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Resection for Esophageal Cancer: Strategies for Optimal Management

2008; Elsevier BV; Volume: 85; Issue: 2 Linguagem: Inglês

10.1016/j.athoracsur.2007.11.078

1552-6259

Arjun Pennathur, James D. Luketich,

Esophageal and GI Pathology

There are several controversies in the optimal management of esophageal cancer, including the surgical approach, extent of resection, and the role of multimodality treatment. Optimal surgical treatment strategies include patient selection, accurate staging and risk assessment, selection of an appropriate surgical approach, and the use of multimodality treatment in the management of these patients. In addition, other factors such as hospital and surgeon volume are important in reducing the risks of esophagectomy. In this article we discuss our approach and review the literature on these aspects that have an impact on outcomes after esophagectomy. There are several controversies in the optimal management of esophageal cancer, including the surgical approach, extent of resection, and the role of multimodality treatment. Optimal surgical treatment strategies include patient selection, accurate staging and risk assessment, selection of an appropriate surgical approach, and the use of multimodality treatment in the management of these patients. In addition, other factors such as hospital and surgeon volume are important in reducing the risks of esophagectomy. In this article we discuss our approach and review the literature on these aspects that have an impact on outcomes after esophagectomy. The incidence of esophageal carcinoma has increased dramatically during the past 3 decades. In the United States, adenocarcinoma now surpasses squamous cell carcinoma as the most common histologic subtype of esophageal carcinoma. The outcome for patients with esophageal carcinoma continues to be poor, with a 5-year survival rate of 14% [1Enzinger P.C. Mayer R.J. Esophageal cancer.N Engl J Med. 2003; 349: 2241-2252Crossref PubMed Scopus (2440) Google Scholar]. Surgical resection is the primary curative therapy for patients with resectable esophageal cancer. There are, however, several controversies in the optimal management of esophageal cancer, including the surgical approach, extent of resection, and the role of multimodality treatment. Optimal surgical treatment strategies include appropriate patient selection, accurate staging, risk assessment, selection of an appropriate surgical approach, and the use of multimodality treatment in the management of these patients. In addition, other factors such as hospital and surgeon volume are important in reducing the risks of esophagectomy. The objective of this article is to discuss our approach and review the literature on these aspects that have an impact on the outcomes after esophagectomy. This review is not intended to be a comprehensive review of these issues but rather to give the reader an overview of the important factors that may have an impact on the outcomes after esophagectomy. We reviewed our experience and the medical literature on the various factors that may have an impact on the outcomes after esophagectomy. These include patient selection, staging strategies, the surgical approach, extent of resection, and the role of multimodality therapy for the treatment of esophageal cancer. The medical literature was searched using United States National Library of Medicine service, PubMed, and the following key words were chosen: esophageal cancer, esophagectomy, risk assessment, staging, mortality, risk reduction, surgical approach, multimodality therapy, neoadjuvant therapy, and adjuvant therapy. The reference lists from the articles retrieved were also reviewed for additional articles. The search was limited to English language and human studies. Proper patient selection includes accurate staging and risk assessment of the patient. Accurate staging is critical for selection of appropriate treatment strategy, enrollment in clinical trials, and in the evaluation of results [2Krasna M.J. Reed C.E. Nedzwiecki D. et al.CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer.Ann Thorac Surg. 2001; 71: 1073-1079Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. The current modalities of staging include computed tomography (CT) scanning, positron emission tomography (PET) scanning, and endoscopic ultrasound (EUS) [3Rasanen J.V. Sihvo E.I. Knuuti M.J. et al.Prospective analysis of accuracy of positron emission tomography, computed tomography, and endoscopic ultrasonography in staging of adenocarcinoma of the esophagus and the esophagogastric junction.Ann Surg Oncol. 2003; 10: 954-960Crossref PubMed Scopus (185) Google Scholar, 4Luketich J.D. Friedman D.M. Weigel T.L. et al.Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans.Ann Thorac Surg. 1999; 68 (discussion 1136–7): 1133-1136Abstract Full Text PDF PubMed Scopus (228) Google Scholar, 5Luketich J.D. Schauer P. Landreneau R.J. et al.Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer.J Thorac Cardiovasc Surg. 1997; 114: 817-882Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 6Kaushik N. Khalid A. Brody D. Luketich J. McGrath K. Endoscopic ultrasound compared with laparoscopy for staging esophageal cancer.Ann Thorac Surg. 2007; 83: 2000-2002Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 7Meyers B.F. Downey R.J. Decker P.A. et al.American College of Surgeons Oncology Group Z0060The utility of positron emission tomography in staging of potentially operable carcinoma of the thoracic esophagus: results of the American College of Surgeons Oncology Group Z0060 trial.J Thorac Cardiovasc Surg. 2007; 133: 738-745Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 8May A. Günter E. Roth F. Gossner L. Stolte M. Vieth M. Ell C. Accuracy of staging in early oesophageal cancer using high resolution endoscopy and high resolution endosonography: a comparative, prospective, and blinded trial.Gut. 2004; 53: 634-640Crossref PubMed Scopus (267) Google Scholar]. In addition, minimally invasive staging (MIS) with laparoscopy in particular is practiced in some institutions including ours, but not practiced routinely for staging in several institutions [2Krasna M.J. Reed C.E. Nedzwiecki D. et al.CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer.Ann Thorac Surg. 2001; 71: 1073-1079Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 4Luketich J.D. Friedman D.M. Weigel T.L. et al.Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans.Ann Thorac Surg. 1999; 68 (discussion 1136–7): 1133-1136Abstract Full Text PDF PubMed Scopus (228) Google Scholar, 5Luketich J.D. Schauer P. Landreneau R.J. et al.Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer.J Thorac Cardiovasc Surg. 1997; 114: 817-882Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 6Kaushik N. Khalid A. Brody D. Luketich J. McGrath K. Endoscopic ultrasound compared with laparoscopy for staging esophageal cancer.Ann Thorac Surg. 2007; 83: 2000-2002Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. Endoscopic mucosal resection (EMR) has also been proposed as a staging modality [9Maish M.S. DeMeester S.R. Endoscopic mucosal resection as a staging technique to determine the depth of invasion of esophageal adenocarcinoma.Ann Thorac Surg. 2004; 78: 1777-1782Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. All these modalities have value, and the choice and sequence of these modalities depends on the preference of the surgeon and institution. At our institution, CT scan, EUS, and minimally invasive laparoscopic staging are performed routinely, while PET scans are used selectively. Computed tomography scanning for staging of esophageal cancer should include an assessment of the extent of esophageal involvement, assessment of regional and distant lymph node involvement, tumor invasion of the periesophageal fat and adjacent structures, and metastases to distant organs such as the liver. Computed tomography scanning is not very accurate for establishing the T status or the N status. Endoscopic ultrasound is extremely useful in evaluation of T status, and EUS-guided fine needle aspiration (EUS-FNA) biopsy is valuable in assessing locoregional and celiac nodal metastases [3Rasanen J.V. Sihvo E.I. Knuuti M.J. et al.Prospective analysis of accuracy of positron emission tomography, computed tomography, and endoscopic ultrasonography in staging of adenocarcinoma of the esophagus and the esophagogastric junction.Ann Surg Oncol. 2003; 10: 954-960Crossref PubMed Scopus (185) Google Scholar]. Positron emission tomography scanning is more accurate than conventional CT imaging, particularly in the detection of distant metastases [4Luketich J.D. Friedman D.M. Weigel T.L. et al.Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans.Ann Thorac Surg. 1999; 68 (discussion 1136–7): 1133-1136Abstract Full Text PDF PubMed Scopus (228) Google Scholar, 7Meyers B.F. Downey R.J. Decker P.A. et al.American College of Surgeons Oncology Group Z0060The utility of positron emission tomography in staging of potentially operable carcinoma of the thoracic esophagus: results of the American College of Surgeons Oncology Group Z0060 trial.J Thorac Cardiovasc Surg. 2007; 133: 738-745Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. Minimally invasive surgical staging is practiced in some institutions such as ours and is a very useful in staging selected patients [2Krasna M.J. Reed C.E. Nedzwiecki D. et al.CALGB 9380: a prospective trial of the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer.Ann Thorac Surg. 2001; 71: 1073-1079Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 4Luketich J.D. Friedman D.M. Weigel T.L. et al.Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans.Ann Thorac Surg. 1999; 68 (discussion 1136–7): 1133-1136Abstract Full Text PDF PubMed Scopus (228) Google Scholar, 5Luketich J.D. Schauer P. Landreneau R.J. et al.Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer.J Thorac Cardiovasc Surg. 1997; 114: 817-882Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 6Kaushik N. Khalid A. Brody D. Luketich J. McGrath K. Endoscopic ultrasound compared with laparoscopy for staging esophageal cancer.Ann Thorac Surg. 2007; 83: 2000-2002Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. We have reported an increased accuracy of MIS staging compared with PET scans [4Luketich J.D. Friedman D.M. Weigel T.L. et al.Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans.Ann Thorac Surg. 1999; 68 (discussion 1136–7): 1133-1136Abstract Full Text PDF PubMed Scopus (228) Google Scholar]. In an analysis of 100 consecutive PET scans from the University of Pittsburgh, we reported that although PET scanning was more accurate than CT scanning, its sensitivity was only 69%, specificity was 94%, and an overall accuracy was 84% compared with MIS. Similarly, we have reported an increase in accuracy with MIS staging compared with EUS in the diagnosis of lymph node metastases [5Luketich J.D. Schauer P. Landreneau R.J. et al.Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer.J Thorac Cardiovasc Surg. 1997; 114: 817-882Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]. In this study comparing EUS with MIS staging, the overall accuracy of EUS in assessment of lymph node metastases in esophageal cancer was 65%. With advances in technique and use of EUS-FNA, a more recent study in our institution that compared EUS and laparoscopy found the accuracy for nodal staging improved, but overall staging accuracy of EUS was only 72% compared with laparoscopy [6Kaushik N. Khalid A. Brody D. Luketich J. McGrath K. Endoscopic ultrasound compared with laparoscopy for staging esophageal cancer.Ann Thorac Surg. 2007; 83: 2000-2002Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. However, MIS is not practiced universally. We have however found that MIS with laparoscopy is particularly valuable in detection of occult distant metastases and exclusion of these patients from definitive surgical resection. This can be performed prior to performing a laparotomy and definitive resection. The patient's physiologic status should be thoroughly evaluated to make an assessment of the risks of esophagectomy. This evaluation should include an assessment of the patient's performance status, cardiovascular function, pulmonary function, and nutritional status. Patient risk assessment at the University of Pittsburgh includes an assessment of comorbidities, evaluation of cardiopulmonary function, and nutritional status. Pulmonary complications, particularly pneumonia, are an important determinant of early postoperative outcome [10Atkins B.Z. Shah A.S. Hutcheson K.A. et al.Reducing hospital morbidity and mortality following esophagectomy.Ann Thorac Surg. 2004; 78 (discussion 1176): 1170-1176Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar]. In a study of preoperative risk assessment by Ferguson and colleagues [11Ferguson M.K. Durkin A.E. Preoperative prediction of the risk of pulmonary complications after esophagectomy for cancer.J Thorac Cardiovasc Surg. 2002; 123: 661-669Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar], pulmonary complications were associated with more than a fourfold increase in mortality. Multivariate analysis showed that age and decreased forced expiratory volume in 1 second (FEV1) were predictive of pulmonary complications. These authors developed a scoring system based on this retrospective analysis, incorporating age, spirometry, and performance status to predict the likelihood of cardiovascular and pulmonary complications [11Ferguson M.K. Durkin A.E. Preoperative prediction of the risk of pulmonary complications after esophagectomy for cancer.J Thorac Cardiovasc Surg. 2002; 123: 661-669Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar]. Avendano and colleagues [12Avendano C.E. Flume P.A. Silvestri G.A. King L.B. Reed C.E. Pulmonary complications after esophagectomy.Ann Thorac Surg. 2002; 73: 922-926Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar] similarly identified age, decreased FEV1, and preoperative chemoradiation as risk factors for development of pneumonia. These criteria, however, need to be prospectively validated. The risk assessment should be individualized, taking into consideration a complete assessment of the patient's physiologic status by the surgeon, and treatment should be individualized according to the risks. The various open approaches used for esophageal resection include transhiatal resection or transthoracic approaches such as Ivor Lewis esophagectomy, resection with a left thoracotomy or a left thoracoabdominal approach, and the "3-incision" McKeown-type esophagectomy [13Hagen J.A. DeMeester S.R. Peters J.H. Chandrasoma P. DeMeester T.R. Curative resection for esophageal adenocarcinoma: analysis of 100 en bloc esophagectomies.Ann Surg. 2001; 234 (discussion 530): 520-530Crossref PubMed Scopus (341) Google Scholar, 14Orringer M.B. Marshall B. Iannettoni M.D. Transhiatal esophagectomy: clinical experience and refinements.Ann Surg. 1999; 230 (discussion 400–3): 392-400Crossref PubMed Scopus (531) Google Scholar, 15Altorki N. Skinner D. Should en bloc esophagectomy be the standard of care for esophageal carcinoma?.Ann Surg. 2001; 234: 581-587Crossref PubMed Scopus (208) Google Scholar, 16Swanson S.J. Batirel H.F. Bueno R. et al.Transthoracic esophagectomy with radical mediastinal and abdominal lymph node dissection and cervical esophagogastrostomy for esophageal carcinoma.Ann Thorac Surg. 2001; 72 (discussion 1924–5): 1918-1924Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 17Visbal A.L. Allen M.S. Miller D.L. Deschamps C. Trastek V.F. Pairolero P.C. Ivor Lewis esophagogastrectomy for esophageal cancer.Ann Thorac Surg. 2001; 71: 1803-1808Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 18Palanivelu C. Prakash A. Senthilkumar P. et al.Minimally invasive esophagectomy: thoracoscopic mobilization of the esophagus and mediastinal lymphadenectomy in prone position--experience of 130 patients.J Am Coll Surg. 2006; 203: 7-16Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar]. The choice of approach depends on various factors, including the location of the tumor, the preference of the surgeon, and the choice for esophageal reconstruction. Large single-institution series have adopted various approaches, but the ideal approach has not been established [13Hagen J.A. DeMeester S.R. Peters J.H. Chandrasoma P. DeMeester T.R. Curative resection for esophageal adenocarcinoma: analysis of 100 en bloc esophagectomies.Ann Surg. 2001; 234 (discussion 530): 520-530Crossref PubMed Scopus (341) Google Scholar, 14Orringer M.B. Marshall B. Iannettoni M.D. Transhiatal esophagectomy: clinical experience and refinements.Ann Surg. 1999; 230 (discussion 400–3): 392-400Crossref PubMed Scopus (531) Google Scholar, 15Altorki N. Skinner D. Should en bloc esophagectomy be the standard of care for esophageal carcinoma?.Ann Surg. 2001; 234: 581-587Crossref PubMed Scopus (208) Google Scholar, 16Swanson S.J. Batirel H.F. Bueno R. et al.Transthoracic esophagectomy with radical mediastinal and abdominal lymph node dissection and cervical esophagogastrostomy for esophageal carcinoma.Ann Thorac Surg. 2001; 72 (discussion 1924–5): 1918-1924Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 17Visbal A.L. Allen M.S. Miller D.L. Deschamps C. Trastek V.F. Pairolero P.C. Ivor Lewis esophagogastrectomy for esophageal cancer.Ann Thorac Surg. 2001; 71: 1803-1808Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 18Palanivelu C. Prakash A. Senthilkumar P. et al.Minimally invasive esophagectomy: thoracoscopic mobilization of the esophagus and mediastinal lymphadenectomy in prone position--experience of 130 patients.J Am Coll Surg. 2006; 203: 7-16Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar]. At our institution, we prefer the use of a minimally invasive transthoracic approach (3-incision or Ivor-Lewis esophagectomy) with lymph node dissection in patients with esophageal neoplasm. Multiple retrospective studies have compared the various approaches to esophagectomy, and no significant differences in outcome have been found [19Hulscher J.B. Tijssen J.G. Obertop H. van Lanschot J.J. Transthoracic versus transhiatal resection for carcinoma of the esophagus: a meta-analysis.Ann Thorac Surg. 2001; 72: 306-313Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar]. Very few randomized trials, however, have compared transthoracic vs transhiatal esophagectomy. Hulscher and colleagues [20Hulscher J.B. van Sandick J.W. de Boer A.G. et al.Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus.N Engl J Med. 2002; 347: 1662-1669Crossref PubMed Scopus (1328) Google Scholar] conducted a randomized trial comparing transthoracic vs transhiatal esophagectomy in patients with mid-distal and gastroesophageal junction neoplasms. Although the perioperative morbidity rate was higher in the transthoracic group, the difference in the mortality rate between the two groups was not significant. During a median follow-up of 4.7 years, there was a trend toward a better 5-year overall (39% vs 29%) and disease free survival (39% vs 27%) in the transthoracic group, although this did not reach statistical significance. These investigators concluded that transhiatal esophagectomy was associated with a lower morbidity and noted a trend towards improved long-term survival at 5 years with an extended transthoracic approach. Other controversies include the extent of lymph node dissection. Proponents of extended three-field lymph node dissection point out the low recurrence rates and the benefits of accurate staging. Nishihara and colleagues [21Nishihira T. Hirayama K. Mori S. A prospective randomized trial of extended cervical and superior mediastinal lymphadenectomy for carcinoma of the thoracic esophagus.Am J Surg. 1998; 175: 47-51Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar] conducted a randomized trial of 62 patients comparing two-field lymphadenectomy (thoracic and abdominal) with three fields, including cervical and superior mediastinal lymphadenectomy. Complications were significantly increased in the extended lymphadenectomy group, including a 53% tracheostomy rate and 13% incidence of phrenic nerve palsy, although a trend towards better survival was noted on long-term follow-up. Three-field lymph node dissection is primarily practiced in Japan and in very few selected centers in the West. A main concern for recommendation of esophagectomy is the risk associated with the surgical procedure. In an effort to decrease the morbidity and mortality from this procedure, recent advances in MIS have allowed us to develop and refine the technique of minimally invasive esophagectomy (MIE) at the University of Pittsburgh. We have described the technique and our experience at the University of Pittsburgh in detail [22Luketich J.D. Alvelo-Rivera M. Buenaventura P.O. et al.Minimally invasive esophagectomy: outcomes in 222 patients.Ann Surg. 2003; 238 (discussion 494–5): 486-494Crossref PubMed Google Scholar]. We reported our results of a series of 222 consecutive MIEs [22Luketich J.D. Alvelo-Rivera M. Buenaventura P.O. et al.Minimally invasive esophagectomy: outcomes in 222 patients.Ann Surg. 2003; 238 (discussion 494–5): 486-494Crossref PubMed Google Scholar]. Minimally invasive esophagectomy was successfully completed in 206 (92.8%) of patients. The median lengths of stay were 1 day in the intensive care unit and 7 days in the hospital. The operative mortality rate was 1.4%. Stage-specific survival was similar to open esophagectomy series. With advances made in surgical techniques and perioperative critical care, a decrease in the mortality and morbidity from esophagectomy has been achieved. However, the long-term quality of life (QOL) after esophagectomy is being increasingly recognized as an important factor in determining the treatment modality. This study used the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey to measure the QOL [22Luketich J.D. Alvelo-Rivera M. Buenaventura P.O. et al.Minimally invasive esophagectomy: outcomes in 222 patients.Ann Surg. 2003; 238 (discussion 494–5): 486-494Crossref PubMed Google Scholar]. Preoperative and postoperative scores were available in 57 patients, and no significant differences were found indicating preservation of QOL. In addition, the Gastroesophageal Reflux Disease Health-Related Quality of Life (HRQOL) scale was used to assess reflux related QOL. The range of this score varies from 0 (no symptoms) to 45 (most severe symptoms). The mean HRQOL score was 4.6, indicating a normal (no reflux) score. Dysphagia scores were excellent, with a mean score of 1.4 using a scale of 1 (no dysphagia) to 5 (severe dysphagia). Thus, the QOL after minimally invasive esophagectomy is well preserved. After MIE in our center, we observed a short hospital stay, a low mortality rate, preserved QOL, and good oncologic results. Our current approach is to perform a minimally invasive Ivor-Lewis esophagectomy with lymph node dissection in most patients with resectable esophageal cancer. A minimally invasive approach to esophagectomy is practiced in selected centers but is not practiced routinely in several institutions. A phase II study is currently in progress by the Eastern Cooperative Oncology Group (ECOG 2202) to evaluate the results of MIE in a multi-institutional setting. The potential benefits of neoadjuvant chemotherapy include earlier treatment of micrometastatic disease and downstaging of tumor with possible increase in curative resection. Neoadjuvant chemotherapy for locally advanced tumors is preferred at our institution. We recently reported the long-term results of a phase II trial of neoadjuvant therapy for the treatment of esophageal cancer at the University of Pittsburgh [23Pennathur A, Luketich JD, Alvelo-Rivera M, et al. Long term results of a phase II trial of neoadjuvant chemotherapy followed by esophagectomy for locally advanced esophageal neoplasm. Presented at Society of Thoracic Surgeons Annual Meeting, San Diego, CA, Jan 2007.Google Scholar]. Patients received preoperative chemotherapy with cisplatin, 5-flurouracil, and paclitaxel, followed by operation and up to two cycles of the same chemotherapy in the adjuvant setting. Most of the 70 patients we enrolled had locally advanced disease: 80% of patients had preoperative pathologically proven N1 disease, and 99% of patients had either a T3 or N1 lesion. Esophagectomy was performed in 63 patients. The operative mortality rate was 0%. The median overall survival of the entire group was 27.4 months, 17 patients are alive at a median follow-up of 62.8 months (range, 39.1 to 142 months), and 14 patients are alive without recurrence at a median follow-up of 79 months (range, 39 to 138 months). Patients who were downstaged experienced a significantly improved survival. Randomized studies have not shown a consistent benefit, however. Kelsen and colleagues [24Kelsen D.P. Ginsberg R. Pajak T.F. et al.Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.N Engl J Med. 1998; 339: 1979-1984Crossref PubMed Scopus (1180) Google Scholar] reported the results of a prospective randomized study in North America in 400 patients comparing preoperative chemotherapy, followed by surgery, vs surgery alone. The two arms had s similar median survival: 16.1 months in the surgical arm and 14.9 months in the treatment arm. The 2-year survival was 37% in the surgery alone arm and 35% in the treatment arm. More recently, the Medical Research Council reported the results of a randomized study using cisplatin and 5-flurouracil, followed by resection vs resection alone [25Medical Research Council Oesophageal Cancer Working PartySurgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomized trial.Lancet. 2002; 359: 1727-1733Abstract Full Text Full Text PDF PubMed Scopus (1283) Google Scholar]. In contrast to the study by Kelsen and colleagues [24Kelsen D.P. Ginsberg R. Pajak T.F. et al.Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.N Engl J Med. 1998; 339: 1979-1984Crossref PubMed Scopus (1180) Google Scholar], there was a significant improvement in the survival, with a 16.8-month median survival in the chemotherapy arm vs 13.3 months in the surgery arm, and the 2-year survival rates were 43% and 34%, respectively, at a median follow-up of 37 months. Finally, the results of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, using a strategy similar to our study with preoperative chemotherapy, surgery, and adjuvant chemotherapy favoring the treatment arm, has recently been published [26Cunningham D. Allum W.H. Stenning S.P. et al.Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.N Engl J Med. 2006; 355: 11-20Crossref PubMed Scopus (4484) Google Scholar]. Only about a quarter of the patients had cancers of the distal esophagus or gastroesophageal junction, and most had gastric cancer. The overall 5-year survival in the treatment arm was 36% vs. 23% at a median follow-up of four years. Another approach to the treatment of esophageal cancer involves the addition of preoperative radiation to chemotherapy [1Enzinger P.C. Mayer R.J. Esophageal cancer.N Engl J Med. 2003; 349: 2241-2252Crossref PubMed Scopus (2440) Google Scholar]. In our institution, neoadjuvant chemotherapy is preferred in locally advanced tumors and neoadjuvant chemoradiation is used only in selected patients with bulky disease. Forastiere and colleagues [27Forastiere 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: 1118-1123Crossref PubMed Scopus (363) Google Scholar] reported the results in 43 patients treated with chemoradiation, followed by transhiatal esophagectomy. In this series, 56% of patients were suspected to have nodal metastases preoperatively, and 8 patients (19%) had T1 disease. The median survival was 29 months, and the 5-year survival was 34%. However, randomized trials with this approach have not shown a consistent benefit [28Urba S.G. Orringer M.B. Turrisi A. et al.Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.J Clin Oncol. 2001; 19: 305-313PubMed Google Scholar, 29Walsh T. Noonan N. Hollywood D. Kelly A. Keeling N. Hennessy T.P. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.N Engl J Med. 1996; 335: 462-467Crossref PubMed Scopus (1802) Google Scholar, 30Burmeister B.H. Smithers B.M. Gebski V. et al.Surgery alone versus hemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial.Lancet Oncol. 2005; 6: 659-668Abstract Full Text Full Text PDF PubMed Scopus (814) Google Scholar]. Urba and colleagues [28Urba S.G. Orringer M.B. Turrisi A. et al.Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.J Clin Oncol. 2001; 19: 305-313PubMed Google Scholar] subsequently reported the results of a randomized trial comparing preoperative chemoradiation, followed by surgery, vs surgery alone and did not find a significant survival benefit: median survival was 16.9 months in the treatment arm vs 17.6 months in the surgery arm. The one trial that showed a benefit was reported by Walsh and colleagues [29Walsh T. Noonan N. Hollywood D. Kelly A. Keeling N. Hennessy T.P. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.N Engl J Med. 1996; 335: 462-467Crossref PubMed Scopus (1802) Google Scholar], which evaluated preoperative chemotherapy with 4000 Gy of radiation. With a median survival of 16 months vs 11 months and a 3-year survival of 32% vs 6%, chemoradiation was associated with survival benefit [29Walsh T. Noonan N. Hollywood D. Kelly A. Keeling N. Hennessy T.P. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.N Engl J Med. 1996; 335: 462-467Crossref PubMed Scopus (1802) Google Scholar]. Their 6% probability of 3-year survival with surgery was lower than expected. Meta-analysis of trials evaluating neoadjuvant chemoradiation has, however, shown a benefit [31Urschel J.D. Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer.Am J Surg. 2003; 185: 538-543Abstract Full Text Full Text PDF PubMed Scopus (559) Google Scholar]. Although, neoadjuvant strategies are commonly used, further prospective studies are required to determine the role of neoadjuvant strategies in the management of esophageal cancer. Some of these trials are summarized in Table 1.Table 1Selected Trials Comparing Neoadjuvant Chemotherapy With or Without Radiation and Surgery vs Surgery Alone in Patients With Localized Esophageal CancerFirst Author, YearStudyNo. of PatientsChemotherapyTotal Radiotherapy Dose (cGy)Median Survival (months)Survival, %Kelsen [24Kelsen D.P. Ginsberg R. Pajak T.F. et al.Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.N Engl J Med. 1998; 339: 1979-1984Crossref PubMed Scopus (1180) Google Scholar], 1998Surgery alone vs pre-op chemotherapy with surgery440Cisplatin, fluorouracil. . .16.13714.935 (2-yr survival)MRC Trial [25Medical Research Council Oesophageal Cancer Working PartySurgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomized trial.Lancet. 2002; 359: 1727-1733Abstract Full Text Full Text PDF PubMed Scopus (1283) Google Scholar], 2002Surgery alone vs pre-op chemotherapy with surgery802Cisplatin, fluorouracil. . .13.33416.8ap < 0.05.43ap < 0.05. (2-yr survival)Cunningham [26Cunningham D. Allum W.H. Stenning S.P. et al.Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.N Engl J Med. 2006; 355: 11-20Crossref PubMed Scopus (4484) Google Scholar], 2006Surgery alone vs pre-op chemotherapy, surgery, and postoperative chemotherapy503Epirubicin, cisplatin, fluorouracil. . .NA2336ap < 0.05. (5-yr survival)Urba [28Urba S.G. Orringer M.B. Turrisi A. et al.Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma.J Clin Oncol. 2001; 19: 305-313PubMed Google Scholar], 2001Surgery alone vs pre-op chemotherapy and radiotherapy with surgery100Cisplatin, vinblastine, fluorouracil450017.61616.930 (3-yr survival)Walsh [29Walsh T. Noonan N. Hollywood D. Kelly A. Keeling N. Hennessy T.P. 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The role of adjuvant chemotherapy in esophageal adenocarcinoma is not established, although there are some encouraging data for adjuvant chemotherapy, particularly for squamous cell neoplasm from Japan. Patients in our institution are evaluated for adjuvant chemotherapy when the final pathology shows nodal disease. Randomized trials, however, have not shown a consistent benefit to the adjuvant strategy [32Ando N. Iizuka T. Kakegawa T. et al.A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study.J Thorac Cardiovasc Surg. 1997; 114: 205-209Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 33Ando N. Iizuka T. Ide H. et al.Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study–JCOG9204.J Clin Oncol. 2003; 21: 4592-4596Crossref PubMed Scopus (556) Google Scholar]. A randomized trial by Ando and colleagues [32Ando N. Iizuka T. Kakegawa T. et al.A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study.J Thorac Cardiovasc Surg. 1997; 114: 205-209Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar] of surgery with or without adjuvant chemotherapy (cisplatin and vindesine) for localized squamous cell neoplasm did not show a benefit for chemotherapy. Another randomized trial conducted by the Japanese Clinical Oncology group (JCOG9204) randomized 242 patients to surgery alone vs surgery and chemotherapy consisting of cisplatin and fluorouracil [33Ando N. Iizuka T. Ide H. et al.Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study–JCOG9204.J Clin Oncol. 2003; 21: 4592-4596Crossref PubMed Scopus (556) Google Scholar]. The 5-year disease-free survival rate was 45% in the surgery-only arm vs 55% in the surgery-plus-chemotherapy arm (one-sided p = 0.037). A further analysis of subgroups showed the N1 subgroup had a significantly improved 5-year disease-free survival rate of 38% in the surgery-alone arm vs 52% in the surgery-plus-chemotherapy arm (p = 0.04). The 5-year overall survival rate was not significantly different. These investigators concluded that postoperative chemotherapy might prevent relapse in patients better than surgery alone. Armonias and colleagues [34Armanios M. Xu R. Forastiere A.A. et al.Adjuvant chemotherapy for resected adenocarcinoma of the esophagus, gastro-esophageal junction, and cardia: phase II trial (E8296) of the Eastern Cooperative Oncology Group.J Clin Oncol. 2004; 22: 4495-4499Crossref PubMed Scopus (56) Google Scholar] reported the results of the ECOG Phase II trial (E8296) of adjuvant chemotherapy consisting of cisplatinum and paclitaxel for resected adenocarcinoma of the esophagus. At a median follow-up of 4 years, the 2-year survival was 60%. The authors' concluded that adjuvant therapy with this regimen might improve survival in completely resected patients with esophageal neoplasm. Further randomized trials are needed to determine if adjuvant chemotherapy after complete resection is beneficial. Adjuvant radiotherapy is generally used only with patients with residual disease. Randomized trials have not shown a benefit for routine adjuvant radiotherapy [35Ténière P. Hay J.M. Fingerhut A. Fagniez P.L. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial French University Association for Surgical Research.Surg Gynecol Obstet. 1991; 173: 123-130PubMed Google Scholar, 36Fok M. Sham J.S. Choy D. Cheng S.W. Wong J. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study.Surgery. 1993; 113: 138-147PubMed Google Scholar]. Several studies have now shown the association between the mortality rate for esophagectomy and hospital volume: the mortality rate is significantly lower in high-volume centers vs low-volume centers [37Birkmeyer J.D. Siewers A.E. Finlayson E.V. et al.Hospital volume and surgical mortality in the United States.N Engl J Med. 2002; 346: 1128-1137Crossref PubMed Scopus (4020) Google Scholar, 38Pennathur A. Landreneau R.J. Luketich J.D. Surgical aspects of the patient with high-grade dysplasia.Semin Thorac Cardiovasc Surg. 2005; 17: 326-332Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Surgeon volume and specialty training also have an impact on the mortality rate. In a recent study by Dimick and coworkers [39Dimick J.B. Goodney P.P. Orringer M.B. et al.Specialty training and mortality after esophageal cancer resection.Ann Thorac Surg. 2005; 80: 282-286Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar], the mortality rate was significantly lower for thoracic surgeons compared with surgeons without specialty training. The difference in mortality rates between high-volume vs low-volume surgeons was even more significant [39Dimick J.B. Goodney P.P. Orringer M.B. et al.Specialty training and mortality after esophageal cancer resection.Ann Thorac Surg. 2005; 80: 282-286Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Further, critical care specialists contribute to better results after esophagectomy [40Dimick J.B. Pronovost P.J. Heitmiller R.E. et al.Intensive care unit staffing is associated with decreased length of stay, hospital cost, and complications after esophageal resection.Crit Care Med. 2001; 29: 904-905Crossref PubMed Scopus (186) Google Scholar]. In another study, daily rounds by an intensive care unit physician independently contributed to fewer instances of pulmonary insufficiency, renal failure, aspiration, and reintubation [40Dimick J.B. Pronovost P.J. Heitmiller R.E. et al.Intensive care unit staffing is associated with decreased length of stay, hospital cost, and complications after esophageal resection.Crit Care Med. 2001; 29: 904-905Crossref PubMed Scopus (186) Google Scholar]. Further, hospital stay was shortened and costs were lower; no significant differences in the mortality rate were noticed. Thus, the risks of esophagectomy can be significantly reduced by a variety of factors, which include a large-volume hospital, a high-volume surgeon, a surgeon with specialty training, and the daily involvement of critical care specialists. Surgical resection is the primary curative modality in patients with resectable esophageal neoplasm. Strategies to optimize surgical outcomes include optimal patient selection, accurate staging, and stage-directed therapies that include a multimodality approach in localized advanced esophageal cancer. The type of surgical approach is typically based on surgeon preference, and in some centers such as ours, a minimally invasive approach is used. Other important factors are hospital and surgeon volume. Further prospective studies are required to clearly define the role of neoadjuvant or adjuvant therapies.