Prevention and Management
of Early Esophageal Cancer
W. Michael Korn, MD
University of California, 2340 Sutter Street, San Francisco, CA 94115, USA.
Current Treatment Options in Oncology 2004, 5:405–416
Current Science Inc. ISSN 1527-2729
Copyright © 2004 by Current Science Inc.
During 2004, an estimated 14,250 new cases of esoph-
ageal cancer will be diagnosed in the United States. The
disease represents a significant medical challenge
because of its dismal prognosis, as indicated by the esti-
mated 13,300 disease-specific deaths in 2004 . Partic-
ularly worrisome is a dramatic increase in incidence of
esophageal adenocarcinomas in white males since the
mid-1970s . Moreover, the disease is the sixth leading
cause of death from cancer worldwide , and there are
regions with extremely high incidence, such as Nan’ao
County in southern China, where a mortality rate of 110/
100,000 has been observed . Thus, improvements in
prevention, detection, and treatment of esophageal can-
cer are urgently needed.
Most esophageal cancers are squamous cell car-
cinomas (SSCs) or adenocarcinomas, and other
malignant tumors (spindle cell carcinomas, mucoepi-
dermoid carcinoma, small cell carcinoma, leiomyosar-
coma, malignant melanoma, rhabdomyosarcoma, and
granular cell tumors) are rare. squamous cell carcino-
mas (SSCs) occur mostly in the midesophagus,
whereas adenocarcinomas are preferentially found in
the lower third. Tumors frequently demonstrate intrae-
sophageal spread and may span more than 10 cm.
Metastasis into regional lymph nodes occurs very early
because of an extensive lymphatic drainage system and
involves cervical, mediastinal, and perigastric nodes.
Unfortunately, tumors are rarely (18%) detected at
early stages. Distant metastases are present in 25% to
30% of cases at the time of diagnosis and involve
mainly liver, lungs, and bone. For the purpose of this
article, early-stage esophageal cancer is defined as a
malignant tumor that is limited to the epithelium
(including high-grade intraepithelial neoplasia) or
lamina propria mucosa (stage T1a), or submucosa
(stage T1b) . The insidious character of esophageal
Early esophageal cancer is defined by its limitation to the esophageal mucosa and
submucosa. It has become a curable malignant disease, in sharp contrast to the dis-
mal prognosis of esophageal cancer at advanced stages, which still represents the
majority of patients. Understanding the risk factors, establishing surveillance pro-
grams for patients at risk, and developing preventative interventions such as dietary
and lifestyle changes or pharmacologic interventions hold the potential of reducing
the incidence of the disease and of shifting the stage distribution toward early cancer.
Endoscopic ultrasound examination is pivotal for distinguishing early from advanced
stages of the disease because it allows for accurate assessment of tumor infiltration
and regional lymph node involvement. The therapeutic mainstay for early esophageal
cancer remains surgery. New, less invasive surgical techniques are being tested that
are associated with less morbidity and mortality than standard radical esophagecto-
mies. For patients who are not candidates for surgery, definitive chemoradiation is a
viable alternative. New endoscopic ablation techniques, such as endoscopic mucosa
resection and photodynamic therapy, are potential alternatives to surgery in patients
with cancers limited to the mucosa. For patients with adenocarcinoma of the gastroe-
sophageal junction with submucosal involvement, adjuvant chemoradiation should be
considered because of its potential to increase survival.
cancer is underscored by the observation that the prev-
alence of lymph node metastases in stage T1b cancers
is as high as 20% .
The spectra of environmental and endogenous risk
factors for the development of squamous cancer and ade-
nocarcinomas show significant differences. squamous
cell carcinoma (SSC) is unambiguously associated with
cigarette smoking and alcohol consumption. Synergistic
tumor promoting effects of both agents have been dem-
onstrated and are associated with an increase in cancer
risk of up to 100-fold [7,8]. Consumption of exception-
ally hot beverages and a lack of fruits and vegetables have
also been reported to be important factors . Further-
more, infection with the human papilloma virus has
been implicated in endemic occurrences of SSC .
Other predisposing conditions include tylosis, a rare
autosomal-dominant inherited disease that is also
known as nonepidermolytic palmo-plantar hyperkerato-
sis and is associated with mutations of the TOC locus on
chromosome 17q25 . Patients with achalasia, an
esophageal motility disorder that is characterized by
abnormally high pressures of the lower esophageal
sphincter, have been demonstrated to have an up to 140-
fold increased risk for the development of SSC of the
esophagus . A history of head and neck cancer and
other conditions, including Plummer-Vinson syndrome
(iron-deficiency anemia, glossitis, chelosis, splenome-
galy, and esophageal webs) and previous caustic injury
has also been associated with SSC of the esophagus.
The dominant risk factor for the development of
adenocarcinoma of the esophagus is Barrett’s esopha-
gus, which is characterized by a specialized columnar
epithelium replacing the normal squamous epithelium
in the distal esophagus. Barrett’s esophagus is a result of
chronic mucosal injury by gastroesophageal reflux and
is associated with progression into adenocarcinoma of
the esophagus at an estimated rate of 0.5% per year
. Patients with long-standing and severe symptoms
of gastroesophageal reflux disease (GERD) are at a 40-
fold increased risk for the development of esophageal
adenocarcinoma [13•]. In patients with GERD, the
increase in risk of developing esophageal cancer was
found to be independent of the presence of Barrett’s
esophagus [13•]. Not surprisingly, obesity, a condition
known to promote gastroesophageal reflux, was found
to be an independent risk factor for adenocarcinoma
. As for squamous cancer, smoking was found to
contribute to the development of esophageal adenocar-
cinoma, although this association appears to be weaker
than for SSC . Furthermore, a diet deficient of fruit,
vegetables, and fiber and high in fat content, increases
the risk of esophageal cancer [14,16,17]. Therefore,
strategies for identifying patients at increased risk may
allow for preventive interventions that are being clini-
Early esophageal cancer is diagnosed on endoscopy
when biopsies are obtained from small mucosal irregu-
larities, nodules, or ulcerations. In patients with Bar-
rett’s esophagus, malignant lesions can be detected by
surveillance endoscopies that include systematic sam-
pling from all four quadrants of the esophageal circum-
ference every 2 cm throughout the entire area of
Barrett’s mucosa. The histologic diagnosis of high-grade
dysplasia or mucosal cancer is sometimes difficult and
should be confirmed by an expert pathologist [18•]. In
the Western world, the value of surveillance programs in
patients with Barrett’s esophagus has been questioned
because most esophageal adenocarcinomas are not
associated with Barrett’s esophagus . However, it
appears that the tumors that are detected during surveil-
lance are of lower stage and associated with improved
survival . Surveillance programs in Western coun-
tries have been credited with improving the rate of early
cancers to 40% of all resected esophageal adenocarcino-
mas in some centers . SSCs are the target of inten-
sive screening efforts in Japan, which has led to frequent
detection of squamous cancers at early stage in that
Although computerized tomographic and positron
emission tomographic scans are crucial for ruling out
tumor spread to distant sites, a significant improvement
of the accuracy of staging of early esophageal cancer
resulted from the introduction of endoscopic ultra-
sound (EUS) techniques. EUS has been demonstrated
to be superior over computerized tomography, mag-
netic resonance imaging, or positron emission tomogra-
phy scanning in assessing local-regional disease, with
false-positive and false-negative detection rates of 5%
and 7%, respectively [22,23]. Because of the strikingly
higher rate of lymph node metastases in T1b tumors, it
is essential to distinguish these from tumors restricted
to the mucosa. Therefore, it is important to note that
conventional echoendoscopes using frequencies of 7.5
or 12 MHz are limited in their ability to make this dis-
tinction. High-resolution (20 MHz) ultrasound probes
provide an improved resolution, which results in an
overall accurate T staging in 80% of early esophageal
cancers [24,25]. However, submucosal infiltration is
still being missed in up to 40% of the cases, particularly
in tumors located at the gastroesophageal junction .
Prevention and Management of Early Esophageal Cancer
Diet and lifestyle
• Although a variety of nutritional factors have been associated with an
increased risk for esophageal cancer, only limited prospective information
regarding the impact of dietary interventions on the incidence of esoph-
ageal cancer is available. However, epidemiologic data suggest that a diet
with high intake of green, cruciferous, and yellow vegetables, and a high
total fruit intake (particularly citrus fruits) is likely to be protective. Esti-
mates based on population-based studies from Sweden suggest that
increasing fresh fruit and vegetable consumption may reduce the risk of
esophageal cancer by as much as 50% . It has been suggested that caro-
tene, vitamins C and E, and selenium are potentially protective against
esophageal cancer . A large, population-based study from the Linxian
region in China, where esophageal cancer occurs at a 100-fold higher inci-
dence than in the United States, has demonstrated a reduction of esoph-
ageal cancer incidence and mortality by 6% and 10%, respectively, in
people receiving a nutritional supplement consisting of ?-carotene, vitamin
E, and selenium . Detailed analyses of serum levels of these factors
revealed that the relative risk of participants to develop esophageal cancer
in the highest serum level concentration quartile compared to the lowest
quartile was 0.56 for selenium and 0.63 for vitamin E [29,30].
• Obesity has been identified as a strong risk factor for the development of
adenocarcinoma of the esophagus. A case-control study conducted in the
United States found a 2.7-fold increased risk for esophageal adenocarci-
noma for patients in the highest quartile of body mass index (BMI) .
Similarly, a Swedish population-based study revealed a 16-fold increased
risk for esophageal cancer in patients with a BMI of greater then 30, com-
pared to patients with a BMI of less than 22 . The exact mechanisms
underlying these findings are unclear, which is highlighted by the fact that
no clear correlation between increased BMI and reflux symptoms could be
established . While it is common sense to recommend weight reduc-
tion to obese patients in general, no intervention studies have been per-
formed addressing the effect of weight loss on esophageal cancer risk.
• Smoking is a clear risk factor for SSC and, to a lesser extent, adenocarci-
noma of the esophagus . The risk of SSC decreases substantially a
decade after smoking cessation. However, the increased risk associated with
smoking does not decrease for adenocarcinomas, even 30 years after cessa-
tion . Alcohol consumption also increases the risk of SSC, but there is
no clear evidence for an increased incidence of adenocarcinoma . Ces-
sation of alcohol intake leads to a decline of risk over time, most promi-
nently for moderate drinkers and less so for heavy drinkers . Stopping
both behaviors is associated with an additive risk reduction .
• Medications with sphincter-relaxing effects, such as nitroglycerin, anticholin-
ergics, ?-adrenergic agonists, aminophyllines, and benzodiazepines, have
been suspected to increase the risk for adenocarcinoma of the esophagus
because they may increase gastroesophageal reflux. This was confirmed by a
large case-control study that demonstrated an estimated incidence rate ratio of
3.8 among daily, long-term users (>5 years) of lower esophageal sphincter–
relaxing drugs, compared with persons who had never used these drugs .
• Because symptomatic gastroesophageal reflux has been found to increase
the risk of adenocarcinoma of the esophagus, it is a reasonable assumption
that acid inhibition could decrease the cancer risk. However, an extensive,
well-controlled clinical study did not confirm this hypothesis. In fact, a
threefold higher risk of developing cancer was observed in patients who
had been medicated for GERD in the past [13•]. This study was performed
before proton-pump inhibitors gained widespread use for GERD, so
incomplete acid suppression may have contributed to the results. However,
other factors may be responsible. For example, reflux of bile acids conse-
quent to duodenogastroesophageal reflux have been demonstrated to pro-
mote the Barrett’s phenotype . It is the current recommendation to
perform screening endoscopies on those patients with the highest risk of
developing Barrett’s esophagus, which are patients with long-standing
GERD symptoms, particular those age 50 years or older . The value of
such screening for the prevention of death from esophageal adenocarcino-
mas has been questioned because fewer than 5% of patients undergoing
surgical resection for adenocarcinomas had known Barrett’s esophagus and
up to 40% of patients with adenocarinomas had no history of reflux symp-
toms . Although it remains to be seen if regular surveillance reduces the
risk of death from esophageal adenocarcinoma, it is a recommended prac-
tice to enroll patients into endoscopic surveillance programs once Barrett’s
esophagus has been diagnosed . The interval of endoscopic examina-
tions in patients with Barrett’s esophagus should be based on the presence
or absence of dysplasia. In patients with no dysplasia, endoscopy should be
performed every 2 to 3 years. In patients with low-grade dysplasia, endos-
copy should be repeated after 6 and 12 months of the initial diagnosis, and
then yearly thereafter. The approach to patients with high-grade dysplasia
has been the subject of controversy, but there is agreement that an experi-
enced pathologist should confirm the histologic diagnosis. At this point,
there are three alternative management strategies for patients with Barrett’s
esophagus and high-grade dysplasia: 1) intensive endoscopic surveillance,
2) endoscopic ablative techniques, or 3) esophagectomy. If intensive endo-
scopic surveillance is selected, endoscopic assessment with systematic
biopsy sampling should be undertaken every 3 months . The two latter
approaches are discussed later in this paper. Recent diagnostic develop-
ments may improve the ability to identify patients at risk for the develop-
ment of cancer. Chromoendoscopy is a new approach that uses the
endoscopic application of a staining dye such as methylene blue, which is
selectively taken up be specialized intestinal-type metaplasia, for the identi-
fication of Barrett’s mucosa, dysplastic regions, and early cancer. Prelimi-
nary clinical studies indicate that this approach improves the detection of
metaplasia and dysplasia in Barrett’s esophagus and a sensitivity for the
detection of Barrett’s mucosa of 95% to 98% has been reported . How-
ever, the procedure is time consuming and has not yet found broad accep-
tance. Other new techniques include high-magnification endoscopy, laser-
induced fluorescence endoscopy, photodynamic diagnosis, and high-fre-
quency endoscopic ultrasound. The potential role of these methods still
needs to be assessed by future clinical trials.
• Epidemiologic data suggest that the intake of nonsteroidal anti-inflamma-
tory drugs reduces the risk for esophageal cancer. A recent meta-analysis of
nine epidemiologic studies suggested a reduction of esophageal cancer risk
(for both histological types) of approximately 40% as a result of aspirin or
nonsteroidal antiinflammatory drug use . These data support the theory
that molecular events associated with inflammation may promote the devel-
Pharmacologic and endoscopic prevention
Prevention and Management of Early Esophageal Cancer
opment of esophageal cancer. The enzyme cyclooxygenase-2, a central proin-
flammatory enzyme involved in prostaglandin metabolism that is suspected
to promote tumor development, is expressed more frequently and at higher
levels in high-grade Barrett’s esophagus and adenocarcinomas compared to
normal esophageal mucosa . Thus, if causative, inhibition of this enzyme
for preventing esophageal cancer in patients who are at increased risk is logi-
cal. Recent modeling analyses suggest that, theoretically, the preventive use of
aspirin would be cost effective, provided that interventional use of this drug
in at-risk patients leads to a reduction in incidence by 50% . Prospective
clinical studies aimed at answering this question are ongoing . However,
these studies are difficult to conduct because of the low yearly rate of progres-
sion from Barrett’s esophagus to cancer, which is estimated to range from
1:250 to 1:350. Thus, before the results of these ongoing trials become avail-
able, the use of antiinflammatory drugs for the prevention of esophageal can-
cer cannot be recommended.
• Surgical resection is the preferred treatment modality for early-stage esoph-
ageal cancer because it allows for removal of the primary tumor and
regional lymph node metastases. The standard surgical approach is radical
subtotal esophagectomy. With this approach, 5-year median survival rates
exceeding 70% have been reported for patients with early esophageal can-
cer [45–49]. However, the procedure is associated with significant morbid-
ity and mortality, in particular in patients with comorbidities, although
high-volume centers consistently report mortality rates of less than 5%
[50–52,53••]. Improved therapeutic outcomes and decreased duration of
hospitalization have been documented in institutions that perform many
of these operations [54,55]. Several operative strategies have emerged with
different emphasis on radicality and safety. Transthoracic esophagectomy
(TTE) allows extensive lymphadenectomy, including removal of lymph
nodes from the mediastinal and upper abdominal compartments (two-
field lymphadenectomy). Some surgeons additionally perform lym-
phadenectomy of the supraclavicular and paratracheal regions (three-field
lymphadenectomy). Although this more invasive approach has been
widely performed in Japan with the goal of preventing cervical recurrence
and prolonged survival , its value in the Western population is the sub-
ject of debate . Transhiatal esophagectomy (THE) with esophageal
stripping after abdominal incision followed by retrosternal or posterior
mediastinal gastric tube reconstruction and establishment of an esophago-
gastric anastomosis through cervical incision is considered a less traumatic
approach . The transhiatal resection plays only a limited role for
tumors in the cervical part of the esophagus and cannot be performed in
patients who had previous esophageal surgery. However, because it is less
traumatic and reduces operating time, this procedure is frequently the
approach of choice for elderly patients or those with poor performance sta-
tus. Randomized trials have failed to demonstrate significant advantage of
either the transthoracic or transhiatal approaches. A randomized prospec-
tive trial from The Netherlands compared both methods in 220 patients
[53••]. A significantly higher rate of postoperative complications occurred
in patients after TTE compared to THE. However, there was no difference in
regard to postoperative mortality. The authors noted a trend toward
improved 5-year disease-free survival in patients who had undergone TTE.
Further follow-up will be necessary to determine the significance of this
observation. Independent of the surgical procedure chosen, it is imperative
to perform a careful risk-benefit analysis, which needs to include an assess-
ment of the patient’s performance status and cardiac, hepatic, and respira-
tory functions to exclude those who are at increased risk for serious
postoperative complications .
• The significant morbidity and mortality associated with the surgical
approaches described earlier in this paper, and the absence of a clear advan-
tage of treatment intensification, stimulated research into less invasive pro-
cedures in patients with early esophageal cancer. In patients with
adenocarcinoma of the distal esophagus, limited resection of the distal
esophagus and gastroesophageal junction has been proposed. In 49
patients, the operative morbidity was 14% (compared to 40% in historic
controls), the postoperative mortality was 0% (compared to 3.7%), and the
recurrence rate was 0% (compared to 4%) . Not as encouraging are
data regarding tumors invading the submucosa. A retrospective analysis of
5-year survival rates in superficial esophageal cancer showed that the 5-year
survival rate of patients treated with limited esophagectomy (31%) was sig-
nificantly less than for patients treated with extended radical esophagec-
tomy (74%) . Minimally invasive surgery, using either laparoscopic
approaches or combinations of laparoscopic and thoracoscopic techniques,
was found to be feasible and safe . Recent studies suggest that mini-
mally invasive esophagectomy actually reduces mortality rates and hospital
stay compared to conventional operations . However, no direct com-
parisons of minimally invasive versus open surgery with respect to the
oncologic outcome have been reported and the role for minimally invasive
esophagectomy as the standard approach to patients with esophageal can-
cer still needs to be defined.
• For patients with early esophageal cancer who are not candidates for sur-
gery, either because of comorbid conditions or unfavorable tumor location
in the proximal upper esophagus, radiation and chemoradiation therapies
have been tested as therapeutic alternatives. However, data on patients with
early esophageal cancer are available only for a subset of clinical studies. A
report from Japan  summarized data on patients with superficial esoph-
ageal cancer who were treated with external radiation therapy at a mean
dose of 65.5 Gy using conventional fractionation. A 100% 5-year survival
for patients with tumors limited to the mucosa was demonstrated, whereas
only 49% of the patients with submucosal involvement survived 5 years. A
study from the United Kingdom  demonstrated a 5-year survival rate of
patients with esophageal tumors smaller than 5 cm in diameter to be 20%.
These data highlight the limited efficacy of primary radiation therapy in
small tumors that are extending beyond the esophageal mucosa.
• To improve the outcome of nonsurgical therapies for esophageal cancer,
combined modality treatments consisting of radiation therapy and con-
comitant chemotherapy have been evaluated extensively. Unfortunately,
outcome data for patients with stage I disease are available only for a subset
of studies and the overall results of these studies may or may not apply to
patients with early-stage disease. A pivotal randomized controlled study
was performed on 123 patients with SSC or adenocarcinoma of the esoph-
agus without metastatic disease. Radiation therapy (64 Gy) was compared
with chemoradiation therapy consisting of cisplatin and 5-fluorouracil
(5FU) infusions in combination with 50 Gy of radiation. The overall 5-year
survival rate in the combined therapy group was 26%, whereas no patient
in the radiation-only group survived longer than 2 years [63••]. A nonran-
Radiation and chemoradiation therapy
Prevention and Management of Early Esophageal Cancer
domized study compared the outcome for patients with T1 or T2 tumors
after chemoradiation with that of a group of patients who underwent
esophagectomy. Patients in the chemoradiation arm were treated with an
initial radiation dose of 44 Gy and concomitant chemotherapy, consistent
of cisplatin and 5FU . Responding patients received additional chemo-
therapy and radiotherapy up to 50 to 60 Gy for T1 tumors. Nonresponders
were eligible for surgery. Overall 1- and 3-year survival rates of patients with
T1 tumors were 100% and 83%, respectively, in the chemoradiation group
versus 82% and 72%, respectively, in the surgery group. The differences
were not statistically significant. The Eastern Cooperative Oncology Group
 performed a trial in patients with early-stage SSC comparing chemora-
diotherapy with radiotherapy alone. The chemotherapy included 5FU and
mitomycin C. A dose of 40 Gy radiation was administered initially. Patients
were then evaluated for surgery. The patients who did not undergo surgery
received additional 20 Gy of radiation. The median survival times for
patients receiving radiotherapy alone, radiation and chemotherapy, radia-
tion and surgery, or radiation with chemotherapy and subsequent surgery
were 0.6, 1.3, 1.3, and 0.9 years, respectively . A recent study published
in abstract form  examined the efficacy of chemotherapy (5FU and cis-
platin) and concurrent radiotherapy (up to 60 Gy) in patients with stage I
esophageal cancer. The rate of complete response was 93% and the 5-year
survival rate was 78%. Adverse events included in particular neutropenia,
esophagitis, stomatitis, and nausea. The authors note that this therapeutic
approach is safe and that the survival data are comparable to the results of
surgical approaches. A meta-analysis of 13 randomized controlled trials in
patients with localized (nonmetastatic) esophageal cancer that compared
radiation alone with radiation and concomitant chemotherapy demon-
strated a significant reduction in mortality at 1 and 2 years with an absolute
reduction in mortality of 7% and 7%, respectively . Concomitant che-
motherapy and radiotherapy were superior over sequential protocols. How-
ever, the increased efficacy of the combined modality approaches was
associated with an increase in acute adverse events, particularly gastrointes-
tinal and hematologic toxicities . Attempts to increase the antitumor
activity of chemoradiation by increasing the radiation dose used resulted in
further increases in toxicity without improvements in survival or locore-
gional disease control [68•]. Based on these results, the authors suggested a
standard radiation dose of 50.4 Gy for patients treated with concurrent 5FU
and cisplatin. At this point, concomitant chemoradiation is the recom-
mended nonsurgical treatment for patients with early esophageal cancer
. Ongoing clinical trials are evaluating the role of new chemotherapeu-
tic agents, particularly the taxanes and irinotecan.
• Advances in endoscopic technology have led to the development of new
treatment options for patients with early esophageal cancer. Because endo-
scopic approaches to esophageal cancer do not allow for resection of
regional lymph nodes, these procedures are limited to patients with high-
grade dysplasia or T1a tumors and, therefore, depend on accurate staging
by using EUS with high-frequency ultrasound probes, as described earlier.
• Endoscopic mucosa resection (EMR) enables the endoscopist to resect the
entire involved mucosa, including the muscularis mucosae and parts of the
submucosa. The procedure is performed by injecting normal saline into the
esophageal wall, resulting in a lifting of the target lesion and separation of
the inner layers of the wall from the muscularis propria. Successful separa-
Endoscopic ablative therapies
tion can be documented by high-frequency endosonography . Subse-
quently, the lesion is further separated by applying suction (suck-and-cut),
or lifting using a grasping device (lift-and-cut), which is followed by snare
resection. Japanese authors reported excellent long-term results for patients
with mucosal tumors after EMR. For example, in a series of 56 patients
treated with EMR, 53 were alive without disease after a median follow-up
of 39 months . A study comparing EMR versus esophagectomy in
patients with mucosal tumors demonstrated 5-year survival rates of 61%
and 71%, respectively, which was not a statistically significant difference
. When interpreting these results, it is important to note that there are
significant differences in the pathologic evaluation of specimens between
Japanese and Western pathologists, resulting in a possible over-representa-
tion of premalignant lesions in the Japanese series . The largest Western
studies demonstrate that, because of persistent or recurrent disease, further
endoscopic treatments are frequently necessary after the initial resection.
Nevertheless, an overall complete local remission rate of 98% was achieved
[72•]. Because of the high rate of persistent, recurrent, and metachronous
cancers, combination of EMR with other endoscopic therapeutic tech-
niques has been proposed, as outlined below. In addition to its therapeutic
potential, EMR offers the possibility of an improved histologic analysis
resulting from the larger and deeper-reaching tissue obtained compared to
standard pinch biopsies. Consistent with this hypothesis, changes in the
original diagnosis were reported in up to 44% of the cases after EMR ,
which included the discovery of invasive cancers in some patients, who
subsequently underwent surgical resection . Despite the depth of the
resection, the complication rate of EMR is low. In studies performed at
Western centers, the major complication was bleeding in a few cases [72•],
and perforations occurred rarely (0.06%–5% of the cases [72•]).
• Photodynamic therapy is a treatment strategy that can be applied to large
areas of mucosa. It capitalizes on the propensity of neoplastic cells to retain
a photosensitizer, such as sodium porfimer (Photofrin; Axcan Pharma, Bir-
mingham, AL) or 5-aminolevulinic acid, more efficiently than normal cells.
After infusion of Photofrin, laser light is used to activate the photosensi-
tizer, resulting in cell death. Only limited data regarding the use of photo-
dynamic therapy for the treatment of early esophageal cancer have been
published and, at this point, do not allow final conclusions. A small study
 reported that elimination of early cancer was achieved in only four of
nine patients. In contrast, cancer was eliminated in 13 of 14 patients
treated at the Mayo Clinic in Jacksonville, FL . A recent retrospective
analysis of a combination of EMR with photodynamic therapy in patients
with early esophageal cancer showed that 20 of 24 patients were cancer free
. Two of the nonresponders underwent alternate therapies and
remained disease-free afterward, whereas the two remaining patients died
of unrelated causes. This approach was associated with significantly fewer
procedure-related complications than surgery, which had been performed
in a comparable group. A prospective randomized controlled trial compar-
ing surgery versus the endoscopic multimodality approach is ongoing, and
this should help to further define the role of these approaches in the treat-
ment of early esophageal cancer .
• In small clinical series, additional endoscopic therapies, including argon
plasma coagulation, laser ablation, and electrocoagulation, have been dem-
onstrated to be potentially effective [77,78]. However, the current data do
not support the use of these methods outside of clinical trials.
Prevention and Management of Early Esophageal Cancer
• The dismal prognosis of esophageal cancer stimulated research into
expanded treatment strategies that involve preoperative and/or postopera-
tive therapeutic interventions. The theoretical benefit of preoperative (neo-
adjuvant) therapies, either in the form of chemotherapy, radiotherapy, or
the combination of both modalities, results from a potential shrinkage of
the primary tumor and reduction of locoregional lymph node and distant
metastases. A substantial body of data addressing the therapeutic value of
this approach has been generated during the past decade. The main target
of these studies was locally advanced esophageal cancer, while only a
smaller number of studies enrolled patients with and reported data on
early cancers. Despite the theoretical advantage, no survival benefit has
been demonstrated for locally advanced or early esophageal cancer for pre-
operative chemotherapy, radiotherapy, or chemoradiation, as documented
in large individual trials and meta-analyses [79–81].
• The possibility of improving survival by postoperative (adjuvant) therapy,
including chemotherapy, radiotherapy, or chemoradiation, has been tested
in several studies. For patients with SSC, no survival benefit was achieved
. On the contrary, patients treated with adjuvant radiotherapy fare
worse than the control group . However, a randomized controlled trial
of radiochemotherapy performed in patients with gastric cancer or adeno-
carcinoma at the gastroesophageal junction demonstrated improvement in
overall median survival from 27 to 36 months . A follow-up report was
recently presented in abstract form  and confirmed the continued ben-
efit for patients in the chemoradiation group, which applied not only to
patients with advanced disease but also to those with pathologic stages I
and II cancers. Thus, adjuvant therapy for patients with adenocarcinoma of
the gastrointestinal junction should be considered after esophagectomy.
• The therapeutic approach to early esophageal cancer has been the subject of
intense research efforts during the past 15 years, which has led to signifi-
cant improvements. In addition, the potential of prevention of this disease
by dietary and lifestyle changes and pharmacologic interventions gives rea-
son for optimism. As a result of the introduction of novel and improved
diagnostic procedures, patients can now be selected with great precision for
therapies that are less invasive than radical esophagectomy. Prospective tri-
als comparing alternative treatment approaches will hopefully generate a
solid data platform that will allow for rationally guided individualized
therapy of early esophageal cancer.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as:
•• Of major importance
1.Jemal A, Tiwari RC, Murray T, et al.: Cancer statistics,
2004. CA Cancer J Clin 2004, 54:8–29.
Devesa SS, Blot WJ, Fraumeni JF Jr: Changing patterns
in the incidence of esophageal and gastric carcinoma
in the United States. Cancer 1998, 83:2049–2053.
3.Parkin DM, Bray F, Ferlay J, et al.: Estimating the world
cancer burden: Globocan 2000. Int J Cancer 2001,
Lin K, Shen W, Shen Z, et al.: Estimation of the poten-
tial for nitrosation and its inhibition in subjects from
high- and low-risk areas for esophageal cancer in
southern China. Int J Cancer 2003, 107:891–895.
Neoadjuvant and adjuvant therapy
5. Tachibana M, Yoshimura H, Kinugasa S, et al.: Clinico-
pathological features of superficial squamous cell car-
cinoma of the esophagus. Am J Surg 1997, 174:49–53.
Stein HJ, Brucher BL, Sendler A, et al.: Esophageal can-
cer: patient evaluation and pretreatment staging. Surg
Oncol 2001, 10:103–111.
Castellsague X, Munoz N, De Stefani E, et al.: Indepen-
dent and joint effects of tobacco smoking and alcohol
drinking on the risk of esophageal cancer in men and
women. Int J Cancer 1999, 82:657–664.
Morita M, Saeki H, Mori M, et al.: Risk factors for
esophageal cancer and the multiple occurrence of car-
cinoma in the upper aerodigestive tract. Surgery 2002,
Castellsague X, Munoz N, De Stefani E, et al.: Influence
of mate drinking, hot beverages, and diet on esoph-
ageal cancer risk in South America. Int J Cancer 2000,
Risk JM, Mills HS, Garde J, et al.: The tylosis esophageal
cancer (TOC) locus; more than just a familial cancer
gene. Dis Esophagus 1999, 12:173–176.
Brucher BL, Stein HJ, Bartels H, et al.: Achalasia and
esophageal cancer: incidence, prevalence, and prog-
nosis. World J Surg 2001, 25:745–749.
Shaheen NJ, Crosby MA, Bozymski EM, et al.: Is there
publication bias in the reporting of cancer risk in Bar-
rett's esophagus? Gastroenterology 2000, 119:333–338.
13.• Lagergren J, Bergstrom R, Lindgren A, et al.: Symptomatic
gastroesophageal reflux as a risk factor for esophageal
adenocarcinoma. N Engl J Med 1999, 340:825–831.
This study established the independent role of GERD as a risk
factor for esophageal adenocarcinoma.
14.Cheng KK, Sharp L, McKinney PA, et al.: A case-control
study of oesophageal adenocarcinoma in women: a
preventable disease. Br J Cancer 2000, 83:127–132.
15.Walther C, Zilling T, Perfekt R, et al.: Increasing preva-
lence of adenocarcinoma of the oesophagus and gas-
tro- oesophageal junction: a study of the Swedish
population between 1970 and 1997. Eur J Surg 2001,
16. Brown LM, Hoover R, Silverman D, et al.: Excess inci-
dence of squamous cell esophageal cancer among US
Black men: role of social class and other risk factors.
Am J Epidemiol 2001, 153:114–122.
17. Engel LS, Chow WH, Vaughan TL, et al.: Population
attributable risks of esophageal and gastric cancers. J
Natl Cancer Inst 2003, 95:1404–1413.
18.• Sampliner RE: Updated guidelines for the diagnosis,
surveillance, and therapy of Barrett's esophagus. Am J
Gastroenterol 2002, 97:1888–1895.
This article contains a comprehensive discussion of the cur-
rent approach to Barrett's esophagus.
19. Corley DA, Levin TR, Habel LA, et al.: Surveillance and
survival in Barrett's adenocarcinomas: a population-
based study. Gastroenterology 2002, 122:633–640.
20. Stein HJ, Siewert JR: Improved prognosis of resected
esophageal cancer. World J Surg 2004, In press.
21.Yoshida S: Endoscopic diagnosis and treatment of
early cancer in the alimentary tract. Digestion 1998,
22.Kelly S, Harris KM, Berry E, et al.: A systematic review of
the staging performance of endoscopic ultrasound in
gastro-oesophageal carcinoma. Gut 2001, 49:534–539.
Dean DA, Detterbeck FC: Esophageal cancer: staging. In
Gastrointestinal Oncology. Edited by Tepper JE, Levin B,
Kelsen D, et al. Philadelphia: Lippincott Williams &
Waxman I: Endosonography in columnar-lined esoph-
agus. Gastroenterol Clin North Am 1997, 26:607–612.
May A, Gunter E, Roth F, et al.: Accuracy of staging in
early oesophageal cancer using high resolution endo-
scopy and high resolution endosonography: a com-
parative, prospective, and blinded trial. Gut 2004,
Terry P, Lagergren J, Hansen H, et al.: Fruit and vegeta-
ble consumption in the prevention of oesophageal
and cardia cancers. Eur J Cancer Prev 2001, 10:365–369.
Chainani-Wu N: Diet and oral, pharyngeal, and
esophageal cancer. Nutr Cancer 2002, 44:104–126.
Blot WJ, Li JY, Taylor PR, et al.: Nutrition intervention
trials in linxian, China: supplementation with specific
vitamin/mineral combinations, cancer incidence, and
disease-specific mortality in the general population. J
Natl Cancer Inst 1993, 85:1483–1492.
Taylor PR, Qiao YL, Abnet CC, et al.: Prospective study
of serum vitamin E levels and esophageal and gastric
cancers. J Natl Cancer Inst 2003, 95:1414–1416.
Wei WQ, Abnet CC, Qiao YL, et al.: Prospective study of
serum selenium concentrations and esophageal and
gastric cardia cancer, heart disease, stroke, and total
death. Am J Clin Nutr 2004, 79:80–85.
Chow WH, Blot WJ, Vaughan TL, et al.: Body mass
index and risk of adenocarcinomas of the esophagus
and gastric cardia. J Natl Cancer Inst 1998, 90:150–155.
Lagergren J, Bergstrom R, Nyren O: Association
between body mass and adenocarcinoma of the
esophagus and gastric cardia. Ann Intern Med 1999,
Lagergren J, Bergstrom R, Nyren O: No relation between
body mass and gastro-oesophageal reflux symptoms
in a Swedish population based study. Gut 2000,
Vaughan TL, Davis S, Kristal A, et al.: Obesity, alcohol,
and tobacco as risk factors for cancers of the esopha-
gus and gastric cardia: adenocarcinoma versus squa-
mous cell carcinoma. Cancer Epidemiol Biomarkers Prev
Gammon MD, Schoenberg JB, Ahsan H, et al.: Tobacco,
alcohol, and socioeconomic status and adenocarcino-
mas of the esophagus and gastric cardia. J Natl Cancer
Inst 1997, 89:1277–1284.
Cheng KK, Duffy SW, Day NE, et al.: Stopping drink-
ing and risk of oesophageal cancer. BMJ 1995,
Castellsague X, Munoz N, De Stefani E, et al.: Smoking
and drinking cessation and risk of esophageal cancer.
Cancer Causes Control 2000, 11:813–818.
Lagergren J, Bergstrom R, Adami HO, et al.: Association
between medications that relax the lower esophageal
sphincter and risk for esophageal adenocarcinoma.
Ann Intern Med 2000, 133:165–175.
Prevention and Management of Early Esophageal Cancer
39.Zhang F, Altorki NK, Wu YC, et al.: Duodenal reflux
induces cyclooxygenase-2 in the esophageal mucosa
of rats: evidence for involvement of bile acids. Gastro-
enterology 2001, 121:1391–1399.
Sampliner RE: Practice guidelines on the diagnosis,
surveillance, and therapy of Barrett's esophagus. Am J
Gastroenterol 1998, 93:1028–1032.
Canto MI, Setrakian S, Willis J, et al.: Methylene blue-
directed biopsies improve detection of intestinal
metaplasia and dysplasia in Barrett's esophagus. Gas-
trointest Endosc 2000, 51:560–568.
Corley DA, Kerlikowske K, Verma R, et al.: Protective
association of aspirin/NSAIDs and esophageal cancer:
a systematic review and meta-analysis. Gastroenterology
Morris CD, Armstrong GR, Bigley G, et al.: Cyclooxygen-
ase-2 expression in the Barrett's metaplasia-dysplasia-
adenocarcinoma sequence. Am J Gastroenterol 2001,
Hur C, Nishioka NS, Gazelle GS: Cost-effectiveness of
aspirin chemoprevention for Barrett's esophagus. J
Natl Cancer Inst 2004, 96:316–325.
Lerut T, Coosemans W, Van Raemdonck D, et al.: Surgical
treatment of Barrett's carcinoma; correlations between
morphologic findings and prognosis. J Thorac Cardiovasc
Surg 1994, 107:1059–1065; discussion 1065–1066.
Holscher AH, Bollschweiler E, Schneider PM, et al.: Early
adenocarcinoma in Barrett's oesophagus. Br J Surg
Ando N, Ozawa S, Kitagawa Y, et al.: Improvement in
the results of surgical treatment of advanced squa-
mous esophageal carcinoma during 15 consecutive
years. Ann Surg 2000, 232:225–232.
Fujita H, Sueyoshi S, Yamana H, et al.: Optimum treat-
ment strategy for superficial esophageal cancer: endo-
scopic mucosal resection versus radical
esophagectomy. World J Surg 2001, 25:424–431.
Bonavina L, Via A, Incarbone R, et al.: Results of surgi-
cal therapy in patients with Barrett's adenocarcinoma.
World J Surg 2003, 27:1062–1066.
Stein HJ, Feith M, Rahden BA, et al.: Approach to early
Barrett's cancer. World J Surg 2003, 27:1040–1046.
Lerut T, Coosemans W, Decker G, et al.: Cancer of the
esophagus and gastro-esophageal junction: poten-
tially curative therapies. Surg Oncol 2001, 10:113–122.
Law S, Kwong DL, Kwok KF, et al.: Improvement in
treatment results and long-term survival of patients
with esophageal cancer: impact of chemoradiation
and change in treatment strategy. Ann Surg 2003,
238:339–347; discussion 347-338.
53.••Hulscher JB, van Sandick JW, de Boer AG, et al.:
Extended transthoracic resection compared with lim-
ited transhiatal resection for adenocarcinoma of the
esophagus. N Engl J Med 2002, 347:1662–1669.
This is an extensive study highlighting differences in out-
comes and treatment-associated mortality as well as mortality
for the two dominating surgical approaches to adenocarci-
noma of the esophagus.
54.Patti MG, Corvera CU, Glasgow RE, et al.: A hospital's
annual rate of esophagectomy influences the opera-
tive mortality rate. J Gastrointest Surg 1998, 2:186–192.
Swisher SG, Deford L, Merriman KW, et al.: Effect of
operative volume on morbidity, mortality, and hospi-
tal use after esophagectomy for cancer. J Thorac Cardio-
vasc Surg 2000, 119:1126–1132.
Nishihira T, Hirayama K, Mori S: A prospective ran-
domized trial of extended cervical and superior medi-
astinal lymphadenectomy for carcinoma of the
thoracic esophagus. Am J Surg 1998, 175:47–51.
Altorki N, Kent M, Ferrara C, et al.: Three-field lymph
node dissection for squamous cell and adenocarci-
noma of the esophagus. Ann Surg 2002, 236:177–183.
Orringer MB, Marshall B, Stirling MC: Transhiatal
esophagectomy for benign and malignant disease. J
Thorac Cardiovasc Surg 1993, 105:265–276; discussion
Swanstrom LL, Hansen P: Laparoscopic total esoph-
agectomy. Arch Surg 1997, 132:943–947; discussion
Luketich JD, Schauer PR, Christie NA, et al.: Minimally
invasive esophagectomy. Ann Thorac Surg 2000,
Nemoto K, Matsumoto Y, Yamakawa M, et al.: Treat-
ment of superficial esophageal cancer by external
radiation therapy alone: results of a multi-institu-
tional experience. Int J Radiat Oncol Biol Phys 2000,
Sykes AJ, Burt PA, Slevin NJ, et al.: Radical radiotherapy
for carcinoma of the oesophagus: an effective alterna-
tive to surgery. Radiother Oncol 1998, 48:15–21.
63.••Herskovic A, Martz K, al-Sarraf M, et al.: Combined che-
motherapy and radiotherapy compared with radio-
therapy alone in patients with cancer of the
esophagus. N Engl J Med 1992, 326:1593–1598.
This is a landmark study that demonstrated the superiority of
combined modality treatment over radiotherapy alone in
patients with esophageal cancer.
64.Murakami M, Kuroda Y, Nakajima T, et al.: Comparison
between chemoradiation protocol intended for organ
preservation and conventional surgery for clinical T1-
T2 esophageal carcinoma. Int J Radiat Oncol Biol Phys
65. Smith TJ, Ryan LM, Douglass HO Jr, et al.: Combined
chemoradiotherapy vs. radiotherapy alone for early
stage squamous cell carcinoma of the esophagus: a
study of the Eastern Cooperative Oncology Group. Int
J Radiat Oncol Biol Phys 1998, 42:269–276.
66.Muro K, Hamaguchi T, Yamada Y, et al.: Definitive
chemoradiotherapy may be standard treatment options
in clinical stage I esophageal cancer. In ASCO Gas-
trointestinal Cancers Symposium; San Francisco: 2004:27.
67.Wong R, Malthaner R: Combined chemotherapy and
radiotherapy (without surgery) compared with radio-
therapy alone in localized carcinoma of the esophagus
(Cochrane Review) [abstract]. The Cochrane Library, 2001.
68.• Minsky B, Pajak T, Ginsberg R, et al.: INT 0123 (Radia-
tion Therapy Oncology Group 94-05) phase III trial of
combined-modality therapy for esophageal cancer:
high-dose versus standard-dose radiation therapy. J
Clin Oncol 2002, 20:1151–1153.
This paper revealed the limitations of dose escalation as a
means of improving multimodality approaches to esophageal
cancer by demonstrating an increased mortality of patients
treated with high-dose radiation therapy.
69.Waxman I, Saitoh Y, Raju GS, et al.: High-frequency
probe EUS-assisted endoscopic mucosal resection: a
therapeutic strategy for submucosal tumors of the GI
tract. Gastrointest Endosc 2002, 55:44–49.
70. Takeshita K, Tani M, Inoue H, et al.: Endoscopic treat-
ment of early oesophageal or gastric cancer. Gut 1997,
71. Schlemper RJ, Kato Y, Stolte M: Diagnostic criteria for
gastrointestinal carcinomas in Japan and western
countries: proposal for a new classification system of
gastrointestinal epithelial neoplasia. J Gastroenterol
Hepatol 2000, 15(Suppl):G49–G57.
72.• May A, Gossner L, Pech O, et al.: Local endoscopic ther-
apy for intraepithelial high-grade neoplasia and early
adenocarcinoma in Barrett's oesophagus: acute-phase
and intermediate results of a new treatment approach.
Eur J Gastroenterol Hepatol 2002, 14:1085–1091.
This paper describes the experiences with endoscopic ablative
treatments at a high-volume European center, including data
on long-term follow-up.
73.Nijhawan PK, Wang KK: Endoscopic mucosal resection
for lesions with endoscopic features suggestive of
malignancy and high-grade dysplasia within Barrett's
esophagus. Gastrointest Endosc 2000, 52:328–332.
74.Overholt BF, Panjehpour M, Halberg DL: Photodynamic
therapy for Barrett's esophagus with dysplasia and/or
early stage carcinoma: long-term results. Gastrointest
Endosc 2003, 58:183–188.
75. Wolfsen HC, Woodward TA, Raimondo M: Photody-
namic therapy for dysplastic Barrett esophagus and
early esophageal adenocarcinoma. Mayo Clin Proc
76.Pacifico RJ, Wang KK, Wongkeesong LM, et al.: Com-
bined endoscopic mucosal resection and photody-
namic therapy versus esophagectomy for management
of early adenocarcinoma in Barrett's esophagus. Clin
Gastroenterol Hepatol 2003, 1:252–257.
Weston AP, Sharma P: Neodymium:yttrium-aluminum
garnet contact laser ablation of Barrett's high grade
dysplasia and early adenocarcinoma. Am J Gastroenterol
Sampliner RE: Prevention of adenocarcinoma by
reversing Barrett's esophagus with mucosal ablation.
World J Surg 2003, 27:1026–1029.
Kelsen DP, Ginsberg R, Pajak TF, et al.: Chemotherapy
followed by surgery compared with surgery alone for
localized esophageal cancer. N Engl J Med 1998,
Urschel JD, Vasan H, Blewett CJ: A meta-analysis of ran-
domized controlled trials that compared neoadjuvant
chemotherapy and surgery to surgery alone for resect-
able esophageal cancer. Am J Surg 2002, 183:274–279.
Arnott SJ, Duncan W, Gignoux M, et al.: Preoperative
radiotherapy for esophageal carcinoma (Cochrane
Review) [abstract]. The Cochrane Library,
Zieren HU, Muller JM, Jacobi CA, et al.: Adjuvant post-
operative radiation therapy after curative resection of
squamous cell carcinoma of the thoracic esophagus: a
prospective randomized study. World J Surg 1995,
Fok M, Sham JS, Choy D, et al.: Postoperative radio-
therapy for carcinoma of the esophagus: a prospec-
tive, randomized controlled study. Surgery 1993,
Macdonald JS, Smalley SR, Benedetti J, et al.: Chemora-
diotherapy after surgery compared with surgery alone
for adenocarcinoma of the stomach or gastroesoph-
ageal junction. N Engl J Med 2001, 345:725–730.
Macdonald JS, Smalley S, Benedetti J, et al.: Postopera-
tive combined radiation and chemotherapy improves
disease-free survival (DFS) and overall survival (OS)
in resected adenocarcinoma of the stomach and gas-
troesophageal junction: update of the results of Inter-
group Study INT-0116 (SWOG 9008). Gastrointest
Cancers Symp 2004, 6.