lymphadenectomy. I have first a philosophical question and then a question pertaining to your study. You used the word “sampling” a lot. Sampling implies that you are just trying to get a global sense of stage. It doesn’t have anything to do with curative outcome. Do you philosophically believe that we are just sampling the disease with a lymphadenectomy in esophageal cancer or do you believe that we actually alter outcome with a lymphadenectomy? That is the philosophical question for you. The question pertaining to your study is, were you able to break down the survival by lymph node dissection or lymph node counts by stage, and if you were able to do that by stage—for example, the N0 patients who had just 15 nodes removed—how often did the stage change when they went up to 25 or 30 nodes removed? That would get at that issue that is always thrown back at us, that it’s just stage migration. If you are not seeing a big stage migration when you take more lymph nodes, then the explanation for better survival is not stage migration but it’s that you are actually doing something about the disease. DR CRABTREE: Thank you, Dr DeMeester. Of course it took us another 8 years to confirm what you published in terms of the absolute lymph node count. I’ll try to address your second question first. That is part of the reason that I demonstrated the last 2 curves as examples. Those are all the same nodal stage patients, N0 or N1, and the difference in survival completely had to do with the absolute number of lymph nodes resected. DR DEMEESTER: But if you had somebody who had 16 nodes taken out and 1 of those nodes was positive, he would no longer be N0. DR CRABTREE: Correct. DR DEMEESTER: So the question is how many people who had 15 nodes stayed N0 versus those who had 25 nodes? Is there any way to get at that in the data; how often you are shifting the stage by taking more than 15 nodes out? That is what I’m getting at. DR CRABTREE: Yes. We could potentially stratify that on clinical stage. I’m sorry, I don’t recall that exact data now, but I can
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tell you that as the number of lymph nodes dissected increased, patients were more likely to have a higher pathologic nodal stage. I don’t have the precise numbers, but it is included in the manuscript. DR DEMEESTER: Because that is always the argument. DR CRABTREE: I still think the point beyond the stage migration, though, is that it is a quality issue. It is something that is actionable; it is something that you can quickly give feedback to a surgeon within 6 months to a year; it is something that they can make quality improvements on, whatever the etiology, whether it’s stage migration or an absolute benefit in survival. DR DEMEESTER: It’s a philosophical question. What is your philosophical feeling? DR CRABTREE: Having looked at some of the data in the non– induction therapy patients, there is the thought that there may be a therapeutic advantage to that lymph node dissection, but then, of course, there is the issue that if you find positive nodal disease, then those patients are more likely to get adjuvant therapy, which also has an impact on subsequent survival, so I can’t say if it’s therapeutic. DR DEMEESTER: Sounds like a political answer, man. Come on. DR CRABTREE: That’s above my pay scale. DR THOMAS J. WATSON (Washington, DC): Traves, very nice presentation and nice work on an important topic. I have 2 questions for you. First of all, did you look at the extent of lymphadenectomy, the number of resected nodes, based on T stage? I am concerned about getting stuck on a number of 15 resected lymph nodes for all T stages. You can make the argument for a T1a well-differentiated cancer, where the risk of lymph node metastasis is essentially zero, you could do a completely adequate cancer operation and take out no lymph nodes whatsoever. For instance, a vagal-sparing esophagectomy with no deliberate lymphadenectomy would be entirely appropriate. For a more advanced tumor, such as a T3 lesion, you need to take a lot of nodes. Tom Rice, utilizing the WECC data, showed nicely that the adequacy of lymphadenectomy for cure varies with T. Did you look at that at all? DR CRABTREE: It was interesting that the WEC data varied based on pathologic T stage, which is challenging in the sense of how do you make a decision prospectively on the number of nodes to dissect using the pathologic stage. We can break it down into clinical T stage, but I don’t have those numbers for you right now. On that note, however, we all know that clinical staging of esophageal cancer is generally very unreliable even in the era of endoscopic ultrasonography, making it difficult to commit to a certain number of lymph nodes based on clinical stage. DR WATSON: Secondly, this idea of lymph node ratio has been around for a long time; its utilization comes and goes. I am a bit concerned about its use as well. It is an interesting mix of cancer biology (how the tumor spreads), surgical technique (how extensive a lymphadenectomy is performed), and perhaps the pathologist’s perseverance at digging out nodes. I would argue that 1 out of 3 lymph nodes positive is prognostically very different than 10 out of 30 lymph nodes positive, yet both scenarios represent the same lymph node ratio. I just want you to think about that as you write your manuscript.
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DR CRABTREE: I think that is a great point. I still think of the idea of using the PEN ratio as a prognostic tool, but we would have to weigh that against the absolute number of positive lymph nodes. Actually, I think we can potentially look at that. I agree with the issue of this number of lymph nodes and T stage, but what I would like to try to emphasize, even based on what we talked about yesterday, is that this is something that we can do better at. Whatever that absolute number is, whether it’s 15 or 23, it shouldn’t be 2. I mean there are some numbers that we can agree on. I think we have a tremendous amount of room for improvement. DR WATSON: My point is that I, as the surgeon, would like to see the numerator and the denominator and not just the ratio. DR GAIL E. DARLING (Toronto, Ontario, Canada): Could you not use PEN? Could you use lymph node ratio, lymph node R, which everybody has been using? Do we have to have a new acronym? DR CRABTREE: Thank you, Dr Darling. DR SETH KRANTZ (Evanston, IL): Traves, great job, great paper.
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Only 37% of patients had adequate lymph nodes. Did you guys look at it by center type and by volume? How much improved were you at an academic center by volume? The reason I ask is because you alluded to the fact that maybe 15 isn’t even enough, that we should be doing 20 or 25, and the Duke paper that you referenced that did the partition analysis, in neoadjuvant N0 patients, it was actually 30 nodes where they stopped seeing a survival advantage. So the reason I ask by center, my assumption is that it’s probably better than 37%, but we have seen in other studies that it’s not much better than 60%, 65%, and given that, even in high-volume centers, if we can’t get it better than that, how do we get people to 25, 30 nodes, and is that realistic if we can’t even get to 15 nodes in 73% of the patients? Thanks. DR CRABTREE: That is a great question. In terms of, let’s say, changes over time, the 37% number was from 2006 to 2012. We got a little better in 2012 and 2013, but it was still under 50%. The odds ratio of having more than 15 lymph nodes was double if you were at an academic cancer center as opposed to being at a community cancer center. I don’t know the absolute numbers of the academic centers, but it did improve your likelihood of having a better dissection.
Background. National Comprehensive Cancer Network (NCCN) guidelines recommend sampling 15 or more lymph nodes during esophagectomy. The proportion of patients meeting this guideline is unknown, as is its influence on overall survival (OS). Methods. Univariate analysis and logistic regression were performed to identify variables associated with sampling 15 or more lymph nodes among patients undergoing esophagectomy in the National Cancer Data Base (NCDB). The NCCN guideline was evaluated in Cox proportional hazards modeling, along with alternative lymph node thresholds. Positive to examined node (PEN) ratios were calculated, and OS was compared using Kaplan-Meier analysis. Results. From 2006 to 2012, only 6,961 of 18,777 (37.1%) patients undergoing esophagectomy had sampling of 15 or more lymph nodes. Variables associated with sampling 15 or more lymph nodes included income greater than or equal to $38,000, procedure performed in an academic facility, and increasing clinical T and N stages. Induction therapy was associated with a decreased likelihood of 15 or more lymph nodes being sampled. The
largest decrease in mortality hazard in patients undergoing upfront esophagectomy was detected when 25 lymph nodes or more were sampled (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.67–0.89; p < 0.001), whereas for patients undergoing induction therapy, sampling of 10 or 15 or more lymph nodes was associated with optimal survival benefit (HR, 0.81; 95% CI, 0.74–0.90; p < 0.001). PEN ratios of 0 to 0.10 were associated with maximum survival benefit among all patients undergoing esophagectomy. For patients with a PEN ratio of 0, increases in OS were detected with higher lymph node sampling (85.3 months for sampling of 20 or more lymph nodes versus 52.0 months for sampling 1–9 lymph nodes; p < 0.001). Conclusions. For patients undergoing upfront esophagectomy, there may be an increased survival benefit for examining 20 to 25 lymph nodes, which is higher than current recommendations. However, only a minority of patients are meeting current guidelines.
F
(NCCN) recommends that patients receiving upfront esophagectomy (operative treatment before systemic therapy or radiation therapy) have at least 15 lymph nodes sampled [6]. The guidelines further state that although the ideal number of lymph nodes sampled after induction therapy is currently unknown, a similar extent of sampling is recommended [6]. Using the National Cancer Data Base (NCDB), our goal was to evaluate perioperative characteristics and long-term survival outcomes of patients who underwent sampling of 15 or more lymph nodes. We hypothesized that the optimal number of lymph nodes obtained may be different for patients undergoing upfront esophagectomy and patients receiving induction therapy, and we used cut-point analysis to investigate the relationship between lymph node number and overall survival (OS) in both patient populations. Finally, we investigated the influence of the positive to examined
or the approximately 17,000 individuals diagnosed with esophageal cancer per year, surgical resection, with multimodality therapy for locally advanced cases, offers the best chance of long-term survival [1]. However, both institutional and national databases have documented that clinical N0 status rarely correlates with pathologic staging in patients undergoing upfront esophagectomy, even with the use of preoperative endoscopic ultrasonography and positron emission tomography [2–5]. Currently, the National Comprehensive Cancer Network Accepted for publication Aug 5, 2016. Presented at the Fifty-second Annual Meeting of The Society of Thoracic Surgeons, Phoenix, AZ, Jan 23–27, 2016. Address correspondence to Dr Crabtree, Division of Cardiothoracic Surgery, Southern Illinois University College of Medicine, 701 N First St, Rm D252, PO Box 19679, Springfield, IL 62794-9679; email: tcrabtree53@ siumed.edu.
Ó 2016 by The Society of Thoracic Surgeons Published by Elsevier
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0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2016.08.010
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node (PEN) ratio on OS for all patients undergoing esophagectomy.
Patients and Methods The NCDB Participant User File (PUF) for esophageal cancer was reviewed to identify patients undergoing esophagectomy from 2006 to 2012. The NCDB is a joint program of the American College of Surgeons Commission on Cancer and the American Cancer Society and records approximately 70% of malignancies in the United States [7]. The PUF reports deidentified patient and treatment center information and was deemed exempt from institutional review board review. Patient, tumor, and treatment variable definitions are detailed on the NCDB PUF data dictionary website (http://ncdbpuf.facs. org/node/259). Patients undergoing esophagectomy were categorized as receiving either upfront esophagectomy or induction therapy followed by esophagectomy. Exclusion criteria for this analysis included clinical M1 disease and patients with a tumor size recorded as 30 cm or larger for likelihood of miscoding. Patients recorded as having no lymph nodes sampled were denied N0 status and recoded as unknown pathologic N stage and unknown positive lymph node number. Descriptive statistics of continuous variables were expressed as mean SD. Independent sample t tests were used to compare normally distributed continuous variables. c2 tests were used to compare categorical variables. Backward stepwise multivariate logistic regression was used to identify variables independently associated with obtaining 15 or more lymph nodes. Variables with a p value of less than 0.05 on univariate analysis were chosen for model entry. Cox proportional hazards modeling identified variables independently associated with mortality. Variables entered into the model included patient characteristics (age, sex, race, education, income, insurance status, Charlson/Deyo score, facility type), tumor data (histologic type, pathologic T and N stages, margin status), and postoperative variables (30-day readmission status and inpatient length of stay). In the upfront esophagectomy model, adjuvant therapy status was also included. The number of examined lymph nodes was included, and repeated models were run with alternative dichotomization categories: less than or greater than or equal to 5, 10, 15, 20, 25, 30, and 35 lymph nodes. With each iteration, the Wald c2 statistic, hazard ratio (HR), 95% confidence interval (CI), and p value were recorded as a measure of the variable’s relative influence and significance in the model. This method of cut-point analysis has been previously described in esophageal lymph node cut-point threshold analysis [8]. The PEN ratio was calculated by dividing the total number of positive lymph nodes by the number of lymph nodes examined for each patient. Patients with zero examined lymph nodes recorded were excluded from this analysis. Patients with a PEN ratio of 0 were selected for subgroup survival analysis based on their number of
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lymph nodes examined (1–9, 10–19, or 20 or more lymph nodes sampled). OS in patients undergoing esophagectomy was analyzed using Kaplan-Meier analysis and the log-rank test. All statistical analyses were performed using IBM SPSS Statistics, version 22.0 (SPSS Inc, Chicago, IL). p values of less than 0.05 were considered statistically significant.
Results From 2006 to 2012, 18,777 patients underwent esophagectomy with complete nodal information reported, 11,816 (62.9%) of whom had 0 to 14 lymph nodes sampled, and 6,961 (37.1%) of whom had sampling of 15 or more lymph nodes (Table 1). The rate of obtaining 15 or more lymph nodes increased from 2006 to 2012 (from 31% to 45% for upfront esophagectomy cases and from 25% to 44% for induction therapy cases. For community centers, the rate of sampling 15 or more lymph nodes increased from 22.4% in 2006 to 36.8% in 2012. For academic centers, this rate increased from 33.4% in 2006 to 49.5% in 2012. Patients undergoing sampling of 15 or more lymph nodes were less likely to have received induction therapy (55.1% versus 58.1%; p < 0.001). Of the 10,997 patients receiving induction therapy, 10,126 (92.1%) received chemoradiation, whereas 871 (7.9%) received chemotherapy alone. Variables associated with an increased likelihood of 15 or more lymph nodes being sampled included higher-income zip code ($38,000; odds ratio [OR], 1.18; 95% CI, 1.08–1.29; p < 0.001), performance in an academic center (OR, 1.26; 95% CI, 1.17–1.36; p < 0.001), increasing clinical T stage (reference, T0/Tis: T1, OR, 1.51; 95% CI, 1.18–1.94; p ¼ 0.001; T2: OR, 1.79; 95% CI, 1.39–2.31; p < 0.001; T3: OR, 1.81; 95% CI, 1.41– 2.34; p < 0.001), and increasing clinical N stage (reference, N0: N1: OR, 1.13; 95% CI, 1.04–1.23; p ¼ 0.003; N2: OR, 1.49; 95% CI, 1.24–1.79; p < 0.001; N3: OR, 2.04; 95% CI, 1.38–3.01; p < 0.001). Only induction therapy was associated with a decreased likelihood of obtaining 15 or more lymph nodes (OR, 0.70; 95% CI, 0.65–0.76; p < 0.001). Patients undergoing esophagectomy who underwent sampling of 15 or more lymph nodes experienced greater improved median OS than did those who had less than 15 lymph nodes sampled (42.0 months 1.44 versus 37.1 0.76, respectively; p < 0.001). However, on subgroup analysis, although improved OS was detected for patients undergoing induction therapy with the NCCN guideline (35.9 months 1.3 versus 32.4 0.70; p < 0.001), there was no difference detected for patients undergoing upfront esophagectomy (51.1 months 2.7 versus 48.0 1.8; p ¼ 0.26) (Fig 1). The results of the upfront esophagectomy Cox proportional hazard model are shown in Table 2. The NCCN guideline of sampling 15 or more lymph nodes was evaluated in the first model and was seen to be associated with a significant reduction in mortality (HR, 0.90; 95% CI, 0.82–0.98; p ¼ 0.02). This is likely because of the fact that the Cox model adjusts for other covariates influencing mortality, whereas the Kaplan-Meier analysis does not.
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Table 1. Univariate Analysis of Patients Who Had 15 or More Lymph Nodes Sampled Variable Age Male sex White race Income $38,000 Distance from treatment center <21% of population in patient’s zip code without high school diploma Private insurance Metropolitan county Academic center Facility esophagectomy cases/y Charlson/Deyo Score 0 1 2 Clinical T stage 0, in situ 1 2 3 4 X Clinical N status 0 1 2 3 X Induction therapy Pathologic tumor size (mm) R0 resection 30-d mortality 90-d mortality 30-d readmission Positive nodes Length of inpatient stay (d)
0–14 Lymph Nodes Examined (n ¼ 11,816 [62.9%])
15 Lymph Nodes Examined (n ¼ 6,961 [37.1%])
p Value
63.0 10.0 9,760 (82.6%) 10,900 (93.3%) 9,650 (83.7%) 42.9 120.8 9,891 (85.7%)
63.0 10.1 5,815 (83.5%) 6,429 (93.5%) 5,872 (86.2%) 62.9 174.6 5,965 (87.5%)
0.68 0.10 0.51 <0.001 <0.001 0.001
5,405 (46.5%) 9,086 (80.4%) 5,725 (48.6%) 8.6 11.6
3,386 (49.4%) 5,433 (81.3%) 4,342 (62.4%) 13.3 14.4
0.001 0.23 <0.001 <0.001
8,511 (72.0%) 2,603 (22.0%) 702 (5.9%)
5,112 (73.4%) 1,462 (21.0%) 387 (5.6%)
0.11
249 1,860 1,837 4,472 284 3,114
110 1,192 1,219 2,929 126 1,385
(2.1%) (15.7%) (15.5%) (37.8%) (2.4%) (26.4%)
5,272 (44.6%) 3,726 (31.5%) 310 (2.6%) 52 (0.4%) 2,449 (20.7%) 6,658 (58.1%) 36.8 25.1 986 (8.7%) 447 (4.4%) 972 (9.6%) 915 (8.1%) 0.87 1.77 14.0 13.1
To investigate the variance in outcomes depending on the number of lymph nodes examined, repeated iterations of the model were performed based on less than or greater than or equal to 5, 10, 20, 25, 30, and 35 lymph nodes sampled. The results of this analysis are shown in Table 3. The relative influence of lymph nodes examined on survival increased in the models with 20 or more lymph nodes sampled or 25 or more lymph nodes obtained (as demonstrated by concordant increases in the Wald c2 statistic and decreases in the HR). On repeated KaplanMeier analysis, a significant difference in median OS was detected at the threshold of 25 lymph nodes examined (55.4 months 4.6 versus 48.0 1.6; p ¼ 0.04) (Fig 2). The results of the Cox proportional hazard model for patients undergoing induction therapy and the examined lymph node cut-point analysis are listed in Tables 4 and 5. In this model, 10 or more lymph nodes or 15 lymph or
(1.6%) (17.1%) (17.5%) (42.1%) (1.8%) (19.9%)
<0.001
3,087 (44.3%) 2,447 (35.2%) 264 (3.8%) 62 (0.9%) 1,099 (15.8%) 3,753 (55.1%) 39.4 26.0 520 (7.6%) 214 (3.7%) 442 (7.7%) 531 (7.9%) 1.93 3.96 14.0 13.0
<0.001
<0.001 <0.001 0.008 0.04 <0.001 0.68 <0.001 0.90
more lymph nodes examined was associated with the greatest relative weight in the model when compared with other nodal dichotomization values, as well as the greatest reduction in overall mortality hazard. For each patient, a PEN ratio was calculated and categorized into 0 to 0.10, 0.11 to 0.20, 0.21 to 0.30, and 0.31 to 1.0. For both patients undergoing upfront esophagectomy and patients receiving induction therapy, with each incremental increase in the PEN ratio category, a decrease in median OS was detected (Fig 3). For patients undergoing upfront esophagectomy, a PEN ratio of 0 to 0.10 resulted in a median OS of 85.3 months (SE not reached), a PEN ratio of 0.11 to 0.20 resulted in a median OS of 27.7 1.8 months, a PEN ratio of 0.21 to 0.30 resulted in a median OS of 17.9 1.7 months, and a PEN ratio of 0.31 to 1.0 resulted in a median OS of 13.5 0.6 months (p < 0.001). For patients undergoing induction therapy, a
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Fig 1. (A) Although no difference in overall survival (OS) was detected in patients who had 15 lymph nodes examined when undergoing upfront esophagectomy, a significant difference was seen for (B) patients who received induction therapy at this threshold. (LN ¼ lymph node; NCCN ¼ National Comprehensive Cancer Network.)
similar trend was seen: for median OS, a PEN ratio of 0 to 0.1 resulted in an OS of 42.3 1.3 months, a PEN ratio of 0.11 to 0.20 resulted in an OS of 25.3 1.25 months, a PEN ratio of 0.21 to 0.30 resulted in an OS of 22.7 1.3 months, and a PEN ratio of 0.31 to 1.0 resulted in an OS of 17.9 0.6 months (p < 0.001).
Finally, for patients with a PEN ratio of 0 (indicating 0 positive nodes, with a range of 1–90 lymph nodes examined), we investigated the effect of an increasing number of lymph nodes examined in pathologically node-negative patients. For patients with pathologic N0 stage, categories of analysis included 1 to 9, 10 to 19, and
Table 2. Cox Proportional Hazards Model Evaluating Variables Independently Associated With Mortality for Patients Undergoing Upfront Esophagectomy Variable Age (per y increase) Academic cancer center Charlson/Deyo score (reference: 0) 1 2 Pathologic T stage (reference: 0) T1 T2 T3 T4 Pathologic N stage (reference: 0) N1 N2 N3 Inpatient length of stay (per d) 30-d readmission Pathologic tumor size (per mm) Positive surgical margins Adenocarcinoma histologic type 15 lymph nodes sampled Received adjuvant chemotherapy CI ¼ confidence interval.
Wald c2
Hazard Ratio (95% CI)
p Value
37.7 6.2 11.6
1.02 (1.01–1.02) 0.89 (0.82–0.98)
<0.001 0.01
1.13 (1.02–1.26) 1.25 (1.07–1.45)
0.02 0.004
204.3 1.05 1.72 2.71 3.45
(0.67–1.67) (1.08–2.74) (1.71–4.31) (2.06–5.77)
0.82 0.02 <0.001 <0.001
1.82 1.86 2.61 1.01 1.17 1.01 1.76 0.85 0.90 0.67
(1.63–2.03) (1.40–2.46) (1.93–3.53) (1.01–1.02) (1.03–1.34) (1.00–1.01) (1.56–2.00) (0.76–0.94) (0.82–0.98) (0.60–0.75)
<0.001 <0.001 <0.001 <0.001 0.02 <0.001 <0.001 0.002 0.02 <0.001
130.4
97.5 5.4 33.6 79.0 9.2 5.4 45.2
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Table 3. Variation in Wald c2 and Hazard Ratio at Different Lymph Node Thresholds Examined for Patients Undergoing Upfront Esophagectomy Number of Nodes Sampled 5 10 15 20 25 30 35
Wald c2 5.5 8.3 5.4 16.0 10.9 2.7 2.5
Hazard Ratio (95% CI) 0.85 0.87 0.90 0.80 0.79 0.86 0.82
(0.74–0.97) (0.79–0.96) (0.82–0.98) (0.72–0.89) (0.69–0.91) (0.72–1.03) (0.64–1.05)
p Value 0.02 0.004 0.02 <0.001 0.001 0.10 0.11
With each iteration, covariate hazard ratios and significance in the model were checked. There were no significant changes in other covariates that were independently associated with mortality hazard in the overall model. CI ¼ confidence interval.
20 lymph nodes or more examined based on the findings of our previous Cox proportional hazards model analysis. Indeed, even for patients with pathologic N0 disease, there was a significant improvement in OS with an increasing number of nodes sampled (Fig 4). Specifically, for 1 to 9 lymph nodes examined, the median OS was 52.0 2.1 months, for 10 to 19 lymph nodes sampled, the median OS was 66.8 2.8 months, and for 20 or more lymph nodes sampled, OS was 85.3 months (p < 0.001).
Comment NCCN guidelines recommend sampling at least 15 lymph nodes at the time of esophagectomy. This analysis found
Fig 2. Kaplan-Meier curve comparing patients undergoing upfront esophagectomy who had less than or greater than 25 lymph nodes sampled demonstrates a significant difference in survival. (LN ¼ lymph node.)
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that although the rate of meeting this measure increased steadily from 2006 to 2012 (from 31% to 45% for upfront esophagectomy cases and from 25% to 44% for induction therapy cases), the majority of esophagectomies are not undergoing this extent of nodal sampling. Furthermore, our analysis found that although examining 15 or more lymph nodes was independently associated with a lower overall mortality hazard, further improvements in survival were seen for patients undergoing upfront esophagectomy when greater than 20 or 25 lymph nodes were sampled. Even for node-negative patients, sampling an increased number of nodes resulted in improved median OS, likely because of increased staging accuracy. To our knowledge, this is the first study to examine the relationship between number of lymph nodes examined and survival for esophageal cancer patients using the NCDB. This description and analysis of almost 19,000 esophagectomies is 1 of the largest to date investigating examined lymph node thresholds. Our findings that examining an increased number of lymph nodes may be associated with further survival improvements are similar to studies that used other national and international databases. One such analysis, with almost 5,000 patients undergoing esophagectomy from 1998 through 2005, found that patients who underwent sampling of 30 or more lymph nodes had the longest OS, independent of other variables [9]. An international collaborative study of 2,300 patients undergoing esophagectomy (60% adenocarcinoma histologic type) found improvement in survival with a cutoff value of 23 lymph nodes sampled [8]. However, 2 other studies (1 a 14-year institutional experience and the other a nationwide analysis in Sweden) failed to demonstrate a survival difference among patients undergoing esophagectomy who had more than 20 nodes or more than 16 nodes examined, respectively [10, 11]. Like our analysis, other groups have analyzed optimum examined lymph node count separately in patients receiving upfront operations versus those receiving induction therapy. An institutional review at Cornell with more than 260 patients undergoing upfront esophagectomy found a mortality reduction for patients who received a lymphadenectomy for any of the highest 3 quartiles (34% decrease for patients with 17–25 nodes, 48% decrease for patients with 26–40 nodes, and 49% decrease for patients with 40 or more nodes examined) when compared with the lowest quartile (16 lymph nodes sampled) [12]. A study of the Worldwide Esophageal Cancer Collaboration (WECC) database found that optimal lymphadenectomy varied according to pathologic T stage: 10/12 nodes for pT1, 15/22 nodes for pT2, and 31/42 nodes for pT3/T4 for adenocarcinomas/squamous cell carcinomas, respectively, receiving upfront esophagectomy [13]. When these pathologic T-stage cut points were applied to the same WECC database for 135 patients receiving induction therapy, improved OS was again detected [14]. Even for patients with persistent nodal disease, those who received lymphadenectomy consistent with the WECC cut points still had significant improvement in 3-year OS [14]. An institutional analysis at
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Table 4. Cox Proportional Hazards Model Evaluating Variables Independently Associated With Mortality for Patients Who Received Induction Therapy Variable Age (per y increase) Income $38,000 Academic cancer center Pathologic T stage (reference: 0) T1 T2 T3 T4 Pathologic N stage (reference: 0) N1 N2 N3 Inpatient length of stay (per d) 30-d readmission Positive surgical margins 15 lymph nodes sampled
Wald c2
Hazard Ratio (95% CI)
p Value
50.5 31.2 6.3 34.0
1.02 (1.01–1.02) 0.69 (0.61–0.79) 0.88 (0.80–0.97)
<0.001 <0.001 0.012
0.99 1.05 1.35 1.78
(0.82–1.19) (0.89–1.25) (1.15–1.57) (1.25–2.54)
0.90 0.56 <0.001 0.001
1.67 1.81 3.47 1.02 1.49 1.63 0.81
(1.50–1.85) (1.43–2.31) (2.47–4.87) (1.01–1.02) (1.26–1.76) (1.39–1.91) (0.74–0.90)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
124.3
115.7 21.5 35.1 16.1
CI ¼ confidence interval.
Duke University found that there was no threshold number of examined lymph nodes for patients receiving induction therapy with pathologic T1/T2 tumors, whereas for pathologic T3/T4 tumors, significant improvements in survival were detected with 7 or more lymph nodes examined [15]. However, given the low correlation between clinical and pathologic staging, it could be challenging to replicate these survival benefits prospectively. PEN ratio has also gained attention as a prognostic indicator for survival, not only for esophageal cancer but also for colonic and gastric cancers [16, 17]. One institutional database found that a ratio of 0.20 or less had greater prognostic significance than the conventional staging system at the time (sixth edition of the UICC TNM classification) [18]. Another institutional analysis found that the PEN ratio was predictive of survival independent of the number of lymph nodes sampled and Table 5. Variation in Wald c2 and Hazard Ratio at Different Examined Lymph Node Thresholds for Patients Who Received Induction Therapy No. of Nodes Sampled
Wald c2
5 10 15 20 25 30
4.5 20.3 16.1 12.2 4.5 0.5
Hazard Ratio (95% CI) 0.87 0.80 0.81 0.80 0.84 0.93
(0.76–0.99) (0.72–0.88) (0.74–0.90) (0.71–0.91) (0.72–0.99) (0.75–1.15)
p Value 0.03 <0.001 <0.001 <0.001 0.03 0.50
With each iteration, covariate hazard ratios and significance in the model were checked. There were no significant changes in other covariates that were independently associated with mortality hazard in the overall model. CI ¼ confidence interval.
has recommended clinical calculation of this value, in addition to traditional TNM staging, to examine probabilities of patient survival [19]. That finding can be illustrated by the following example: Although a patient with 2 of 4 positive lymph nodes would be classified as stage N2, and a patient with 12 of 24 positive lymph nodes would be classified as stage N3, both patients have a PEN ratio of 0.5. It is likely that the patient with N2 disease with only 4 lymph nodes sampled was actually understaged; however, the PEN ratio of 0.5 groups him with other patients with significant positive nodal burden. However, the increased accuracy of staging with an increased number of lymph nodes sampled still likely has a role to play here: If an increasing number of negative lymph nodes are found, even in a patient with 1 to 2 positive lymph nodes, it increases the confidence that the patient’s disease truly is stage N1, rather than stage N2 or N3. This logic is likely why we see significant survival improvements among patients with pathologic N0 disease who have an increasing number of lymph nodes examined; this has also been documented by other investigators [20]. With our NCDB analysis, as well as the works from other institutional and national databases cited previously, there is a strong case for increased nodal sampling at the time of esophagectomy being associated with improved survival, most likely by more accurate staging or nodal disease clearance, or both. Our study found that variables independently associated with having at least met the NCCN guidelines of 15 or more lymph nodes examined included increasing clinical T stage and N stage (perhaps increasing the surgeon’s suspicion for pathologic nodal disease) and patients from higher-income zip codes (possibly reflecting referral patterns to specialists). Additionally, patients receiving care at academic centers or high-volume cancer centers were more likely to meet
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Fig 3. Kaplan-Meier curves by positive to examined node (PEN) ratio for (A) patients undergoing upfront esophagectomy and (B) patients receiving induction therapy.
this minimum number, which may also be associated with the presence of a general thoracic surgeon or a surgeon with oncologic training. Finally, induction therapy was also independently associated with a decreased likelihood of obtaining at least 15 lymph nodes, possibly because of more difficult dissection conditions (for the surgeon) or identification of nodes (by the pathologist). There are limitations to our analysis. Although we were able to confirm that patients meeting the NCCN guideline
Fig 4. Kaplan-Meier curve for patients undergoing esophagectomy with a positive to examined node (PEN) ratio of 0 by examined lymph node number. (LN ¼ lymph node.)
of sampling 15 or more lymph nodes actually had improved 30- and 90-day mortality (although this may be confounded by unmeasured variables accounting for the patient’s ability to tolerate a more extensive lymphadenectomy or a surgeon’s case volume), and there was no difference in 30-day readmission or length of stay, we were not able to capture more granular complications that may be associated with extended lymphadenectomy, such as anastomotic leak or vocal cord injury [21]. Furthermore, surgical approach (open versus minimally invasive) was not reported for approximately 60% of patients and therefore was not analyzed. There also is no available variable for surgical technique (Ivor-Lewis versus transhiatal esophagectomy or 2-field versus 3-field lymphadenectomy). From our own experience, we chose to focus on ranges of lymph node value dichotomization rather than an absolute cut point number of lymph nodes. We know that lymph node counts can be significantly lower when they are delivered to the pathology department as an en bloc specimen versus in labeled packets [22] and that there may be variability between how many nodes the surgeon believes they have sampled and what is ultimately reported by the pathology department. In lung cancer, interventions such as a lymph node collection kit with prelabeled stations has been shown to increase lymph node yield as well as the proportion of patients diagnosed with positive lymph nodes [23]. We also acknowledge that there are a variety of statistical approaches that could have been used in this analysis, each with their respective benefits and limitations [8–11]. Although we chose an analysis method similar to that of Peyre and colleagues [8], we recognize that alternative approaches may have given slightly different thresholds. Finally, we were not able to examine disease-free survival
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as part of this analysis. This would certainly be helpful in further investigating if survival benefits result from accurate staging allocation or the possible increased clearance of microscopic disease burden at the time of operation resulting in decreased recurrence rates, or both. In conclusion, our analysis suggests that although the NCCN guideline of sampling 15 or more lymph nodes is associated with an optimal benefit for patients who undergo induction therapy, a higher number of sampled lymph nodes was associated with further improvements in survival for patients undergoing upfront esophagectomy. This was also true for patients whose disease was ultimately node negative, likely because of more accurate stage allocation. Although the NCDB allows us to probe national trends in lymph node retrieval, it should serve as a starting point to investigate institutional practices and comparisons regarding surgical approach and technique, with end points of both disease-free survival and OS. Pamela Samson, MD, MPHS, has received grant support through NIH Cardiothoracic Surgery T32 HL07776. Varun Puri, MD, MSci, has received grant funding through NIH K07CA178120 and K12CA167540-02. The NCDB is not responsible for the analytic methodology used in this study, and the conclusions drawn are solely those of the authors.
References 1. Surveillance, Epidemiology, and End Results Program, SEER statistical fact sheets: esophageal cancer. Available at http:// seer.cancer.gov/statfacts/html/esoph.html. Accessed January 15, 2016. 2. Crabtree TD, Yacoub WN, Puri V, et al. Endoscopic ultrasound for early stage esophageal adenocarcinoma: implications for staging and survival. Ann Thorac Surg 2011;91:1509–16. 3. Stiles BM, Mirza F, Coppolino A, et al. Clinical T2-T3N0M0 esophageal cancer: the risk of node positive disease. Ann Thorac Surg 2011;92:491–8. 4. Crabtree TD, Kosinski AS, Puri V, et al. Evaluation of the reliability of clinical staging of T2N0 esophageal cancer: a review of the Society of Thoracic Surgeons Database. Ann Thorac Surg 2013;96:382–90. 5. Dubecz A, Kern M, Solymosi N, et al. Predictors of lymph node metastasis in surgically resected T1 esophageal cancer. Ann Thorac Surg 2015;99:1879–86. 6. National Comprehensive Cancer Network (NCCN) guidelines: esophageal and esophagogastric junction cancers, version 3, 2015. Available at http://www.nccn.org/professionals/ physician_gls/pdf/esophageal.pdf. Accessed January 15, 2015. 7. American College of Surgeons, National Cancer Database. Available at https://www.facs.org/quality-programs/cancer/ ncdb. Accessed January 15, 2016.
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8. Peyre CG, Hagen JA, DeMeester SR, et al. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg 2008;248:549–56. 9. Groth SS, Virnig BA, Whitson BA, et al. Determination of the minimum number of lymph nodes to examine to maximize survival in patients with esophageal carcinoma: data from the Surveillance Epidemiology and End Results database. J Thorac Cardiovasc Surg 2010;139:612–20. 10. Lagergren J, Mattsson F, Zylstra J, et al. Extent of lymphadenectomy and prognosis after esophageal cancer surgery. JAMA Surg 2015;151:32–9. 11. van der Schaaf M, Johar A, Wijnhoven B, et al. Extent of lymph node removal during esophageal cancer surgery and survival. J Natl Cancer Inst 2015;107:djv043. 12. Altorki NK, Zhou XK, Stiles B, et al. Total number of resected lymph nodes predicts survival in esophageal cancer. Ann Surg 2008;248:221–6. 13. Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg 2010;251:46–50. 14. Stiles BM, Nasar A, Mirza FA, et al. Worldwide Oesophageal Cancer Collaboration guidelines for lymphadenectomy predict survival following neoadjuvant therapy. Eur J Cardiothorac Surg 2012;42:659–64. 15. Hanna JM, Erhunmwunsee L, Berry M, et al. The prognostic importance of the number of dissected lymph nodes after induction chemoradiotherapy for esophageal cancer. Ann Thorac Surg 2015;99:265–9. 16. Tong LL, Gao P, Song YX, et al. Can lymph node ratio take the place of pN categories in the UICC/AJCC TNM classification system for colorectal cancer? Ann Surg Oncol 2011;18: 2453–60. 17. Zhang BY, Yuan J, Cui ZS, et al. Evaluation of the prognostic value of metastatic lymph node ratio for gastric cancer. Am J Surg 2014;207:555–65. 18. Mariette C, Piessen G, Briez N, Triboulet JP. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg 2008;247: 365–71. 19. Tan Z, Ma G, Yang H, Zhang L. Can lymph node ratio replace pn categories in the tumor–node–metastasis classification system for esophageal cancer? J Thorac Oncol 2014;9: 1214–21. 20. Greenstein AJ, Litle VR, Swanson SJ, et al. Effect of the number of lymph nodes sampled on postoperative survival of lymph-node negative esophageal cancer. Cancer 2008;112: 1239–46. 21. Ma GW, Situ DR, Ma QL, et al. Three-field vs two-field lymph node dissection for esophageal cancer: a metaanalysis. World J Gastroenterol 2014;20:18022–30. 22. Veeramachaneni NK, Zoole JB, Decker PA, et al. Lymph node analysis in esophageal resection: American College of Surgeons Oncology Group Z0060 trial. Ann Thorac Surg 2008;86:418–21. 23. Osarogiagbon RU, Ramirez RA, Wang CG, et al. Dual intervention to improve pathologic staging of resectable lung cancer. Ann Thorac Surg 2013;96:1975–81.
DISCUSSION DR PAUL SCHIPPER (Portland, OR): Traves, I think that the quanta of a lymph node is actually kind of a nebulous thing to define, and I’m going to push that just a bit. If you had somebody who did a lymph node dissection of just the left gastric and got 15 nodes there, would you consider that an adequate dissection, or is it the fact that if you want to get greater lymph node counts, you have to go into other lymph node stations in order to do that because there are only so many nodes per
station and what you are really looking at with lymph node count is a surrogate of how many stations that that surgeon went into, they went a little further afield? The other thing I noticed with your talk is that with the induction therapy, there was a greater count of lymph nodes if they did not have it versus if they did, and maybe with induction therapy those lymph nodes just all got stuck together and it was in fact the same number of stations dissected, same operation; it’s just that the
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pathologist found 15 stuck nodes or 25 very discrete nonstuck nodes. DR CRABTREE: Paul, that is a great observation. We don’t have data from the database on what nodal stations were taken. That would be a great subsequent analysis instead of the total lymph node count. The issue of the pathologist is a confounding variable, but generally one would think that that would be a consistent variable at your institution. I think from a quality perspective, it is still reasonable to consider the total lymph node count as long as you are consistent in the process that you are doing. That is a great point. I don’t have adequate data on whether it was a 2-field or a 3-field lymphadenectomy. All I have is the total lymph node count. There was a great paper by Dr Watson’s group that was presented here last year that actually in the induction therapy patients tried to focus on looking at the actual pathology or treatment effect of the treated lymph nodes in those patients. That is something I cannot get to in the database but also a factor in what you described. DR STEVEN R. DEMEESTER (Los Angeles, CA): Traves, great job. Congratulations on reinforcing what a lot of papers are demonstrating, the benefit of lymphadenectomy. I have first a philosophical question and then a question pertaining to your study. You used the word “sampling” a lot. Sampling implies that you are just trying to get a global sense of stage. It doesn’t have anything to do with curative outcome. Do you philosophically believe that we are just sampling the disease with a lymphadenectomy in esophageal cancer or do you believe that we actually alter outcome with a lymphadenectomy? That is the philosophical question for you. The question pertaining to your study is, were you able to break down the survival by lymph node dissection or lymph node counts by stage, and if you were able to do that by stage—for example, the N0 patients who had just 15 nodes removed—how often did the stage change when they went up to 25 or 30 nodes removed? That would get at that issue that is always thrown back at us, that it’s just stage migration. If you are not seeing a big stage migration when you take more lymph nodes, then the explanation for better survival is not stage migration but it’s that you are actually doing something about the disease. DR CRABTREE: Thank you, Dr DeMeester. Of course it took us another 8 years to confirm what you published in terms of the absolute lymph node count. I’ll try to address your second question first. That is part of the reason that I demonstrated the last 2 curves as examples. Those are all the same nodal stage patients, N0 or N1, and the difference in survival completely had to do with the absolute number of lymph nodes resected. DR DEMEESTER: But if you had somebody who had 16 nodes taken out and 1 of those nodes was positive, he would no longer be N0. DR CRABTREE: Correct. DR DEMEESTER: So the question is how many people who had 15 nodes stayed N0 versus those who had 25 nodes? Is there any way to get at that in the data; how often you are shifting the stage by taking more than 15 nodes out? That is what I’m getting at. DR CRABTREE: Yes. We could potentially stratify that on clinical stage. I’m sorry, I don’t recall that exact data now, but I can
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tell you that as the number of lymph nodes dissected increased, patients were more likely to have a higher pathologic nodal stage. I don’t have the precise numbers, but it is included in the manuscript. DR DEMEESTER: Because that is always the argument. DR CRABTREE: I still think the point beyond the stage migration, though, is that it is a quality issue. It is something that is actionable; it is something that you can quickly give feedback to a surgeon within 6 months to a year; it is something that they can make quality improvements on, whatever the etiology, whether it’s stage migration or an absolute benefit in survival. DR DEMEESTER: It’s a philosophical question. What is your philosophical feeling? DR CRABTREE: Having looked at some of the data in the non– induction therapy patients, there is the thought that there may be a therapeutic advantage to that lymph node dissection, but then, of course, there is the issue that if you find positive nodal disease, then those patients are more likely to get adjuvant therapy, which also has an impact on subsequent survival, so I can’t say if it’s therapeutic. DR DEMEESTER: Sounds like a political answer, man. Come on. DR CRABTREE: That’s above my pay scale. DR THOMAS J. WATSON (Washington, DC): Traves, very nice presentation and nice work on an important topic. I have 2 questions for you. First of all, did you look at the extent of lymphadenectomy, the number of resected nodes, based on T stage? I am concerned about getting stuck on a number of 15 resected lymph nodes for all T stages. You can make the argument for a T1a well-differentiated cancer, where the risk of lymph node metastasis is essentially zero, you could do a completely adequate cancer operation and take out no lymph nodes whatsoever. For instance, a vagal-sparing esophagectomy with no deliberate lymphadenectomy would be entirely appropriate. For a more advanced tumor, such as a T3 lesion, you need to take a lot of nodes. Tom Rice, utilizing the WECC data, showed nicely that the adequacy of lymphadenectomy for cure varies with T. Did you look at that at all? DR CRABTREE: It was interesting that the WEC data varied based on pathologic T stage, which is challenging in the sense of how do you make a decision prospectively on the number of nodes to dissect using the pathologic stage. We can break it down into clinical T stage, but I don’t have those numbers for you right now. On that note, however, we all know that clinical staging of esophageal cancer is generally very unreliable even in the era of endoscopic ultrasonography, making it difficult to commit to a certain number of lymph nodes based on clinical stage. DR WATSON: Secondly, this idea of lymph node ratio has been around for a long time; its utilization comes and goes. I am a bit concerned about its use as well. It is an interesting mix of cancer biology (how the tumor spreads), surgical technique (how extensive a lymphadenectomy is performed), and perhaps the pathologist’s perseverance at digging out nodes. I would argue that 1 out of 3 lymph nodes positive is prognostically very different than 10 out of 30 lymph nodes positive, yet both scenarios represent the same lymph node ratio. I just want you to think about that as you write your manuscript.
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DR CRABTREE: I think that is a great point. I still think of the idea of using the PEN ratio as a prognostic tool, but we would have to weigh that against the absolute number of positive lymph nodes. Actually, I think we can potentially look at that. I agree with the issue of this number of lymph nodes and T stage, but what I would like to try to emphasize, even based on what we talked about yesterday, is that this is something that we can do better at. Whatever that absolute number is, whether it’s 15 or 23, it shouldn’t be 2. I mean there are some numbers that we can agree on. I think we have a tremendous amount of room for improvement. DR WATSON: My point is that I, as the surgeon, would like to see the numerator and the denominator and not just the ratio. DR GAIL E. DARLING (Toronto, Ontario, Canada): Could you not use PEN? Could you use lymph node ratio, lymph node R, which everybody has been using? Do we have to have a new acronym? DR CRABTREE: Thank you, Dr Darling. DR SETH KRANTZ (Evanston, IL): Traves, great job, great paper.
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Only 37% of patients had adequate lymph nodes. Did you guys look at it by center type and by volume? How much improved were you at an academic center by volume? The reason I ask is because you alluded to the fact that maybe 15 isn’t even enough, that we should be doing 20 or 25, and the Duke paper that you referenced that did the partition analysis, in neoadjuvant N0 patients, it was actually 30 nodes where they stopped seeing a survival advantage. So the reason I ask by center, my assumption is that it’s probably better than 37%, but we have seen in other studies that it’s not much better than 60%, 65%, and given that, even in high-volume centers, if we can’t get it better than that, how do we get people to 25, 30 nodes, and is that realistic if we can’t even get to 15 nodes in 73% of the patients? Thanks. DR CRABTREE: That is a great question. In terms of, let’s say, changes over time, the 37% number was from 2006 to 2012. We got a little better in 2012 and 2013, but it was still under 50%. The odds ratio of having more than 15 lymph nodes was double if you were at an academic cancer center as opposed to being at a community cancer center. I don’t know the absolute numbers of the academic centers, but it did improve your likelihood of having a better dissection.