| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Cardiothoracic Surgery, Division of Thoracic Surgery, New York Presbyterian Hospital – Weill Cornell Medical College, New York, New York
Accepted for publication March 25, 2009.
* Address correspondence to Dr Altorki, Department of Cardiothoracic Surgery, Suite M404, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021 (Email: nkaltork{at}med.cornell.edu).
Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
Methods: We conducted a retrospective review of a prospective database over a 20-year period to identify patients with resected esophageal carcinoma with nonregional lymph node metastases. Medical records were reviewed and risk factors were analyzed.
Results: Sixty-seven patients underwent esophagectomy for M1a or M1b disease from 1987 to 2007. Esophagectomy was transthoracic in 62 patients and transhiatal in 5. The median number of lymph nodes harvested was 36. Sites of nodal metastases were the following: recurrent nodal chain in 42 patients, celiac in 20, both recurrent and celiac in 4, and paratracheal in 1. Median length of follow-up was 66 months. The 5-year overall survival for the entire cohort was 25%. The 5-year overall survival was significantly higher with earlier T-status, (pathologic tumor [pT]1/T2 vs pT3/T4; 62% vs 15%, p = 0.006). Thirteen patients who had nonregional nodal metastases without involvement of regional nodes (pN0) had a significant improvement in 5-year survival (67% vs 15%; p < 0.001). Patients with squamous cell carcinomas had higher 5-year survival compared with those with adenocarcinomas (42% vs 14%; p = 0.009). Patients treated with induction chemotherapy had prolonged 5-year survival (41%, p = 0.06) compared with those treated with adjuvant chemotherapy (11%) or no therapy (20%). Multivariate analysis demonstrated that chemotherapy treatment, squamous cell type, and early T stage (pT1/T2) are significant positive predictors of survival.
Conclusions: Surgical resection for patients with esophageal cancer associated with nonregional nodal metastases results in 25% survival at five years. Squamous histology, earlier T status, and perioperative chemotherapy are independent positive predictors of long-term survival.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
Preoperative Evaluation
Preoperative assessment was directed toward establishing a clinical TNM stage as well as assessing the patients' ability to tolerate the planned operation. Standard diagnostic and staging workup in this cohort included an upper endoscopy with biopsy and a computed tomography (CT) of the chest and upper abdomen to evaluate locoregional extent of the disease and exclude distant metastases. A subset of patients underwent endoscopic ultrasonography (EUS) as well as positron emission tomography (PET). Generally, patients were considered for surgical resection if preoperative evaluation revealed no evidence of distant visceral metastases or clear evidence of direct tumor invasion of the airway or major vascular structures. The presence of extensive nodal disease was not considered a contraindication to resection unless it clearly extended beyond the proposed fields of dissection. Finally, all patients underwent detailed evaluation of pulmonary and cardiac function to determine their ability to withstand the planned procedure. Generally, patients with a forced expiratory volume in the first second of expiration (FEV1) less than 1.5 liters per second, despite aggressive physiotherapy and optimal bronchodilator therapy, were considered ineligible for resection. Cardiac disease, if suspected, was carefully assessed using either noninvasive stress testing or angiocardiography if necessary.
Induction and Adjuvant Therapies
Most patients received platinum-based induction chemotherapy prior to surgical resection as part of an ongoing institutional protocol. Twenty patients underwent surgical resection alone. Another subset of patients received adjuvant chemotherapy and (or) radiotherapy at the discretion of the surgeon and (or) oncologist.
Surgical Resection
Surgical resection in this cohort of patients consisted of transhiatal esophagectomy or transthoracic en bloc esophagectomy with 2-field or 3-field lymphadenectomy. The basic technique of en bloc esophagectomy has been described previously [8]. En bloc esophagectomy was almost always carried out through three incisions: a right thoracotomy, followed by a laparotomy, and a collar neck incision. The basic technical principle underlying the en bloc esophagectomy was resection of the tumor-bearing esophagus with a wide envelope of periesophageal tissue, which included both pleural surfaces laterally, a patch of pericardium anteriorly, all lymphovascular tissue, and the thoracic duct posteriorly, along with the mediastinal lymph nodes from the tracheal bifurcation to the hiatus. An upper abdominal lymphadenectomy was performed that included the common hepatic, celiac, left gastric, parahiatal, lesser curvature, and retroperitoneal lymph nodes. A "third field" lymphadenectomy was incorporated in some patients by extending the nodal dissection to include the superior mediastinal nodes and the nodes along the course of both recurrent laryngeal nerves and the deep cervical nodes located lateral to the jugular veins.
Transhiatal esophagectomy was performed as described by Orringer and colleagues [9] through an upper abdominal incision and a left neck incision. Parahiatal dissection and abdominal nodal dissection were performed similar to the en bloc approach. The paraesophageal and mediastinal lymph nodes were removed as exposure allowed. Reconstruction in all patients in this cohort was with a greater curvature gastric tube. Pathologic staging was done according to the TNM classification of the AJCC [1].
Follow-Up
After hospital discharge, patients were seen in the office at intervals of 3 months for the first 2 years and every 6 months thereafter. Patients from distant geographic regions were followed by contacting their local physician as well as direct patient contact. A CT of the chest and upper abdomen was obtained every 6 months for 2 years and every year thereafter. Other studies such as endoscopy and PET scanning were done in symptomatic patients.
Statistical Analysis
Statistical analysis was performed using SPSS statistical software (SPSS Inc, Chicago, IL). Overall survivals for the entire cohort and the various subgroups were analyzed using the Kaplan-Meier method. In this study, overall survival was defined as the percentage of patients who have survived for a defined period of time after surgical resection. The log-rank test was used to determine significance of survival distributions among groups. Independent t tests were used for two-group comparisons of continuous variables. Categoric data in cross-tabulation tables were compared using the Fisher exact test or the Pearson 
2 test. Nonparametric data were analyzed with the Mann-Whitney U test. Multivariate analyses were performed by Cox regression. Results were considered significant for p values less than or equal to 0.05. This study was approved by the Institutional Review Board of the Weill Medical College of Cornell University, with a waiver of the need for patient consent.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
Surgical Approach and Extent of Resection
Sixty-two patients had a transthoracic resection (53 en bloc and 9 non-en bloc). Among the en bloc group, two-field lymphadenectomy was performed in 3 patients and three-field lymphadenectomy was performed in 50 patients (Table 1). Five patients had a transhiatal resection. Sixty-two patients (92.5%) had a complete R0 resection. The median number of lymph nodes recovered among all patients was 36.
|
Hospital Morbidity
Forty-one patients (61%) had an uncomplicated postoperative course. Complications occurred in 23 patients. Complications were minor in 10 patients (15%) and major in 13 patients (19%) excluding the three postoperative deaths. The most frequent morbidity was pulmonary which occurred in 16 patients (24%). Recurrent nerve injury occurred in 4 patients (6%), which was unilateral in 3 and bilateral in 1 patient. Anastomotic leak occurred in 6 patients (9%).
Pathologic Findings
Primary tumor location and sites of nodal metastases are presented in Table 2. Most of the patients had distal third esophageal carcinoma, with the recurrent nodal chain as the most common site of nonregional nodal metastases. Sites of nodal metastases were recurrent in 42, celiac in 20, combined recurrent and celiac in 4 and paratracheal in 1. Interestingly, recurrent nodal metastases were not limited to tumors in the proximal third of the esophagus. Among those patients with recurrent nodal metastases, 64% of their tumors (27 out of 42) were located in the distal third of the esophagus. The histopathologic characteristics of all 67 patients with resected esophageal carcinomas are presented in Table 3. Adenocarcinoma was the more common cell type. One patient with a proximal third squamous cell carcinoma had a complete pathologic response locally after preoperative chemotherapy (T0N0), despite persistent recurrent nodal disease (M1a).
|
|
Overall Survival
Median follow-up for all surviving patients was 66 months. The 5-year overall survival for the entire cohort was 25% (Fig 1). There was no significant difference in 5-year survival between the M1a and the M1b groups of patients (27.0% vs 19.5%; p = 0.363) (Fig 2). Primary tumor location had no bearing on overall survival. The 5-year overall survival was significantly higher with early T-stage (pT1/T2) compared with late T-stage (pT3/T4) (62% vs 15%; p = 0.006) (Fig 3). Thirteen patients had nonregional nodal metastases without involvement of regional nodes (pN0). This subset had significantly higher 5-year survival (67% vs 15%; p < 0.001) (Fig 4). Patients with squamous cell carcinomas had better 5-year survival than those with adenocarcinomas (42% vs 14%; p = 0.009) (Fig 5). Patients treated with induction chemotherapy had a 5-year survival of 41% compared with a 5-year survival of 11% in those treated with adjuvant chemotherapy or no adjuvant therapy (20%) (p = 0.06) (Fig 6). Multivariate analysis showed that perioperative chemotherapy treatment, squamous cell histology, and early T-stage (pT1/T2) were significantly and positively associated with improved survival (Table 4).
|
|
|
|
|
|
|
|
Comment |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
The goal of our study was to review our surgical experience in esophageal cancer patients with nonregional nodal metastases and to analyze factors predicting long-term survival. We report here an overall 5-year survival of 25% for patients with resected esophageal carcinoma with nonregional nodal metastases. In this study 92.5% of all patients had a complete surgical resection (R0). The majority of patients underwent en bloc esophagectomy with three-field lymphadenectomy, with acceptable morbidity and mortality. The median number of lymph nodes harvested was 36, twofold the minimal number of nodes considered acceptable for accurate staging [10]. We have shown that early pathologic tumor (pT) stage carried a significant survival advantage in patients with nonregional nodal metastases. The notion that T stage is a strong predictor of survival has been extensively reported previously [1, 2, 6, 11]. Tachimori and colleagues [6] reported a similar finding in patients with resected esophageal carcinoma with clinically positive cervical nodes. Their published 5-year survivals for pT1, T2, T3, and T4 tumors were 87.5%, 66.7%, 13.7%, and 0%, respectively. It appeared that patients with less degree of transmural invasion have a better chance of survival. This survival difference might be attributed to our previous findings that the prevalence of nodal metastases increased with increasing depth of tumor penetration into the esophageal wall [12]. In the current study, we have found that N0 status conferred a significant improvement in survival in patients with nonregional nodal metastases. The 5-year survival is superior at 67%. Several investigators, including our group, have correlated worse survival with increasing number as well as size of metastatic regional lymph nodes [6, 8, 11, 13, 14]. We reported previously [8] that the presence of 7 or more positive nodes as suggested by Akiyama and colleagues [13] predicted worst prognosis. Tachimori and colleagues have noted that, although not statistically significant, survival was also correlated with number of regional N1 nodes involved. Five-year survival was 11.5% if more than 7 regional N1 nodes were involved in contrast to survival of 46.2% if only 1 to 3 N1 nodes were involved [6]. Furthermore, Dhar and colleagues [14] demonstrated that in patients with squamous esophageal cancer, the size of metastatic lymph nodes was an independent predictor of survival by multivariate analysis. In summary, both local T and regional N1 status appear to be important factors determining survival even for patients with nonregional M1 nodal status.
It is interesting to note that 13 (19%) patients in our cohort have nonregional M1 nodal metastases without involvement of regional N0 nodes. It has been established by anatomic investigations that the esophagus has abundant intramural lymphatic channels running in the longitudinal direction [15]. Therefore, it is reasonable to assume that cancer cells metastasize directly to the extrathoracic lymph nodes adjacent to the proximal and distal ends of the esophagus through this lymphatic pathway to recurrent nerve nodes and paracardial-celiac nodes. Recently, there has been much enthusiasm to reclassify these nodal stations as regional rather than nonregional nodes as governed by the location of the primary tumor [7, 16]. Our superior survival results in those patients with pathologic N0/M1 nodal status support the reclassification of recurrent and celiac nodes as regional lymph nodes. In addition, we did not observe any significant survival differences between the M1a and M1b subgroups, further highlighting the artificial notion of nonregional nodes as dictated by the location of the primary tumor under the current staging system.
In this study, we have observed that patients with M1 nodal metastases with squamous cell carcinomas had a significant survival advantage compared with those with adenocarcinomas. We and others have made this observation previously [7, 12, 17]. Lerut and colleagues [7] have noted in their cohort of 174 patients that squamous cell carcinoma showed an improved 5-year survival (15.8%) compared with 7.3% for adenocarcinomas for patients with cervical lymph node positive patients. In another study, Alexiou and colleagues [17] analyzed survival difference after esophageal resection between squamous cell carcinoma and adenocarcinoma and found that overall survival was significantly better for squamous cell type. Squamous cell type was found to be a significant predictor of survival by multivariate analysis. Even in patients with nodal disease, squamous cell type had a relatively improved survival compared with adenocarcinoma. Taken together, these results suggest that there is an inherent difference in biologic behavior between adenocarcinoma and squamous cell type in terms of tumor aggressiveness and distant metastatic potential, with squamous cell carcinoma carrying a more clinically benign course.
Patients in our cohort who were treated with preoperative chemotherapy had improved 5-year survival compared with those patients who received no therapy or adjuvant chemotherapy. This is not a surprising finding given the advanced nature of the disease in our series of patients. Multiple other studies have confirmed the survival advantage of preoperative chemotherapy [18–21]. Adjuvant chemotherapy has been shown by others to have no significant survival benefit after esophagectomy [22–24]. Our treatment strategies have evolved through the 20-year study period, with increasing use of preoperative chemotherapy in the recent years. Given our findings, the current standard of care of patients with resectable nonregional nodal metastases should routinely involve the use of preoperative chemotherapy.
There are several limitations in this study. This is a cohort of patients with esophageal carcinoma with nonregional nodal metastases surgically resected in a single tertiary care center. Patients with solid organ metastases and compromised cardiopulmonary status were excluded. Our overall survival of 25% reflected a selected group of M1 patients, subjected to a prereferral selection bias. This survival result should not be extrapolated to all patients with M1 disease at the time of diagnosis, because patients with obvious distant organ metastases or bulky nodal disease might not have been referred for surgical evaluation. This is also a study cohort spanned over a 20-year period, during which there has been much evolution in staging techniques and multimodality treatment of esophageal cancer. More recently, there has been an obvious shift toward the increasing use of PET scan in preoperative staging as well as use of preoperative chemotherapy. Large prospective multicenter studies incorporating both induction therapies and surgical resections are necessary to confirm our findings.
In summary, for patients with completely resected esophageal carcinoma with nonregional nodal metastases, squamous cell type, early tumor pT stage, and chemotherapy treatment are positive independent factors affecting long-term survival. Preoperative chemotherapy and surgical resection with appropriate lymphadenectomy may be considered in well-selected patients with esophageal carcinomas with nonregional nodal metastases, particularly in those patients with squamous cell pathology and early T stage.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
And is it your feeling that lymphadenectomy for M1 disease is one of the reasons those patients do better or is it more of an associated phenomenon?
DR LEE: Thank you, Dr Swanson. That was an excellent question.
In our center, we do advocate en bloc esophagectomy with three-field lymphadenectomy. As you know, there are multiple series published by us, Dr Lerut, and Japanese surgeons showing that the local regional recurrence rate is extremely low after en bloc esophagectomy, 8% in contrast to 30 or 40% in other surgical series.
There is also a recent paper published in the JTCVS June of last year by Dr DeMeester looking at neoadjuvant chemotherapy and radiation followed by either transhiatal esophagectomy versus en bloc esophagectomy. In his paper, it's quite clear that the group who underwent en bloc esophagectomy had a significantly higher survival rate compared to those patients who had transhiatal esophagectomy, and I believe their local regional recurrence rate was extremely low as well.
There are also several other reasons why I think our results are so much better than other similar series published before. Thirty-seven percent of our patients have squamous cell histology. As we have shown here, those patients tend to do better than patients with adenocarcinoma. If you look at most of the Western series published in the United States, the majority was of the adenocarcinoma cell type, and the majority of the nonregional nodal metastases was in the celiac axis.
I also believe that patients in those series were understaged because three-field lymphadenectomies were not performed. In our series of 24 patients who had celiac nodal metastases, 4 patients have concomitant recurrent as well as celiac nodal metastases. So I suspect a number of the patients who did not receive cervical or recurrent nodal dissection had occult nodal disease there. In our series, all 4 of those patients died from their disease.
And finally, other than the low local regional recurrence rate achieved by en bloc esophagectomy, a distinct survival benefit has been well shown by published studies by our group, Dr Lerut's group, Japanese groups as well as Dr DeMeester's group.
DR SWANSON: So you do three-field for everyone?
DR LEE: Unless they have compromised cardiopulmonary or performance status, then we don't do it.
DR ARA A. VAPORCIYAN (Houston, TX): Quick question. I may have missed this in the presentation. I didn't see it in the abstract.
Are these patients staged clinically as being M1A, or are these patients that were identified using pathologic stage? I ask because if they are identified postoperatively by your extensive lymphadenectomy, then are you simply finding a population of clinically unidentified N1 patients much like the inadvertent N2 patient in lung cancer?
DR LEE: That's a very good question. We used pathologic staging to identified patients for our current review. We do have clinical staging for these patients, and I didn't have the time to present it here. There is an 80% correlation between clinical and pathologic stages in our series.
Now, 28 of these patients had received preoperative chemotherapy. I didn't show the data here, but 10 patients in that group had downsizing of either the T stage or the N stage, and those patients in our analysis seemed to do better as well. In our practice, if patients received preoperative chemotherapy, they are restaged by PET scan. Even though if there is persistent evidence of disease either in the cervical lymph nodes or the celiac axis, if we think we can encompass those areas by our fields of dissection, we do offer them three-field lymphadenectomy with en bloc esophagectomy.
DR SETH D. FORCE (Atlanta, GA): Dr Lee, I had one question for you. You had a 24% incidence of pulmonary complication, 6% incidence of recurrent nerve injury. Given that all or most of your patients had neck dissections and anastomoses, are you doing modified barium swallows in these patients to look for aspiration in addition to looking for a leak in your patients?
DR LEE: Yes, we do a modified barium swallow. A number of patients did have some aspiration, and most of them resolve over time.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  H. TANAKA, M. OHIRA, N. KUBO, K. MUGURUMA, Y. YAMASHITA, T. SAWADA, and K. HIRAKAWA Association of Location of Lymph Node Metastases with Postoperative Recurrence of Esophageal Squamous Cell Carcinoma Anticancer Res, August 1, 2012; 32(8): 3421 - 3426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Stiles, F. Mirza, J. L. Port, P. C. Lee, S. Paul, P. Christos, and N. K. Altorki Predictors of Cervical and Recurrent Laryngeal Lymph Node Metastases From Esophageal Cancer Ann. Thorac. Surg., December 1, 2010; 90(6): 1805 - 1811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yuequan, C. Shifeng, and Z. Bing Prognostic Factors and Family History for Survival of Esophageal Squamous Cell Carcinoma Patients After Surgery Ann. Thorac. Surg., September 1, 2010; 90(3): 908 - 913. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
