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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 908-909 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.9309
In ReplyDepartment of Surgery, Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands
Department of Pathology, Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands
Department of Clinical Epidemiology and Biostatistics, Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands
Department of Surgery, Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands We appreciate the comments of Dr Ajani on our review concerning prognostic factors in adenocarcinoma of the esophagus and gastroesophageal junction. He questions the relevance of postsurgery pathological staging now that many centers apply preoperative chemo- and/or radiotherapy (CRT) to improve local control and overall survival. Unfortunately, the randomized trials published so far on the value of neoadjuvant CRT have shown equivocal results.1 In our opinion preoperative CRT should still be considered experimental and should only be applied in the context of a clinical trial. We currently participate in a randomized multicenter Dutch trial comparing CRT plus surgery (41.4 Gy in 23 fractions of 1.8 Gy plus paclitaxel 50 mg/m2 and carboplatin area under the curve = 2 on days 1, 8, 15, 22, and 29) to surgery alone. The recently published favorable results of the British MAGIC trial,2 which compared perioperative chemotherapy and surgery versus surgery alone in gastric cancer, have changed the clinical management of (distal) gastric cancer, but in our view, these results are not applicable to esophageal and junctional cancer. The trial was originally designed specifically for gastric cancer patients. Only later during the course of the trial esophageal cancer patients also were allowed to enter the study because of the disappointing accrual, for which the trial was almost stopped. This afterthought should be considered as a major methodologic flaw. Although the impact of currently available preoperative CRT on survival is unproven, we agree with Dr Ajani that patients who have a complete pathologic response have a better survival, also in multivariate analysis as recent research indicated.3 Outside clinical trials, surgery is presently still offered as the primary therapy of first choice, to which all alternative (combinations of) therapies should be compared. The conventional postsurgery pathological TNM system is widely applied, but its prognostic accuracy is limited and can be substantially increased by simple, generally available pathologic parameters, such as lymph node ratio and extracapsular lymph node involvement.4 The impact of neoadjuvant CRT on pathologic factors as described in our review remains unknown.5 A recent study showed that the number of positive lymph nodes remained an independent prognostic factor in patients with residual adenocarcinoma of the esophagus after preoperative chemoradiotherapy.6 This might indicate that, in patients who do not have a complete response, strong predictive factors may hold their prognostic value. The genetic signature both of the tumor and of the patient play a pivotal role in the ultimate outcome of the patient. Until recently, most genetic studies focused on one or only a few molecular factors.7,8 Recently, microarray technology has become available, enabling whole genome analysis. This will supply detailed molecular insight into complex processes such as hematogenous and lymphatic dissemination.9 The original enthusiasm about the prognostic potential of this new technology has somewhat silenced because its bioinformatic analysis appears to be much more complicated and demanding than originally thought.10-12 But indeed individual tumor biology will ultimately be unraveled and thus (at least partly) replace TNM classification. We are also grateful for the comments of Dr Pedrazzani et al on our review. They propose a separate classification system for gastroesophageal junction adenocarcinomas. There is an ongoing discussion about the classification of tumors originating at the gastroesophageal junction, mainly due to their borderline location between distal esophagus and cardia.13 While some investigators classify all these tumors as esophageal, others consider them to be gastric carcinomas and others (including the authors of the letter) regard them as separate entities. One factor contributing to this controversy is the precise identification of the gastroesophageal junction. The normal gastroesophageal junction is defined differently by anatomists (peritoneal reflection, muscle bundles), physiologists (lower esophageal sphincter), endoscopists (upper border of gastric folds), and pathologists (transition of squamous into columnar epithelium, presence of esophageal glands). Even bigger definition problems arise, when a Barrett’s esophagus or a sliding hernia is present.13 Also gastroesophageal junction cancers have been classified in three different subtypes by Siewert et al.14,15 One limitation is that in their original article, the gastroesophageal junction was defined as the Z-line.16 However, this reference point can move proximally into the esophagus when Barrett’s metaplasia develops. In addition, they claim that preoperative diagnostic tests can correctly classify gastroesophageal junction cancers in 95% of cases, but this has never been properly and independently evaluated.17 Clearly, the classification of tumors arising at the gastroesophageal junction elicits substantial problems. Until these problems have been solved, the separate classification of gastroesophageal junction adenocarcinomas can hardly be recommended. Staging systems should be dynamic, and increased knowledge of cancers will definitely change staging systems in the future. A large number of prognostic factors have already been described. Therefore, our aim was to supply a review of these factors. It can be used as a guideline for which factors to include in multivariate analysis when new prognostic factors are investigated. It is well possible that a single new factor, when compared with the conventional TNM system of the esophagus, has significant prognostic power in multivariate analysis. However, when additional factors (for example, the number of positive nodes and the presence of extracapsular lymph node involvement) are also included in the analysis, this new factor may lose its significance in multivariate analysis. In this respect, the site of nodal metastasis remains a controversial issue. Pedrazzani et al have shown that patients with involvement of second tier nodes or beyond have a very poor survival. However, it has been shown by others that patients with distal esophageal cancers and cervical lymph node metastasis still have a reasonable chance for survival.18,19 We also found that patients with cardiac cancer and relatively distant mediastinal nodes have a poor prognosis because it is a reflection of advanced disease.20 We look forward to the publication of the results of the new pN classification of Pedrazzani et al and hope that their classification system will show additional value when independently validated. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES 1. Greer SE, Goodney PP, Sutton JE, et al: Neoadjuvant chemoradiotherapy for esophageal carcinoma: A meta-analysis. Surgery 137:172-177, 2005[CrossRef][Medline] 2. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006 3. Rohatgi P, Swisher SG, Correa AM, et al: Characterization of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response. Cancer 104:2365-2372, 2005[CrossRef][Medline] 4. Lagarde SM, Reitsma JB, de Castro SM, et al: Prognostic nomogram for patients after oesophagectomy for adenocarcinoma of the oesophagus or gastro-oesophageal junction. Br J Surg (in press) 5. Lagarde SM, ten Kate FJ, Reitsma JB, et al: Prognostic factors in adenocarcinoma of the esophagus or gastroesophageal junction. J Clin Oncol 24:4347-4355, 2006 6. Gu Y, Swisher SG, Ajani JA, et al: The number of lymph nodes with metastasis predicts survival in patients with esophageal or esophagogastric junction adenocarcinoma who receive preoperative chemoradiation. Cancer 106:1017-1025, 2006[CrossRef][Medline] 7. Buskens CJ, van Rees BP, Sivula A, et al: Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology 122:1800-1807, 2002[CrossRef][Medline] 8. Lagarde SM, ten Kate FJ, Richel DJ, et al: Molecular prognostic factors in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol 14:977-991, 2007 9. Lagarde SM, Ver Loren van Themaat PE, et al: Analysis of gene expression discovers pathways associated with hematogenous metastasis in patients with adenocarcinoma of the esophagus. J Clin Gastroenetrol 40: S164, 2006 (abstr 3) 10. Wang Y, Klijn JG, Zhang Y, et al: Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671-679, 2005[Medline] 11. van’t Veer L, Dai H, Van de Vijver V, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002[CrossRef][Medline] 12. Michiels S, Koscielny S, Hill C: Prediction of cancer outcome with microarrays: A multiple random validation strategy. Lancet 365:488-492, 2005[CrossRef][Medline] 13. Marsman WA, Tytgat GN, ten Kate FJ, et al: Differences and similarities of adenocarcinomas of the esophagus and esophagogastric junction. J Surg Oncol 92:160-168, 2005[CrossRef][Medline] 14. Siewert JR, Stein HJ: Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 85:1457-1459, 1998[CrossRef][Medline] 15. Siewert JR, Feith M, Werner M, et al: Adenocarcinoma of the esophagogastric junction: Results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 232:353-361, 2000[CrossRef][Medline] 16. Siewert JR, Holscher AH, Becker K, et al: Cardia cancer: Attempt at a therapeutically relevant classification. Chirurg 58:25-32, 1987[Medline] 17. Fein M, Fuchs KH, Ritter MP, et al: Application of the new classification for cancer of the cardia. Surgery 124:707-713, 1998[CrossRef][Medline] 18. Lerut T, Nafteux P, Moons J, et al: Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: Impact on staging, disease-free survival, and outcome: A plea for adaptation of TNM classification in upper-half esophageal carcinoma. Ann Surg 240:962-972, 2004[CrossRef][Medline] 19. Altorki N, Kent M, Ferrara C, et al: Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg 236:177-183, 2002[CrossRef][Medline] 20. Lagarde SM, Cense HA, Hulscher JB, et al: Prospective analysis of patients with adenocarcinoma of the gastric cardia and lymph node metastasis in the proximal field of the chest. Br J Surg 92:1404-1408, 2005[CrossRef][Medline] Related Correspondence
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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