ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Laterza, E.
Right arrow Articles by Cordiano, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laterza, E.
Right arrow Articles by Cordiano, C.

Ann Thorac Surg 1999;67:1466-1469
© 1999 The Society of Thoracic Surgeons

Original Articles

Endoscopic ultrasonography in the staging of esophageal carcinoma after preoperative radiotherapy and chemotherapy

Ernesto Laterza, MDa, Giovanni de Manzoni, MDa, Alfredo Guglielmi, MDa, Luca Rodella, MDa, Pietro Tedesco, MDa, Claudio Cordiano, MDa

a First Division of General Surgery, University of Verona, Verona, Italy

Accepted for publication December 4, 1998.

Address reprint requests to Dr de Manzoni, 1st Department of General Surgery, Borgo Trento Hospital, Piazza Stefani 1, 37126 Verona, Italy


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. In past years multimodal neoadjuvant treatment for carcinoma of the esophagus has been used with increased frequency. Staging of the neoplasm still remains fundamental in evaluating the response to therapy and in planning operation. The aim of the present study was to assess the accuracy of endoscopic ultrasonography (EUS) in a group of patients with squamous cell carcinoma of the thoracic esophagus after undergoing radiotherapy and chemotherapy.

Methods. Among a group of 111 patients with squamous cell carcinoma of the thoracic esophagus and treated with preoperative radiotherapy and chemotherapy, 87 were operated. In these patients it was possible to compare the results of EUS, with regard to depth of invasion of esophageal wall (T) and lymph node involvement (N), with the results of operation and histopathologic study.

Results. Feasibility of EUS before and after neoadjuvant treatment was 71.2% and 83.9%, respectively. The overall accuracy of EUS regarding the wall invasion was 47.9%. The more frequent error was overstaging, especially in patients with complete response and in patients with minimal residual disease. In the assessment of lymph node involvement, EUS showed an overall accuracy of 71.2% with a moderate {kappa} value. Sensitivity for N1 and N0 was 73.7% and 68.6%, respectively.

Conclusions. Endoscopic ultrasonography was feasible in most patients after preoperative radiotherapy and chemotherapy, but our study documented a worsening of accuracy of EUS in the evaluation of T attributable to the confounding presence of radiation fibrosis and soft tissue reaction after radiotherapy and chemotherapy.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Appropriate management of patients with esophageal cancer greatly depends on accurate staging of the disease at the time of diagnosis. To date, endoscopic ultrasonography (EUS) has been shown to be the most accurate technique to detect the depth of tumor invasion and regional lymph node involvement [1, 2].

The past 10 years have witnessed the widespread use of adjuvant treatment for esophageal squamous cell carcinoma; in particular, combined chemotherapy and radiotherapy before operation seems to be the treatment that has yielded the best results [3–7]. This type of therapeutic approach has brought to light new problems regarding several aspects, such as patient selection and preoperative staging or the choice of surgical treatment [8].

The aim of this prospective study was to assess the accuracy of EUS in a group of patients with squamous cell carcinoma of the thoracic esophagus undergoing preoperative radiotherapy and chemotherapy.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
During the period from June 1987 to June 1995, a group of 111 patients with squamous cell carcinoma of the thoracic esophagus were recruited into a study of preoperative adjuvant chemotherapy and radiotherapy conducted by the 1st Division of General Surgery of the University of Verona. A total of 87 patients underwent operation, and the results of EUS in terms of depth of tumor invasion of the esophageal wall (T staging) and lymph node involvement (N staging) were compared with the data obtained in the course of operation and at definitive histologic examination of the surgical specimens removed.

The preoperative therapeutic protocol consisted of two courses of cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1,000 mg/m2 by continuous infusion from day 1 to day 4). The time interval between the two courses was 25 days. High energy radiotherapy was started on the same day as the first course of chemotherapy and continued for a period of 3 weeks with administration of a total of 30 Gy.

The surgical operation was performed on average 25 days after the end of induction therapy. The treatment plan and eligibility criteria have been discussed in greater detail elsewhere [6]. All 87 patients were submitted to EUS before the start of adjuvant treatment and 2 weeks after the second course of chemotherapy.

Endoscopic ultrasonography was performed using a Machida-Toshiba (Tokyo, Japan) front-view endoscope with a 7.5-MHz linear probe at the distal end. All endoscopic appearances were interpreted by the same endoscopist (GdM). The assessment of tumor infiltration depth was based on the generally accepted five-layer structure of the gastrointestinal wall; the lymph nodes regarded as metastatic were relatively hypoechoic with the same ultrasonographic pattern as the primary tumor and with clearly defined boundaries [9, 10]. The staging model adopted was the 1987 TNM-UICC model [11].

In the group of patients receiving preoperative chemotherapy and radiotherapy, a new category emerges in terms of T staging, namely T0 tumors presenting no evidence of malignancy at histology of the surgical specimen. Moreover, in some patients only microscopic clusters of tumor cells within the esophageal wall were detected (minimal residual disease). These patients were staged according to the outermost layer in which tumor cells were found (T1–T3).

Statistical analysis
The degree of agreement between EUS findings and the gold standard (histopathologic examination of the specimen) was determined statistically using Cohen’s {kappa} test. Cohen’s kappa is a measure of the agreement in excess of the amount of agreement that we would expect by chance. When the value of {kappa} is less than 0.20, 0.21 to 0.40, 0.41 to 0.60, 0.61 to 0.80, 0.81 to 1.00, the strength of agreement is considered to be, respectively, poor, fair, moderate, good, and very good [12].

The overall accuracy of the technique and the sensitivity of each of the T and N classes were calculated. The sensitivity of an investigation is the proportion of positive tests in all patients with proven stage of disease; the accuracy is the ratio of correct results (true positive and true negative) to the total number of tests.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Before combined chemotherapy and radiotherapy, EUS was completed in 62 of the 87 patients (feasibility, 71.2%), whereas after induction treatment the number of complete EUS examinations increased to 73 (feasibility, 83.9%). The remaining 14 patients in which tumor stenosis prevented passage of the endoscope were excluded from the study.

In Figure 1 the results of preinduction EUS staging are compared with those of postinduction EUS staging in the 62 patients in which the examination was completed either before or after preoperative radio-chemotherapy. Induction therapy appeared to result in a significant overall downstaging of the primary tumor (T category), whereas the N status did not change significantly.



View larger version (21K):
[in this window]
[in a new window]
  		Fig 1. Comparison of endoscopic ultrasonographic staging in the 62 patients who underwent complete examination either before or after preoperative combination radiotherapy and chemotherapy. Before induction treatment (white bar); after induction treatment (black bar).

 
T staging
The T staging in the group as a whole was correct in 35 of 73 patients (overall accuracy, 47.9%); the degree of agreement between EUS and histology was fairly low with a {kappa} value of 0.34. The results of T staging are compared with those of histopathologic examination of specimens in Table 1. In patients with complete histologic disappearance of the tumor (T0), EUS indicated the presence of tumor in 9 patients, as many as 5 of which were assessed as T3, probably attributable to peritumoral and inflammatory changes after chemotherapy and radiotherapy. Only in 4 of 14 patients (28.6%), with presence of minimal residual disease, did the EUS tumor staging prove correct. In 7 of 10 patients the inaccuracies consisted in understaging errors. In the group of T4 tumors, 4 of 6 understaged patients presented invasion of the airways. In the evaluation of false-negative results, the sensitivity proved particularly poor in the early stages of the disease, but even in the T3 and T4 cases it was barely better than 50%.


View this table:
[in this window]
[in a new window]
  		Table 1. Comparison of Endoscopic Ultrasonography Staging of the Respective T Classes With Definitive Histopathology Results

 
N staging
Table 2 shows the correlation between the EUS assessment of nodal status and the definitive histologic findings. The overall diagnostic accuracy in the N category was 71.2%, and also in the N staging, the agreement between EUS and histology was moderate ({kappa} value, 0.423).


View this table:
[in this window]
[in a new window]
  		Table 2. Comparison of Endoscopic Ultrasonography Diagnosis of Lymph Node Metastases With Definitive Histopathology Results and Staging Sensitivity

 
Endoscopic ultrasonography correctly predicted nodal involvement in 28 of 38 patients with metastatic nodes (sensitivity, 73.7%). Twenty-four of the 35 patients without lymph node involvement were thought to be free of nodal disease (sensitivity, 68.6%).


   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
During the past decade, in an attempt to improve on the disappointing results achieved in the treatment of esophageal cancer with traditional therapies (operation or radiotherapy), study protocols have been developed involving multimodal treatments. Among the multimodal treatments available the combination of radiotherapy, chemotherapy, and operation has made it possible to achieve a substantial reduction of tumor stage with an increase in the number of tumors confined to the more superficial layers of the esophageal wall. In particular, in 21.5% of patients, we obtained complete disappearance of the tumor in the esophagus and in 17.7 % of patients only residual microfoci of cancer cells were present in the esophageal wall (minimal residual disease) [13].

Clearly, tumor staging after adjuvant treatment and before operation, if any, is of fundamental importance both for identifying the degree of response and for planning subsequent treatment. Endoscopic ultrasonography has proved to be the best procedure to assess the local extent of esophageal cancer, providing results that are significantly better than those afforded by other procedures [2, 14].

In our experience, in patients not submitted to radiotherapy and chemotherapy pretreatment, the T staging accuracy was more than 80%, which is in line with the data reported by most investigators [15]. With regard to the use of EUS in tumor staging after adjuvant treatment, few published reports are available. The study populations are limited in number and there is often no comparison with definitive histologic examinations of surgical specimens [8, 16–21].

One initial consideration emerging from our experience, as in the case of other similar studies [8, 19], is that the feasibility of EUS improves appreciably after induction treatment (84% versus 71.2%). Esophageal stenosis, in fact, is the only limitation to the use of EUS in 25% to 36% of patients, preventing passage of the endoscope and thus making it impossible to perform examination of the entire lesion [10, 22, 23].

In contrast, comparing the EUS results in patients receiving preoperative chemotherapy and radiotherapy with those obtained in patients undergoing operation alone, a distinct worsening of diagnostic accuracy in the T evaluation is noted. This finding is also confirmed by the results of other studies [16, 18–21] in which the accuracy reported is invariably lower than that obtained in patients receiving no preoperative treatment and, in any event, no better than 60%. Giovannini and colleagues [8] report results at variance with these, with accuracy rates ranging from 77.7% to 91.3%. In our opinion, the appreciable discrepancy may be attributable to the endosonographic criteria adopted by these investigators, which are not commonly used in other centers.

Overstaging is generally the most frequent error encountered [19, 20]. In our series overstaging occurred in 30.1% of patients, mainly in the group histologically staged as T0. Unlike other investigators [8], we take the view that the accurate diagnoses achieved in this group of patients must be regarded as purely casual, in that only a histologic examination is capable of establishing the complete absence of tumor cells.

The gross overstaging errors present in all the T categories and particularly striking in the T0 group (6 patients staged with advanced cancers) were probably attributable to the presence of peritumoral inflammatory or fibrous reactions or to residual necrosis after chemotherapy and radiotherapy.

The understaging errors occurred mainly as a result of poor accuracy in diagnosing infiltration of the airways in the T4 patients staged as T3 (4 of 6 patients) and as a result of the presence of residual microfoci of disease within the esophageal wall (7 of 11 patients). Understaging errors are comprehensible in these latter patients, as these are tumors that responded well to treatment despite persistence of microscopic clusters of tumor cells, which, as in the case of T0 tumors, prove impossible to identify at ultrasonography.

In the assessment of mediastinal lymph node involvement, no such inferior diagnostic performance was observed after induction treatment, the results being practically identical to those obtained in patients without preoperative treatment (71.2% versus 73% to 77%) [15, 16, 24].

In conclusion, multimodal neoadjuvant treatment constitutes a major obstacle to accurate preoperative staging of esophageal cancer and appreciably reduces the reliability of EUS in estimating the depth of invasion of the esophageal wall by the malignancy. In particular, the fact that, at present, we are unable to diagnose T0 and minimal residual disease cancers preoperatively prompts us to regard tumor staging before neoadjuvant treatment as being of fundamental importance for the choice of therapy and to adopt a more aggressive policy, with performance of an exploratory thoracotomy in the majority of patients, excluding those with systemic metastases or unmistakable signs of infiltration of adjacent organs.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

  1. Holscher A.H., Dittler H.J., Sievert J.R. Staging of squamous esophageal cancer: accuracy and value. World J Surg 1994;18:312-320.[Medline]
  2. Caletti G., Ferrari A. Endoscopic ultrasonography. Endoscopy 1996;28:156-173.
  3. Austin J.C., Postier R.G., Elkins R.C., et al. Treatment of esophageal cancer: the continued need for surgical resection. Am J Surg 1986;152:592-596.[Medline]
  4. Wolfe W.G., Burton G.V., Seigler H.F., et al. Early results with combined modality therapy for carcinoma of the esophagus. Ann Surg 1987;205:563-571.[Medline]
  5. Forastiere A.A., Orringer M.B., Perez-Tamayo C., et al. Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: final report. J Clin Oncol 1993;11:1118-1123.[Abstract/Free Full Text]
  6. Laterza E., Griso C., Urso S.U., et al. Induction therapy for squamous carcinoma of thoracic esophagus. Ann Thorac Surg 1994;57:1126-1132.[Abstract]
  7. Stahl M., Wilke H., Fink U., et al. Combined preoperative chemotherapy and radiotherapy in patients with locally advanced esophageal cancer: interim analysis of a phase II trial. J Clin Oncol 1996;14:829-837.[Abstract/Free Full Text]
  8. Giovannini M., Seitz J.F., Thomas P., et al. Endoscopic ultrasonography for assessment of the response to combined radiation therapy and chemotherapy in patients with esophageal cancer. Endoscopy 1997;29:4-9.[Medline]
  9. Murata Y., Suzuka S., Hashimoto H. Endoscopic ultrasonography of the upper gastrointestinal tract. Surg Endosc 1988;2:180-183.[Medline]
  10. Tio T.L., Cohen P., Coene P.P., et al. Endosonography and computed tomography of esophageal carcinoma: preoperative classification compared to the new (1987) TNM system. Gastroenterology 1989;96:1478-1486.[Medline]
  11. Hermaneck P., Sobin L.H. Union Internationale contre le Cancer. TNM classification of malignant tumours, 4th ed. Geneva: Springer-Verlag, 1987.
  12. In: Artman D.G., ed. Practical statistic for medical research. London: Chapman Hall, 1991:403-409.
  13. Laterza E., de Manzoni G, Griso C., Urso S.U., Guglielmi A., Cordiano C. Induction treatment for squamous carcinoma of the thoracic esophagus. Analysis of "good responders.". J Chemotherapy 1996;8:63-64.
  14. Chak A., Canto M., Gerdes H., et al. Prognosis of esophageal cancers preoperatively staged to be locally invasive (T4) by endoscopic ultrasound (EUS): a multicenter retrospective cohort study. Gastrointest Endosc 1995;42:501-506.[Medline]
  15. De Manzoni G, Laterza E., Urso S.U., Borzellino G., Rodella L., Cordiano C. Endosonography and computerized tomography in the evaluation of tumor invasion in esophageal cancer after preoperative chemo-radiotherapy. In: Nabeya K., Hanaoka T., Nogami H., eds. Recent advances in disease of the esophagus. New York: Springer, 1993:532-539.
  16. Dittler H.J., Fink U., Siewert R., et al. Response to chemotherapy in esophageal cancer. Endoscopy 1994;26:769-771.[Medline]
  17. Nousbaum J.B., Robaszkiewicz M., Cauvin J.M., Calament G., Gouerou H. Endosonography can detect residual tumour infiltration after medical treatment of oesophageal cancer in the absence of endoscopic lesions. Gut 1992;33:1459-1461.[Abstract/Free Full Text]
  18. Isenberg G., Chak A., Canto M., et al. Endoscopic ultrasound (EUS) in restaging of esophageal cancer after adjuvant chemoradiation. Gastrointest Endosc 1997;45:AB174.
  19. Quirk D, Lynch T, Grossbard M, et al. A prospective study of pre- and post-adjuvant treatment EUS in patients with esophageal cancer. In: American Gastroenterological Association: Proceeding of Digestive Disease Week, Washington DC, 1997:A-844, No. 3370.
  20. Balmain L.G., Chong W., Mertz H. Accuracy of endoscopic ultrasound in tumor staging after radiation and chemotherapy. Gastrointest Endosc 1997;45:AB167.
  21. Roubein L.D., DuBrow R., David C., et al. Endoscopic ultrasonography in the quantitative assessment of response to chemotherapy in patients with adenocarcinoma of the esophagus and esophagogastric junction. Endoscopy 1993;25:587-591.[Medline]
  22. Van Dam J., Rice T.W., Catalano M.F., Kirlay T., Sivak M.V. High-grade malignant stricture is predictive of esophageal tumor stage. Cancer 1993;71:2910-2917.[Medline]
  23. Catalano M.F., Van Dam J.V., Sivak M.V. Malignant esophageal strictures: staging accuracy of endoscopic ultrasonography. Gastroint Endosc 1995;41:535-539.
  24. Rosch T. Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin North Am 1995;5:537-547.[Medline]



This article has been cited by other articles:


Home page
 J. Thorac. Cardiovasc. Surg.Home page
I. Higuchi, T. Yasuda, M. Yano, Y. Doki, H. Miyata, M. Tatsumi, H. Fukunaga, S. Takiguchi, Y. Fujiwara, J. Hatazawa, et al.
Lack of fludeoxyglucose F 18 uptake in posttreatment positron emission tomography as a significant predictor of survival after subsequent surgery in multimodality treatment for patients with locally advanced esophageal squamous cell carcinoma
J. Thorac. Cardiovasc. Surg., July 1, 2008; 136(1): 205 - 212.
[Abstract] [Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
X.-B. D'Journo, P. Michelet, L. Dahan, C. Doddoli, J.-F. Seitz, R. Giudicelli, P. A. Fuentes, and P. A. Thomas
Indications and outcome of salvage surgery for oesophageal cancer
Eur. J. Cardiothorac. Surg., June 1, 2008; 33(6): 1117 - 1123.
[Abstract] [Full Text] [PDF]

Home page
 RadiologyHome page
M. Westerterp, H. L. van Westreenen, J. B. Reitsma, O. S. Hoekstra, J. Stoker, P. Fockens, P. L. Jager, B. L. F. Van Eck-Smit, J. T. M. Plukker, J. J. B. van Lanschot, et al.
Esophageal Cancer: CT, Endoscopic US, and FDG PET for Assessment of Response to Neoadjuvant Therapy--Systematic Review
Radiology, September 1, 2005; 236(3): 841 - 851.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
C. J. Lightdale and K. G. Kulkarni
Role of Endoscopic Ultrasonography in the Staging and Follow-Up of Esophageal Cancer
J. Clin. Oncol., July 10, 2005; 23(20): 4483 - 4489.
[Abstract] [Full Text] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
R. J. Cerfolio, A. S. Bryant, B. Ohja, A. A. Bartolucci, and M. A. Eloubeidi
The accuracy of endoscopic ultrasonography with fine-needle aspiration, integrated positron emission tomography with computed tomography, and computed tomography in restaging patients with esophageal cancer after neoadjuvant chemoradiotherapy
J. Thorac. Cardiovasc. Surg., June 1, 2005; 129(6): 1232 - 1241.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
M. Koshy, N. Esiashvilli, J. C. Landry, C. R. Thomas Jr., and R. H. Matthews
Multiple Management Modalities in Esophageal Cancer: Epidemiology, Presentation and Progression, Work-up, and Surgical Approaches
Oncologist, April 1, 2004; 9(2): 137 - 146.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. RIEDEL, H. J. STEIN, L. MOUNYAM, F. ZIMMERMANN, U. FINK, and J. R. SIEWERT
Influence of Simultaneous Neoadjuvant Radiotherapy and Chemotherapy on Bronchoscopic Findings and Lung Function in Patients with Locally Advanced Proximal Esophageal Cancer
Am. J. Respir. Crit. Care Med., November 1, 2000; 162(5): 1741 - 1746.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Laterza, E.
Right arrow Articles by Cordiano, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laterza, E.
Right arrow Articles by Cordiano, C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS