Neoadjuvant Therapy

The current information on neoadjuvant treatment can be divided into studies evaluating preoperative

radiation, preoperative chemotherapy, and combined preoperative chemoradiation therapy. In operable

patients with resectable tumors, the results of any preoperative therapy followed by resection must be

compared with the results of primary resection alone. It is important that this analysis takes into

account the toxicities associated with multimodality therapy and the impact on the intended resection

and quality of life. Several randomized trials have failed to show any benefit from preoperative

radiation therapy alone. Proponents of preoperative radiotherapy argue that the trials are too small to

demonstrate the advantages of this approach. A meta-analysis of available randomized trials comprising

1,147 patients, however, found no improvement in survival with preoperative radiotherapy alone in

patients with resectable esophageal cancer.55 At this time, there is no indication for preoperative

radiation therapy alone followed by resection.

Table 43-5 Summary of Changes from AJCC Sixth to Seventh Edition Esophagus

and Esophagogastric Junction Cancers Staging System

Table 43-6 American Joint Committee on Cancer (AJCC) Stage Groupings with

Recommended Treatment and 5-Year Survival

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The utility of preoperative chemotherapy alone is much more poorly defined. A large multicenter

randomized trial in the United States (Intergroup Trial) of 440 patients failed to show any improvement

in survival after three cycles of combined cisplatin and fluorouracil followed by surgery and two

postoperative cycles when compared to surgery alone.56 This is in contrast to a large randomized

European study (Medical Research Council), which suggested that neoadjuvant chemotherapy resulted

in nearly a 10% improvement in survival at 2 years.57 Unfortunately, the preoperative staging

techniques and duration of treatments were quite different, making the two studies difficult to compare.

More recently, another European neoadjuvant chemotherapy trial (MAGIC trial) demonstrated

improved survival with perioperative chemotherapy versus surgery alone (36% vs. 23% at 5 years).58

Of note, 75% of the MAGIC trial participants had gastric cancer. Also, only 41.6% of patients

randomized to perioperative chemotherapy were able to complete all six prescribed cycles of therapy.

In a recent Cochrane review of the topic, 11 randomized controlled trials with 2,051 patients suggested

that preoperative chemotherapy plus surgery may offer a survival advantage compared to surgery alone

for resectable esophageal cancer.59 There was no demonstrable difference in the rate of resection, tumor

recurrence, or postoperative morbidity. There was some chemotherapy-related morbidity. Presumably

based on the relative success of the MRC and MAGIC trials, chemotherapy alone is used quite commonly

as neoadjuvant therapy in Europe, whereas combined chemotherapy and radiation is used more

commonly in the United States. Several small randomized trials have evaluated combined preoperative

chemoradiation followed by surgical resection. The most widely cited trial to justify the use of

combined treatment followed by surgery was published by Walsh et al. in 1996.60 This study projected a

3-year survival of 32% in the neoadjuvant treatment group as compared to 6% in the surgery alone

group for patients with adenocarcinoma. Critics were quick to point out the lack of appropriate staging,

the poor survival in the surgical group as compared with other surgical series, and the small study size.

A more recent study found equivalent median and 3-year survival in patients with squamous cell

carcinoma of the esophagus randomized to either preoperative chemoradiation followed by surgery or

surgery alone.61 An increased complication rate was noted in the patients undergoing preoperative

chemoradiation therapy. A recent metaanalysis of 10 randomized controlled trials of neoadjuvant

chemoradiotherapy versus surgery alone demonstrated an absolute survival advantage of 13% at 2 years

favoring neoadjuvant therapy.62 Despite a paucity of conclusive data, there seems to be an evolving

consensus at most centers that patients with T3 and/or N1 disease should receive neoadjuvant

chemoradiation. This issue remains unresolved, and operation remains the standard treatment for

localized esophageal cancer outside of a clinical trial. At this time we consider neoadjuvant

chemoradiotherapy to be investigational. Unfortunately, a large intergroup trial designed to answer this

question was closed because of poor accrual.

More recently, the CROSS Trial enrolled 363 patients from the Netherlands, of which 75% had GE

junction adenocarcinoma.63 They were randomized to chemotherapy with concurrent XRT (41.4 Gy)

then surgery versus upfront surgery. Improved survival was seen in the neoadjuvant group at 5 years

suggesting that chemoradiotherapy followed by surgery provided a survival advantage. Both arms in

the trial were noted to have an unusually high leak rate related to surgery (CRT 22% vs. surgery 30%).

This called into question the validity of the surgical standardization in the operative approach as this

leak rate is quite high. The long-term results (minimum 5-year follow-up) were recently reported and

confirmed the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery (43

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months vs. 27 months, p < 0.03) in patients with resectable esophageal or EG junctional cancer.64

6 Recently the Society of Thoracic Surgeons released a consensus statement on neoadjuvant therapy

for the treatment of esophageal cancer stating the following class IIA recommendations based on level A

evidence65:

1. “Neoadjuvant platinum-based doublet chemotherapy alone is beneficial before resection for patients

with locally advanced esophageal adenocarcinoma.”

2. “Neoadjuvant chemoradiotherapy should be used for locally advanced squamous cell cancer and

either neoadjuvant chemotherapy or chemoradiotherapy for locally advanced adenocarcinoma as

multimodality therapy has advantages over operation alone.”

SURGICAL CONSIDERATIONS IN APPROACHING THE ESOPHAGUS

The esophagus is generally considered one of the most problematic organs to manage when it comes to

the indication for operation, patient fitness, operative approach, and the postoperative consequences of

complications. There is no doubt that surgical experience and expertise play a critical role in all phases

of esophageal disease ending up in the operating room.

A complete working knowledge of the anatomical relationships between the esophagus and adjacent

structures is vital. We feel it is a requirement and marked advantage for those formally trained in

general thoracic surgery to be the ones performing these operations. The upper esophagus is in contact

with the posterior membranous trachea, the left mainstem bronchus, and the aortic arch. Patients with

cancers involving the upper thoracic esophagus must undergo preoperative bronchoscopy to rule out

involvement of the airway as this generally precludes safe resection.

From a surgical perspective the esophagus is divided into thirds. The upper third can be reached

through a cervical incision. The middle third is best approached through the right chest as access

through the left chest is limited by the aortic arch. The distal third of the esophagus is best approached

through the left chest. The short segment of intra-abdominal esophagus may be approached through the

upper abdomen.

7 When esophagectomy is required, several surgical approaches have been described. Generally

speaking, no one surgical approach fits all. These approaches include the transhiatal approach,66

transabdominal transthoracic approach (Ivor Lewis),67 the three-stage or “three-field” approach

(McKeown),68 and the thoracoabdominal approach.69,70 In the current era, both minimally invasive and

robotic approaches have been championed and our group has led pioneering efforts in this regard. Each

approach has its own set of risks and benefits as well as clear opinions on those merits. Our belief is that

selection of the approach should be coupled with surgical expertise and patient pathology. Generally

speaking, several studies have shown equivalent outcomes when it comes to removal of the esophagus

and one trades one variable for another when critically evaluating the results. Careful review of the

literature draws on two important variables: surgeon experience and volume.71 Failures in technique

that occur during the performance of esophagectomy are associated with increased length of stay, inhospital mortality, and poorer overall long-term survival.72

OPERATIVE MANAGEMENT

Approaches to Esophagectomy

There are several surgical approaches to esophagectomy and the master esophageal surgeon should be

familiar with all approaches as they have different indications depending on the individual patient, the

location of the tumor, and surgeon experience. Options for reconstruction include a gastric tube, colonic

interposition, and in selected small cases an intestinal free graft. We opt for the use of colon or small

bowel in patients where the stomach is not usable because of the morbidity associated with these

conduits. The highlights of the main approaches will be presented along with an in-depth description of

the approach to minimally invasive esophagectomy (MIE) to help outline the critical considerations for

the steps of the operation.

Transhiatal Esophagectomy

Mark Orringer has championed this approach for esophagectomy with outstanding results and leak rates

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in the 3% to 5% range.73 The procedure starts with an upper midline laparotomy and left cervical

incision as shown in Figure 43-8. A gastric conduit based on the right gastroepiploic artery is used to

establish gastrointestinal continuity. A modified stapled anastomosis is performed to complete the EG

anastomosis (Fig. 43-9).

Many surgeons prefer THE in the current era, as historically it has been compared to open Ivor Lewis

esophagectomy. Debate continues over the effectiveness of it as a cancer operation, as thoracic

lymphadenectomy is not a part of the procedure as seen in the Ivor Lewis Approach. Proponents for the

operation argue that the approach has lower morbidity and mortality than the Ivor Lewis approach.

Should a leak occur in the neck, it can be treated by simple bedside cervical drainage. A leak in the

chest following the Ivor Lewis approach is far more likely to result in severe mediastinitis and other

significant complications. The arguments and debates are certainly quite different in the current era

with the excitement surrounding MIE.

Ivor Lewis Esophagectomy

The transabdominal transthoracic approach to esophagectomy as initially described is more commonly

referred to as the Ivor Lewis esophagectomy. The specific steps are covered in the section on MIE as we

perform this operation through minimal access surgery. Following laparotomy and creation of the

gastric conduit, the stomach is mobilized and a posterolateral thoracotomy is performed through the 5th

interspace. The intrathoracic esophagus is mobilized under direct vision and the EG anastomosis is

performed at the level of the azygos vein. This approach is especially useful for bulky tumors or where

there are concerns regarding airway injury. As discussed above, critics of this approach point out the

increased morbidity of the operation and the potential perils of a chest anastomosis. The

lymphadenectomy is clearly superior with this approach and the risk of local recurrence, in theory,

reduced.

Three-Field Esophagectomy

This approach is carried out through a separate laparotomy, thoracotomy, and left cervical incision.68

The anastomosis is performed in the neck. This approach is appropriate for mid-esophageal tumors

where there is concern of airway injury during the dissection. Another potential advantage is a threefield lymphadenectomy. In summary, the operation has the potential to provide the patient with a more

complete resection and thus improves long-term survival. This claim has not been overtly substantiated

in the literature.

Thoracoabdominal Approach

The left thoracoabdominal approach is the least frequently used of all the approaches to the esophagus.

It is performed by making an oblique incision from the midpoint between the xiphoid and the umbilicus

across the costal arch to the tip of the scapula. The abdomen is opened and the diaphragm divided along

the chest wall to spare any phrenic nerve branches. This approach is sometimes useful in those patients

who have had hiatal work done previously. For patients with distal tumors and inadequate conduit for

esophageal replacement, the anastomosis can be made in the left chest just below the inferior

pulmonary vein. For those with adequate conduit, the esophagus can be mobilized and a left cervical

anastomosis can be performed. The morbidity of this approach is quite high, however the largest series

of 64 patients reported no anastomotic leaks and 2% mortality.74

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