Journal of Surgical Oncology 2010;101:725729

Advances in the Surgical Treatment of Esophageal Cancer

THOMAS NG,
MD* AND

MICHAEL P. VEZERIDIS,

{ MD

Department of Surgery, Alpert Medical School of Brown University, Providence, Rhode Island

Surgical resection remains the predominant modality in the management of esophageal cancer. Transthoracic and transhiatal esophagectomy are the procedures that are most frequently performed. Minimally invasive esophagectomy is feasible but will require further evaluation with welldesigned trials and long-term follow-up before it can be widely adopted. Technical improvements have lowered the rate of cervical anastomotic leak and improved the management of thoracic anastomotic leak. Outcome studies demonstrated that the optimal mortality, morbidity, and survival outcomes are obtained when esophageal resections are performed by experienced surgeons in high-volume institutions.

J. Surg. Oncol. 2010;101:725729. 2010 Wiley-Liss, Inc.

KEY WORDS: transthoracic esophagectomy; transhiatal esophagectomy; three-eld esophagectomy; minimally invasive esophagectomy; anastomotic leak

INTRODUCTION
Surgical resection continues to be the most important treatment modality for esophageal cancer. The technique of esophageal resection is constantly under renement as the treatment of esophageal cancer becomes increasingly more complex. With the advent of multimodality approaches aimed to improve cure rates, surgical therapy continues to evolve and rates of postoperative morbidity and mortality continue to be low.

performed a meta-analysis showing no clear difference between TTE and THE. This meta-analysis however, also included retrospective comparison studies and case series in addition to randomized trials. It seems that current data does not clearly indicate superiority of one procedure over the other. It is likely that TTE and THE are equivalent. As modern day therapy for esophageal cancer shifts to multimodality approaches, more studies are needed to compare TTE and THE in the setting of neoadjuvant chemotherapy and radiation.

TRANSTHORACIC VERSUS TRANSHIATAL ESOPHAGECTOMY

Signicant debate continues regarding the optimal procedure for esophageal resection. The transthoracic esophagectomy (TTE) combines thoracotomy and laparotomy with or without cervical incision. This includes the two-incision Ivor Lewis approach [1] and the threeincision Mckeown approach [2]. The transhiatal esophagectomy (THE), popularized by Orringer et al. [3,4], is performed by laparotomy and cervical incision without thoracotomy. Possible advantages of TTE include safer dissection of the thoracic esophagus and a more complete thoracic lymphadenectomy. Possible advantages of THE include less morbidity from avoiding thoracotomy and better tolerance and easier treatment of an anastomotic leak in the neck compared to one in the chest. There have been four randomized trials comparing TTH versus THE. Small randomized studies by Goldminc et al. [5], Jacobi et al. [6], and Chu et al. [7] showed no difference in morbidity, mortality, and overall survival. In the largest randomized trial (n 220) comparing the two techniques, Hulscher et al. [8] found signicant differences in operative time, operative blood loss, ICU days, ventilator days, hospital days, pulmonary complications and cost, favoring THE (P < 0.001 for all). Operative mortality also favored THE but did not reach statistical signicance (2% vs. 4%, P 0.45). The number of resected lymph nodes was signicantly more with TTE (mean 31 vs. 16, P < 0.001). This original report noted a trend towards improved 5-year overall survival favoring TTE but in an update of this trial after longer follow-up by Omloo et al. [9], no difference was found (TTE 36% vs. THE 34%, P 0.71). Subgroup analysis, however, showed a possible benet in TTE for patients with 18 positive lymph nodes (5-year survival 64% vs. 23%, P 0.02). Hulscher et al. [10] also

EFFECT OF HOSPITAL AND SURGEON VOLUME

Although the debate of TTE versus THE continues, it is clear that performing esophageal resection at an experienced institution provides the best outcomes. Using the national Medicare claims database, Birkmeyer et al. [11,12] showed that postoperative mortality was improved when esophagectomy was performed by high-volume surgeons (annual volume >6, 9.2% vs. 18.8%, P < 0.001) and at high-volume hospitals (annual volume >19, 8.1% vs. 23.1%, P < 0.001). Even in high-volume hospitals, esophagectomy by highvolume surgeons improved mortality (8% vs. 17.2%). Overall 5-year survival also favored esophagectomy at high-volume hospitals (34% vs. 17%, P 0.001) [13]. The effect of both surgeon and hospital volume demonstrates the importance of having an experienced institution supporting the esophageal surgeon. This includes specialists dedicated to caring for the esophageal cancer patient from medical oncology, radiation oncology, gastroenterology, radiology, pulmonary

The authors have no disclosures related to the subject matter discussed in this paper. { Chief, Surgical Service; Professor of Surgery. *Correspondence to: Dr. Thomas Ng, MD, Associate Professor of Surgery, University Surgical Associates, Two Dudley Street, Suite 470, Providence, RI. Fax: 401-868-2322. E-mail: tng@usasurg.org Received 22 January 2010; Accepted 12 February 2010 DOI 10.1002/jso.21566 Published online in Wiley InterScience (www.interscience.wiley.com).

2010 Wiley-Liss, Inc.

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and meta-analysis [26] have been performed, however, no conclusions can be made from these studies as the level of evidence is poor, the technique of MIE is not uniform and the follow-up is short. MIE appears feasible in experienced hands and may have benets of less blood loss, less pain, and shorter length of hospital stay. However, MIE does require a longer operative time and a signicant learning curve for this complex procedure is required. Due to the short follow-up reported in the current literature, no conclusions can be made regarding oncologic efcacy of MIE. For these reasons until more studies are performed, specically randomized trials, MIE should not be widely adopted as the procedure of choice for esophageal cancer.

medicine, critical care medicine, anesthesiology, nursing, physical therapy, and respiratory therapy.

RADICAL EN BLOC THREE-FIELD ESOPHAGECTOMY

For esophageal cancer, TTE and THE remain the procedures most frequently performed and studied. However, there are advocates of an even more radical approach. Such a procedure involves right thoracotomy, laparotomy, and cervical incision for three-eld lymphadenectomy and esophagectomy with resection of pleura, diaphragm, pericardium, and thoracic duct en bloc. Altorki et al. [14] reported a series of 80 patients, with 16 receiving preoperative chemotherapy and 4 receiving preoperative radiation. The morbidity and mortality was 46% and 5%, respectively. Metastasis to cervical nodes was noted in 36% and the overall survival at 5 years was a remarkable 51%. The favorable outcomes of this series may be the result of careful patient selection. Certainly more studies are needed to conrm these results, to compare this procedure prospectively with TTE and THE, and to evaluate whether such a radical approach is necessary in the setting of neoadjuvant chemotherapy and radiation.

ANASTOMOTIC LEAK
Anastomotic leak after esophageal resection results in signicant morbidity and mortality. Wound infection, mediastinitis, empyema, sepsis, delay in oral intake, stricture formation, and increased cost are some of the adverse sequelae of an anastomotic leak. As compared with thoracic leaks, cervical anastomotic leaks are better tolerated and more easily treated by opening the cervical incision for drainage. However, cervical anastomosis carries a higher risk of leak than a thoracic anastomosis. This may be due to an increase in tension and ischemia to the gastric conduit as it stretches to reach the cervical esophagus through a tight thoracic inlet. In Orringer et al.s [3] original report of over 1,000 cases of THE, anastomotic leak was found in 13%. He then changed his anastomotic technique from hand sewn to a stapled side-to-side technique [27]. This technique involves positioning the gastric conduit posterior to the cervical esophagus, followed by a conduit gastrotomy and the creation of a 3 cm anastomosis using the endoscopic linear stapler. During this maneuver, care is taken to ensure that the greater curvature aspect of the gastric conduit is used for the anastomosis. This allows for the greatest distance of separation between the anastomotic staple line and the lesser curvature staple line, thus preventing ischemia of the intervening gastric wall. The hood of the esophagus is then sewn to the stomach in two layers to complete the anterior closure of the anastomosis. Using propensity score adjusted analysis, Orringer et al. [27] reported a lower anastomotic leak rate (3% vs. 14%, P 0.002) and a decrease in the need for esophageal dilation (35% vs. 48%, P 0.02), favoring the side-to-side stapled technique over the hand sewn. Favorable results using this anastomotic technique have also been reported by others. In a propensity matched study, Ercan et al. [28] found a decrease in the incidence of anastomotic leak (4% vs. 11%, P 0.09), wound infection (P < 0.001), and need for dilation (P 0.001), again favoring the side-to-side stapled technique. Today, the side-to-side stapled technique is routinely used during cervical esophageal anastomosis. The devastating nature of a non-contained thoracic anastomotic leak classically mandated re-operation for anastomotic repair or anastomotic take-down with diverting cervical esophagostomy. With the evolution of esophageal stent technology, thoracic anastomotic leaks can now be successfully treated using covered stents. Published series have shown a greater than 90% success rate of leak exclusion with covered stents [2931]. Two types of covered stents are commonly used, the expandable plastic stent consisting of braided polyester covered entirely with a silicone membrane [2931] and the expandable nitinol metal stent covered centrally with polyurethane [32]. Because of the exposed metal ends, the nitinol covered stent has a lower migration rate than the plastic stent (6% [32] vs. 2337% [29 31]). However for the same reason, the nitinol covered stent, if left in situ long enough, can result in tissue in-growth, bleeding, and perforation. In a series of anastomotic leaks treated with stenting, Tuebergen et al. [32] reported a 12% incidence of mucosal tears after extraction of the nitinol covered stent. In the treatment of thoracic anastomotic leaks using covered stents, patient selection becomes important. Any patient who is unstable or

MINIMALLY INVASIVE ESOPHAGECTOMY

Recently, minimally invasive esophagectomy (MIE) has evolved in an attempt to further minimize operative morbidity and mortality of esophageal resection. Many approaches have been described using thoracoscopy and laparoscopy or the combination of a minimally invasive approach with an open procedure (i.e., thoracoscopy with laparotomy and cervical incision). The true MIE technique, however, includes laparoscopy and thoracoscopy for MIE Ivor Lewis esophagectomy [15,16]; thoracoscopy, laparoscopy, and cervical incision for MIE three-incision esophagectomy [17,18]; and laparoscopy with cervical incision for MIE THE [19,20]. Modern technology has allowed the completion of such complex procedures by minimally invasive surgery. Endoscopic linear stapling devices are now routinely used during the creation of the gastric conduit and during division of large vessels such as the left gastric artery [17]. These staplers now provide 6 rows of staples with 3 rows on the patient side and 3 on the specimen side. The staples are available in four different leg lengths for different tissue thickness. Staples with short leg lengths are used to divide blood vessels, while staples with longer leg lengths are used to divide the stomach during creation of the gastric conduit. In addition, the endoscopic linear staplers rotate 3608 and articulate up to 458 to facilitate its proper positioning. The use of the trans-oral circular stapler anvil has simplied the anastomotic technique for MIE Ivor Lewis [16]. With the aid of an attached exible guide, the anvil of the circular stapler is passed trans-orally into the divided/ stapled thoracic esophagus. The guide and then ultimately the center rod of the anvil are brought through the stapled end of the esophagus. The guide is then removed and the anvil is connected to the circular stapler handle to allow for the creation of a doubled stapled anastomosis. Finally, ligation and division of small vessels such as the left gastroepiploic and short gastric arteries are easily facilitated by either the endoscopic ultrasonic coagulating shears [1719] or the endoscopic pressureenergy tissue sealing device [20]. In the largest series reported by Luketich et al. [17], 222 patients underwent MIE, with 35.1% receiving preoperative chemotherapy and 16.2% receiving preoperative radiation. The mean operative time was 7.5 hr with a conversion rate of 7.2%. Major morbidity occurred in 32% (leak in 12%) and mortality was 1.4%. To date, there have been no randomized trials comparing open esophagectomy with MIE. Matched retrospective comparisons [21], systematic reviews [2225],
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clinically deteriorating should undergo operative therapy rather than stenting. The extent of the anastomotic dehiscence should be less than one-third of the circumference and gastric conduit necrosis should be absent [30]. Following stent placement, immediate imaging to conrm the absence of leak is mandatory. Even when stent placement has been successful, further drainage procedures should be aggressively pursued to remove any remaining contamination that may exist. In the poststent period, close monitoring of the patients condition and stent position is required as stent migration can lead to the recurrence of leak and sepsis. The technique of stent placement requires uoroscopic image guidance. Upper endoscopy is performed, measurements are taken, and external markers are positioned. This maneuver is important to ensure that the covered aspect of the stent excludes the leak and that the stent does not encroach near the upper esophageal sphincter. Over a guide wire the stent is advanced into the esophagus, positioned according to the external markers and deployed. Oral intake may resume in 23 days after successful stenting depending on patient condition. Stent removal, especially with metal stents, should be considered in 46 weeks time. In the treatment of thoracic anastomotic leaks, stent technology has allowed surgeons to add an endoscopic option to their armamentarium. Although no randomized trials exist, it does makes sense to consider an endoscopic option with high reported success rates to treat the fragile patient with thoracic anastomotic leak, thus avoid the morbidity of re-operation. Careful patient selection as discussed above and vigilance during the poststent monitoring period is required to optimize success. However, one should never lose sight of operative treatment when considering stent therapy for anastomotic leaks.

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MULTIMODALITY THERAPY FOR ESOPHAGEAL CANCER

There is emerging evidence that multimodality therapy in combination with surgery provides the best chance of cure for patients with esophageal cancer. The most frequently studied regimen involves preoperative chemotherapy (cisplatin-based) and radiation followed by surgical resection (CRS). There have been nine published randomized trials comparing CRS versus surgery alone, with two favoring CRS. A randomized trial by Walsh et al. [33] of 113 patients showed a 3-year survival benet for CRS over surgery alone (32% vs. 6%, P 0.01). This trial however, was criticized for the poor survival reported in surgery alone arm, worse than historic controls. A randomized trial by Tepper et al. [34] of 56 patients, CALGB 9781, showed a 5-year survival benet for CRS over surgery alone (39% vs. 16%, P 0.002). This trial however, was closed early due to poor accrual. Although only 2 of 9 randomized trials showed statistically signicant survival benet for CRS, many of the remaining seven trials showed a trend towards improved survival favoring CRS [3541]. In a randomized study by Urba et al. [39], the 3-year survival for CRS was 30% and for surgery alone was 16%. However due to inadequate power, this did not reach statistical signicance (P 0.15). Pooling the data from all the randomized trials, a signicant overall survival advantage favoring CRS over surgery alone was found by meta-analysis. Meta-analysis by Malthaner et al. [42] and Fiorica et al. [43] showed a 3-year survival advantage for CRS over surgery alone (P 0.004 and P 0.03, respectively, for each study). A meta-analysis by Gebski et al. [44] showed a survival advantage at 2 years for CRS over surgery alone (P 0.002) and this advantage was maintained for subgroups of squamous cell carcinoma (P 0.04) and adenocarcinoma (P 0.02). A meta-analysis by Urschel and Vasan [45] showed a 3-year survival advantage for CRS over surgery alone (P 0.016) with the advantage being most pronounced when chemotherapy and radiation was delivered concurrently (P 0.005).
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Other combinations of multimodality therapy, either neoadjuvant or adjuvant to surgery, have been evaluated. In a detailed meta-analysis of randomized trials by Malthaner et al. [42], no signicant benet was found with preoperative radiation and surgery versus surgery alone, postoperative radiation and surgery versus surgery alone, preoperative chemotherapy and surgery versus surgery alone, postoperative chemotherapy and surgery versus surgery alone, and preoperative/postoperative chemotherapy and surgery versus surgery alone. The only combination with a signicant survival benet over surgery alone was CRS as discussed above. Although long-term survival benet has been shown with CRS, questions remain with regard to the adverse effects of preoperative chemotherapy and radiation on the immune system, nutrition status, wound healing, and anastomotic healing; all of which can potentially increase postoperative morbidity and mortality after esophagectomy. Only 1 of the 9 randomized trials, that by Bosset et al. [38], showed an increase in postoperative mortality with CRS when compared with surgery alone (12.3% vs. 3.6%, P 0.012). A meta-analysis by Fiorica et al. [43] showed an increase in postoperative mortality (P 0.01), while meta-analyses by Urschel and Vasan [45] and Kaklamanos et al. [46] showed trends toward increase in postoperative mortality (P 0.07 and P 0.2, respectively) with CRS when compared with surgery alone. However, when examining these studies in detail, it is the ve earlier trials that show some increase in operative mortality; while the four most recent trails [34,3941], published after the year 2000, show no difference in both operative morbidity and mortality. This illustrates how constant improvements in perioperative care have kept surgical morbidity and mortality low even in the setting of neoadjuvant chemotherapy and radiation. Advances in chemotherapy and radiation delivery, preoperative nutrition, anesthesia techniques, surgical techniques, and postoperative care including intensive care have all contributed. Despite the success of multimodality therapy for esophageal cancer, specically CRS, more studies are needed to further improve outcomes. Studies that incorporate targeted small molecule therapy to multimodality treatment are essential. The optimal dose of radiation in the neoadjuvant setting needs to be claried. Of the 9 randomized trials evaluating CRS, only 1 study, that by Tepper et al. [34], delivered more than 50 Gy of radiation. Also needed are more uniform trails in terms of cell type and surgical technique.

CONCLUSIONS
Esophageal cancer continues to be a devastating disease with low rates of survival. THE and TTE appears to be equivalent in terms of morbidity, mortality, and long-term survival. The esophageal surgeon however, needs to be familiar with both operative techniques as patient factors and tumor factors may dictate the use of one approach over the other. The stapled side-to-side anastomosis has lowered the rate of cervical anastomotic leaks. In carefully selected patients, thoracic anastomotic leaks can be successfully treated with covered stents thereby avoiding re-operation. MIE is feasible in experienced hands but needs more evaluation with quality studies and longer follow-up before it can be widely adopted for treatment of esophageal cancer. Current data indicate that the combination of preoperative concurrent chemotherapy and radiation followed by surgical resection offers the best chance of cure for patients with esophageal cancer, but may result in an increase rate of postoperative morbidity and mortality. Therefore, for optimal outcomes in terms of morbidity, mortality and survival, the delivery of such complex treatments to the esophageal cancer patient should be performed by experienced physicians at experienced institutions.

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