Journal of Surgical Oncology 2010;101:725–729

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 well-

designed 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;101:725–729. � 2010 Wiley-Liss, Inc.

KEY WORDS: transthoracic esophagectomy; transhiatal esophagectomy; three-field esophagectomy; minimally invasiveesophagectomy; anastomotic leak

INTRODUCTION

Surgical resection continues to be the most important treatment

modality for esophageal cancer. The technique of esophageal resection

is constantly under refinement 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.

TRANSTHORACIC VERSUSTRANSHIATAL ESOPHAGECTOMY

Significant debate continues regarding the optimal procedure for

esophageal resection. The transthoracic esophagectomy (TTE) com-

bines thoracotomy and laparotomy with or without cervical incision.

This includes the two-incision Ivor Lewis approach [1] and the three-

incision 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 (n¼ 220) comparing

the two techniques, Hulscher et al. [8] found significant 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 significance (2% vs. 4%, P¼ 0.45). The number of

resected lymph nodes was significantly 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%, P¼ 0.71). Subgroup analysis, however, showed

a possible benefit in TTE for patients with 1–8 positive lymph nodes

(5-year survival 64% vs. 23%, P¼ 0.02). Hulscher et al. [10] also

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.

EFFECT OF HOSPITAL ANDSURGEON 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 high-

volume surgeons improved mortality (8% vs. 17.2%). Overall 5-year

survival also favored esophagectomy at high-volume hospitals (34%

vs. 17%, P¼ 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 inthis 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.

medicine, critical care medicine, anesthesiology, nursing, physical

therapy, and respiratory therapy.

RADICAL EN BLOC THREE-FIELDESOPHAGECTOMY

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-field

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

confirm 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.

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 esopha-

gectomy [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 simplified the anastomotic technique for

MIE Ivor Lewis [16]. With the aid of an attached flexible 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

[17–19] or the endoscopic pressure–energy 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 [22–25],

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 benefits of less

blood loss, less pain, and shorter length of hospital stay. However, MIE

does require a longer operative time and a significant 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 efficacy of MIE. For these reasons until more studies are

performed, specifically randomized trials, MIE should not be widely

adopted as the procedure of choice for esophageal cancer.

ANASTOMOTIC LEAK

Anastomotic leak after esophageal resection results in significant

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 position-

ing 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%, P¼ 0.002) and a decrease in the need for esophageal

dilation (35% vs. 48%, P¼ 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%, P¼ 0.09), wound infection

(P< 0.001), and need for dilation (P¼ 0.001), again favoring the

side-to-side stapled technique. Today, the side-to-side stapled techni-

que 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 [29–31]. Two types of covered stents are

commonly used, the expandable plastic stent consisting of braided

polyester covered entirely with a silicone membrane [29–31] 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. 23–37% [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

Journal of Surgical Oncology

726 Ng and Vezeridis

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 confirm

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 patient’s condition and stent position is

required as stent migration can lead to the recurrence of leak and

sepsis.

The technique of stent placement requires fluoroscopic 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

2–3 days after successful stenting depending on patient condition.

Stent removal, especially with metal stents, should be considered in

4–6 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.

MULTIMODALITY THERAPY FORESOPHAGEAL 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 benefit for CRS over surgery alone (32% vs. 6%, P¼ 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 benefit for CRS over surgery alone (39% vs. 16%, P¼ 0.002).

This trial however, was closed early due to poor accrual. Although only

2 of 9 randomized trials showed statistically significant survival benefit

for CRS, many of the remaining seven trials showed a trend towards

improved survival favoring CRS [35–41]. 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 significance (P¼ 0.15). Pooling the data from all the

randomized trials, a significant 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 (P¼ 0.004 and P¼ 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

(P¼ 0.002) and this advantage was maintained for subgroups of

squamous cell carcinoma (P¼ 0.04) and adenocarcinoma (P¼ 0.02).

A meta-analysis by Urschel and Vasan [45] showed a 3-year

survival advantage for CRS over surgery alone (P¼ 0.016) with the

advantage being most pronounced when chemotherapy and radiation

was delivered concurrently (P¼ 0.005).

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 significant benefit

was found with preoperative radiation and surgery versus surgery

alone, postoperative radiation and surgery versus surgery alone,

preoperative chemotherapy and surgery versus surgery alone, post-

operative chemotherapy and surgery versus surgery alone, and

preoperative/postoperative chemotherapy and surgery versus surgery

alone. The only combination with a significant survival benefit over

surgery alone was CRS as discussed above.

Although long-term survival benefit 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%, P¼ 0.012). A meta-analysis by

Fiorica et al. [43] showed an increase in postoperative mortality

(P¼ 0.01), while meta-analyses by Urschel and Vasan [45] and

Kaklamanos et al. [46] showed trends toward increase in postoperative

mortality (P¼ 0.07 and P¼ 0.2, respectively) with CRS when

compared with surgery alone. However, when examining these

studies in detail, it is the five earlier trials that show some increase

in operative mortality; while the four most recent trails [34,39–41],

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, specifically 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 clarified. 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.

Journal of Surgical Oncology

Treatment of Esophageal Cancer 727

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