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J Thorac Cardiovasc Surg 1999;117:960-968
© 1999 Mosby, Inc.
GENERAL THORACIC SURGERY |
From the University of Southern California, Departments of Surgery and Cardiothoracic Surgery, Los Angeles, Calif.
Read at the Twenty-fourth Annual Meeting of The Western Thoracic Surgical Association, Whistler, British Columbia, June 24-27, 1998.
Received for publication July 15, 1998. Revisions requested Oct 1, 1998. Revisions received Jan 11, 1999. Accepted for publication Jan 12, 1999. Address for reprints: Steven R. DeMeester, MD, University of Southern California, Department of Cardiothoracic Surgery, Norris Comprehensive Cancer Center, 1441 Eastlake Ave, MS 74, Los Angeles, CA 90033.
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Abstract |
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAppendix: DiscussionReferences |
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1 Esophageal adenocarcinoma is one of the most lethal malignant diseases known to mankind. Within 5 years of diagnosis the majority of patients will die.
Despite liberal endoscopy in patients with reflux symptoms and routine endoscopic surveillance for Barrett's esophagus, most patients who have adenocarcinoma of the esophagus present de novo with dysphagia and have large tumors. Using endoscopic ultrasound, we now have the capability to identify patients with advanced disease, including those with transmural tumors. 2,3 In many centers these patients are targeted for neoadjuvant therapy. Before this alternative therapy is widely adopted, it is imperative that the results of complete surgical resection alone be defined. Since 1981 our group has used en bloc esophagectomy with systematic mediastinal and abdominal lymphadenectomy to treat patients with esophageal adenocarcinoma. We reviewed our experience with this procedure in patients with transmural adenocarcinoma of the lower esophagus and gastroesophageal junction to determine the prevalence and location of node metastases, the feasibility of performing an R0 resection, and the outcome in terms of disease recurrence and survival.
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Methods |
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Operative approach
En bloc esophagogastrectomy with systematic mediastinal and abdominal lymphadenectomy was performed as previously described. 4,5 In brief, the esophagus, azygos vein, and surrounding mediastinal tissues were removed in continuity. The thoracic dissection extended superiorly to the carina, laterally to include the left and right mediastinal pleura, anteriorly to the membranous trachea and pericardium, posteriorly to the spine and aorta, and inferiorly to the diaphragm. The abdominal dissection included removal of the proximal two thirds of the stomach, the greater omentum, spleen, left gastric and splenic arteries along with their surrounding fibro-areolar tissue, and nodal tissue along the portal vein, common hepatic artery, and celiac axis (Fig. 1). Overall, this dissection allowed a reproducible, systematic removal of all lymph nodes in the following locations: low paratracheal, subcarinal, paraesophageal, parahiatal, porta hepatis, hepatic artery, celiac axis, and the retroperitoneal area of the upper part of the abdomen (Fig. 2). In most patients, gastrointestinal continuity was established by an isoperistaltic colon interposition.
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Follow-up
Patients were followed up by the operating surgeon at 3-month intervals for the first 3 years, twice a year for the next 2 years, and yearly thereafter. Median follow-up was 23 months (range 4-118 months). Each follow-up visit included serum and liver chemistry panels, carcinoembryonic antigen level, and computed tomographic scans of the chest and abdomen. All surviving patients were either seen in person or contacted by telephone within 3 months of the preparation of this manuscript. Recurrent tumor located within the field of the original en bloc resection was considered local recurrence. All patients were included in the survival analysis, including those dying in the perioperative period and those dying of causes other than cancer.
Statistical analysis
The 
2 and Fisher exact tests were used to compare proportions. Survival probabilities were calculated by the method of Kaplan and Meier, and survival curves were compared by the log-rank method.
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Results |
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A total of 2340 lymph nodes were excised and examined histologically. The median number of lymph nodes removed per patient after systematic mediastinal and abdominal lymphadenectomy was 51 (range 18-92). Lymph nodes metastases were identified in 37 of the 44 patients (84%). Despite transmural invasion, 7 patients (16%) had no lymph node metastases. Of the 37 patients with lymph node metastases, 16 (43%) had 4 or fewer involved nodes, and in these patients the majority (69%) had only local node involvement. In contrast, the majority (62%) of patients with more than 4 involved lymph nodes were found to have distant node metastases. Thus there was a trend toward an increased likelihood of distant node metastases with increasing number of involved lymph nodes (2, P = .13). The prevalence of metastatic nodes in patients with tumors located at the gastroesophageal junction or in the distal esophagus is shown in Fig. 3. We found that the frequency and distribution of nodal metastases was similar for both primary tumor locations.
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6 was not a statistically significant predictor of survival.
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Discussion |
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A problem with using the absolute number of involved lymph nodes after resection to predict the likelihood of long-term survival is the lack of a measure for the completeness of the lymphadenectomy. Recently, the ratio of involved to total number of nodes removed has been proposed as a more quantitative method to assess the adequacy of a lymphadenectomy. Holscher and colleagues 7 reported that a ratio of involved to total removed nodes of 0.3 was the most effective prognostic parameter to stratify patients into those likely to die of their disease (>0.3) versus those likely to have better survival. Our data suggest that a ratio of 0.1 is a better predictor. A likely explanation for this apparent discrepancy is that the median number of removed nodes in our series was 51, compared with 26 in the series by Holscher and coworkers. 7 A more extensive lymphadenectomy results in a greater number of uninvolved nodes removed, thereby driving down the node ratio. This emphasizes that the critical number is not the ratio itself, but instead the total number of involved and removed nodes. Consequently, a systematic lymphadenectomy is fundamental in allowing an accurate assessment of the patient's lymphatic tumor burden and in determining the likelihood of long-term survival. The importance of a complete, systematic thoracic and abdominal lymphadenectomy has been confirmed in our own experience after transhiatal resection in patients with a transmural esophageal adenocarcinoma who are elderly or have poor cardiopulmonary physiology. In these patients, despite a complete abdominal lymphadenectomy, the node ratio was unable to predict the likelihood of survival.
We found that adenocarcinomas of the gastroesophageal junction and lower esophagus tend to metastasize to similar lymph node regions and that distant or celiac nodal involvement occurred with primary tumors in either location and did not preclude long-term survival. We did note that patients with distant node metastases tended to have more involved nodes and, as a consequence, were more likely to have a recurrence and die of their disease. However, in the absence of a greater number of involved nodes, distant nodal metastases per se were not predictive of the likelihood of survival and should not deter resection.
Comparing outcomes between various reports in the literature is difficult because of the confusion in staging. However, the 26% 5-year survival in our series compares favorably with the 25% to 33% 5-year survival reported by others for esophagectomy with limited lymphadenectomy. 8,9 The survival in our series is particularly noteworthy in that it involved exclusively patients with transmural disease, whereas the other series included a variety of stages. Altorki and colleagues 10 have recently reported favorable results similar to ours, with a 34.5% 4-year survival after en bloc resection in patients with advanced (stage III) esophageal cancer. They concluded, and we would agree, that en bloc resection improves survival compared with lesser resections. 10 In our center, during the same period as this study, we performed 40 transhiatal resections in patients with transmural adenocarcinoma because of advanced age or compromised physiologic condition. In this group survival at 5 years was 7%, and recurrent local disease developed in 15% of the patients.
Of importance, survival after an en bloc resection for transmural esophageal adenocarcinoma in this series compares favorably with published results for various stages of resectable esophageal cancer treated with neoadjuvant therapy followed by surgery. The two most widely quoted randomized trials both report a 3-year survival of 32% in the neoadjuvant group, with the best survival occurring in the 20% with complete pathologic response (Table III). 11,12 Three-year survival for the group of patients with transmural tumors treated only by en bloc resection in this series was 36%. Given our results with en bloc surgical resection alone, one must question the utility of routine neoadjuvant therapy. However, we found that the subgroup of patients with a transmural tumor and more than 4 lymph node metastases had a 90% likelihood of developing systemic disease after resection alone. In our opinion, these patients should be targeted for neoadjuvant therapy. Furthermore, despite the lack of improvement in survival reported with previous trials, consideration should be given to early adjuvant postoperative chemotherapy in those patients found on pathologic review of the specimen to be at high risk for recurrence. Perhaps aggressive chemotherapy directed at a group of patients known to have a 90% likelihood of recurrence would demonstrate an improvement in survival.
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10 reported recurrent local disease in 5.4% of patients after en bloc resection for stage III esophageal cancer. In contrast, Urba and colleagues 11 noted that local failure occurred in 39% of patients who had transhiatal esophagectomy alone and in 19% of patients after multimodality therapy that included the same type of resection. It is interesting to speculate whether, with better surgical therapy in these trials, the difference in outcome would vanish, or perhaps even be in favor of complete surgical resection alone. |
Conclusions |
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Appendix: Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAppendix: DiscussionReferences |
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I have a few questions that reflect my skepticism about the validity of this study to really prove its point about the role of en bloc esophagectomy.
First, I noticed that you had accrued 44 patients over 17 years, but the median follow-up was under 2 years, which suggests that you are comparing patients accrued very recently with patients distributed over a significant amount of earlier time. I think everyone believes that the biologic behavior of adenocarcinoma has changed. Does that disturb you at all or do you think this is a homogeneous patient population?
Dr Nigro. Undoubtedly the epidemiology of esophageal cancer has changed over the past 20 years and patients are now referred for treatment with earlier disease. This may be partially due to our more substantial understanding of those groups at risk and the recognition of the relationship between gastroesophageal reflux disease and esophageal adenocarcinoma. But there is no evidence that the biologic behavior of esophageal adenocarcinoma has changed. Since all of these patients had transmural disease, they should be relatively comparable.
Dr Little. It would seem so, but I am concerned. I do not think that adenocarcinoma of the gastroesophageal junction is behaving now the way it did 17 years ago, so that is at least a concern.
The second question has to do with the fact that even though all patients have transmural primary tumors, a surprisingly high number had no nodes involved, which actually makes them have somewhat early disease, certainly stage II. Since your paper does not address the symptoms in this patient group, were some of these patients actually identified in surveillance approaches, rather than being taken care of because of symptoms?
Dr Nigro. All of the patients in this study presented with transmural tumors and had symptoms of dysphagia and weight loss; none of these patients were discovered during Barrett's surveillance. In our experience those cancers found during surveillance tend to have mucosal or submucosal invasion only, and we now consider these (tumors) to represent early disease.
Dr Little. My final comment and question have to do with the crux of interpretation of these data. My conclusion continues to be that survival is more a function of the biologic behavior and the stage at which the disease is detected rather than the operative technique, as much as I would like to believe the latter. For example, survival was excellent in patients with N0 disease, as one would expect. I understand the theory that you may detect some micrometastatic deposits in lymph nodes. Nonetheless, in patients with N0 disease, extended dissection does not seem to be very beneficial. My other observation is that patients who had 5 or more lymph nodes involved did very badly and their 5-year actuarial survival was just over 10%. I would argue that those patients did not benefit significantly from an extended resection.
Finally, the survival in the patients with 1 to 4 involved nodes was 23%, which is certainly good, but not obviously or dramatically better than what has been reported with the so-called standard techniques. If you follow the argument that in that case there is no benefit to going beyond what you call local nodes, the hiatal, left gastric artery, lesser curve, and periesophageal nodes, which I think most surgeons would routinely resect, then there is no benefit to going beyond that. That allows you to keep the greater curvature and use the stomach for reconstruction, which is a much less complicated and a much less morbid operation than routinely using the colon.
Do you really believe you have established the role for routine radical en bloc esophagogastrectomy with removal of two thirds of the stomach in all patients with adenocarcinoma of the gastroesophageal junction?
Dr Nigro. We believe that this operation provides for good survival, excellent local disease control, and accurate stratification for subsequent adjuvant therapy. With more limited resections we have observed a lower survival, a high local recurrence rate, and inability to accurately stratify patients for risk of recurrence and cancer-related death.
Dr Gundry. Do you plan to continue this approach or are you going to investigate some adjuvant therapy or multiple-modality protocols?
Dr Nigro. One of the main objectives of our work with esophageal adenocarcinoma has been to establish the relationship between depth of tumor invasion, node status, and survival. This information was available only after performing a resection that included a systematic abdominal and thoracic lymphadenectomy. Our results indicate that patients with transmural tumors and more than 4 involved lymph nodes are at especially high risk for recurrence and are unlikely to be cured with surgery alone. We have incorporated these results into our treatment protocol and believe that this group of patients should be targeted for neoadjuvant and adjuvant therapy.
Dr Little. I would like to make one complimentary comment in closing. This paper based survival statistics on all deaths, perioperative deaths as well as the late deaths due to cancer, and that is the way these data should be presented. It is the most honest way, and I hope that others will adopt this method as well.
Dr Douglas E. Wood (Seattle, Wash). I had some of the same comments and questions that Dr Little had. The recurrence rate and survival of patients after esophagectomy for esophageal cancer is related to the biology of the tumor. One of your early slides showed that the majority of your survivors had N0 disease. If those patients are the long-term survivors, it is hard to imagine that an extended procedure is going to benefit them. In fact, there is no good evidence in any series that a more radical resection does result in better survival. I would urge us all to participate in developing prospective trials to examine the role of neoadjuvant and adjuvant therapies and different surgical techniques rather than multiple parochial case studies within each of our institutions.You had mentioned in the conclusion a potential role for adjuvant therapy. No data have been presented that show that postoperative or adjuvant therapy improves survival in esophageal cancer. Can you tell me what you mean by selecting patients for adjuvant therapy?
Dr Nigro. We believe that patients with N0 disease will not benefit from neoadjuvant or systemic therapy. We now know that those patients with greater than 4 involved nodes have an extremely poor prognosis, and we believe that it would be more appropriate to target this group for systemic therapy in a manner analogous to the application of adjuvant therapy in colon adenocarcinoma.
Dr Wood. If you could identify that before resection, would you prefer to avoid resection in those patients and treat them nonoperatively? I would point out that not only did patients with more than 4 positive lymph nodes do poorly, but the patients with any lymph node metastases as a group did not do well in your study.
Dr Nigro. The presence of lymph node metastases is a poor prognostic indicator, but it remains difficult to determine this preoperatively. Although patients with involved nodes have a poor prognosis, local disease control remains an important goal that is rarely obtained with nonoperative therapy. In our opinion, surgical resection provides the best palliation for patients with advanced tumors and is the only therapy that is potentially curative.
Dr Wood. Have you used endoscopic ultrasound, computed tomographic scanning, or any of the laparoscopic methods of sampling lymph nodes before resection?
Dr Nigro. Currently our preoperative assessment includes a computed tomographic scan of the abdomen and pelvis and endoscopic ultrasound. As we all know, endoscopic ultrasound is able to determine depth of tumor invasion in approximately 80% of cases, but it does not always accurately reveal node status. We do not believe it is beneficial to add additional invasive procedures such as thoracoscopy and laparoscopy to stage the disease when we can obtain accurate disease staging, along with local disease control and good survival, with one primary operation.
Dr John R. Benfield (Sacramento, Calif). I think there is no better place than The Western Thoracic Surgical Association to recognize that thoracic surgery is a family affair.
Dr John Nigro is the son of one of my close friends who is also a thoracic surgeon. Dr Nigro, I think you said that one of your patients who had a peritracheal recurrence had a second resection and then became a long-term survivor. Did I hear that correctly?
Dr Nigro. That is correct.
Dr Benfield. Is it your practice to reoperate on patients who have recurrence? Did this patient have additional nonoperative therapy? If so, do you think the resections or the nonoperative treatment was more important in achieving long-term survival after reresection?
Dr Nigro. We are in the process of reviewing our experience with these patients. We now have a series of 5 to 7 patients with isolated lymph node recurrence who have undergone a second resection and now have no evidence of disease. We believe that these patients can benefit from surgery. The patient you referred to received no therapy other than surgery.
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