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Ann Thorac Surg 2006;82:480-485
© 2006 The Society of Thoracic Surgeons
a Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York
b Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York
Accepted for publication March 22, 2006.
* Address correspondence to Dr Altorki, Department of Cardiothoracic Surgery, Suite M404, Weill Medical College of Cornell University, 525 E 68th St, New York, NY 10021 (Email: nkaltork{at}med.cornell.edu).
Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.
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Abstract |
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METHODS: A cohort of patients who underwent neoadjuvant chemotherapy followed by radical surgical resection for carcinoma of the esophagus was identified from a large, prospectively maintained, single-institution database of esophageal cancer patients. Patients were included if they had an accurate pretreatment clinical stage determined by the authors. Data collected included demographic data, the type of staging regimen, the chemotherapy agents used, clinical and pathologic data and stages, and survival data. Downstaging of T or N was determined by comparing the pretreatment, clinical stage to the postresection, pathologic stage. Downstaging was then evaluated in the context of survival.
RESULTS: Seventy-seven patients were identified who had an accurate clinical stage assigned and underwent neoadjuvant chemotherapy followed by radical resection. Patients were clinically staged before treatment using computed tomography, positron emission tomography, and endoscopic ultrasonography. Thirty-seven patients (48%) experienced downstaging of T or N, and this group of patients had a 5-year overall actuarial survival of 63%, compared with 23% for those who were not downstaged (p = 0.002). Three patients had a complete pathologic response to neoadjuvant chemotherapy (3.9%).
CONCLUSIONS: Patients who experience downstaging of T or N after neoadjuvant chemotherapy and radical surgical resection for esophageal carcinoma have a significantly higher survival rate compared with those who do not experience downstaging. This enhanced survival is comparable to survival rates reported in complete pathologic responders after neoadjuvant chemoradiation.
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Introduction |
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In contrast to neoadjuvant chemoradiation, the rate of complete pathologic response appears to be significantly lower (2.5% to 13%) for patients who undergo neoadjuvant chemotherapy without radiation before esophagectomy [6–8]. Although a significant proportion of patients have some evidence of an objective, clinical response to preoperative chemotherapy [7, 8], there is yet little or no information regarding actual tumor downstaging as the majority of these studies were conducted without the use of endoscopic ultrasound (EUS) or positron emission tomography as part of the pretreatment staging regimen. Given this information, we hypothesized that although neoadjuvant chemotherapy without radiation may result in fewer complete pathologic responses compared with previous reports of chemoradiation, local tumor downstaging induced by chemotherapy would correlate with enhanced survival in a group of patients with esophageal carcinoma subjected to both contemporary clinical staging and meticulous pathologic staging.
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Material and Methods |
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For all patients in the study cohort, individual chart review was performed, with approval obtained from the Institutional Review Board, which waived the need for informed consent. Data collected included patient demographics, type of induction therapy, clinical stage and staging evaluation, tumor location and histology, pathologic stage, and treatment-related mortality, as well as overall and disease-specific survival. Treatment-related mortality was defined as any death that occurred (1) during or after induction therapy, (2) during hospitalization after surgery, or (3) within 30 days of resection.
Pretreatment Staging
Clinical stages were assigned according to the American Joint Committee on Cancer staging guidelines using the modalities depicted in Table 1. Clinical stages were individually reviewed for the purposes of this study by the authors. All patients except one underwent computed tomography (CT) of the chest and upper abdomen and at least one other modality (EUS or positron emission tomography). The one exception was clinically staged with CT alone, and had obvious, large lymph node disease and a bulky tumor in the lower third of the esophagus. This patient was assigned a clinical stage of T3 N1 M0 (stage III). Seventy-one patients (92%) had EUS before the initiation of the induction regimen. All 6 patients who did not undergo EUS as part of their staging evaluation were assigned a T3 designation on the basis of the bulkiness of their primary tumors on CT. Overall, 51 of 77 patients (66%) underwent all three modalities before treatment. Fine-needle aspiration for cytology was not routinely used for assessment of the nodal status by EUS.
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Survival Analysis and Statistics
All patients were followed through December 2005. During the follow-up period, disease status was assessed in all patients using both clinical (interim medical history and physical examination) and radiographic (CT of chest and upper abdomen) methods. Survival was assessed using the method of Kaplan and Meier. Survival curves were compared using the log-rank analysis. Proportions were compared using 
2 contingency tables.
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Results |
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The mean age of the study cohort was 60.4 years (range, 37 to 78 years), and the male to female ratio was 4.9 to 1. The tumor was located in the distal third of the tubular esophagus in 42 patients, the middle third in 9, and the upper third of the thoracic esophagus in 7. Nineteen patients had gastroesophageal junction tumors. Fourteen underwent a two-field lymphadenectomy, whereas 63 had three fields dissected. The treatment-related mortality was 1 patient (1.4%), who died of sepsis in the postoperative period. Fifty-eight patients had adenocarcinoma, and the remaining 19 had squamous cell carcinoma. Twenty-seven patients received adjuvant (postoperative) chemotherapy, whereas the remaining 50 underwent no further treatment after resection.
Clinical and Pathologic Staging
Pretreatment clinical stage as well as the corresponding pathologic stage for all 77 patients is demonstrated in Figure 1. The mean number of lymph nodes resected and examined by the pathologist was 38. The T stage, N stage, or both were downstaged in a total of 37 patients (48%). Downstaging of T alone occurred in 18 patients (23.3%), N alone in 13 patients (16.9%), and both descriptors in 6 (7.8%). Despite this, only 3 patients had a pathologic complete response to induction chemotherapy (3.9%). Patients with squamous cell carcinoma were more likely to be downstaged (14 of 19; 74%) with neoadjuvant chemotherapy compared with those with adenocarcinoma (24 of 58; 41%), a difference that was statistically significant (p = 0.01).
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Patients with adenocarcinoma who were downstaged had a 5-year, overall actuarial survival of 56%, whereas this figure was 75% for those with squamous cell carcinoma, a difference that did not reach statistical significance (p = 0.1). The 5-year, overall, actuarial survival was 48% for patients who received postoperative, adjuvant chemotherapy versus 58% for those who underwent no further therapy after resection (p = 0.4).
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Comment |
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Response to Neoadjuvant Chemotherapy
The low rate of complete pathologic response reported in the present study is consistent with previously published reports using preoperative chemotherapy alone followed by resection [6–9, 11]. Nonetheless, downstaging of T or N after neoadjuvant chemotherapy was observed in nearly 50% of the patients in study. Given that this is a surgical cohort, with all patients undergoing resection, this figure may overestimate the actual response rate to induction chemotherapy in esophageal cancer patients. However, this experience is roughly similar to the proportion of patients who are described as having responded to preoperative chemotherapy in earlier reports in which the response to therapy was described as change in tumor size [7, 8]. However, changes in tumor size may not represent the optimal technique for measuring response to therapy in patients with carcinoma of the esophagus, as a decrease in tumor size does not necessarily correlate with an earlier stage and a better prognosis. The T status reflects the depth of invasion, not tumor size. As an example, just because an esophageal tumor is reduced by one half of its original size by chemotherapy does not necessarily mean that the depth of invasion has changed. As a result, we believe that response to therapy in patients with esophageal cancer may be best assessed by evaluating any effect on downstaging.
Ideally, the present study would have compared pretreatment clinical stage with posttreatment clinical stage rather than the postsurgical, pathologic stage alone. We avoided this comparison because of the known unreliability of these staging modalities after induction therapy [12, 13]. Unlike previous reports of neoadjuvant chemotherapy, patients were clinically staged before treatment with combinations of CT, positron emission tomography, and EUS, with 92% having EUS and 66% of patients undergoing all three modalities. Although clinical staging for esophageal carcinoma has its drawbacks, the fact that the majority of patients underwent all three contemporary staging modalities attests to the accuracy of the clinical staging in this study cohort. Similarly, the accuracy of the postsurgical, pathologic stage was ensured by including only patients who underwent radical, en bloc esophagectomy.
Effect of Downstaging on Survival
In the present study, the data show that patients experiencing downstaging of their T status, N status, or both had a longer overall and disease-specific survival compared with those patients who were not downstaged. Unfortunately, objective data concerning downstaging and survival are not provided in the large, randomized trials of neoadjuvant chemotherapy without radiation reported by Kelson and associates [6] and the Medical Research Council Oesophageal Cancer Working Party [11]. In a much smaller randomized trial of neoadjuvant chemotherapy followed by surgery versus surgery alone reported by Ancona and colleagues [7], only patients who achieved a complete pathologic response to neoadjuvant chemotherapy had a statistically significant improvement in overall survival. Patients who achieved a partial response, measured pathologically, survived only as long as those in the control arm. However, downstaging was not assessed in the study by Ancona and colleagues [7], and the trial was performed before the era of positron emission tomography and EUS. In a phase II assessment of preoperative chemotherapy without radiation in patients with exclusively squamous cell carcinoma of the esophagus, Darnton and colleagues [8] reported that patients who achieved either a complete or partial radiographic (CT scan) response to systemic therapy enjoyed significantly longer survival than nonresponders. Once again, these data were generated before the availability of positron emission tomography and EUS.
Our data are in concordance with some information reported from centers administering combinations of chemotherapy and radiation before esophagectomy. At the MD Anderson Cancer Center, response to therapy, as measured pathologically, correlated with improved survival, even for partial responders [14]. The technique used to measure response, however, differed in that responders were determined by pathologic evaluation alone, with no comparison to pretreatment stages.
Clinical Implications
For patients with esophageal carcinoma undergoing surgical resection preceded by neoadjuvant therapy, it is becoming increasingly clear that patients who respond to either chemotherapy or chemoradiotherapy are the individuals who seem to derive the most survival benefit from these strategies. This seems to be evident even in trials in which there is no survival benefit demonstrated as a whole for the groups who received neoadjuvant therapy [1, 7]. As a result, future investigation needs to focus on techniques that may help to predict those who will respond before treatment, and certainly, before resection.
One potential strategy would be the use of in vitro testing for chemoresistance [15]. If biopsy samples can be successfully tested for their response to chemotherapeutic agents before their systemic administration, nonresponders could potentially be weeded out and referred directly for surgery. Whether or not this strategy becomes a realistic option remains to be determined.
Another area of future investigation is the enhancement of clinical staging techniques, especially if they are accurate immediately after the administration of neoadjuvant therapy and before surgery. Novel imaging techniques, including endoluminal magnetic resonance imaging [16] as well as magnetic resonance imaging using magnetic nanoparticles [17], are actively being investigated for the staging of solid tumors and esophageal cancer. If no response is measured using more accurate staging modalities after the first cycle of chemotherapy, patients could opt out of the neoadjuvant therapy protocol and proceed directly to surgical resection. Whether this becomes a reality remains to be seen.
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Discussion |
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I have just a couple of quick comments I'd like to mention. First of all, your results are excellent. Not only the survival results, but the mortality statistics are something we should all try to achieve. With your endoscopic ultrasound (EUS) being the most important T and N clinical stager, I think you don't have to worry about your pretreatment clinical stage. You have very accurate data, at least the best you could have without actually doing surgical staging.
I have two questions. You had excellent survival, with only a 4% pathologic complete response (CR) rate. If you were going to add radiation and give chemoradiation together, which is associated with a pathologic CR rate of approximately 47% to 50%, is it possible that that might not improve your overall survival? At last week's GI ASCO, we presented the final data from the trimodality versus surgery alone study in esophageal cancer, and the difference was stark, 4.5-year survival versus 1.8 years (median).
My second question, Bob, you and Nasser have a history of excellent surgical resections, and I notice that you had very good results overall. Could you tell us a little bit about the local recurrence rate versus distant metastases in these patients?
Thank you.
DR KORST: I'm going to answer the second question first because it leads into the first. Our local recurrence rate with the radical, en bloc resection is 9%, and that is essentially the reason why our interest lies in induction chemotherapy without radiation for esophageal cancer. In addition to that, the Medical Research Council study from Europe showed a significant survival advantage for induction chemotherapy compared with surgery alone, and that has also spurred on our interest.
To address the first question regarding the addition of radiotherapy to enhance the complete response rate, I think the pathologic CR rate would indeed be enhanced. However, what I'm really concerned about is what's happening to the systemic disease, not the local disease. I think our data suggest that any downstaging after chemotherapy alone is analogous to the complete responders when radiotherapy is added in terms of predicting prognosis.
DR FRANCIS C. NICHOLS III (Rochester, MN): I have two questions. In your preoperative staging with EUS, are you using fine-needle aspiration (FNA) for lymph nodes?
The second question, just a practical one, what staging do you do after neoadjuvant therapy before surgical resection?
DR KORST: As a rule, we do not use FNA. In this cohort of patients, I think 65 of 70 patients had T3 or T4 disease by EUS, and the incidence of lymph node metastases in patients with T3 disease is probably about 85%. We're convinced that the majority of these patients had lymph node metastases.
Just refresh my memory on the second question.
DR NICHOLS: The second question was just the posttherapy—
DR KORST: Restaging?
DR NICHOLS: Yes, restaging. What modalities do you use?
DR KORST: For the patients in one of the prospective protocols, posttherapy positron emission tomography (PET) scans and computed tomography (CT) scans were performed.
DR FRANK DETTERBECK (New Haven, CT): Bob, I'm curious what your thoughts are about the best surrogate end point for better outcomes. Should it be downstaging? Should it be pathologic CR? Should it be 90% nonviable tumor cells? Should it be decreased PET intensity? What do you think?
DR KORST: I think all of those options need to be investigated, clearly, because recent publications are suggesting that these strategies all may be important. At this juncture I don't know what the best end point is, frankly.
DR WAYNE L. HOFSTETTER (Houston, TX): Doctor Korst, congratulations on a great presentation, I enjoyed it very much.
I have a couple of questions. Some of the things that we're interested in as well echo the things that you're talking about, and specifically criteria for lymph node positivity based on EUS is dependent on certain criteria used. Did you use specific criteria? In other words, the positive predictive value for lymph nodes can be as low as 60% or as high as maybe 80%, 90% when you're looking at EUS depending on the criteria that you use.
DR KORST: We don't perform EUS, our gastroenterologists do, but they use standard criteria, which are hypoechoic nodes, greater than 1 cm, and a smooth border. But I will again emphasize that when we're dealing with about 90% T3 and T4 lesions, and EUS is an outstanding test to determine T3 and T4, the vast majority of these patients will have node-positive disease.
DR HOFSTETTER: Yes, clearly, and what we're trying to establish is those patients who are actually becoming N-negative. You know you have 75% to 80% lymph node involvement for your T3 patients, but it's nice to know what your criteria are so that you know that you're actually downstaging on the N criteria and also, then, able to later quantify your analysis for treatment evaluation.
The second question comes with your M1a patients. Were you including M1a patients, and if they were downstaged, were you operating on them? Thank you, and again, congratulations on an excellent presentation.
DR KORST: Yes, we do include M1a patients. You may have noticed that there were 4 patients that were listed as T0 N0, and I told you there were 3 pathologic complete responders. That fourth patient was T0 N0 M1a, and is 4 years out and disease-free.
DR STEPHEN G. SWISHER (Houston, TX): Doctor Korst, your study demonstrates a very important observation about the association of survival with response to preoperative chemotherapy. It is in agreement with our data from MD Anderson that a partial pathologic response as well as a complete pathologic response is independently important for survival.
I was wondering if you saw a correlation with this pathologic downstaging and PET, and what your institution plans to do with these patients who do not respond. Are you thinking of giving them additional treatment to see if they will respond and perhaps be put in a better prognostic group?
DR KORST: Those are both very good questions. I can't give you the data on the posttreatment clinical staging because I just don't know that. We have that information in our database and we can pull that out. Whether or not patients ought to undergo further therapy before resection if they are not downstaged is a difficult question to answer; however, to go ahead and give patients who have not responded to therapy additional therapy and perhaps add radiation does not seem to make sense.
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References |
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