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Evidence-Based Surgical Treatment of Esophageal Cancer: Overview of High-Quality Studies

2010; Elsevier BV; Volume: 89; Issue: 4 Linguagem: Inglês

10.1016/j.athoracsur.2009.09.062

1552-6259

Sjoerd M. Lagarde, Bart C. Vrouenraets, Laurents P. S. Stassen, J. Jan B. van Lanschot,

Gastric Cancer Management and Outcomes

Evidence-based medicine is the conscientious, explicit, and judicious use of best available evidence in making decisions for individual patient care. The present review gives an evidence-based review of esophageal cancer surgery. The literature search was restricted to the highest level of evidence on the surgical treatment of esophageal cancer. Evidence-based medicine is the conscientious, explicit, and judicious use of best available evidence in making decisions for individual patient care. The present review gives an evidence-based review of esophageal cancer surgery. The literature search was restricted to the highest level of evidence on the surgical treatment of esophageal cancer. Only few adequately powered randomized controlled trials (RCTs) have been performed in esophageal cancer (EC) surgery. In a systematic review of other surgical procedures, less than 5% of reported studies had a prospective design [1Sackett D.L. Rosenberg W.M. Gray J.A. et al.Evidence based medicine: what it is and what it isn't.BMJ. 1996; 312: 71-72Crossref PubMed Google Scholar, 2Sackett D.L. Rosenberg W.M. Gray J.A. et al.Evidence based medicine: what it is and what it isn't.Clin Orthop Relat Res. 2007; 455: 3-5PubMed Google Scholar, 3Ubbink D.T. Legemate D.A. Evidence-based surgery.Br J Surg. 2004; 91: 1091-1092Crossref PubMed Scopus (35) Google Scholar]. Possibly, surgeons may not consider RCTs as a feasible strategy to resolve specific surgical questions. Indeed, standardization of surgical techniques, defining end points and study designs that are acceptable to both surgeons and patients may be problematic. Another problem is the number of resections performed. Although high-volume centers achieve better results [4van Lanschot J.J. Hulscher J.B. Buskens C.J. et al.Hospital volume and hospital mortality for esophagectomy.Cancer. 2001; 91: 1574-1578Crossref PubMed Scopus (221) Google Scholar, 5Wouters M.W. Wijnhoven B.P. Karim-Kos H.E. et al.High-volume versus low-volume for esophageal resections for cancer: the essential role of case-mix adjustments based on clinical data.Ann Surg Oncol. 2008; 15: 80-87Crossref PubMed Scopus (120) Google Scholar], only few hospitals perform esophageal surgery with sufficient frequency to exclude technical factors and overcome a learning curve in performing novel operations or techniques. Moreover, compared with pharmaceutical trials, fundraising for surgical trials is difficult. Finally, a commonly held view is that the timing is never right for RCTs. On the one hand, surgeons are reluctant to randomize while a procedure is being developed, and on the other hand they are reluctant after a steady state has been reached because they are already using the procedure on consecutive patients and are convinced of its value [6Horton R. Surgical research or comic opera: questions, but few answers.Lancet. 1996; 347: 984-985Abstract PubMed Scopus (303) Google Scholar]. The present review gives an overview on evidence-based studies that focus on surgical topics related to the treatment of EC. Systematic reviews and RCTs are considered the highest level of evidence [1Sackett D.L. Rosenberg W.M. Gray J.A. et al.Evidence based medicine: what it is and what it isn't.BMJ. 1996; 312: 71-72Crossref PubMed Google Scholar, 2Sackett D.L. Rosenberg W.M. Gray J.A. et al.Evidence based medicine: what it is and what it isn't.Clin Orthop Relat Res. 2007; 455: 3-5PubMed Google Scholar, 3Ubbink D.T. Legemate D.A. Evidence-based surgery.Br J Surg. 2004; 91: 1091-1092Crossref PubMed Scopus (35) Google Scholar]. For the purpose of this overview, the literature search was restricted to this highest level of evidence related to the surgical treatment of EC. Nonsurgical issues, such as (neo)-adjuvant chemo(radio)therapy, preoperative staging, and the value of a palliative resection are not addressed. All available systematic reviews and RCTs were independently selected by two investigators (SML, BCV) by using PubMed, MEDLINE, and the Cochrane Controlled Trial register through November 2008. Electronic links to related articles and references of selected articles were hand searched as well. The present systematic review only includes studies published in English. The following search terms were used: esophageal cancer, adenocarcinoma/squamous cell carcinoma, and esophagus. Searches were restricted to randomized controlled trials, systematic reviews, and meta-analyses. Ideally, level 1a evidence was reviewed, if available, and if not, then evidence from the next level was reviewed [1Sackett D.L. Rosenberg W.M. Gray J.A. et al.Evidence based medicine: what it is and what it isn't.BMJ. 1996; 312: 71-72Crossref PubMed Google Scholar, 2Sackett D.L. Rosenberg W.M. Gray J.A. et al.Evidence based medicine: what it is and what it isn't.Clin Orthop Relat Res. 2007; 455: 3-5PubMed Google Scholar, 3Ubbink D.T. Legemate D.A. Evidence-based surgery.Br J Surg. 2004; 91: 1091-1092Crossref PubMed Scopus (35) Google Scholar]. Two major surgical strategies can be used to optimize outcome after esophagectomy. To improve cure, an en bloc transthoracic resection or an extended resection with two-field lymphadenectomy have been proposed. Alternatively, early postoperative morbidity and mortality may be decreased by limiting the extent of dissection using a transhiatal technique. English-language literature was systematically reviewed. With only three small RCTs (including a total of 138 patients) published at that time [7Goldminc M. Maddern G. Le P.E. et al.Oesophagectomy by a transhiatal approach or thoracotomy: a prospective randomized trial.Br J Surg. 1993; 80: 367-370Crossref PubMed Scopus (303) Google Scholar, 8Chu K.M. Law S.Y. Fok M. et al.A prospective randomized comparison of transhiatal and transthoracic resection for lower-third esophageal carcinoma.Am J Surg. 1997; 174: 320-324Abstract Full Text PDF PubMed Scopus (232) Google Scholar, 9Jacobi C.A. Zieren H.U. Muller J.M. et al.Surgical therapy of esophageal carcinoma: the influence of surgical approach and esophageal resection on cardiopulmonary function.Eur J Cardiothorac Surg. 1997; 11: 32-37Crossref PubMed Scopus (86) Google Scholar], 50 studies were reviewed including 7,527 patients. There were no important differences between perioperative complications, although blood loss was significantly higher after transthoracic resection. Transthoracic resections had a higher risk of pulmonary complications, chylous leakage, and wound infection. Anastomotic leakage and vocal cord paralysis were more frequent after transhiatal resections. Intensive care unit stay and hospital stay was significantly longer after transthoracic resection. Furthermore, in-hospital mortality was significantly higher after transthoracic resections (9.2% vs 5.7%). There was no significant difference in 5-year survival (23.0% vs 21.7%) after transthoracic and transhiatal resections, respectively. Although transthoracic resections had significantly higher early morbidity and mortality rates, it was concluded that 5-year survival was comparable [10Hulscher J.B. Tijssen J.G. Obertop H. et al.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 (498) Google Scholar]. However, this meta-analysis merely compared surgical access rather than extent of dissection, limiting these conclusions. Subsequently, a RCT was conducted. Patients were randomized to either transhiatal (106 patients) or transthoracic resection with two-field en bloc lymphadenectomy (114 patients) for adenocarcinoma of the distal esophagus or cardia. Perioperative morbidity was higher after transthoracic esophagectomy without significant difference in-hospital mortality. After transhiatal and transthoracic resection, 5-year survival was 34% and 36%, respectively. The median number of quality-adjusted life-years after transhiatal resection was not significantly different (p = 0.26). The cost of treatment with transthoracic resection was 56% higher. It was concluded that transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomy. There appeared a trend toward improved long-term survival at 5 years with the extended transthoracic approach [11Hulscher 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 (1385) Google Scholar, 12Omloo J.M. Lagarde S.M. Hulscher J.B. et al.Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial.Ann Surg. 2007; 246: 992-1000Crossref PubMed Scopus (11) Google Scholar]. Randomization was stratified according to tumor location. In a subgroup analysis based on post-surgery classification, the long-term benefit of transthoracic esophagectomy was more substantial in patients with esophageal tumors. In 90 patients with an adenocarcinoma located in the esophagus, a survival benefit of 14% was seen with the transthoracic approach compared with the transhiatal approach (51% vs 37%). No overall survival benefit for either surgical approach was seen in 115 patients with junctional or cardiac tumors [12Omloo J.M. Lagarde S.M. Hulscher J.B. et al.Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial.Ann Surg. 2007; 246: 992-1000Crossref PubMed Scopus (11) Google Scholar]. Therefore, the authors now consider transthoracic esophagectomy standard treatment for otherwise fit patients with potentially curable EC, whereas transhiatal esophagectomy is the preferred approach in patients with junctional or cardiac cancer [13Hulscher J.B. van Lanschot J.J. Individualised surgical treatment of patients with an adenocarcinoma of the distal oesophagus or gastro-oesophageal junction.Dig Surg. 2005; 22: 130-134Crossref PubMed Scopus (51) Google Scholar]. Only one small RCT (62 patients) compared extended cervical and superior mediastinal lymphadenectomy with conventional two-field dissection and demonstrated a slightly (not significantly) better survival in the extended lymphadenectomy group at 2 years (83% vs 66%) and 5 years (65% vs 48%), respectively. The patients undergoing three-field dissection had significantly more phrenic nerve palsy (13% vs 0%) and tracheostomies (53% vs 10%), but fewer anastomotic leakages (6% vs 20%). The authors stated that larger RCTs were needed to establish the value of cervical lymphadenectomy [14Nishihira 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 (243) Google Scholar]. Therefore, there is no evidence to support the routine use of a three-field lymphadenectomy. Hayes and colleagues [15Hayes N. Shaw I.H. Raimes S.A. et al.Comparison of conventional Lewis-Tanner two-stage oesophagectomy with the synchronous two-team approach.Br J Surg. 1995; 82: 426Crossref PubMed Google Scholar, 16Hayes N. Shaw I.H. Raimes S.A. et al.Comparison of conventional Lewis-Tanner two-stage oesophagectomy with the synchronous two-team approach.Br J Surg. 1995; 82: 95-97Crossref PubMed Scopus (11) Google Scholar] randomized 27 patients with esophageal carcinoma to a standard two-stage Lewis-Tanner transthoracic subtotal esophagectomy or a synchronous two-team approach. Although the synchronous operations were completed significantly more quickly (230 vs 305 minutes), they produced a higher incidence of complications (in 7 vs 4 patients after standard esophagectomy), with significantly more blood transfusions (5 vs 3 units), and 3 postoperative deaths after the two-team approach. Therefore, use of the two-stage procedure is recommended. Esophagectomies are associated with high risk postoperative morbidity. Therefore, minimally invasive esophagectomy is gaining in popularity, despite concerns of the learning curve and oncological results. No RCTs have been performed to compare minimally invasive surgery with open surgery. However, Gemmill and McCulloch [17Gemmill E.H. McCulloch P. Systematic review of minimally invasive resection for gastro-oesophageal cancer.Br J Surg. 2007; 94: 1461-1467Crossref PubMed Scopus (114) Google Scholar] systematically reviewed the English-language literature. The review included relatively weak case studies and case-matched studies. There were 1,398 patients described who underwent some form of minimally invasive esophagectomy. There were 32 (2.3%) of these 1,398 patients who died within 30 days after the esophagectomy. There were 628 (46%) who had a reported complication. Anastomotic leakage affected 106 (7.7%) of 1,381 patients. Respiratory infections occurred in 167 (13%) of 1,268 patients. Mean blood loss was 316 mL. The duration of operation was 281 minutes 56 (4.9%). There were 1,138 esophagectomies that were converted to open surgery. Only in 222 patients, the complete resection rate was stated clearly. Overall the complete resection rate was 91.0%, and the mean number of resected nodes was 17.6 (607 patients). It can be concluded that the quality of the studies is poor; therefore, the data must be analyzed with caution. The reports describe a variety of different techniques. However, in experienced hands, minimally invasive surgery seems feasible and safe, but its generalizability should be questioned. Potential bias is that patients selected for minimally invasive surgery are not representative of the population of patients with cancer (eg, patients with smaller tumors and avoidance of candidates with serious co-morbidity). Moreover, surgeons whose results were unsatisfactory may have been less inclined to publish their results (publication bias). Until large randomized studies are available, minimally invasive resection should be seen as investigational. The stomach is the method of reconstruction in most patients. The esophageal substitute can be placed in the anatomical prevertebral position or in an extra-anatomical (retrosternal or subcutaneous) position. Extra-anatomical reconstruction could offer the advantage that a recurrent intrathoracic tumor mass will not invade the neo-esophagus. However, it may lead to increased anastomotic leakage rates and worse long-term functional results. A meta-analysis of RCTs to determine the effect of the route of reconstruction on patient outcomes was performed. Six RCTs containing 342 patients were reviewed [18Imada T. Ozawa Y. Minamide J. et al.Gastric emptying after gastric interposition for esophageal carcinoma: comparison between the anterior and posterior mediastinal approaches.Hepatogastroenterology. 1998; 45: 2224-2227PubMed Google Scholar, 19van Lanschot J.J. van B.M. Oei H.Y. et al.Randomized comparison of prevertebral and retrosternal gastric tube reconstruction after resection of oesophageal carcinoma.Br J Surg. 1999; 86: 102-108Crossref PubMed Scopus (83) Google Scholar, 20Gawad K.A. Hosch S.B. Bumann D. et al.How important is the route of reconstruction after esophagectomy: a prospective randomized study.Am J Gastroenterol. 1999; 94: 1490-1496Crossref PubMed Scopus (78) Google Scholar, 21Bartels H. Thorban S. Siewert J.R. Anterior versus posterior reconstruction after transhiatal oesophagectomy: a randomized controlled trial.Br J Surg. 1993; 80: 1141-1144Crossref PubMed Scopus (80) Google Scholar, 22Coral R.P. Constant-Neto M. Silva I.S. et al.Comparative anatomical study of the anterior and posterior mediastinum as access routes after esophagectomy.Dis Esophagus. 2003; 16: 236-238Crossref PubMed Scopus (33) Google Scholar, 23Zieren H.U. Muller J.M. Pichlmaier H. Prospective randomized study of one- or two-layer anastomosis following oesophageal resection and cervical oesophagogastrostomy.Br J Surg. 1993; 80: 608-611Crossref PubMed Scopus (82) Google Scholar]. Relative risk, expressed as posterior versus anterior mediastinal route (treatment vs control) was 0.56 (95% CI, 0.17–1.82) for mortality, 1.01 (95% CI, 0.35–2.94) for anastomotic leaks, 0.43 (95% CI, 0.17–1.12) for cardiac complications, and 0.67 (95% CI, 0.34–1.33) for pulmonary complications. Systematic qualitative review of the data did not suggest any difference in other perioperative outcomes or conduit function for the two routes of reconstruction. Therefore, posterior and anterior mediastinal routes of reconstruction are considered to have similar functional outcome and quality of life. However, they erroneously included the RCT of Zieren and colleagues [23Zieren H.U. Muller J.M. Pichlmaier H. Prospective randomized study of one- or two-layer anastomosis following oesophageal resection and cervical oesophagogastrostomy.Br J Surg. 1993; 80: 608-611Crossref PubMed Scopus (82) Google Scholar], who did not randomize for the route of reconstruction. More RCTs would be needed to definitively resolve the controversies [24Urschel J.D. Urschel D.M. Miller J.D. et al.A meta-analysis of randomized controlled trials of route of reconstruction after esophagectomy for cancer.Am J Surg. 2001; 182: 470-475Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. At present, the commonly used prevertebral route seems safe and suffices for most situations. When a macroscopically incomplete (R2) resection is done, there are theoretical grounds to support extra-anatomical reconstruction, because the risk of developing a symptomatic locoregional recurrence is high [25van Lanschot J.J. Hop W.C. Voormolen M.H. et al.Quality of palliation and possible benefit of extra-anatomic reconstruction in recurrent dysphagia after resection of carcinoma of the esophagus.J Am Coll Surg. 1994; 179: 705-713PubMed Google Scholar]. Cervical anastomosis allows for a larger proximal margin of resection and is believed to result in less dangerous leakage, and an increased risk of injury to the recurrent laryngeal nerve compared with intrathoracic anastomosis. However, the technique of first choice remains controversial. Thus far, three RCTs have been published. Chasseray and colleagues [26Chasseray V.M. Kiroff G.K. Buard J.L. et al.Cervical or thoracic anastomosis for esophagectomy for carcinoma.Surg Gynecol Obstet. 1989; 169: 55-62PubMed Google Scholar] compared stapled intrathoracic with cervical anastomoses after esophagectomy. Transfusion requirements and operating time were similar for the 49 patients having a thoracic anastomosis (TA) and the 43 patients who had a cervical anastomosis (CA). A CA resulted in a greater median margin of macroscopically normal esophagus above the tumor (4.0 vs 1.5 cm for TA; p < 0.05). One patient from each group had involvement of the resected proximal anastomotic doughnut. Overall, 41 patients (44%) sustained one or more complications (22 vs 19 patients). Leakage was significantly more frequent after cervical anastomosis (11 vs 2 patients; p < 0.02). Thirty-day mortality rates were comparable: 7 deaths occurred after TA (14.3%) and 4 after CA (9.3%). Length of hospital stay was similar. Postoperative strictures occurred in 14% of TA and 23% of CA patients (p = not significant) and were most common after an anastomotic leak. Median survival time was comparable. The authors concluded that the greater length of tumor-free esophagus removed did not result in improved survival period, but was associated with a higher incidence of anastomotic leakage. This study is difficult to evaluate because of the variety of techniques used. Ribet and colleagues [27Ribet M. Debrueres B. Lecomte-Houcke M. Resection for advanced cancer of the thoracic esophagus: cervical or thoracic anastomosis?.J Thorac Cardiovasc Surg. 1992; 103: 784-789PubMed Google Scholar] randomized 60 consecutive patients with cancer of the thoracic esophagus to undergo a cervical anastomosis (30 patients) or a thoracic anastomosis (30 patients). The surgical technique was identical. Proximal resection margins were more frequently involved in patients undergoing TA (10 vs 3 patients after CA). Morbidity consisted of 8 anastomotic leaks in the neck (6 of which were subclinical) and 3 in the chest (with one subclinical). Respiratory complications (21 vs 11 patients; p = 0.01) and recurrent laryngeal trauma (6 vs 1 patient) were more frequently seen in patients having CA. Postoperative mortality was comparable (5 deaths after CA and 4 after TA). Median survival was comparable (9 months vs 12 months). Although mortality was comparable, the authors concluded that subclinical leaks, respiratory morbidity, and recurrent laryngeal nerve trauma were more prevalent after CA. However, it remained unclear as to what extent the neck dissection added to the morbidity. Walther and colleagues [28Walther B. Johansson J. Johnsson F. et al.Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis.Ann Surg. 2003; 238: 803-812Crossref PubMed Scopus (209) Google Scholar] compared a manually sutured esophagogastric anastomosis in the neck with stapled anastomosis in the chest after transthoracic esophagectomy. Apart from anastomosis, surgical procedures were identical. No cervical lymphadenectomy was carried out. There were 83 patients who were randomized to receive an anastomosis in the neck (41 patients) or in the chest (42 patients). To evaluate selection bias, patients undergoing esophageal resection during the same period but not randomized (n = 29) were also followed and compared with those in the study (n = 83). The anastomosis was checked for leakage by roentgenograms with water-soluble contrast medium 5 days postoperatively. Anastomotic leakage was defined as extravasation of contrast or clinical symptoms of leakage, or both. Objective measurements of anastomotic level and diameter were assessed with an endoscope and balloon catheter at 3, 6, and 12 months after surgery. Two patients (1.8%) died in the hospital, and the remaining 110 patients were followed until death or for a minimum of 60 months. No differences were seen in operating time. The 5-year survival rate was comparable (29% for TA vs 30% for CA). The leakage rate was 1.8% (one radiologic and one clinical) with no relation to mortality or anastomotic method. All patients in the randomized group had tumor-free proximal and distal resection margins, but 1 patient in the nonrandomized group had tumor infiltrating into the proximal resection margin. At 3, 6, and 12 months after the operation, there was no difference in anastomotic diameter (p = 0.771). Both increased with time (p = 0.004). Experience of dysphagia, number of anastomotic dilatations and body weight were comparable. With similar results in randomized and nonrandomized patients, study bias was eliminated. The authors concluded that when neck and chest anastomoses are performed in a standardized way after esophageal resection, they are equally safe. The additional esophageal resection of 5 cm in the neck group did not increase tumor removal or survival; on the other hand, it did not adversely influence morbidity, anastomotic diameter, or eating as reflected by body weight development. Considering the latter trial as the best available evidence at the present time, one could conclude that there are no major differences in clinical outcomes for anastomoses in the neck or chest after transthoracic esophagectomy. Hospital mortality was not influenced by the site of the anastomosis in any of the RCTs. One can hardly imagine that the resection of 5 cm of (uninvolved) proximal esophagus will result in a detectable survival benefit. The increased incidence of anastomotic complications after neck anastomosis is not uniformly confirmed. Therefore, it seems prudent to advice surgeons to use the anastomotic site with which they are best familiar. Anastomoses can be fashioned by hand or mechanical. Early (leakage) and late (stricturing) patient outcomes may be influenced by the technique. A meta-analysis of RCTs to determine the effect of the anastomotic technique on patient outcomes was performed. Five RCTs containing 467 patients were reviewed [29Suturing or stapling in gastrointestinal surgerya prospective randomized study.Br J Surg. 1991; 78: 337-341Crossref PubMed Scopus (96) Google Scholar, 30Laterza E. de' M.G. Veraldi G.F. et al.Manual compared with mechanical cervical oesophagogastric anastomosis: a randomised trial.Eur J Surg. 1999; 165: 1051-1054Crossref PubMed Scopus (51) Google Scholar, 31Law S. Fok M. Chu K.M. et al.Comparison of hand-sewn and stapled esophagogastric anastomosis after esophageal resection for cancer: a prospective randomized controlled trial.Ann Surg. 1997; 226: 169-173Crossref PubMed Scopus (204) Google Scholar, 32Craig S.R. Walker W.S. Cameron E.W. et al.A prospective randomized study comparing stapled with handsewn oesophagogastric anastomoses.J R Coll Surg Edinb. 1996; 41: 17-19PubMed Google Scholar, 33Valverde A. Hay J.M. Fingerhut A. et al.Manual versus mechanical esophagogastric anastomosis after resection for carcinoma: a controlled trial.Surgery. 1996; 120: 476-483Abstract Full Text PDF PubMed Scopus (114) Google Scholar]. Only one RCT compared hand-sewn and stapled esophagogastric anastomoses in the neck. Relative risk (expressed as hand-sewn versus stapled) was 0.45 (95% CI, 0.20–1.00) for operative mortality, 0.79 (95% CI, 0.44–1.42) for anastomotic leaks, 0.60 (95% CI, 0.27-1.33) for anastomotic strictures, 0.99 (95% CI, 0.55–1.77) for cardiac morbidity, and 0.93 (95% CI, 0.63–1.37) for pulmonary morbidity. Outcomes examined by systematic qualitative review demonstrated that the hand-sewn methods led to a longer operation time in three of four studies, but only one was significantly longer. Although both techniques gave similar results for anastomotic outcomes, the stapled method seemed to be associated with an increased operative mortality, a finding which is difficult to explain [34Urschel J.D. Blewett C.J. Bennett W.F. et al.Handsewn or stapled esophagogastric anastomoses after esophagectomy for cancer: meta-analysis of randomized controlled trials.Dis Esophagus. 2001; 14: 212-217Crossref PubMed Scopus (94) Google Scholar]. More recently, Hsu and colleagues [35Hsu H.H. Chen J.S. Huang P.M. et al.Comparison of manual and mechanical cervical esophagogastric anastomosis after esophageal resection for squamous cell carcinoma: a prospective randomized controlled trial.Eur J Cardiothorac Surg. 2004; 25: 1097-1101Crossref PubMed Scopus (88) Google Scholar] randomized 63 patients with squamous cell cancer. Patients were randomized to receive either hand-sewn (32 patients) or circular stapled (31 patients) cervical anastomosis. Transthoracic esophagectomy with mediastinal lymphadenectomy was performed in 59 patients, 4 patients underwent transhiatal resection. The hand-sewn anastomosis was accomplished using a double layer of interrupted sutures. The mean operating time was 37 minutes longer when the hand-sewn method was used (524 vs 447 min; p < 0.001). Anastomotic leakage (7 in the hand-sewn versus 8 patients in the stapler group), hospital mortality (4 vs 3 patients), and benign esophageal stricture (4 vs 5 patients) were comparable in both groups. The authors concluded that using a circular mechanical stapler shortens operating time with comparable outcome to the hand-sewn technique for cervical esophagogastric anastomoses. Recently, another RCT was undertaken in 117 patients with squamous cell carcinoma of the thoracic esophagus who all underwent Ivor-Lewis esophagectomy. The results of this study showed that both the hand-sewn method and the staple method were safe. Hand-sewn anastomosis took 15 minutes longer to perform. The stapled method had a higher incidence of anastomotic stricturing in patients with a small diameter of the esophagus [36Luechakiettisak P. Kasetsunthorn S. Comparison of hand-sewn and stapled in esophagogastric anastomosis after esophageal cancer resection: a prospective randomized study.J Med Assoc Thai. 2008; 91: 681-685PubMed Google Scholar]. Another recently performed small RCT with 32 patients showed similar results. In this small study the incidence of recurrent laryngeal nerve injury was higher after handsewn anastomosis, and operation times were longer. This did not lead to a difference in postoperative symptoms and long-term survival [37Okuyama M. Motoyama S. Suzuki H. et al.Hand-sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study.Surg Today. 2007; 37: 947-952Crossref PubMed Scopus (80) Google Scholar]. In summary, the difference in operating times between hand-sewn and stapled groups is not consistent in the literature, probably because different methods of hand-sewn suturing were used. It seems that both methods have comparable results in experienced hands. Costs were not mentioned in these studies. Zieren and colleague [23Zieren H.U. Muller J.M. Pichlmaier H. Prospective randomized study of one- or two-layer anastomosis following oesophageal resection and cervical oesophagogastrostomy.Br J Surg. 1993; 80: 608-611Crossref PubMed Scopus (82) Google Scholar] reported an RCT comparing one-layer and two-layer cervical anastomoses after esophagectomy. After transthoracic resection (24 patients) and palliative transhiatal resection (16 patients), the gastric tube was placed retrosternally and after “curative” transhiatal resection (67 patients) in the posterior mediastinum. Anastomotic leakage and late stricture were the study endpoints. On postoperative day 7, a water-soluble contrast study was ca