adenocarcinoma esophageal

8/11/2019 adenocarcinoma esophageal

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H. MatthewsMary Koshy, Natia Esiashvilli, Jerome C. Landry, Charles R. Thomas, Jr. and Richard

Presentation and Progression, Work-up, and Surgical ApproachesMultiple Management Modalities in Esophageal Cancer: Epidemiology,

doi: 10.1634/theoncologist.9-2-1372004, 9:137-146.The Oncologist

http://theoncologist.alphamedpress.org/content/9/2/137

located on the World Wide Web at:The online version of this article, along with updated information and services, is
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Multiple Management Modalities in Esophageal Cancer:Epidemiology, Presentation and Progression, Work-up,

and Surgical Approaches

MARY KOSHY,a NATIA ESIASHVILLI,a JEROME C. LANDRY,a CHARLES R. THOMAS JR.,b

RICHARD H. MATTHEWSc,d

aEmory University School of Medicine, Department of Radiation Oncology, Atlanta, Georgia, USA;bUTHSCSA/San Antonio Cancer Institute, Department of Radiation Oncology, San Antonio, Texas, USA;

cBeth Israel/Deaconess Medical Center, Harvard Medical School, Department of Radiation Oncology, Boston,

Massachusetts, USA; dBoston VA Health Care Radiation Oncology Service, Boston, Massachusetts, USA

Key Words.Esophageal carcinoma Multimodal treatment Survival Surgeries

ABSTRACT

Annually, approximately 13,200 people in the U.S. are

diagnosed with esophageal cancer and 12,500 die of this

malignancy. Of new cases, 9,900 occur in men and 3,300

occur in women. In part I of this two-part series, we

explore the epidemiology, presentation and progression,

work-up, and surgical approaches for esophageal cancer.

In the 1960s, squamous cell cancers made up greater than

90% of all esophageal tumors. The incidence of

esophageal adenocarcinomas has risen considerably over

the past two decades, such that they are now more preva-

lent than squamous cell cancer in the western hemisphere.

Despite advances in therapeutic modalities for this dis-

ease, half the patients are incurable at presentation, and

overall survival after diagnosis is grim. Evolving knowl-

edge regarding the etiology of esophageal carcinoma may

lead to better preventive methods and treatment options

for early stage superficial cancers of the esophagus. The

use of endoscopic ultrasound and the developing role of

positron emission tomography have led to better diagnos-

tic accuracy in this disease. For years, the standard of care

for esophageal cancer has been surgery; there are several

variants of the surgical approach. We will discuss

combined modality approaches in part II of this series.

The Oncologist 2004;9:137-146

The Oncologist 2004;9:137-146 www.TheOncologist.com

Correspondence: Richard H. Matthews, M.D., Ph.D., Beth Israel/Deaconess Medical Center, Harvard Medical School, 330Brookline Avenue, Boston, Massachusetts 02215, USA. Telephone: 617-232-9500, ext 4457 or ext 5628; Fax: 617-524-0643; e-mail: [email protected] Received May 13, 2003; accepted for publication September 18, 2003.AlphaMed Press 1083-7159/2004/$12.00/0

TheOncologistGastrointestinalCancer

LEARNING OBJECTIVES

After completing this course, the reader will be able to:

1. Describe the epidemiology, work-up, and staging of esophageal cancer.

2. Identify the disease presentation, progression, and prognostic factors for esophageal cancer.

3. Discuss the surgical approach and management of esophageal cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.comCMECME

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Koshy, Esiashvilli, Landry et al. 138

INTRODUCTION

It has been estimated that in 2001 there were 13,200

new cases and 12,500 deaths attributable to esophageal

carcinoma in the U.S. [1]. Table 1 presents new cancer

cases and deaths in the U.S. for a few selected sites for

comparison. We use the ratio of deaths to new cases as a

rough index of the overall degree of success of treatments

for various cancers. We can, thus, anticipate that, nation-

wide and for all presentations and all management

approaches, the curative success in dealing with cancer of

the esophagus is less than 10%. Cancer of the esophagus

occurs much less frequently than cancers of the breast,

prostate, lung, or rectum (Table 1). With reference to ratios

of deaths to new cases, roughly 80% of cancers of the

breast, prostate, and rectum can be treated successfully in

the U.S. Lung cancer, however, resembles esophageal can-

cer in that less than 10% of patients in our country are

treated successfully. Lung cancer occurs less commonly

than breast or prostate cancers, but accounts for more can-

cer deaths than the other four sites combined.

There is an approximate 3:1 male predominance in

esophageal cancer incidence and death. One factor in the

poor results obtained for the treatment of esophageal carci-

nomas is that half the cases are unresectable or metastatic at

presentation.

The cervical esophagus begins at the cricopharyngeus

muscle at the level of the cricoid cartilage and extends 6 cm

to enter the thoracic inlet. The intrathoracic esophagus

extends for another 20-25 cm to the gastroesophageal junc-tion. The American Joint Committee on Cancer (AJCC)

divides the esophagus into four regions: cervical, upper tho-

racic, midthoracic, and lower thoracic [2].

The predominant histological types of esophageal car-

cinoma are squamous cell carcinoma (SCC) and adenocar-

cinoma (AC). Less common histologies include adenoid

cystic, mucoepidermoid, adenosquamous, undifferentiated,

and malignant melanoma, all of which have poor prog-

noses. Small cell carcinoma can also occur in the esopha-

gus, and it has a course similar to that in the lung [3].

Nonepithelial tumors in the esophagus are rare; the most

common type is leiomyosarcoma and the most common

metastatic source to the esophagus is the breast [4]. In the

1960s, more than 90% of all esophageal tumors were SCCs.

The incidence of esophageal AC has risen considerably

over the past two decades such that it is now more preva-

lent than SCC in the western hemisphere. The rise in

esophageal AC, particularly in the distal esophagus, has

been paralleled by a rise in gastric cardia AC. This leads to

the concept of gastroesophageal junction AC.

The standard of care for esophageal cancer had been

surgery alone for many years. There are several different

surgical approaches in use, with various advantages and

disadvantages and with differences in procedure preference

in different parts of the world. We review the epidemiol-

ogy, etiology, presentation and work-up, and surgical

approaches for esophageal cancer in this paper.

EPIDEMIOLOGY AND ETIOLOGYThe incidence of esophageal cancer varies considerably

with geographic location and also, to some extent, among

ethnic groups within a common area. Some of the highest

rates occur in northern China and northern Iran, where inci-

dence exceeds 100 in 100,000 individuals; in the U.S., the

incidence is less than 5 per 100,000, although rates are

nearly quadruple for African Americans [4]. In Linxian,

Hunan province, China, esophageal cancer is endemic and

has been directly related to nitrosamines and inversely

related to consumption of riboflavin, nicotinic acid, magne-

sium, and zinc [5]. SCC predominates in African Americans

over Caucasians by a ratio of 6:1, and AC has the opposite

preponderance, occurring in Caucasians over African

Americans at a ratio of 4:1 [6]. Nearly 30 years ago, AC

accounted for only 15% of cases of esophageal cancer, but

the incidence of AC has increased more than 350% since

1970, surpassing SCC since 1990; this increase is also seen,

to a lesser extent, in African Americans [7, 8]. In the Far

East, no increase in AC has been observed, and SCC con-

tinues to be the more common histology [9]. In the western

world, there is less impact from dietary factors, such as

nitrosamines, due to different food preservation techniques,

and the primary etiology of esophageal cancer is the use of

tobacco and alcohol, which have a synergistic effect; they

are very strong risk factors for SCC and moderate risk fac-

tors for AC [10]. Tobacco exposure has been linked to a ten-

fold higher risk for esophageal SCC in heavy smokers

relative to nonsmokers, and the risk is directly related to the

duration of exposure [7, 11]. In contrast, smoking has been

linked to only a two- to threefold greater risk for esophageal

AC in smokers relative to nonsmokers [8, 12]. There is a

greater than multiplicative effect between smoking and

alcohol consumption that occurs in SCC; for AC, the effect

Table 1. Comparison of new cases and deaths for selected cancersites, 2001 [109]

Cancer site New cases Deaths Ratio

Esophagus 13,200 12,500 0.95

Breast 193,700 40,600 0.21

Prostate 198,100 31,500 0.16

Lung 169,500 157,400 0.93

Rectum 37,200 8,600 0.23


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139 Esophageal Carcinomas

is only additive [13]. The exception to this may be the con-

sumption of hard liquor, which has been found to have a

stronger association with AC than with SCC [14]. The rela-

tive risk of esophageal AC remains high up to 30 years after

smoking cessation, in contrast to the significant decline in

risk of SCC within a decade of smoking cessation [15].

Several studies have linked obesity to the risk for

esophageal AC. Increasing body mass index (obesity) corre-

lates with increasing risk for esophageal AC, but decreasing

risk for esophageal SCC [4]. Obesity promotes gastroe-

sophageal reflux disease (GERD) by increasing intra-abdom-

inal pressure; GERD, in turn, promotes the formation of

Barretts esophagus (BE)a metaplastic precursor of AC

[16, 17]. Multiple studies have shown that the bacterium

Helicobacter pylori has an inverse relationship with the risk

for esophageal cancer but causes a greater risk for gastric

cancer [18].H. pylori is thought to protect against the risk of

esophageal AC because it promotes achlorhydria, implyinglower acid production and reflux [15]. As rates of H. pylori

infection have decreased in the U.S. and Europe, there has

been a parallel rise in the incidence of GERD (an indepen-

dent risk factor for esophageal AC) and BE [9]. Prior aerodi-

gestive tract malignancies predispose to a higher risk for

esophageal cancer, primarily through field cancerization.

Ten percent of second primary cancers in patients with prior

oropharyngeal cancer or lung cancer occur in the esophagus

[19, 20]. Chronic inflammation and stasis, which occur with

strictures caused by caustic injury and achalasia, are long-

term risks for esophageal SCC; in addition, patients withtylosis, which is inherited in an autosomal dominant fashion,

and Plummer Vinson syndrome have a definite greater risk

for esophageal SCC [21].

The definition of BE has evolved from simply a colum-

nar-lined esophagus to at least 3 cm of columnar lining or

metaplasia in the esophagus [21, 22]. Approximately 0.5%-

2% of adults in the western world have BE, with prevalences

greater in Caucasians and men and with increasing age until

the eighth decade of life [23, 24]. In a review of 51,311

patients at the Mayo Clinic, the length of BE epithelium did

not increase significantly with age, suggesting that BE does

not progress with age and is latent for several years before

being discovered [24]. GERD affects up to 44% of the gen-

eral population in the U.S., but only 10% of people with

GERD develop BE [25, 26]. Recurrent symptoms of reflux

have been associated with a 7.7 times greater risk for

esophageal AC, with more frequent, more severe, and

longer-lasting reflux resulting in a 43.5 times higher risk for

esophageal AC [26]. Patients with BE have a 40-fold greater

risk or 0.5% risk per patient year of developing esophageal

AC [27]. A middle-aged patient who develops BE has a 10%-

15% risk of developing esophageal AC during his lifetime

[28]. Specific risk factors that predispose for the progression

of BE to AC include hiatal hernia of at least 3 cm in length,

length of BE, and the presence of dysplasia [29]. In addition,

increased bile acid exposure is thought to exacerbate

esophageal mucosal injury and to promote the neoplastic

process [23, 30].

Esophageal cancers, both SCC and AC, typically have

aberrant cell-cycle regulation. Mutations occur in onco-

genes such as EGFR, erbB-2, and cyclin D1, and in tumor

suppressors such as 3p(FHIT), Rb, p53, p16, p14ARF, and

telomerase, which affect the G1 restriction point. Cyclin D1

directly regulates phosphorylation of the Rb protein at the

G1 restriction point facilitating G1/S transit. About 40%-

60% of esophageal carcinomas and 30% of premalignant

lesions overexpress cyclin D1. Cancers that retain normal

Rb expression typically overexpress cyclin D1, whereas

those that lack normal Rb have normal cyclin D1 levels.

The p53 gene product regulates cell-cycle progression,DNA repair, neovascularization, and apoptosis; 50%-80%

of esophageal carcinomas havep53 mutations. Malignancy

is facilitated by inactivation of the growth constraints

imposed by the Rb and p53 suppressor pathways, but also

requires activation of telomerase, a ribonucleoprotein that

adds hexamer DNA repeats to the ends of chromosomes to

prevent loss of telomere length in DNA replication.

Elevated telomerase expression is found in high-grade dys-

plasia as well as virtually all esophageal carcinomas.

Several of the individual aforementioned factors have been

shown to carry prognostic significance [21].Part of the problem in dealing with esophageal carcino-

mas is that half the patients present with unresectable or

metastatic cancers; if a screening program could detect dis-

ease at an earlier stage, there could be a greater possibility

of cure. In comparison, there is considerable evidence that

the combination of physical examination with mammogra-

phy used as a screening tool decreases the death rate from

breast cancer [31]. However, several studies have failed to

demonstrate the benefit of a decreased death rate due to

lung cancer from screening chest x-rays and physical exam-

inations [32]. Unfortunately, the value and cost-effective-

ness of endoscopic surveillance for esophageal cancers has

not been demonstrated. In 11 screening studies with 1,127

patients with BE, only 3.5% actually progressed to cancer

[33]. To date, there is no solid evidence that screening

reduces the esophageal AC death rate [34].

Proponents argue that screening, to be productive, should

be focused on patients with multiple risk factors: GERD,

Caucasian race, male gender, age greater than 50 years, and

long duration of symptoms. Small studies have suggested

that surveillance can identify neoplasms that are at an ear-

lier stage and, thus, potentially curable [35-38]. However,


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these hopeful results may be confounded by lead time bias,

length time bias, and pseudodisease [37]. Furthermore,

even if surveillance were effective, it is unlikely to impact

mortality soon because few patients with esophageal cancer

are diagnosed via surveillance programs. Less than 5% of

patients with esophageal cancer were known to have had BE

before they sought help for symptoms of cancer, and up to

40% had no prior history of GERD [39, 40]. Most patients

with BE die from unrelated causes, and the presence of BE

does not change life expectancy or overall survival [41, 42].

Currently, the American College of Gastroenterology recom-

mends that surveillance endoscopy for BE be guided by the

presence of dysplasia. If dysplasia is not present, endoscopy

is recommended every 3 years, and if low-grade dysplasia is

present, it is recommended that endoscopy be done every 6

months for 1 year and yearly thereafter if no progression is

seen [43]. If high-grade dysplasia is present, this finding

should be confirmed by an experienced pathologist and the

patient should be offered either esophagectomy or intensive

surveillance (endoscopy every 3 months) [43]. The technique

of four-quadrant biopsies taken every 2 cm of BE segment

during endoscopy is optimal [44]. Dysplasia is currently the

best pathological predictor of cancer development.

DISEASE PRESENTATION, PROGRESSION, AND

PROGNOSTIC FACTORS

The most common presenting symptoms of esophageal

cancer are dysphagia and weight loss. Less common symp-

toms include odynophagia, cachexia, melena, retrosternalpain, and hoarseness [45]. Cancers of the esophagus must

involve at least 75% of the circumference before the sensa-

tion of food sticking or blockage is experienced. As noted

above, about one-half of esophageal cancer patients present

with locally advanced unresectable disease or distant

metastasis. The extent of wall penetration and lymph node

metastases are more important prognosticators of survival

than tumor length or functional obstruction [21].

Esophageal AC spreads via transverse penetration

through the full thickness of the wall, whereas SCC tends to

spread linearly in a submucosal fashion [46]. Esophageal

cancer spreads through extensive lymphatic channels with an

erratic pattern including skip metastases being observed in

autopsy specimens; in addition, up to 71% of frozen tissue

sections classified as tumor free by conventional histopathol-

ogy have been positive for lymphatic micrometastases when

tested by immunohistochemistry [47]. This micrometastatic

disease has been shown to be a significant independent

adverse prognostic factor for relapse-free survival and over-

all survival [48]. Routine use of immunohistochemistry in

conjunction with extensive lymph node sampling has been

advocated as an advance over the traditional staging work-up.

Histologic tumor type is an independent prognostic fac-

tor in esophageal cancer patients who have had surgical

treatment. Siewert et al. analyzed 1,059 patients who had

undergone resection and found that overall survival at 5 years

was 46.8% for the AC group versus 37.4% for the SCC

group; patients with early-stage AC had a much lower inci-

dence of lymph node involvement than their SCC counter-

parts, and it was hypothesized this was due to occlusion of

lymphatic channels secondary to the inflammatory changes

of GERD in AC [49]. Tumor size less than 5 cm, upper

third esophageal location, female sex, and age less than 65

years have all been noted to positively influence outcome

[50, 51]. Conversely, weight loss, low Karnofsky perfor-

mance status, deep ulceration of tumor, sinus tract forma-

tion, and fistula formation have all been found to be poor

prognostic factors [21, 50].

STAGING AND WORK-UP

The AJCC has established a staging system for

esophageal cancer that is based on the tumor-node-metasta-

sis (TNM) system and is, in essence, a pathological staging

system [2]. Table 2 illustrates the AJCC staging classifica-

tion of esophageal cancer. Only the depth of penetration is

taken into account for the T staging, not the length of the

tumor, extent of involved circumference, or degree of

lumen narrowing. Clinical staging takes into account the

amount of disease that is present before treatment and is

based on history, physical examination, biopsy, laboratory

studies, endoscopic examination, and imaging such asendoscopic ultrasound (EUS), computed tomography (CT)

scan and positron emission tomography (PET) scan.

Pathologic staging is based on examination of the surgically

resected esophagus and lymph nodes. Spread to the celiac

lymph nodes is considered a site of distant metastasis, as

are cervical nodes occurring with an esophageal primary

elsewhere than in the cervical esophagus [2].

The appropriate work-up for a patient suspected of hav-

ing esophageal cancer should include a thorough history and

physical exam with special attention to the supraclavicular

and cervical lymph nodes. Fine-needle aspiration should be

performed on any palpable cervical lymph node to rule out

extrathoracic spread of disease. Blood tests, a chest x-ray,

and a double-contrast barium swallow should follow. CT

scans of the chest and upper abdomen should be obtained to

further characterize the lesion and evaluate for metastatic dis-

ease. Esophagoscopy, with the intent of tissue biopsy and

detailed characterization of the lesion, should be pursued

with an emphasis on how far the lesion is from the incisors

and the squamocolumnar junction; in addition, the presence

of esophagitis or BE should be noted [21]. Brushings should

be obtained before biopsy, and these two procedures together


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achieve a diagnostic accuracy of 99% [52]. In lesions that

appear borderline for the endoscopist, the use of Lugols

iodine can help distinguish normal mucosa by selectively

staining it and leaving the abnormal mucosa identifiable forbiopsy [53]. Finally, patients with upper- or middle-third

esophageal cancers or symptoms of hoarseness or hemopty-

sis should have a bronchoscopy to rule out laryngeal nerve

involvement or tracheobronchial fistula [21].

Conventional CT scans can accurately determine

resectability 65%-88% of the time [54, 55]. CT accurately

predicts T stage in 70% of cases and N stage in about 50%-

70% of cases [54-56]. Secondary to poor sensitivity, CT may

not be the optimal modality to evaluate celiac lymph nodes

and T4 disease or response to neoadjuvant chemoradiother-

apy. The sensitivity and specificity of CT for pathologically

positive celiac lymph nodes are 30% and 93%, respectively,

and for T4 disease, are 25% and 94%, respectively [57, 58].

With respect to assessing response after chemotherapy, no

correlation has been found between tumor volume reduction

on serial CT examinations and pathological assessment of

tumor response or patient survival [55].

EUS has improved the preoperative staging of

esophageal cancer, particularly in regard to T and N staging

[59]. In a meta-analysis of 27 studies, the accuracy of EUS

for T staging was 90% and for N staging was 80%, and a

further review of the literature supports an overall accuracy

for EUS of approximately 85% for T staging and 75% for N

staging [59-61]. However, the utility of EUS in detecting dis-

tant metastases other than celiac metastases is low, secondary

to limited depth of penetration, and therefore, CT is still anecessary and complementary part of the staging work-up

[62]. EUS detection of celiac lymph node disease correlates

with overall survival and has a sensitivity of 70%-80% and a

specificity of 97% [57, 63-65]. EUS has also been useful in

evaluating recurrence after resection; in a study evaluating 40

patients with suspected recurrence, the sensitivity and speci-

ficity of EUS were found to be 95% and 80%, respectively

[66]. One problem with EUS specificity in that study of pos-

sible recurrences were the false positives reported for anasto-

motic thickening because of inflammation. Other limitations

to EUS include its decreased sensitivity in the presence of

stenosis and its unreliability in assessment of the response to

neoadjuvant therapy [67, 68]. In three studies involving 196

patients, the accuracy of EUS after neoadjuvant therapy

ranged from 27%-48% for T staging and 38%-71% for N

staging [68-70]. This significantly lower accuracy is attribut-

able to the failure of EUS to distinguish between tumor and

postradiation fibrosis and inflammation.

Fluorodeoxyglucose (FDG)-PET is rapidly evolving as

an important tool in the noninvasive staging of patients with

esophageal cancer. Kole et al. prospectively evaluated 26

patients and found the diagnostic accuracies in determining

Table 2. AJCC staging classification of esophageal cancer

Primary tumor (T) Regional lymph nodes Distant metastasis (M)

TX: Primary tumor cannot be assessed NX: Regional lymph nodes cannot be assessed MX: Presence of distant metastasis cannotbe assessed

T0: No evidence of primary tumor N0: No regional lymph node metastasis M0: No distant metastasis

N1: Regional lymph node metastasis M1: Distant metastasis

Tis: Carcinoma in situ

T1: Tumor invades lamina Tumors of the lower thoracic esophagus

T2: Tumor invades muscularis propria M1a: Metastasis to celiac lymph nodes

T3: Tumor invades adventitia M1b: Other distant metastasis

T4: Tumor invades adjacent structures

Stage grouping Tumors of the midthoracic esophagus

Stage I: T1N0M0 M1a: Not applicable

Stage IIA: T2N0M0; T3N0M0 M1b: Nonregional lymph nodes and/orStage IIB: T1N1M0; T2N1M0 other distant metastasis

Stage III: T3N1M0; T4, any N, M0

Stage IV: Any T, any N, M1 Tumors of the upper thoracic esophagus

Stage IVA: Any T, any N, M1a M1a: Metastasis in cervical lymph nodes

Stage IVB: Any T, any N, M1b M1b: Other distant metastasis

For the cervical esophagus, the cervical nodes (including the supraclavicular nodes) are considered regional; for the intrathoracic esophagus, themediastinal and perigastric lymph nodes (excluding the celiac nodes) are considered regional.

T1 has been further subdivided into T1m, cancer confirmed to the mucosa, and T1sm, cancer invading the submucosa.


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resectability to be 65% for CT and 88% for PET; for CT and

PET together, an accuracy of 92% was achieved [54]. The

accuracy of PET in detecting primary tumors is 78%; nodal

metastases are visualized by PET in 86% of cases [71, 72].

A particular advantage of FDG-PET has been its greater accu-

racy in detecting distant metastatic disease than CT alone or

combined with EUS (86% versus 62%), but it has a lower

accuracy in detecting local nodal disease than CT alone or

combined with EUS (48% versus 69%) [73-75]. FDG-PET

has also demonstrated greater accuracy than other methods in

detecting recurrences other than perianastomotic recurrences

[76]. The quantitative decrease in FDG uptake seen after

neoadjuvant therapy has been correlated with histopathologic

assessment of viable tumor cells, time to disease progression,

and overall survival [77-79]. FDG-PET may assist in deter-

mining response to neoadjuvant therapy, which subsequently

could aid in the selection of patients who will benefit from

surgery and avoid excess morbidity and mortality in those

who are unlikely to respond [80]. Minimally invasive staging,

including thoracoscopic and laparoscopic methods, remains

the most accurate method to detect distant metastases and

determine resectability. Although PET had a better accuracy

than CT in detecting distant metastases (84% versus 63%),

minimally invasive staging was even better, determining

resectability with an accuracy of 97%, compared with only

61% with EUS and CT [81, 82].

SURGERY

Esophagectomy remains the standard of care for thetreatment of early-stage tumors confined to the esophagus

and paraesophageal region. There is controversy about

whether en bloc resection with extended lymph node dis-

section confers any advantage in curative management. The

two most common approaches for definitive resection are

the transthoracic esophagectomy (TTE) and the transhiatal

esophagectomy (THE). TTE is the most common approach

used worldwide, whereas THE is more common in the

western world. Advantages of TTE include better visual-

ization, access, and resection of the upper two-thirds of the

esophagus and mediastinal disease and avoidance of blind

blunt dissection with tumors of the midthoracic esophagus

[21]. The rate of resectability of esophageal cancer is

reported to range from 60%-90%, hospital mortality after

resection ranges from 1.4%-23%, and the resulting 5-year

overall survival rate ranges from 10%-25% [83-86]. Five-

year survival rates reported for stage I esophageal cancer

range from 80%-94% and, for stage III, rates range from

10%-14% [83, 84]. Advantages of THE include the avoid-

ance of morbidity, including the respiratory compromise

associated with thoracotomy, and the fact that if a leak does

occur it will be in the neck where it is more accessible [82].

Operative mortality has ranged from 1% to 4%, and the 5-

year survival rate has ranged from 20%-25% overall, with

that of stage I as high as 65% and that of stage III as low as

10% [87-91]. Two randomized trials and a meta-analysis

concluded that there were no significant differences

between TTE and THE with respect to overall morbidity,

operative mortality, and long-term survival [87, 92].

For tumors below the tracheal bifurcation, radical en bloc

esophagectomy or two-field dissection has been recom-

mended [93, 94]. The surgical objective is to achieve exten-

sive margins, with removal of the upper abdominal,

retroperitoneal, and mediastinal lymph nodes, the peri-

cardium, periaortic tissue, bilateral pleura, azygous vein, and

thoracic duct [93, 95]. Proponents of this radical operation

argue that the technique is a better attempt to obtain the

benefits of a resection with no residual disease (R0).

Achievement of R0 status has been reported to be a prognos-

tic factor for long-term survival [96, 97]. In a study of 500

patients undergoing TTE, patients with an R0 resection had

a 5-year survival rate of 29% in contrast to those with micro-

scopic residual (R1) or macroscopic residual (R2) disease,

none of whom survived 5 years [84]. Some have doubted the

value of the en bloc approach, theorizing that esophageal

cancer systemically spreads at onset and lymphatic dissec-

tion is, therefore, palliative rather than curative [98]. The

counter argument from those viewing the disease progression

as sequential, from primary site to lymph nodes and then to

distant sites, is that dramatically low rates of local recurrence

are better achieved with en bloc resection, which results inbetter long-term survival [94, 99, 100]. Local recurrence

rates after en bloc resection have ranged from 1%-8%, oper-

ative mortality rates have ranged from 3%-6%, and the 5-

year overall survival rate has ranged from 30%-52% [98,

100, 101]. A survival advantage for patients with advanced

primary and nodal disease with en bloc resection has been

claimed in small retrospective studies [94, 101, 102]. The

superior survival evinced in node-positive patients lends cre-

dence to the theory that disease progression is sequential and

that removal of the involved nodal groups is therapeutic and

potentially curative. Reservations in asserting a superiority

for the en bloc resection include dependence on retrospective

rather than randomized study data, with selection bias and

stage migration as a result of more accurate staging (Will

Rogers effect). In a study byHagen et al., patients selected

to undergo en bloc resection were chosen based on the pres-

ence of limited disease and good general health, while

those with poor physiologic reserve and more advanced

disease underwent THE, clearly a selection bias [102]. The

selection of young patients with limited disease and excel-

lent performance statuses for en bloc resection has been

corroborated by others [103].


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Japanese surgeons routinely extend the en bloc or two-

field dissection into the neck, mediastinum, and upper

abdomen, creating a three-field dissection. This is based on

the finding that cervical nodal metastases occur in up to

46.3% of upper-third tumors and in up to 27% of lower-

third tumors in patients undergoing three-field lymph node

dissection [104]. Two randomized trials have been done in

Japan comparing three-field radical surgery with two-field

radical surgery. In one study, the 5-year survival rate was

significantly better with the three-field procedure (48% ver-

sus 33%) and, in the other study, a survival difference was

not noted; however, in both studies, there was a selection

bias toward younger, earlier stage patients being allocated

to three-field radical surgery [105, 106]. In the western

world, three-field surgery has also been investigated in the

institutional setting.Lerut et al. analyzed 37 patients under-

going three-field radical resection and found that the extended

field improved staging accuracy (30% of patients had patho-logic cervical nodes and 17% of gastroesophageal junction

tumors had positive cervical nodes) but did not change over-

all survival [107].Altorki et al., in the largest western study of

three-field radical resection, prospectively analyzed 80

patients undergoing the procedure and found an operative

mortality of 5%, cervical nodal involvement of 36%, and a 5-

year survival rate of 51% (88% in node-negative patients and

25% in node-positive patients) [108]. Differences in dissec-

tion technique around the recurrent laryngeal nerve may

account for the low rates of recurrent laryngeal nerve injury,

only 6% in that study, dramatically lower than the up to 70%

observed in Japanese reports [96, 108].

An impairment to quality of life with respect to speech

and swallowing has been chronicled in up to 20% of

patients for up to 5 years postoperatively and must also be

a serious consideration. Both en bloc dissection and three-

field resection may offer a survival benefit but, before these

techniques can be widely adopted, we need more experi-

ence and randomized studies to substantiate the benefit of

such radical surgery.

CONCLUSIONS

The overall results of treatment for esophageal cancer in

our country continue to be poor, with over 90% of the new

cases each year eventually succumbing to this disease. In part

I of this two-part series we have covered the issues of epi-

demiology, work-up and staging, prognostic factors, and sur-

gical treatment. More radical surgical approaches may havethe potential of gaining an advantage in local-regional control,

and perhaps ultimately survival, although perhaps at a cost in

terms of the morbidity of the procedure. In part II we will

explore the integration of chemotherapy and radiation therapy

into multimodal management approaches to the disease.

ACKNOWLEDGMENTS

The authors disclaim any proprietary interest and

acknowledge that there have been no grants, equipment, or

drugs provided.

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