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a Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
b Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
c Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
d Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
e Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
f Department of Nuclear Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
g Department of Gastroenterology, Hepatology and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
h Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio
Accepted for publication March 26, 2010.
* Address correspondence to Dr Hofstetter, Department of Thoracic and Cardiovascular Surgery, Unit 445, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (Email: whofstetter{at}mdanderson.org).
Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, January 25–27, 2010.
| GENERAL THORACIC SURGERY:
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Abstract |
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Methods: We reviewed 336 esophageal cancer patients who received neoadjuvant chemoradiotherapy followed by complete resection. We identified 20 patients who obtained complete pathologic response at the primary tumor with persistent metastatic disease to regional lymph nodes (ypT0N1). These patients were compared to 123 patients with pathologic complete response and 193 with partial response for overall survival.
Results: Demographics among the three groups of patients were similar except that this cohort of patients with ypT0N1 had higher initial clinical stage (p = 0.013) and had more squamous cell carcinoma pathology (p = 0.005). Eighty-six percent of the ypT0N1 patients who had modern preoperative staging were felt to have clinical complete response. Five-year survival of ypT0N1 patients was intermediate, similar to pathologic partial response stage II patients in both the sixth and seventh editions of the American Joint Committee on Cancer staging criteria.
Conclusions: Clinical staging of complete response to chemoradiotherapy may not translate to pathologic complete response. Patients with ypT0N1 disease at resection have intermediate but reasonable survival, justifying an aggressive approach to curative therapy. Future revisions of the staging system should place this group of patients with patients who have metastatic regional lymph nodes, stratified by number of nodes involved.
For locoregionally advanced esophageal cancers, neoadjuvant chemoradiotherapy and surgery have provided reasonable survival [1, 2]. Moreover, posttherapy pathologic stage has been shown to be a predictor of a patient's long-term outcome [3], and patients with pathologic complete response (pCR) have a better long-term survival than partial response [4–7]. After chemoradiotherapy, the pathology may show a complete response in the primary esophageal cancer with residual tumor in lymph nodes (ypT0N1). Although the incidence of ypT0N1 has previously been reported to occur 7% to 10% in limited series [8–10], this stage has not been included in the sixth or the new seventh edition of the American Joint Committee on Cancer (AJCC) esophageal staging systems [11]. Moreover, reports in the literature on the survival of patients with ypT0N1 have been mixed. The five-year survival in different series with a small group of patients for ypT0N1 has not been well characterized, especially in patients with adenocarcinoma [8, 9]. Our aims of this study were threefold: (1) to describe the clinical presentation of ypT0N1 in a series of patients treated with neoadjuvant therapy followed by resection; (2) to characterize the outcome in this group of patients; and (3) to propose the inclusion of this group of patients into revisions of the AJCC esophageal cancer staging systems.
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Patients and Methods |
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Patients who presented with localized, potentially resectable carcinoma of the esophagus were evaluated by a medical oncologist, gastroenterologist, radiation oncologist, and thoracic oncology surgeon. The typical clinical staging workup included computed tomography (CT) scan of the chest and abdomen, esophagogastroduodenoscopy (EGD), and when more recent modalities became available endoscopic ultrasound (EUS) and fluorodeoxyglucose- integrated positron emission tomography (FDG-PET/CT). All of the information was evaluated to determine the clinical stage according to the sixth edition of the AJCC guidelines [11]. Patients with clinical stage II–IV received induction concurrent chemoradiotherapy. The planned radiation dose was typically 45 gray (Gy) in 25 fractions or 50.4 Gy in 28 fractions. The radiation fields encompassed the primary tumors with a minimal 5-cm margin in the cephalad and caudal directions and a 2-cm margin radially. The chemotherapy agents used concurrently with radiotherapy predominantly included cisplatin, 5-fluorouracil, camptothecin-11, and paclitaxel or docetaxel. All patients included in the analysis completed at least two regimens of platinum-based therapy and at least 30 Gy of radiation. After chemoradiation, patients underwent restaging evaluation within 4 weeks prior to surgery. Patients without signs of residual tumor on restaging EGD-EUS or no PET activity were determined to have clinical complete response. A curative esophagectomy was performed about 4 to 6 weeks after completion of chemoradiotherapy. The type of resection was individualized according to tumor location and surgeon preference. Patients underwent Ivor Lewis, transhiatal, 3-field McKeown, or minimally invasive esophagectomy. Pathologic stage was determined after evaluation of the esophagectomy specimen and lymph nodes. Hematoxylin-eosin staining was performed on the resected specimen. Histologic response to therapy was assessed using a reproducible grading system that estimates the percent viable tumor in the specimen [3, 12].
We compared the demographics, comorbidities, clinical stage, surgical procedure, pathologic stage, and tumor histology among the ypT0N1, pPR, and pCR groups. Categoric variables were analyzed using multinomial logistic regression and cross-tabulations with 
2 analysis, and continuous variables were analyzed using the analysis of variance. Survival curves were calculated using standard Kaplan-Meier survival analysis. All statistical analysis was two-sided; a p value of 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software (version 11.5.2.1 for Windows; SPSS Inc, Chicago, IL).
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Results |
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Comment |
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We compared patients who achieved a complete local tumor response but persistent lymph node involvement to similar patients who achieved either a pCR or an incomplete response. We chose patients who had greater than 10% histology-viability as a comparison group because previous data have shown that this group consistently performs similarly to nonresponders [3, 14, 15]. The overall survival of patients with ypT0N1 in our comparison study was intermediate, similar to a posttherapy stage II patient, but this differed from previous studies. Law and colleagues [8] looked at esophageal squamous cell cancer patients who had either chemotherapy or chemoradiotherapy and found a median survival of 21 months with 5-year survival of 18%, similar to pathologic stage III patients. On the other hand, a study by Rizk and colleagues [9] that also analyzed posttreatment patients with squamous cell carcinoma of the esophagus showed a very favorable survival in patients with ypT0N1 disease, which was similar to that of patients with pCR attaining a 5-year survival rate of 52%. Although our study population is relatively small, it represents the largest group of patients reported on thus far and illustrates the need to consider where to appropriately classify them into a formal cancer staging system. The disparity in long-term survival data from different series may be due to the small number of ypT0N1 patients in the studies or variations in the number of positive lymph nodes among ypT0N1 patients or histology. A number of studies have shown that the number of positive lymph nodes in esophageal cancer is an important prognostic indicator for survival [16–20], which led to its addition in the seventh edition of the AJCC staging system for esophageal cancer.
It is interesting that 86% of the ypT0N1 group were thought to have clinical complete response after chemoradiation therapy. This underscores the fact that it is difficult to predict the true status of a posttherapy patient and no study to date has shown an effective method of interpreting response outside of observation or resection. In a randomized control study comparing chemoradiation therapy followed by surgery to chemoradiation therapy alone for squamous cell carcinoma of the esophagus, Bedenne and colleagues [13] argued that patients with clinical complete response after chemoradiation should not undergo surgery because the study showed there was no difference in overall survival between two treatment arms. Given the findings of our study, we believe this strategy may lead to inadequately treating patients with low volume regional disease. In our study, we used the more accurate postneoadjuvant staging studies of PET and EGD with EUS, whose findings correlated with pathologic response [21]. Even though we utilized these advanced clinical staging studies, the majority of our study populations were thought to have clinical complete response.
This underscores the continued need for an accurate postneoadjuvant therapy staging modality. Sarkaria and colleagues [15] showed that endoscopic biopsy after neoadjuvant chemoradiotherapy for esophageal cancer had a negative predictive value of only 31% for identifying pCR. One study at our institution, looking at the accuracy of PET-CT after chemoradiotherapy, showed that 18% of patients with negative PET-CT after chemoradiotherapy had residual disease in regional lymph nodes [22]. One could argue that patients with untreated ypT0N1 disease who are thought to have a clinical complete response after definitive chemoradiotherapy will likely develop either distant metastasis obviating the need for resection or regional recurrence which may be amenable to salvage esophagectomy. However, retrospective series [23] have shown that patients who undergo salvage esophagectomy more than 4 months after definitive chemoradiotherapy have significantly higher rates of morbidity and mortality and require longer hospital stays than do patients who undergo immediate esophagectomy. Further study is required to determine the most appropriate course of care; immediate resection versus selective surgery. At this time we feel that it is appropriate to individualize recommendations for posttreatment resection, favoring complete resection of all local-regional disease in patients who are capable of tolerating esophagectomy.
There are several limitations of our study. This is a retrospective analysis on a limited number of patients. There was variation in surgical treatment of esophageal cancer, which could confer bias in terms of extent of lymph node dissection. In addition, as we did not use a comparison group of patients who were observed after induction chemoradiation therapy, one could argue that patients with residual nodal disease may ultimately have similar survival with salvage resection. This remains to be discovered, and this study serves as a benchmark of survival in ypT0N1 patients. Ultimately, collaboration will allow larger groups to be analyzed to validate our findings. Finally, the groups that we compared for the Kaplan-Meier curve had some dissimilarity. The patients with ypT0N1 disease had more patients with squamous cell histology and more patients with a single positive lymph node. This may have conferred bias in the sixth edition of the AJCC staging; however, in the seventh edition these factors are controlled. Furthermore, the fact that the patients with ypT0N1 disease presented with more advanced pretreatment staging may contribute to a bias in the study.
The true incidence of ypT0N1 patients after induction concurrent chemoradiation therapy is unknown; however, they may represent a small but significant group of patients. This group is often believed to have a clinical complete response using the modern staging techniques of PET-CT scan and EUS. Our series showed that this group of patients has intermediate survival after surgical resection. The overall survival in this group is similar to pathologic stage II patients using both the sixth and seventh editions of the AJCC staging system. It would be appropriate to note that the seventh edition of AJCC esophageal cancer staging is based on pathologic results of surgery alone patients. Future revisions should account for patients treated with neoadjuvant therapy and pathologic T0N1 should be included in the revised staging system for esophageal cancer.
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Discussion |
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I'm a little perplexed, I have to admit, because your group presented, I believe, four or six years ago now on a series of persistent positive celiac nodes. At that time, there were a total of 18 out of I think 186 patients, I believe that Chris Malaisrie presented that paper. And that was the one group that had the worst survival overall.
Now, here you have another small subgroup, basically 14 out of 338 or 20 out of the 338, and that small subgroup has an intermediate stage difference. But you're proposing that we now split the already split staging system again.
My bigger question to you and your colleagues is, if you knew that this patient was a ypT0N1 before the resection, would it keep you from operating? That was the proposal from the M.D. Anderson group originally about the persistent celiac nodes; that had you known those patients had persistent celiac nodes, you might consider a nonoperative approach.
If you would do that, then I could support the idea that you would want to separate this group out from the others. But if you're going to still operate on these patients because they're not celiac, they may be ypT0N1 peritumoral nodes, then why does it make a difference?
DR KIM: That's an excellent question and you have an equally excellent memory. Our group did present that paper of persistent positive celiac nodal disease detected on EUS. In that group there were no patients that were T0. And, in this study, we initially used the 6th edition staging system, indicating that the ypToN1 patients had only regional lymph node involvement without celiac nodes. We did not specifically address your question of celiac nodal involvement in this paper, however, in retrospect, we did not have any patients that match that description. Unfortunately, the N1 here doesn't mean that it was a positive celiac lymph node.
DR DAVID H. HARPOLE (Durham, NC): I think the importance of this is really the quandary of what we do. And if I'm a half-glass-full surgeon and my patients ask me (after we've given induction chemoradiotherapy and they have an EUS [endoscopic ultrasound] that looks like there has been a complete response), "why are you going to do my surgery," and they're still swallowing; I've always said that, well, there's a chance that you may have microscopic residual disease in your primary tumor or possibly in some nodes that we take out. And there is a theoretical advantage that we could actually cure you from that. We certainly would give you better local control.
And so what my question is, I think what you've shown, and your data actually support these, is that we never had enough patients to really look at this subset, which we all see. We all know what to do when we have somebody who was originally, say T3N1, and posttherapy ends up being microscopic disease in the primary but all-node negative, but we didn't know what the prognosis of someone who had their tumor sterilized and still has microscopic disease in their nodes. I mean, we know these patients all die of systemic disease, but what exactly does that mean?
Now, what you've shown us here is, I think, these patients are very similar to those that have microscopic residual disease in the primary.
And so I guess what I'm asking is maybe if you're talking about a change in the staging system would be to have that grouping together, these patients plus those as microscopic residual disease, to fit them somewhere, pigeon-hole them in the staging system, maybe around stage II. I don't know exactly where it would be. I mean, what would be your feeling about that?
DR KIM: I think that's exactly the point of the talk. That these patients don't behave like pathologic complete responders, but they don't behave like pathologic stage III patients. And they have an intermediate survival that's consistent with pathologic stage II on the new staging system.
DR PAUL HENRY SCHIPPER (Portland, OR): When you looked at where these positive regional or N+ nodes were, were these nodes right next to the tumor, within the radiation field, or were these nodes that were sort of on the edge of your field or maybe even outside the field? I guess I am trying to understand if this persistent disease was resistant to the neoadjuvant therapy or if it was just not treated (outside the field).
DR KIM: That's a very good question, and unfortunately, I didn't do the analysis on the exact location of these particular regional lymph nodes, so I can't answer that.
DR DONALD E. LOW (Seattle, WA): With respect to your approach to post neoadjuvant screening, you demonstrated a variation. Was that due to a change in protocol over time?
DR KIM: Yes.
DR LOW: Are you currently using endoscopic ultrasound routinely with respect to post neoadjuvant staging?
And I guess the question should be, if you're going to operate on people that are node-positive or node-negative, what is the role that endoscopic ultrasound is playing if it's not going to direct your treatment?
DR KIM: The current practice at M. D. Anderson Cancer Center is to perform a selective endoscopic ultrasound and biopsy if the patient is thought to have pathologic complete response if the patient wants to be observed instead of undergoing surgical resection. So if a patient has a pathologic complete response on a PET (positron emission tomographic) and CT (computed tomographic) scan, we perform selective endoscopic ultrasound to search for regional disease that would escape detection by other imaging. If the patient is not opting for observation, our routine is to proceed to surgery after integrated PET/CV shows no evidence of metastatic disease.
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