J Gastrointest Surg (2013) 17:1562–1569 DOI 10.1007/s11605-013-2259-5
2012 SSAT PLENARY PRESENTATION
Extent of Lymphadenectomy Does Not Predict Survival in Patients Treated with Primary Esophagectomy Joyce Wong & Jill Weber & Khaldoun Almhanna & Sarah Hoffe & Ravi Shridhar & Richard Karl & Kenneth L. Meredith
Received: 17 May 2012 / Accepted: 11 June 2013 / Published online: 2 July 2013 # 2013 The Society for Surgery of the Alimentary Tract
Abstract Background The number of lymph nodes resected and its impact on survival for patients with esophageal cancer remains undefined. Current guidelines recommend extended lymphadenectomy in patients not receiving neoadjuvant therapy. We reviewed our single institutional experience with nodal harvest for esophageal cancer in a non-neoadjuvant therapy setting. Methods Patients who underwent esophagectomy as primary therapy were indentified from a prospectively maintained database consisting of 704 patients who underwent esophagectomy. Patients were stratified by number of lymph nodes (LN) resected: >5, 10, 12, 15, or 20. Survival, clinical, and pathologic parameters were analyzed with Kaplan–Meier curves, chi-square, or Fisher’s exact tests where appropriate. Results We identified 246 patients who underwent esophagectomy as initial treatment. The mean age was 65±10 years. The majority of patients were male (87 %). Ivor–Lewis esophagectomy was performed for 71 %, minimally invasive esophagectomy for 15 %, transhiatal esophagectomy for 12 %, and three-field esophagectomy for 2 %. At 60 months follow-up, there was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) between patients with < vs. >5 LN resected (p=0.74 and p=0.67, respectively) or in the < vs. >10 (p=0.33, p=0.11), 12 (p=0.82, p=0.90), 15 (p=0.45, p=0.79), or 20 (p=0.72, p=0.86) resected LN groups. Patients were then subdivided into node-positive and node-negative cohorts and stratified by nodal harvest. In the subgroups of patients with node-negative and node-positive disease, OS and DFS also did not significantly differ between groups with respect to number of nodes resected (p>0.05). A total of 49 (20 %) patients developed recurrent disease; however, recurrence was not statistically associated with number of LN resected (p>0.05). Conclusion We found no impact of extent of lymphadenectomy on overall or disease-free survival in patients treated with esophagectomy without neoadjuvant therapy. In addition, the number of nodes resected at esophagectomy did not affect recurrence rates. Current recommendations for increased nodal resection during esophagectomy in patients not receiving neoadjuvant therapy may not improve patient outcomes, and this phenomenon warrants further investigation.
J. Wong : J. Weber : R. Karl : K. L. Meredith (*) Department of Gastrointestinal Surgery, H. Lee Moffitt Cancer Center, Tampa, FL, USA e-mail:
[email protected] J. Wong e-mail:
[email protected] K. Almhanna Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA S. Hoffe : R. Shridhar Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
Keywords Esophageal cancer . Lymphadenectomy . Survival
Introduction The incidence of esophageal cancer has risen in recent years in the USA, particularly adenocarcinoma, with over 17,000 new cases estimated to occur annually.1 Despite improvements in survival for localized and regionally advanced disease, 5-year survival rates are still under 50 % for patients with regional disease and only 2–3 % for patients with metastatic disease.1 Identifying patients with earlier stage and surgically resectable
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disease, as well as optimizing therapeutic interventions, are paramount to improving survival. Controversy still exists regarding the optimal treatment strategy for esophageal cancer, with surgery, chemotherapy, and radiation therapy forming the primary modalities utilized. With respect to surgery, both the transthoracic and transhiatal approaches have been advocated, with advantages to each. While there has been no 5-year survival benefit shown for either technique, the proponents of the transhiatal approach have documented a shorter hospital length of stay, smaller perioperative mortality rate, and fewer postoperative complications, particularly pulmonary complications. In contrast, those who advocate the transthoracic approach have demonstrated greater lymph node retrieval, which may lead to improved accuracy of stage determination.2,3 A recent meta-analysis failed to demonstrate an advantage to either approach.2 Clearly, the number of positive lymph nodes has been shown to be a poor prognostic factor. A decreased overall survival with increasing number of positive lymph nodes has been shown,4,5 and is so reflected in the most recent American Joint Committee on Cancer (AJCC) seventh edition staging system.6 Proponents of the transthoracic surgical approach have argued that increased lymph node yield is important for accurate staging and therefore determination of prognosis. The extent of lymphadenectomy has also remained controversial and is not reflected in the current AJCC staging system. While lymph node status takes into account up to seven positive lymph nodes, there is no recommendation for total number of lymph nodes to evaluate at resection as reflected by AJCC staging.6 The National Comprehensive Care Network (NCCN) consensus guidelines recommend evaluation of a minimum of 15 lymph nodes to ensure adequate staging in patients not treated with preoperative chemoradiation therapy. These recommendations, however, are based on retrospective data, with no clear survival benefit demonstrated in a prospective fashion. To date, multiple studies have examined lymph node count at the time of resection and correlated an improved survival with higher number of lymph nodes retrieved. Recommendations for extent of lymphadenectomy, however, range widely from at least 6 lymph nodes to 30, with some benefit with >40 lymph nodes retrieved in one study.7–10 The ratio of positive lymph nodes to total lymph nodes examined has also been proposed as an independent prognostic factor in esophageal cancer, with disease-specific survival rates decreasing with increasing lymph node ratio. This ratio may be beneficial in patients who are thought to have been inadequately staged.11–13 The best ratio, however, remains to be determined and has not yet been defined for clinical practice. With the variability in recommendations concerning extent of lymphadenectomy for esophageal cancer, we sought to examine our own single-institution experience with patients who underwent esophagectomy as primary therapy for esophageal carcinoma.
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Methods In 2006, following institutional review board approval, the GI Department at Moffitt Cancer Center (MCC) established a database of esophagectomy cases by performing a retrospective chart review of patients operated on at MCC between June 1994 and January 2008. The data collected for the database included patient demographics, preoperative symptoms, Charlson comorbidity Index, risk factors, family history, tumor stage and histopathologic features, perioperative events, and complications. Chart reviews were performed solely by experienced clinicians and recorded on standardized abstraction forms. Data were entered into a secure web-based data entry system and uploaded into an Access database by a data analyst. Ambiguities in any data points were discussed, researched, reviewed, and corrected by the Moffitt Esophageal Research Team. All patients included in our study underwent staging with physical exam, esophagogastroduodenoscopy, endoscopic ultrasound when available, CT scans, CT/PET or PET scans, and cardiopulmonary clearance. All pathology specimens from the initial endoscopic biopsies were read and confirmed by MCC pathologists prior to surgery. Given that this study was retrospective in design, a power calculation was not performed. Rather, all available patients that met inclusion criteria were included within the analyses. Currently, 704 patient charts have been abstracted and were available for analysis. Within the database, patients who did not undergo neoadjuvant chemoradiation therapy were selected. Only patients who underwent resection and had 30-day follow-up were included in this analysis. Patients were stratified according to number of lymph nodes retrieved at resection: < or ≥ 5, 10, 12, 15, or 20 lymph nodes. The cutoff of 15 was chosen because it is the NCCN guideline recommendation for lymph node evaluation in both gastric and esophageal cancer; 12 was chosen because it is the recommendation for colorectal cancer; 20 was chosen as an upper limit for lymph node count; and 5 and 10 were chosen to determine if there were any survival differences with small numbers of lymph nodes evaluated. Patients were then followed prospectively for disease recurrence and mortality.
Surgery All operations were performed with curative intent and included removal of the primary tumor en bloc with its draining lymph nodes. Esophagogastrectomy was defined as resection of the proximal stomach and thoracic esophagus with an esophagogastric anastomosis in the chest (Ivor–Lewis approach) or transabdominal esophagectomy with an anastomosis in the neck (transhiatal approach). Minimally invasive esophagectomy via transhiatal or transthoracic technique was performed on selected patients. The choice of operation
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was based on the site of the primary tumor and surgeon preference. Statistical analyses, including chi-squared or Fisher’s exact tests were utilized as appropriate for categorical data, and mean differences were examined for continuous data using ANOVA. Survival analyses were performed using Kaplan– Meier curves with log rank tests for significance. All statistical tests performed were two-sided and declared 5 % significance level. Statistical analyses were performed with STATA IC (Stata Statistical Software, Release 10.0; Strata Corp., College Station, TX, USA).
Results Patient Cohort We identified 246 of the 704 patients within the database that did not receive neoadjuvant chemoradiation therapy and underwent esophagectomy as primary therapy. The mean age was 65±10 years. The majority of patients were male (N=213, 87 %) and adenocarcinoma was the main histology present (N=219, 89 %; Table 1). Transthoracic resection was performed in 195 (79 %) patients, which included Ivor–Lewis esophagectomy in 173 (71 %), minimally invasive Ivor–Lewis esophagectomy in 18 (7 %), and three-field esophagectomy in 4 (2 %). Transhiatal esophagectomy was performed in 47 (19 %), of whom 19 (8 %) were via a minimally invasive approach (Table 1). Pathologic Characteristics Postoperative pathologic stage was determined according to the AJCC sixth and seventh edition, depending upon year of resection. Most commonly, patients had stage I disease (41 %), based on final pathology. A similar proportion of patients had stages II
Table 1 Patient cohort Patient Characteristics Age (years) Sex Cancer histology Surgical technique Open
Minimally invasive
65±10 Male (N=213, 87 %) Female (N=33, 13 %) Adenocarcinoma (N=219, 89 %) Squamous cell carcinoma (N=27, 11 %) Ivor–Lewis (N=173, 71 %) Transhiatal (N=28, 12 %) Three field (N=4, 2 %) Laparoscopic Ivor–Lewis (N=18, 7 %) Laparoscopic transhiatal (N=19, 8 %)
or III disease (22 and 21 %, respectively). Small subsets of patients had stage 0 (13 %) or stage IV (2 %) disease (Table 2). Stage IV disease was determined based upon the AJCC sixth edition staging, when celiac lymph nodes were considered M1 disease. No patient with distant metastatic disease underwent resection. The mean number of lymph nodes retrieved for the cohort was 10. Ninety (37 %) patients had positive lymph nodes; of these, the mean number of lymph nodes retrieved was 12. For lymph node negative disease, the mean number was 9. For patients who developed recurrent disease, the mean number of lymph nodes was 9; for those that did not recur, the mean number of lymph nodes was 11, p=0.39. Of patients with lymph node-negative disease, 11 (12 %) developed recurrence. The mean number of lymph nodes retrieved was 7. In comparison, the mean number of lymph nodes retrieved in node-negative patients without recurrence was 9 (p=0.10). When stratified by surgical procedure, both the transthoracic (range, 2–31 lymph nodes) and transhiatal (range, 1–26 lymph nodes) approaches obtained a mean of 10 nodes, and the minimally invasive approach 12 nodes (range, 2–22 lymph nodes). There was no significant difference in lymph node yield based on surgical approach or disease recurrence. Patients with positive lymph nodes had a greater lymph node retrieval (p=0.007). Adjuvant Therapy The majority did not receive chemotherapy or radiation postresection, 77 and 85 %, respectively. Patients who received chemotherapy were stratified according to number of lymph nodes retrieved at resection: < vs. ≥ 5, 10, 12, 15, or 20 lymph Table 2 Postoperative stage and adjuvant treatment, overall, and stratified by number of lymph nodes examined Postoperative pathologic stage Unknown
N=3 (1 %)
Stage 0
N=31 (13 %)
Stage I
N=102 (41 %)
Stage II
N=54 (22 %)
Stage III
N=51 (21 %)
Stage IV
N=5 (2 %)
Adjuvant therapy
Received
Did not receive Unknown
Radiation (overall cohort) N=29 (13 %)
N=188 (85 %)
N=4 (2 %)
Chemotherapy (overall N=51 (22 %) cohort) Chemotherapy Received (<) based on LN examined <5 vs. ≥5 LN 3/31
N=179 (77 %)
N=16 (7 %)
Received (≥)
p value
48/199
0.07
<10 vs. ≥10 LN
25/110
26/120
0.85
<12 vs. ≥12 LN
36/138
15/92
0.08
<15 vs. ≥15 LN
42/172
9/58
0.16
<20 vs. ≥20 LN
47/207
4/23
0.56
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Survival and Recurrence Mean follow-up for the cohort was 44 months. At 60 months follow-up, overall survival was compared between patients stratified by lymph node count, again based on 5, 10, 12, 15, or 20 lymph nodes. There was no difference in overall survival between any groups (Fig. 1). Disease-free survival was also not impacted between patients with five lymph nodes retrieved vs. ≥5 (p=0.67), 10 (p=0.11), 12 (p=0.90), 15 (p=0.79), and 20 (p=0.86) lymph nodes (Fig. 2). Patients were then grouped according to whether positive or negative nodes were identified on pathology. Of those with positive lymph nodes; there was no significant difference in overall survival in patients whom had five lymph nodes retrieved at surgery compared with those patients with ≥5 lymph nodes retrieved (p=0.06). Similarly, no difference in overall survival was identified when stratifying lymph node positive patients by < vs. ≥10 (p=0.53), 12 (p=0.52), 15 (p=0.99), or 20 (p=0.92) lymph nodes (Fig. 3). Of the patients with node-negative disease, overall survival was analyzed in similar subgroups with no difference found between any lymph node group comparison: < vs. ≥5(p=0.56), 10 (p=0.72), 12 (p=0.33), 15 (p=0.10), or 20 (p=0.76). 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00
Probability of Survival
The role of extensive lymph node sampling, including sampling of levels 7, 8, and 9 or all paraesophageal, subcarinal, paraaortic, inferior pulmonary ligament and celiac axis lymph nodes, or obtaining >15 lymph nodes during resection
<5 ≥5
a 0
P=0.73 12
24
36
48
60
<10 ≥10
b 0
0.00 0.25 0.50 0.75 1.00
Discussion
P=0.33 12
24
36
4
<15 ≥15
d 0
0.00 0.25 0.50 0.75 1.00
Fig. 1 Overall survival of patients, stratified by number of lymph nodes examined: a < vs. ≥5, b < vs. ≥10, c < vs. ≥12, d < vs. ≥15, and e < vs. ≥20
A total of 49 (19.9 %) patients developed recurrent disease during follow-up. These patients were also compared according to lymph node retrieval: < vs. ≥5, 10, 12, 15, or 20 lymph nodes. No significant difference was observed in disease recurrence between any of the lymph node groups (Table 3). Twenty-six (10.6 %) patients recurred with systemic disease which represented 53.1 % of the recurrences, 3 (1.2 %) with regional disease (6.1 % of recurrences), and 12 (4.8 %) with local disease (24.5 % of recurrences). Eight (3.3 %) patients developed disease recurrence at an unknown site (16.3 % of recurrences). Patients who developed disease recurrence were compared by site of recurrence (local vs. regional vs. systemic), stratified by lymph node count. When comparing the 12 patients who developed local disease recurrence, stratified by < vs. ≥5 lymph nodes, there were 9 patients who developed local recurrence with <5 lymph nodes examined versus 3 with ≥5 lymph nodes examined, which was not statistically significant (p=0.30). There was also no difference in patients who developed regional or systemic disease when stratified by < vs. ≥5 lymph nodes examined, p=0.30. Similarly, there was no difference in local, regional, or systemic disease recurrence when stratifying patients by < vs. ≥10, 12, 15, or 20 lymph nodes (p>0.05) among all sites of recurrence
0.00 0.25 0.50 0.75 1.00
nodes. Thirty-one patients had <5 lymph nodes retrieved at resection; of these, three (10 %) received adjuvant chemotherapy. Of 199 patients with ≥5 lymph nodes retrieved at resection, 48 (24 %) received chemotherapy. There was no statistically significant difference between these two groups, p=0.07 (Table 2). Similarly, there was no statistically significant difference between patients receiving adjuvant chemotherapy when stratified by 10, 12, 15, or 20 lymph nodes (Table 2).
60
24
36
48
48
60
≥20 0
P=0.82 12
36
P=0.72
e
≥12 0
24
<20
<12
c
P=0.45 12
60
Time (Months)
12
24
36
48
60
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<5 ≥5
a
P=0.67
0.00 0.25 0.50 0.75 1.00
12
24
36
48
≥10
b 12
24
P=0.11
36
48
<15 ≥15
d
P=0.79
0
60
<10
0 0.00 0.25 0.50 0.75 1.00
Probability of Survival
0
0.00 0.25 0.50 0.75 1.00
0.00 0.25 0.50 0.75 1.00
Fig. 2 Disease-free survival of patients, stratified by number of lymph nodes examined: a < vs. ≥5, b < vs. ≥10, c < vs. ≥12, d < vs. ≥15, and e < vs. ≥20
0.00 0.25 0.50 0.75 1.00
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12
36
48
60
<20 ≥20
e
P=0.86
0
60
24
12
24
36
48
60
<12 ≥12
c 12
0
24
P=0.90
36
48
60
Time (Months)
for esophageal carcinoma, remains controversial. Some authors have advocated a more extensive lymphadenectomy in order to ensure adequate staging and avoid missing a positive lymph node metastasis potentially by affecting stage migration. Additionally, clearance of all positive disease may allow for improved survival. Several large analyses of the Surveillance, Epidemiology and End Results (SEER) database demonstrated improved overall and disease-specific survival when over 30 lymph nodes were resected.9,14 When comparing to patients with no lymph node evaluation, only patients with >12
<5
a
P=0.06
0.00 0.25 0.50 0.75 1.00
12
24
36
48
60
<10 ≥10
b 0
0.00 0.25 0.50 0.75 1.00
Probability of Survival
0
P=0.53 12
24
36
48
60
<12 ≥12
c 0
P=0.52 12
24
36
0.00 0.25 0.50 0.75 1.00
≥5
48
Time (Months)
60
<15 ≥15
d 0
0.00 0.25 0.50 0.75 1.00
0.00 0.25 0.50 0.75 1.00
Fig. 3 Overall survival of patients with positive lymph node metastases, stratified by number of lymph nodes examined: a < vs. ≥5, b < vs. ≥10, c < vs. ≥12, d < vs. ≥15, and e < vs. ≥20
lymph nodes had lower all-cause and cancer-specific mortality at a median of 5 years follow-up 14. Greenstein, et al. interrogated the SEER database and evaluated 972 patients with node-negative esophageal cancer.15 Interestingly, those authors reported an improved disease-specific survival with a higher number of lymph nodes sampled during surgery: 55 % fiveyear disease specific survival with ≤10 negative lymph nodes vs. 75 % for ≥18 lymph nodes (p<0.01). They concluded that a minimum of 18 lymph nodes should be removed at the time of surgery.15 Data from a Chinese study of node-negative patients
P=0.99 12
24
36
48
60
<20 ≥ 20
e 0
P=0.92 12
24
36
48
60
J Gastrointest Surg (2013) 17:1562–1569 Table 3 Recurrent disease, overall, and stratified by number of lymph nodes examined
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Developed recurrent disease Overall cohort Developed recurrent disease, based on LN examined < 5 vs. ≥5 LN
No N=193 (78 %) Yes (<)
Yes N=49 (20 %) Yes (≥)
Unknown N=4 (2 %) p value
6/35
43/207
0.41
<10 vs. ≥10 LN <12 vs. ≥12 LN <15 vs. ≥15 LN <20 vs. ≥20 LN
24/120 33/147 39/181 45/216
25/122 16/95 10/61 4/26
0.53 0.19 0.25 0.36
also concluded a minimum of 18 lymph nodes should be sampled for reduced hazard ratio of death.8 While the SEER analyses analyzed large numbers of patients, the database has limitations, particularly lack of detailed clinical information and uniform parameters. Peyre et al. incorporated data from nine centers: five European, three US, and one from China and excluded patients treated with either neoadjuvant or adjuvant therapy, patients with T4 tumors, or patients with involved celiac axis nodes or systemic metastases. They reported a maximal survival benefit when a minimum of 23 regional lymph nodes were removed.16 More recently, Rizk et al. used the Worldwide Esophageal Cancer Collaboration data and recommended lymphadenectomy on a continuum, based on T stage.17 Patients treated with either neoadjuvant or adjuvant therapy was also excluded. To maximize 5-year survival, the authors proposed a minimum of 10 lymph nodes be resected for T1 cancers, 20 nodes for T2 cancer, and 30 or more nodes for T3/T4 cancers or if the T stage was uncertain.17 While this study had robust numbers, the database inherently has limitations similar to that of SEER, including lack of similar data fields among the included 13 institutions.18 While our current treatment algorithm for esophageal cancer recommends neoadjuvant chemoradiation for patients with locally advanced cancers, this study only evaluated patients who were treated with primary esophagectomy. The clinical impact of lymph node harvest was assessed without the confounding variable of preresection therapy. In this study, we observed no difference in overall or disease-free survival, at a median 5-year follow-up, in patients with increased lymph node examination compared with patients with lower lymph node counts. In patients with lymph nodes positive for metastatic disease, associated with stage IIB or greater disease, there was also no increased overall or disease-free survival benefit with an increased lymph node count. The majority of patients underwent transthoracic Ivor–Lewis esophagectomy. Twenty percent of the cohort developed recurrent disease. There was no impact on development of disease recurrence or site of recurrence seen with an increasing lymph node count. It is unclear as to the reasons behind the lack of survival benefit seen with greater
lymph node retrieval; arguably, this is contrary to a number of previously published studies.15–17 It is possible that because a majority of patients within this study had pathologic stages 0, I, or II disease, the probability of stage migration was less than if the cohort encompassed more advancedstage tumors. Similar to other studies which have evaluated the clinical impact of transthoracic resection versus transhiatal resection, we did not observe any significant improvement in survival with extended lymphadenectomy, one of the proposed advantages to the transthoracic resection technique.19,20 Other studies have evaluated impact of lymph node resection in the setting of neoadjuvant chemoradiation therapy. There was no difference in number of lymph nodes resected between patients treated with surgery only or those who had either a minor or major histopathologic response to neoadjuvant therapy.21 A multicenter, international study evaluated predictors of survival in patients with locally advanced esophageal cancers treated with neoadjuvant chemoradiation or chemotherapy with complete histopathologic response.22 Number of lymph nodes resected was not an independent predictor of survival. Clearly, pathologic response to neoadjuvant therapy has been shown to be associated with improved overall and disease-free survival.23 Whether response to neoadjuvant therapy should factor into lymphdadenectomy recommendations at the time of surgical resection remains to be determined. Extended lymph node dissection with a requisite number of nodes for submucosal or early stage cancers is also debatable, with recent studies demonstrating no significant difference in survival in patients with lymph node metastases or higher lymph node sampling compared to those without.24–26 The heterogeneity of the data calls into question whether patients should be routinely subjected to extended lymphade nectomy when survival benefit is controversial. The practical implication of deriving lymphadenectomy recommendations from these studies remains unclear but has significant clinical implications, particularly when treatment recommen dations are based upon presence of nodal metastases. This study does have limitations inherent in retrospective analyses. Due to this review spanning a wide range of dates, multiple surgical approaches and preoperative assessments
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were performed; this may represent a confounding bias. In particular, the paradigm of utilizing neoadjuvant chemoradiation therapy has become more popular recently, particularly for locally advanced tumors and was not addressed in this study.
Conclusion Current clinical recommendations for extended lymphadenectomy with increased lymph node examination remain controversial. Multiple studies have failed to demonstrate definitive survival benefit when comparing extended lymph node resection in early stage esophageal cancers or in patients treated with neoadjuvant chemoradiation. This study examines patients who were treated with surgical resection as primary therapy and also found no survival benefit, either overall or disease-free, with increasing lymph node examination. Lower recurrence was also not associated with increasing lymph node examination. In the authors’ opinion, further evaluation regarding optimal lymphadenectomy must be carried out. Now that a significant proportion of patients are treated with multimodality therapy, lymphadenectomy must also be considered in the context of neoadjuvant therapy and potentially treatment response.
References 1. American Cancer Society. Cancer facts & figures 2012. Atlanta: American Cancer Society; 2012. 2. Boshier PR, Anderson O, and Hanna GB. Transthoracic Versus Transhiatal Esophagectomy for the Treatment of Esophagogastric Cancer. A meta-analysis. Annals of Surgery, 2011; 254: 894–906. 3. Omloo JMT, Law SYK, Launois B, et al. Short and long-term advantages of transhiatal and transthoracic oesophageal cancer resection. EJSO, 2009; 35: 793–797. 4. Eloubeidi MA, Desmond R, Arguedas MR, et al. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer, 2002; 95(7): 1434–43. 5. Gertler R, Stein HJ, Langer R, et al. Long-term outcome of 2920 patients with canceres of the esophagus and esophagogastric junction: evaluation of the New Union Internationale Contre le Cancer/ American Joint Cancer Committee staging system. Annals of Surgery, 2011; 253(4): 689–98. 6. AJCC (2010) Esophagus and esophagogastric junction. In: Edge SB, Byrd DR, Compton CC, et al. (eds). AJCC Cancer Staging Manual 7th edition. New York, NY: Springer, pp 103–11 7. Hu Y, Hu C, Zhang H, et al. How does the number of resected lymph nodes influence TNM staging and prognosis for esophageal carcinoma? Annals of Surgical Oncology, 2010; 17: 784–790. 8. Yang HX, Xu Y, Fu JH, et al. An evaluation of the number of lymph nodes examined and survival for node-negative esophageal carcinoma: data from China. Annals of Surgical Oncology, 2010; 17: 1901–1911. 9. Schwarz RE and Smith DD. Clinical impact of lymphadenectomy extent in resectable esophageal cancer. Journal of Gastrointestinal Surgery, 2007; 11: 1384–1394.
J Gastrointest Surg (2013) 17:1562–1569 10. Altorki NK, Zhou XK, Stiles B, et al. Total number of resected lymph nodes predicts survival in esophageal cancer. Annals of Surgery, 2008; 248(2): 221–226. 11. Greenstein AJ, Litle VR, Swanson SJ, et al. Prognostic significance of the number of lymph node metastases in esophageal cancer. Journal of the American College of Surgeons, 2008; 206(2): 239– 46. 12. Mariette C, Piessen GP, Briez N, et al. 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. Annals of Surgery, 2008; 247(2): 365–371. 13. Kelty CJ, Kennedy CW, Falk GL. Ratio of metastatic lymph nodes to total number of nodes resected is prognostic for survival in esophageal carcinoma. Journal of Thoracic Oncology, 2010; 5: 1467–1471. 14. 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. Journal of Thoracic and Cardiovascular Surgery, 2010; 139: 612–20. 15. 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. 16. Peyre CH, 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. Annals of Surgery, 2008; 248: 549–556. 17. Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Annals of Surgery, 2010; 251: 46–50. 18. Rice TW, Rusch VW, Apperson-Hansen C, et al. Worldwide esophageal cancer collaboration. Diseases of the Esophagus, 2009; 22(1): 1–8. 19. Hulscher JB, Van Sandick JW, De Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. New England Journal of Medicine, 2002; 347(21): 1662–9. 20. Omloo JM, Lagarde SM, Hulscher JB, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial. Annals of Surgery, 2007; 246(6): 992–1000. 21. Bollschweiler E, Besch S, Drebber U, et al. Influence of neoadjuvant chemoradiation on the number and size of analyzed lymph nodes in esophageal cancer. Annals of Surgical Oncology, 2010; 17: 3187–3194. 22. Vallbohmer D, Holscher AH, DeMeester S, et al. A multicenter study of survival after neoadjuvant radiotherapy/chemotherapy and esophagectomy for ypT0N0M0R0 esophageal cancer. Annals of Surgery, 2010; 252: 744–749. 23. Meredith KL, Weber JM, Turaga KK, et al. Pathologic response after neoadjuvant therapy is the major determinant of survival in patients with esophageal cancer. Annals of Surgical Oncology, 21010; 17(4): 1159–67 24. Tanaka T, Matono S, Nagano T, et al. Esophagectomy with extended lymphadenectomy for submucosal esophageal cancer: long-term outcomes and prognostic factors. Annals of Surgical Oncology, 2012; 19(3): 750–6. 25. Bogoevski D, Bockhorn M, Koenig A, et al. How radical should surgery be for early esophageal cancer? World Journal of Surgery, 2011; 35(6): 1311–20. 26. Grotenhuis BA, Van Heijl M, Zehetner J, et al. Surgical management of submucosal esophageal cancer: extended or regional lymphadenectomy? Annals of Surgery, 2010; 252(5): 823–30.
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Discussant
Closing Discussant
Dr. Marcelo S. Rocha (Montes Claros, Brazil): The results of surgical therapy in patients with esophageal cancer are still precarious so continuing search for better results in patients with esophageal cancer underwent esophagectomy should be the focus of research and studies like this are illuminating. Comments The main criticism of the study is the lack of information on the initial staging and histologic type of tumors with the choice of surgical approach option since there are many surgical procedures involved. Do patients with lower numbers of lymph nodes removed were submitted to transhiatal resections because they had smaller tumors?
Dr. Joyce Wong: Thank you so much for the comments and question. While multiple resection techniques were employed, 80 % of the patients underwent a form of transthoracic resection, either an Ivor–Lewis or a three-field approach. The majority of our patients, >80 %, had preoperative stages I or II disease. Although we did not specifically correlate preoperative stage with operative technique, the technique utilized was often dependent upon surgeon preference. We did compare the lymph node count between patients undergoing transhiatal versus transthoracic resection and there was no statistically significant difference in lymph node yield between techniques.
