J Thorac Cardiovasc Surg 2007;133:317-324
© 2007 The American Association for Thoracic Surgery
T2N0M0 esophageal cancer
Thomas W. Rice, MDa,b,*,
David P. Mason, MDa,b,
Sudish C. Murthy, MD, PhDa,b,
Gregory Zuccaro, Jr, MDa,c,
David J. Adelstein, MDa,d,
Lisa A. Rybicki, MSe,
Eugene H. Blackstone, MDa,e
a Center for Swallowing and Esophageal Disorders, Cleveland Clinic, Cleveland, Ohio.
b Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio.
c Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio.
d Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio.
e Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.
Presented at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Penn, April 29-May 3, 2006.
Received for publication May 10, 2006; revisions received August 10, 2006; accepted for publication September 5, 2006.
* Reprint requests: Thomas W. Rice, MD, Cleveland Clinic, 9500 Euclid Avenue/Desk F24, Cleveland, OH 44195. (Email: ricet{at}ccf.org).
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Abstract
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OBJECTIVE: The study objective was to develop a treatment algorithm for cT2N0M0 esophageal cancer by determining (1) errors in clinical staging and (2) consequences of overtreatment and undertreatment of incorrectly clinically staged patients.
METHODS: Of 742 clinically staged patients, 61 (8.2%) had cT2N0M0 cancer; 45 underwent surgery alone; 8 underwent surgery and postoperative adjuvant therapy; and 8 underwent induction therapy, then surgery. As reference, 31 of 666 patients (4.7%) who underwent surgery first had pT2N0M0 cancer and a 5-year survival of 61% ± 9.3%. Referent values were calculated from 445 clinically staged patients who underwent surgery first. Unmatched and matched survival comparisons were made using the log-rank test.
RESULTS: Only 7 of 53 cT2N0M0 cancers treated with surgery first were pT2N0M0 (13% positive predictive value). Of incorrectly staged cT2N0M0 cancers (46/53), 29 (63%) were overstaged and 17 (37%) were understaged. Most overstaged cancers were pT1 (11 [38%] T1a and 15 [52%] T1b), and most understaged cancers were pN1 (13 [76%]). Matched overstaged patients treated by surgery alone (25/28) had a 5-year survival similar to that of patients with pTNM (69% ± 9.8% vs 63% ± 13%, P =.8). Understaged patients did better at 5 years than patients with pTNM if they had postoperative adjuvant therapy, not surgery alone (43% ± 22% vs 10% ± 9.5%, P = .17). Induction therapy decreased 5-year survival compared with all other treatment strategies (13% ± 12% vs 52% ± 7.4%, P =.05).
CONCLUSIONS: Patients with cT2N0M0 cancers should undergo surgery first with lymphadenectomy. Clinically understaged patients should receive postoperative adjuvant therapy. In the unlikely event that patients with cT2N0M0 cancers are found to have an uncommon pT2N0M0 cancer, they will have acceptable survival with surgery alone.
Abbreviations and Acronyms EUS = endoscopic ultrasound
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Introduction
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Decision making in stage-directed therapy of esophageal cancer is easy at the extremes of stage grouping: surgery alone for early-stage cancers and multimodality therapy for advanced-stage cancers. Patients with pT2N0M0 esophageal cancer have intermediate survival with surgery alone (Figure 1). If decisions could be made on the basis of pathologic stage, surgery alone would be a logical choice for this cancer because adjuvant therapy is toxic and unlikely to measurably improve these patients’ survival. However, decisions must be made on the clinical stage, and currently, this is guesswork for cT2N0M0 patients. The purpose of this study was to develop a logical algorithm for treating this cancer by determining (1) errors in its clinical staging and (2) consequences of overtreatment and undertreatment of incorrectly clinically staged patients.
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Figure 1. Survival after surgery alone for esophageal cancer according to pTNM. Each step represents a death, and vertical ticks represent a censored patient.
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Patients and Methods
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Patients
A total of 742 patients with esophageal cancer who had clinical staging and esophagectomy from February 1987 through May 2005 were identified from the Cleveland Clinic Thoracic Surgery Database, which has been approved for use in research by the institutional review board. Three hundred forty patients underwent surgery alone, 105 patients underwent surgery and postoperative adjuvant therapy, 121 patients underwent induction therapy and surgery, and 176 patients underwent induction therapy, surgery, and postoperative adjuvant therapy.
Clinical Staging
Clinical staging of T and N classifications was obtained by esophageal endoscopic ultrasound (EUS) performed under local sedation after flexible esophagoscopy. The currently available Olympus echoendoscope (Olympus Optical Co Ltd, Tokyo, Japan) (primarily EU-M2, EU-M3, and EU-M20) was used. Clinical classification of cT2 was invasion limited to the fourth ultrasound layer.1,2 Clinical classification of cN0 was no evidence of regional lymph node metastases. Classification was accomplished using established criteria for size, shape, border, and ultrasound "texture," and was routinely assessed using the 7.5-MHz setting.2-4 Fifty-eight patients had EUS fine-needle aspiration of regional and nonregional lymph nodes. Clinical classification of cM0 was no evidence of distant metastases; all patients underwent computed tomography, and 273 patients underwent fluorodeoxyglucose positron emission tomography.
Errors in Clinical Staging
Referent values for EUS clinical classification of cT, cN, and cTNM were calculated from 445 clinically staged patients who underwent surgery first. The results are presented as sensitivity, specificity, positive and negative predictive values, and accuracy of EUS to identify T2, N0, and T2N0M0 cancers.5
Consequences of Treating Incorrectly Staged Patients
Overstaged patients
A total of 177 patients treated with surgery alone had <pT2N0M0 cancer. Among these, 28 patients were overstaged as cT2N0M0 and the remaining 149 patients were not. For fair survival comparisons, differences between these 2 groups of patients were accounted for with propensity methods.6,7 The probability of being a patient with overstaged cT2N0M0 cancer (propensity score) was estimated from a logistic regression model containing 5 variables: age, pT, histology, differentiation, and surgical approach. Patients were then matched using the propensity score. Twenty-five matched pairs were obtained.
Patient and tumor characteristics were compared between unmatched and matched groups using the t test or chi-square test. Survival after esophagectomy was estimated nonparametrically by the Kaplan–Meier method8 and compared between unmatched and matched groups using the log–rank test. Analyses were performed using SAS software (version 8, SAS Institute, Inc, Cary, NC).
Understaged patients
A total of 114 patients treated with surgery alone had >pT2N0M0 cancer; 10 patients were understaged as cT2N0M0, and 104 patients were not. One hundred patients treated with surgery followed by adjuvant therapy had >pT2N0M0 cancer; 7 patients were understaged as cT2N0M0, and 93 patients were not. Propensity models were developed separately for patients treated with surgery alone and patients treated with surgery followed by adjuvant therapy. In each analysis, the probability of being an understaged cT2N0M0 patient was estimated from a logistic regression model containing 3 variables: pT, pN, and pM. Patients were then matched using the propensity score. Nine matched pairs were obtained for those treated with surgery alone, and 7 matched pairs were obtained for those treated with surgery followed by adjuvant therapy. Comparisons were made as previously described.
Presentation
Data are presented as frequencies and percentages or as means and standard deviations. Survival estimates are provided at selected time points, along with the standard error and number at risk.
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Results
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Errors in Clinical Staging
Of 742 clinically staged patients, 61 (8.2%) had cT2N0M0 cancer and 53 (7.1%) had surgery as first therapy. Of the 445 clinically staged patients who underwent surgery first, 24 (5.4%) had pT2N0M0 cancer. Scoring matrices and referent values for T2, N0, and T2N0M0 are listed in Table 1.
Of the 53 cT2N0M0 patients treated with surgery first, 7 (13%) were correctly staged, 29 (55%) were overstaged, and 17 (32%) were understaged (Table 2). Twenty-six overstaged patients (90%) had pT1N0M0: 11 (38%) T1a (intramucosal) and 15 (52%) T1b (submucosal). Thirteen (76%) understaged patients had pN1.
Consequences of Treating Incorrectly Staged Patients
Treatment of overstaged patients
Although survival after surgery alone of 28 overstaged patients seemed to be worse than that of 149 patients with <pT2N0M0 cancer treated by surgery alone (P =.07, Figure E1), this was because tumor characteristics and treatment of the groups differed. Overstaged patients had more cancers with high pT, squamous histology, and poor differentiation than the comparison group, and were more likely to have a thoracotomy (Table 3). When patients were matched, survival was similar (P =.8, Figure 2).
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Figure E1. Comparison of survival after surgery alone in overstaged cT2N0M0 patients versus non-cT2N0M0 patients with <pT2N0M0 cancers (unmatched patients treated with surgery alone). Format is as in Figure 1.
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Figure 2. Comparison of survival after surgery alone in overstaged cT2N0M0 patients versus non-cT2N0M0 patients with <pT2N0M0 cancers (propensity-matched surgery-alone patients). Format is as in Figure 1.
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Treatment of understaged patients
Treating understaged cT2N0M0 patients by surgery alone (n = 10) resulted in poor survival, similar to that for 104 patients with >pT2N0M0 cancer (P =.4; Figure E2
, Table 4), and this was also true of matched patients (P = .4; Figure 3,
Table 4). Treating understaged patients by surgery first followed by adjuvant therapy (n = 7) resulted in similar intermediate survival as for 93 such patients with >pT2N0M0 cancer (P =.5; Figure E3,
Table 5), and this was also true of matched patients (P =.8; Figure 4,
Table 5). In understaged patients, survival after surgery and postoperative adjuvant therapy was better than after surgery alone (P =.17, Figure 5).
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Figure E2. Comparison of survival after surgery alone in understaged cT2N0M0 patients versus non-cT2N0M0 patients with >pT2N0M0 cancers (unmatched patients treated with surgery alone). Format is as in Figure 1.
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Figure 3. Comparison of survival after surgery alone in understaged cT2N0M0 patients versus non-cT2N0M0 patients with >pT2N0M0 cancers (propensity-matched surgery-alone patients). Format is as in Figure 1.
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Figure E3. Comparison of survival after surgery followed by adjuvant therapy in understaged cT2N0M0 patients versus non-cT2N0M0 patients with >pT2N0M0 cancers (unmatched patients treated similarly). Format is as in Figure 1.
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TABLE 5. Comparison of unmatched and matched understaged cT2N0M0 patients treated by surgery followed by adjuvant therapy
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Figure 4. Comparison of survival after surgery followed by adjuvant therapy in understaged cT2N0M0 patients versus non-cT2N0M0 patients with >pT2N0M0 cancers (propensity-matched similarly treated patients). Format is as in Figure 1.
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Figure 5. Comparison of survival after surgery alone versus surgery followed by adjuvant therapy in understaged cT2N0M0 patients. At 1 and 3 years, 4 and 2 patients remained at risk in the postoperative adjuvant therapy group, with 68% confidence limits of 72% to 99% and 20% to 65% at these intervals, respectively. After surgery alone, 5 and 3 patients remained at risk, with confidence limits of 34% to 66% and 16% to 44% at 1 and 3 years, respectively. Format is as in Figure 1.
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Impact of Induction Therapy
Empirical treatment of 8 cT2N0M0 patients who had induction therapy before surgery resulted in poorer survival than in those undergoing surgery first (P =.05, Figure 6).
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Figure 6. Comparison of survival after induction therapy followed by surgery versus surgery first in cT2N0M0 patients. At 1 and 3 years, 37 and 24 patients remained at risk in the surgery-first group, with 68% confidence limits of 84% to 73% and 47% to 61% at these intervals, respectively. After induction therapy, 4 patients and 1 patient remained at risk, with confidence limits of 32% to 68% and 1% to 24% at 1 and 3 years, respectively. Format is as in Figure 1.
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Discussion
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Errors in Clinical Staging
Survival of patients with cT2N0M0 and pT2N0M0 cancers is similar (Figure E4), from which one might infer that clinical staging accurately reflects pathologic staging. This is not the case; on close examination, clinical staging seems to be nearly useless. The good survival of the majority of patients who were overstaged balances the poor survival of the minority of patients who were understaged, leading to an intermediate pT2N0M0-like survival for the group.
However, overstaged patients were an atypical group, composed not of a balance of patients with superficial cancer with either high-grade dysplasia or variably invasive T1 cancers,9 but of a majority with deeply invasive submucosal T1b cancers. We previously showed that survival is similar for such patients and those with pT2N0M0 tumors; it is worse, however, for both these groups of patients than for those with more superficial tumors.10 Thus, overstaging errors of ultrasound classification predominately occurred about the interface of the third (submucosa) and fourth (muscularis propria) ultrasound layers. Ultrasound layers are only an approximate reflection of this anatomic boundary: The third ultrasound layer is composed of the submucosa and acoustic interface between the submucosa and muscularis propria.11,12 Therefore, the anatomic information necessary to differentiate deep T1b submucosal cancers from more superficial T2 cancers may not be available to the ultrasonographer.
Classification errors in understaged patients were different. Approximately one quarter of errors were in T, one third were in N, and the remaining were in both T and N. Approximately 50% of patients with pT2 cancer have N1 regional nodal metastases.13 This underscores the need for improved technology to facilitate EUS fine-needle aspiration of regional lymph nodes without false-positive cytology resulting from the sampling needle passing through the primary cancer.
These overstaging and understaging errors in classifying cT2N0M0 reflect 3 sources: 2 anatomic boundaries and regional lymph nodes. Although these errors lead to poor determination of T2N0M0 tumors, understanding their nature actually allows this inaccurate EUS information to be usefully interpreted for optimal treatment decision making.
Consequences of Treating Incorrectly Staged Patients
As well as being more deeply invasive, cancers of overstaged patients were more likely to be poorly differentiated and of squamous histology. This accounts in part for the survival difference seen in overstaged versus other patients with <pT2N0M0 cancer. In addition, esophagectomy by thoracotomy, a predictor of worse survival in patients with superficial cancers than transhiatal resection,14 reflects our practice of performing a 2-field lymphadenectomy in patients with a high probability of regional lymph node metastases. This information is crucial for prognostication and postoperative treatment decision making and seems to be appropriate for cT2N0M0 tumors. Further, there seems to be no adverse consequences of treating overstaged cT2N0M0 patients by esophagectomy first.
Understaged patients did as poorly as other patients with >pT2N0M0 cancer, a reflection of the impact of pT3 and pN1 classification on survival. However, as previously shown in matched patients, postoperative adjuvant therapy improves survival.14 Thus, consequences of understaging cT2N0M0 patients can be mitigated by accurate pathologic staging and use of adjuvant therapy after esophagectomy.
Impact of Induction Therapy
Despite the small number of patients, the association of induction therapy with the poor survival of cT2N0M0 patients is striking. This is due not only to treatment toxicity but also to cancer deaths, because 5 of 7 deaths occurred in patients with early cancer recurrence. We know of no trial of induction therapy that includes cT2N0M0 patients, nor is such a trial likely to be conducted given the present knowledge; thus, these results should not be ignored, but they should be considered cautiously. However, even if results were at the upper confidence limits of our experience rather than the mean, there would be no survival advantage of induction therapy.
Strengths and Weaknesses
This is a single-institution study of an uncommon cancer for which treatment was nonrandomized and heterogeneous over an 18-year period. Propensity analysis was used to minimize bias.
Because the tumor is uncommon, its treatment has not been subjected, to our knowledge, to rigorous study. Until it has, we have exploited heterogeneity in treatment selection to derive a clinically logical strategy, supported by these nonrandomized data, that should minimize harm to overstaged patients while providing an effective alternative for understaged patients. Nevertheless, our protocols for managing esophageal cancer do not permit us to examine the large variety of other treatments. Some survival differences in our own treatment strategies could have been due to chance or may be real, but small sample sizes precluded all but rather large differences from being detected as distinctive. Despite practicing utmost care, clinical staging was incorrect in the majority of cT2N0M0 patients, a reflection of current technology. It is possible, but not yet demonstrated, that new generations of echoendoscopes may improve the clinical staging of patients with T2N0M0 cancers.
Treatment Algorithm
Patients with cT2N0M0 cancers should undergo surgery first, with lymphadenectomy. Clinically understaged patients should receive postoperative adjuvant therapy. In the unlikely event that any cT2N0M0 patients are found to have pT2N0M0 cancer, they will have acceptable survival with surgery alone; the role of postoperative adjuvant therapy is yet to be defined.
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Acknowledgments
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The authors thank Tess Parry for editorial assistance and Ann Gamber for data entry.
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References
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- Galen RS, Gambino SR. Beyond Normality: The Predictive Value and Efficiency of Medical Diagnoses. New York: John Wiley & Sons; 1975.
- Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70:41-55.[Abstract/Free Full Text]
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- Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.
- Rice TW, Blackstone EH, Goldblum JR, DeCamp MM, Murthy SC, Falk GW, et al. Superficial adenocarcinoma of the esophagus. J Thorac Cardiovasc Surg 2001;122:1077-1090.[Abstract/Free Full Text]
- Rice TW, Blackstone EH, Rybicki LA, Adelstein DJ, Murthy SC, DeCamp MM, et al. Refining esophageal cancer staging. J Thorac Cardiovasc Surg 2003;125:1103-1113.[Abstract/Free Full Text]
- Kimmey MB, Martin RW, Haggitt RC, Wang KY, Franklin DW, Silverstein FE. Histologic correlates of gastrointestinal ultrasound images. Gastroenterology 1989;96:433-441.[Medline]
- Bolondi L, Casanova P, Santi V, Caletti G, Barbara L, Labo G. The sonographic appearance of the normal gastric wall: an in vitro study. Ultrasound Med Biol 1986;12:991-998.[Medline]
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Abstract
Introduction
