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Ann Thorac Surg 1995;59:1090-1091
© 1995 The Society of Thoracic Surgeons
DR SAFUH ATTAR (Baltimore, MD): I congratulate Dr Naunheim and his associates on their excellent results and rise to confirm them. At the University of Maryland Medical Center under the direction of Dr Mark Krasna, we have treated 24 patients with trimodality therapy similar to that presented here.
We used three courses of 5-FU and cisplatinum instead of 2 used by the Naunheim and associates followed by 5,040 cGy over 5 weeks. There were 6 adenocarcinomas and 18 squamous cell carcinomas. They all were treated by thoracotomy and esophagectomy except in 3 patients who refused resection. There was one death due to perforation of the esophagus preoperatively, and two deaths postoperatively, one due to radiation pneumonitis at 6 months with evidence of N3 disease and the other at 2 months because of adult respiratory distress syndrome without evidence of disease. The remaining patients are all alive and well without evidence of disease at 2 years.
We believe that all patients with esophageal cancer should be staged not only by thoracic thoracoscopy but also by laparoscopy. When thoracoscopy only was done, 3 cases of N3 disease in celiac nodes were missed. This was demonstrated at operation. With laparoscopy the staging can be downstaged after the above treatment. Four cases of N3 disease were downstaged to N0.
Doctor Naunheim, if you had evidence or if you knew of the presence of N3 disease in the 4 patients, 16% of this series, would you still have operated on them? Also, do you think there is any difference in the results of trimodality therapy between squamous cell carcinoma and adenocarcinoma?
DR NAUNHEIM: Thank you, Dr Attar. In a prior report we had looked at and specifically compared squamous and adenocarcinoma and found no significant difference in their long-term survival. As you look at the results of other multimodality series from McFarlane, Dr Wolfe, and Dr Orringer, very few, if any, have found significant survival differences. Now, the numbers are small, but no one other than Gill and Jamieson has ever demonstrated that adenocarcinoma carries a worse prognosis.
With regard to N3 disease, we did find patients who we suspected to have matted celiac adenopathy; not surprisingly, upon laparotomy we confirmed this finding and the disease was unresectable. We were not using laparoscopy at that point, nor thoracoscopy. I think these videoscopic techniques open up exciting avenues and, in the future, are going to be critical when performing neoadjuvant studies. Pathologic determination of node involvement must be undertaken before induction therapy if we are to stage and stratify patients accurately. We now realize that some of the earlier induction studies for lung cancer are not valid because of a lack of histologic confirmation of mediastinal node status. With mediastinoscopy, it certainly is easy to get that information, which is critical if we wish to be certain we are making a difference. I think similar staging issues pertain to esophageal carcinoma, and that preinduction laparoscopy and thoracoscopy for staging are going to be valuable tools.
DR CAROLYN E. REED (Charleston, SC): Thank you, Dr Naunheim; I enjoyed your paper and I thank you for a copy in advance. It is an important paper because you are dealing with adenocarcinoma alone. With a rising incidence of adenocarcinoma, this should lead us to look carefully at patient characteristics, patterns of recurrence, and survival data. I believe it is very important to record whether the treated group includes a population undergoing endoscopic surveillance for Barrett's esophagus. Inclusion of these patients may lead to better results artificially. Doctor Naunheim, how many of your patients with Barrett's esophagus were under surveillance?
There are a couple of points I would like to emphasize. Your postoperative neoadjuvant staging, computed tomographic scan, esophagoscopy, and biopsy, led you to believe that you had achieved a good response in a very large number of patients. For example, 21 of 28 endoscopic biopsies were negative. However, only a disappointing 16% pathologic complete resection rate was demonstrated. A recent study by Laterza also has demonstrated that postneoadjuvant staging, including endoscopic ultrasound and biopsy, are accurate less than 40% of the time. Your best results were in complete responders, as others have shown. However, your 5-year results are disappointing, indicating that we must search for better induction chemoradiotherapy and, perhaps more importantly, markers of complete response.
In your report you discuss the option of not adding operation to chemoradiotherapy. However, with staging being so poor and with a need to confirm pathologically the impact of any new treatment arm by showing the number of complete responders and potential long-term survivors, do you believe that operation can be abandoned?
Finally, I would make a plea that unless you are investigating novel drugs or novel sequencing, phase II studies should be abandoned in favor of large multiinstitutional phase III studies such as the present intergroup trial. I enjoyed this report.
DR NAUNHEIM: Thank you, Dr Reed. None of these patients were being followed up on a continuing basis with regard to surveillance for Barrett's esophagus. I do believe that unfortunately the postoperative staging does raise some false hopes. It makes you believe that you are doing a better job than it turns out you are actually doing. In the end, only 1 of 6 patients had no histologic evidence of tumor despite the fact that 3 of 4 were biopsy negative endoscopically.
I think that your point that the results are somewhat disappointing at 5 years is accurate. I certainly was disappointed when we reanalyzed our data. Our initial report suggested 3- and 5-year survivals that were 10 to 15 points higher than this, and as everybody knows, the longer you follow up patients, the lower your actuarial survival curves; they rarely improve with time. Unfortunately most of the reports in the literature have median follow-up intervals of 12 to 24 months. This is one of the few reports that has a long interval. We essentially had a median of more than 4 years of follow-up with some followed up for up to 7 years, and I think we found that the exciting early results were not really borne out in the long-term analysis. We do appear to increase the median survival and patients do have a longer disease-free survival, but I am not certain the eventual cure rate will be any higher.
Whether or not I think there is a role for nonsurgical therapy is a touchy issue. When I brought that up about 4 years ago at the meeting of the Western Thoracic Surgical Association I was afraid I would not make it off the podium. Since that time there have been some studies, including one oft-quoted one in the New England Journal of Medicine, suggesting that nonoperative therapy is indeed effective in a subset of patients. The Herskovic study demonstrated a 31% 3-year survival in a prospective, randomized series of patients with esophageal carcinoma, with 14 long-term survivors, greater than 3 years, out of a cohort of 61 patients.
Yes, I think there are going to be a subset of patients who can be treated and probably should be treated without surgical resection. I think the challenge in the next decade is going to be to identify those who should be treated in such a fashion. Once again, we should be complementing and not competing with our oncologic colleagues. If we can identify those patients who are going to be complete responders and who have a good chance for survival without resection of their esophagus, we probably ought to institute a hands-off policy. If that is done reliably, we then can turn our attention to those patients who will not respond to chemotherapy and radiation therapy and in whom we can provide some significant benefit.
DR HARVEY I. PASS (Bethesda, MD): After you took the specimens out and looked at them, what happened to the Barrett's esophagus in your specimens independent of tumor? What are some of the things that were peculiar to those patients who had a complete response? Did they have an earlier stage or was it a mixed sort of situation? Did you think they had nodes to begin with?
DR NAUNHEIM: Obviously we looked hard at those patients, trying to identify some predictors of complete response, and could not find any. None of those patients were noted to have N3 disease. We did not achieve complete response in anyone who had on computed tomographic scan what appeared to be matted celiac adenopathy or T3 aortic invasion. As to the Barrett's mucosa, the only person who could look at the Barrett's mucosa was the pathologist, because it was excised. We do a very high intrathoracic anastomosis and resected all the Barrett's mucosa in each and every patient.
DR PASS: Was there still Barrett's mucosa left? In other words, after this treatment were there any changes in the Barrett's mucosa from what you had seen endoscopically before?
DR NAUNHEIM: There were some who had had preoperative severe dysplasia in whom the dysplasia had disappeared; however, I do not remember the status of the carcinoma in situ.
DR WALTER G. WOLFE (Durham, NC): I enjoyed and congratulate you on your results. Our mortality rate for this operation is about 6% with a 2% death rate due to chemoradiation. We use three courses and 4,500 cGy. We get a sterility rate of about 25%, which has been reported by others also.
I would like to talk about markers for a brief minute. From our 70 patients, we had 40 biopsy specimens we stained for p53 and c-erbB-2; interestingly enough, 55% of patients who had overexpression of c-erbB-2 had 5-year survival, and the sterility rate was very high there. As you know, it was reported in the New England Journal of Medicine recently that women with breast cancer who had overexpression of c-erbB-2 were better responders to chemotherapy. So it may well be that the staining of the diagnostic biopsy specimen might lead us to select people who we know will be good responders. It is clear that the sterility of the specimen conveys a very favorable prognostic situation in these patients, and perhaps you could avoid chemotherapy and radiation in a fairly large group if in fact you could predict that they were not responders as therapy in this group does not convey any survival benefit.
DR NAUNHEIM: Thank you, Dr Wolfe. I think that kind of work is going to be critical in the future to help guide therapy, and I urge all of you who have an interest in this disease to continue along those avenues.
Related Article
Ann. Thorac. Surg. 1995 59: 1085-1090.
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