Barrett's esophagus: management of high-grade dysplasia and cancer.

Abstract

Esophagectomy remains the treatment of choice for the appropriate patient with Barrett's adenocarcinoma invading beyond the mucosa, without evidence of distant metastasis or invasion of adjacent organs. On the other hand, therapeutic management of patients with Barrett's high-grade dysplasia (HGD) or mucosal adenocarcinoma should be individualized, taking into account the patient's preferences, willingness to return for frequent endoscopic biopsies, and medical fitness to undergo esophagectomy. Surgery has to be considered the best treatment for HGD or superficial carcinoma, unless contraindicated by severe comorbidities, because it has proven to be the only treatment that is successful in curing the condition and preventing recurrent HGD or the development of invasive cancer. Nonsurgical treatment by photodynamic therapy or endoscopic mucosal resection may be a less invasive and organ-sparing option for elderly, poor-risk patients but it is still to be considered an investigational therapy that should only be conducted under a clinical trial protocol. Finally, intensive endoscopic biopsy surveillance of patients with HGD is another investigational option that may allow prompt treatment of cancer if it develops. However, few data document the safety of this observational approach.

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Barrett’s Esophagus: Management of High-Grade Dysplasia and Cancer
Alberto Ruol, M.D.,1Giovanni Zaninotto, M.D., Mario Costantini, M.D., Giorgio Battaglia, M.D.,
Matteo Cagol, M.D., Rita Alfieri, M.D., Magdalena Epifani, and Ermanno Ancona, M.D.
Clinica Chirurgica 3°, University of Padova, Padova, Italy
Submitted for publication October 29, 2003
Esophagectomy remains the treatment of choice for
the appropriate patient with Barrett’s adenocarci-
noma invading beyond the mucosa, without evidence
of distant metastasis or invasion of adjacent organs.
On the other hand, therapeutic management of pa-
tients with Barrett’s high-grade dysplasia (HGD) or
mucosal adenocarcinoma should be individualized,
taking into account the patient’s preferences, willing-
ness to return for frequent endoscopic biopsies, and
medical fitness to undergo esophagectomy. Surgery
has to be considered the best treatment for HGD or
superficial carcinoma, unless contraindicated by se-
vere comorbidities, because it has proven to be the
only treatment that is successful in curing the condi-
tion and preventing recurrent HGD or the develop-
ment of invasive cancer. Nonsurgical treatment by
photodynamic therapy or endoscopic mucosal resec-
tion may be a less invasive and organ-sparing option
for elderly, poor-risk patients but it is still to be con-
sidered an investigational therapy that should only be
conducted under a clinical trial protocol. Finally, in-
tensive endoscopic biopsy surveillance of patients
with HGD is another investigational option that may
allow prompt treatment of cancer if it develops. How-
ever, few data document the safety of this observa-
tional approach.
© 2004 Elsevier Inc. All rights reserved.
Key Words: Barrett’s esophagus; high-grade dyspla-
sia (HGD); adenocarcinoma.
INTRODUCTION
In the last two decades, a growing body of literature
from North America and Western Europe has revealed
that adenocarcinoma of the esophagus is increasing in
incidence more rapidly than any other cancer; parallel,
steadily rising incidence rates of adenocarcinoma of the
cardia are reported [1–5]. Although this could reflect
increased awareness of adenocarcinoma concomitant
with Barrett’s esophagus, it probably represents an
absolute increase.
Adenocarcinoma of the esophagus arises through a
progression of molecular, genetic, and histological
changes characterized by specialized intestinal meta-
plasia of the esophageal mucosa (Barrett’s metaplasia)
and evolving through progressive grades of dysplasia
to high-grade dysplasia (HGD) and ultimately invasive
cancer. The risk of Barrett’s mucosa to progress to
adenocarcinoma is not well established: published es-
timates of the annual risk of cancer range from 0.2 to
2.9%, and a calculated risk from 30 to 125 times higher
than in the general population is reported [6, 7]. It is
estimated, in North America, that 25,000 to 35,000
people suffer from HGD associated with Barrett’s
esophagus, and that approximately 5000 to 7000 new
patients are diagnosed with this condition each year
[8]. Estimates of the risk that HGD will progress
within 5 years to invasive cancer range widely, from 16
to 59% [6, 9]. The risk of developing adenocarcinoma
may also depend on the length of Barrett’s metaplasia
[10] and the extent of dysplasia, with a worse prognosis
for patients with diffuse dysplastic changes. Buttar
followed 100 patients with HGD with continued endo-
scopic surveillance and found cancer at 1 and 3 years in
38 and 56% of the patients with diffuse HGD, and in 7
and 14% of patients with focal HGD [11]. During the
follow-up period of up to 8 years, 32 of the 100 patients
with HGD were found to have cancer.
Current strategies for improved survival in patients
with Barrett’s adenocarcinoma focus on cancer detec-
tion at an early and potentially curable stage. This can
be obtained by screening programs in high-risk cohorts
of patients and/or endoscopic biopsy surveillance of
patients with known Barrett’s esophagus. The current
1To whom correspondence and reprint requests should be ad-
dressed at Clinica Chirurgica 3°, Universita’ di Padova, Via
Giustiniani, 2. 35128 Padova, Italy. Fax: ?39-049-8213152. E-mail:
alberto.ruol@unipd.it.
Journal of Surgical Research 117, 44–51 (2004)
doi:10.1016/j.jss.2003.10.021
44
0022-4804/04 $30.00
© 2004 Elsevier Inc. All rights reserved.

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goal of surveillance is the detection of dysplasia, which
is still the best available marker of cancer risk. Despite
the continuing debate on the cost-effectiveness of
screening and surveillance programs in patients with
Barrett’s esophagus, in Europe and North America,
adenocarcinoma of the esophagus is increasingly diag-
nosed at early stages just because of endoscopic sur-
veillance. Ferguson has recently reported on 80 pa-
tients whounderwent
adenocarcinoma [12]. Pathological stage was 0 or 1 in 9
(75%) of 12 patients who were followed with endoscopic
surveillance compared to 12 (18%) of 68 of those in the
no surveillance group. Median survival for patients in
the surveillance group was 107 months compared to 12
months for those in the no surveillance group. Also,
Corley reported that surveillance detected cancer pa-
tients had earlier tumor stage and longer survival than
non-surveillance-detected patients [13]. However, only
3.9% of the 589 patients with esophageal adenocarci-
noma had Barrett’s diagnosed before their cancer and
were therefore eligible for surveillance. This indicates
that Barrett’s esophagus goes undetected in the vast
majority of patients with esophageal adenocarcinoma
and that the potential benefit of endoscopic surveil-
lance seems to be limited to only a fraction of those
individuals at risk. Similar results are reported by
other authors [14].
Current screening and surveillance strategies, even if
potentially beneficial on a single patient basis, are very
expensive, far from efficient, and their cost-effectiveness
is questionable [12, 13]. Because the focal nature of
dysplasia makes targeting of biopsy specimens prob-
lematic, endoscopic biopsy surveillance, using novel
modalities such as vital staining chromoendoscopy,
high-magnification endoscopy [15], fluorescence endos-
copy, or molecular biomarkers (e.g., p53, p16, abnor-
mal ploidy) in biopsied tissue [9, 16–20], may allow the
better recognition of patients with dysplastic lesions
and any mucosal abnormalities that are at increased
risk of cancer progression. In the near future, the use of
a panel of molecular markers in patients with Barrett’s
esophagus may prove to represent a superior diagnos-
tic tool to identify patients with elevated malignant
potential, to establish the diagnosis of malignancy at
an early stage, and to expedite a patient’s tailored
therapy.
Treatment strategies, when Barrett’s HGD or ade-
nocarcinoma is detected, often depend on the fact that
many patients are older than 60 years of age and suffer
from severe comorbidities that may preclude esopha-
gectomy.Becausethediagnostic
treatment-related morbidity and mortality rates are
better in institutions where a high number of patients
with Barrett’s HGD or cancer are observed, consider-
ation should be given to the referral of these patients to
specialty centers that have adequate expertise and
resection forBarrett’s
accuracyand
availability of the different treatment modalities [21–
25].
HIGH-GRADE DYSPLASIA AND EARLY CANCER
It is of paramount importance, first and foremost,
that the correct diagnosis is established. In many in-
stances, especially in the presence of severe inflamma-
tion, there is an interobserver disagreement on the
diagnosis and grading of dysplasia. It may also be
difficult to distinguish between HGD and intramucosal
carcinoma. To improve diagnostic accuracy when se-
vere inflammation is present, biopsies should be re-
peated after 1 month of intensive acid suppression
using proton pump inhibitors. The new guidelines of
the American College of Gastroenterologists recom-
mend that patients who have a diagnosis of HGD un-
dergo a second endoscopic biopsy procedure to mini-
mize sampling error and maximize the chance of
detecting cancer, if present, and that all biopsies are
reviewed by a second expert pathologist [7, 26]. It is
now widely recommended that patients with Barrett’s
HGD should have four-quadrant biopsies, using jumbo
forceps, at every 1-cm interval along the entire length
of the Barrett’s lining, as well as additional biopsies
targeted to any mucosal abnormalities of the Barrett’s
lining [7, 21, 26–29].
The management of patients with HGD in Barrett’s
esophagus is controversial [7, 26, 30–33]. At the
present, treatment options for HGD include resection
surgery (i.e., esophagectomy), endoscopic ablation
therapies, and intensive endoscopic biopsy surveil-
lance. Esophagectomy is the standard recommended
treatment for Barrett’s HGD because 30 to 50% of the
patients who undergo esophagectomy for HGD actually
have an invasive adenocarcinoma detected in the re-
sected specimen [25, 30, 31, 34–40]. Endoscopic abla-
tion techniques represent an alternative therapeutic
option: they are promising but still investigational
treatments. Schnell has recently reported that the ac-
tual risk of developing invasive cancer from Barrett’s
HGD has been overstated and that endoscopic surveil-
lance alone may be a reasonable approach [41]. There-
fore, since a significant number of patients with HGD
may not develop cancer when followed for many years
by endoscopic biopsy surveillance [9, 11, 40–44], a
third option is to enter these patients in a surveillance
program, reserving treatment for cancer if it develops
[7, 21, 26–28, 41]. The strategy chosen in patients with
Barrett’s HGD or early cancer depends on histological
characterization of the lesion, and the clinical assess-
ment of a patient’s suitability and willingness to un-
dergo an operation. Therapeutic decision-making must
always include a thorough explanation of the risks and
benefits of the different therapeutic options to the pa-
tient.
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Surgery
Esophagectomy is generally considered the treat-
ment of choice for patients with Barrett’s HGD or early
adenocarcinoma [5, 7, 26, 35], provided that the patient
is a good surgical candidate. This recommendation has
been largely based on the frequent multicentricity of
neoplastic alterations within Barrett’s mucosa, and on
surgical studies showing that 30–50% of the patients
with Barrett’s HGD actually have invasive carcinoma
on the resected specimen [25, 30, 31, 34–40]. Also, the
presence of lymph node metastases should be taken
into account because they are detected in less than 5%
of the patients with mucosal (T1a) adenocarcinoma
and in 18–30% of the cases with submucosal (T1b)
cancer [45]. Results have also shown that early detec-
tion of adenocarcinoma and subsequent esophageal re-
section, preferably at the stage of HGD or early cancer
invading the mucosa, is extremely important in terms
of long-term survival [4, 5, 12, 34, 39, 41, 45].
Headrick performed prophylactic esophagectomy in
54 patients with HGD: the incidence of occult invasive
adenocarcinoma was 36%; postoperative morbidity was
57%; operative mortality was 1.8%, and the overall
5-year survival rate was 86%. The survival was signif-
icantly better for HGD compared to infiltrating carci-
noma, 96 and 68%, respectively [46].
Tseng and Heitmiller performed prophylactic esoph-
agectomy in 60 patients with Barrett’s HGD, using a
transhiatal surgical approach in 82% of the cases. The
incidence of invasive adenocarcinoma in the resected
specimen was 30%; postoperative morbidity was 29%,
and operative mortality was 1.7%. In the last 30 pa-
tients, operated from 1994 to 2001, operative mortality
declined from 3.3% (1 of 30) to 0%. Patients were fol-
lowed up for a median of 4.6 years: the actuarial 5-year
survival rate was 88% [47].
Esophagectomy with regional lymphadenectomy is
the only proven treatment of esophageal HGD and
early cancer that cures the condition, completely elim-
inates the risk of recurrence and prevents the develop-
ment of incurable cancer. Esophagectomy also liber-
ates patients with Barrett’s HGD from rigorous
endoscopic surveillance for the rest of their lives. On
the other hand, esophagectomy is reported to have a
significant postoperative morbidity, up to 45%, and a
mortality rate of 2–6% [22–24, 35, 48]. Furthermore,
because of the presence of severe comorbidities, a sig-
nificant proportion of patients may not be candidates
for surgery, and some patients, despite being suitable
for surgery, may refuse the operation.
To summarize, esophagectomy for patients with Bar-
rett’s HGD or early adenocarcinoma can be accom-
plished with low mortality and excellent long-term sur-
vival when it is performed at a center with high volume
and experience. Patients who are poor surgical risks, or
if they refuse surgery, have to be referred for some
alternative form of endoscopic ablation therapy.
Endoscopic Ablation Techniques
Endoscopic ablative treatments can be performed by
either a chemical, a thermal, or a mechanical method
that causes destruction or removal of the Barrett’s
epithelium or mucosa. The various endoscopic ablation
techniques are often to be considered complementary
rather than competitive to each other. Therefore, pa-
tients should be referred to centers that have adequate
expertise, the appropriate equipment, and also high
volume of patients. Following initial therapy, patients
require aggressive acid suppression and acid reflux
control to allow the normal squamous epithelium to
grow back in place of the Barrett’s lining. Patients
must also remain in intensive endoscopic biopsy sur-
veillance for the rest of their lives.
Unfortunately, all these techniques are not stan-
dardized and can have significant complications, in-
cluding perforation, bleeding, and strictures; another
problem that cannot be minimized is that Barrett’s
metaplasia, and even dysplasia or invasive cancer, ly-
ing beneath the neosquamous epithelium may persist
or develop during follow-up [33, 49–52]. There are still
limited long-term data regarding endoscopic ablative
therapies in patients with Barrett’s HGD or intramu-
cosal carcinoma. Therefore, ablative therapies are to be
considered investigational treatment modalities and
should be reserved for nonsurgical candidates who are
both educated and motivated to pursue a protracted
course of endoscopic surveillance and multimodal en-
doscopic therapy. Despite the above problems, some of
the ablative therapies show promise in the treatment
of HGD and early carcinoma in Barrett’s esophagus.
Chemical ablation.
Chemical ablation using photo-
dynamic therapy (PDT) is based on the accumulation of
externally administered photosensitizing drugs (i.e.,
intravenous Photofrin or oral 5-aminolevulinic acid),
which accumulate rather selectively in Barrett’s epi-
thelium. The drug is then activated by endoscopic ap-
plication of low-power laser light. This results in a
photochemical reaction that leads to selective destruc-
tion of Barrett’s epithelium. PDT may prove to be a
safe, highly effective, outpatient option for patients
who are not candidates for surgery. Complications in-
clude chest pain in most patients, esophageal stric-
tures requiring dilation in one-third of the patients,
severe photosensitivity reactions, pleural effusions,
and tachyarrhythmias.
Overholt reported the largest series of patients
treated with PDT, of whom 80 had HGD and 9 had
intramucosal cancer [51]. Complete eradication of both
dysplasia and Barrett’s mucosa was achieved in 54% of
the patients with HGD; another 24% of the patients
had eradication of dysplasia but persistence of Bar-
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rett’s metaplasia. Complete eradication of disease was
obtained in 3 of 9 patients with early adenocarcinoma,
and one more patient had eradication of cancer and
dysplasia with persistent Barrett’s metaplasia. During
a mean follow-up period of 50 months, 30% of the
patients developed significant strictures that required
dilation and three patients with HGD developed sub-
squamous adenocarcinoma after PDT.
The use of Photofrin-PDT has received recent ap-
proval from the U.S. FDA in the ablation of HGD in
Barrett’s esophagus patients who do not undergo
esophagectomy, based on the results of a study on 138
patients who received PDT and omeprazole. Patients
were followed every 3 months until four consecutive
endoscopic results were negative for HGD and then
semiannually until the last enrolled patient had com-
pleted at least 24 months of follow-up. The length of
follow-up ranged from 2 to 3.6 years. PDT resulted in
the complete ablation of HGD in 77% of treated pa-
tients. Patients who failed to achieve complete re-
sponse had an approximately 10-fold higher risk of
progression to cancer than patients who achieved a
complete response (from http://www.pslgroup.com/dg/
237e52.htm).
ALA-PDT seems to be associated with less strictures
and a shorter period of photosensitivity. Gossner re-
ported on 10 patients with HGD and 22 with mucosal
cancer who were treated with ALA-PDT. Dysplasia
was eradicated in all of the patients with HGD, and
there was complete remission in 17 of 22 (77%) pa-
tients with carcinoma. However, ALA was ineffective
in the treatment of tumors greater than 2 mm in depth
[53].
Thermal ablation.
Thermal ablation is done using
multipolar electrocoagulation, heater probe electroco-
agulation, argon plasma coagulation (APC), Nd:YAG
laser, or KTP laser photoablation. These techniques
are still considered experimental for the treatment of
Barrett’s HGD because, to date, little information is
available in this regard [49, 54]. Complications after
these procedures include chest pain, esophageal stric-
tures, pleural effusion, and, more important, the pos-
sibility that metaplastic tissue may persist deeper to
the normal-appearing neosquamous epithelium [49].
Mechanical ablation.
Mechanical ablation is done
using ultrasonic aspiration or endoscopic mucosal re-
section (EMR). EMR, which allows the separation of
the target lesion from the muscularis propria by inject-
ing fluid into the submucosa directly beneath the le-
sion, can also be used in the treatment of early carci-
noma. EMR is appealing because it also provides the
diagnostic tissue that permits the histological assess-
ment of the adequacy of therapy. EMR has been used
extensively in Japan for the treatment of early gastric
cancer, and most Japanese studies suggest that the
long-term recurrence rate and mortality in patients
treated with EMR are equivalent to those achieved by
surgical resection. However, limited information on the
role of EMR in Barrett’s HGD or early adenocarcinoma
is available to date.
Nijhawan performed EMR in 25 patients suspected
of having either early cancer or HGD within Barrett’s
mucosa: superficial cancer was found in 13, and HGD
in 4. On the other hand, three lesions thought to have
HGD or cancer had no evidence of dysplasia or carci-
noma. Forty-four percent of the patients had their di-
agnoses modified after EMR. Therefore, EMR is not
only potentially therapeutic, but it has diagnostic im-
plications as well [55].
May reported the results of EMR in 7 patients with
HGD and 63 with early carcinoma [56]. No major com-
plications, such as perforation and severe bleeding,
occurred after EMR; minor complications, such as mild
bleeding episodes and cicatricial strictures, occurred in
10% of the patients. Overall, 98% of the patients had
complete local remission. During a mean follow-up of
34 months (range 24–60 months), metachronous/
recurrent HGD or cancer was detected in 21 (30%) of
the 70 patients. All these patients except one, who died
from Barrett’s adenocarcinoma, underwent successful
repeat endoscopic treatment. In a previous report, the
same group reported that complete remission was
achieved in only 59% of the patients with high-risk
lesions characterized by the following features: diam-
eter ? 20 mm, poorly differentiated histology, lesion
extending into the submucosa, or ulcerated lesion [57].
Multimodal treatments.
eradication or recurrence of the lesion, a combination
of different types of treatment can be used: series of
patients treated with PDT followed by other forms of
local ablation or EMR followed by PDT as salvage
therapy have been published [56, 58]. In clinical prac-
tice, it is likely that improved results may be obtained
by using the various endoscopic ablation techniques as
complementary therapeutic modalities. In fit patients,
esophagectomy can be the final option.
Panjehpour reported his experience with PDT fol-
lowed by Nd:YAG laser ablation or retreatment with
PDT for residual or recurrent disease [59]. Sixty pa-
tients with Barrett’s dysplasia or early cancer were
treated, and follow-up endoscopies were performed ev-
ery 3–6 months to evaluate response. All cancers were
successfully eradicated, and persistent HGD was de-
tected in only 2 of 43 patients (eradication rate, 96%).
Barrett’s mucosa was totally eliminated in 25 of 60
patients (42%).
In a recent report, Wolfsen reported results on 34
patients with HGD and 14 patients with superficial
cancer (T1N0) who were treated with PDT followed 4 to
6 weeks later by APC for residual metaplastic mucosa:
after PDT, 27 of the patients had complete eradication;
after bimodal therapy 47 of 48 patients showed com-
Because ofincomplete
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Page 5

plete remission, and 1 patient was found to harbor
adenocarcinoma deeper to the overlying neosquamous
epithelium [52].
To summarize, mucosal ablative therapy cannot be
accepted as standard therapy at the present time be-
cause of its questionable ability to completely eradicate
the abnormal mucosa and to limit follow-up, and be-
cause patients require continued rigorous endoscopic
surveillance for the rest of their lives.
Intensive Endoscopic Biopsy Surveillance
The argument for continuing endoscopic biopsy sur-
veillance in patients with Barrett’s HGD is that pro-
gression to invasive carcinoma may take many years
and is not inevitable [9, 11, 21, 27, 40–44]. In patients
with a diagnosis of HGD, endoscopic biopsy surveil-
lance has to be performed 1 month after the initial
diagnosis, then after 3 months, and subsequently at
least every 6 months for the rest of their lives to detect
cancer, if it develops, when it is early and curable with
surgery [7, 28]. Prolonged delay of treatment may re-
sult in undue risk of spread of tumor to a degree which
is no longer curable. Contrasting data are reported in
the literature on this subject. Reid, in a large study of
76 patients with HGD, reported a 59% probability of
developing cancer over a 5-year period [9]. On the other
hand, Schnell reported another large study of 79 pa-
tients with HGD without evidence of cancer: 4 (12%) of
the 34 patients with prevalent HGD had unsuspected
cancer diagnosed during the first year, and 2 additional
patients with prevalent HGD plus 10 of the 45 patients
with incident HGD developed cancer during surveil-
lance; 5 (42%) of the above 12 patients who developed
cancer had their cancer diagnosed within 1 year of the
diagnosis of HGD [41]. Overall, it has to be emphasized
that the time interval between the first diagnosis of
HGD and the diagnosis of cancer was less than 10
months in 9 (60%) of 15 patients who eventually devel-
oped cancer.
Endoscopic biopsy surveillance has been questioned
because of its clinical impracticality, high costs, in-
creased workload for endoscopic and pathology units,
possibility of sampling errors, procedure-related com-
plications, discomfort to the patient, and patient’s risk
of developing invasive, and perhaps incurable, cancer.
On the other hand, these drawbacks of endoscopic sur-
veillance have to be weighed against the potential mor-
tality and morbidity rates of esophagectomy, which are
not negligible.
To summarize, since many patients with Barrett’s
HGD are elderly and not ideal candidates for surgery,
or some patients may refuse surgery, surveillance en-
doscopy may be one possible option, reserving esopha-
gectomy as a treatment of cancer if it develops [7, 9, 21,
26, 41]. However, few data document the safety of this
observational approach.
INVASIVE ADENOCARCINOMA
Adenocarcinoma of the esophagus or esophagogas-
tric junction carries one of the lowest 5-year survival
rates of all malignancies [6, 12]. Because of the pres-
ence of comorbid illness and/or advanced tumor stage,
a significant proportion of these patients are not can-
didates for surgery. Surgery remains the only poten-
tially curative option for esophageal adenocarcinoma
without evidence of distant metastasis or invasion of
adjacent structures even though the overall prognosis
after surgery alone remains dismal, with a 25% 5-year
survival rate [4, 5, 60]. Therefore, esophageal adeno-
carcinoma must be detected early, before the patient
develops symptoms, in order for the patient to have a
high likelihood of a cure [12, 27, 34, 35, 61, 62]. The
most frequently used surgical technique is esophago-
gastric resection and gastric pull-up, which is per-
formed through a laparotomy and right thoracotomy.
Transhiatal esophagectomy can be used in patients for
whom thoracotomy is contraindicated. Excision volume
should include the whole length of Barrett’s mucosa
and at least 4–6 cm of healthy esophagus above the
tumor, the gastric fundus, the lesser gastric curvature,
and regional lymph nodes in the upper abdomen and
mid-lower mediastinum.
In cases of potentially resectable adenocarcinoma
that invades beyond the mucosa, surgical resection is
the standard of care for patients with an acceptable
operative risk. However, the overall long-term progno-
sis after esophagectomy, even after complete R0 resec-
tion, remains dismal and significant postoperative
morbidity (up to 45%) and mortality rates (range, ?2–
6%) are reported [5, 39, 63, 64]. To improve long-term
prognosis, neoadjuvant chemoradiation is frequently
used, within study protocols, in patients with a poten-
tially resectable tumor [5, 60]. Today there is no abso-
lute evidence that neoadjuvant treatments prolong
survival of patients with potentially resectable esoph-
ageal adenocarcinoma. However, a recent meta-
analysis of randomized clinical trials showed that
there seems to be a modest survival advantage (of 6.4%
at 2 years, and of 5.1% at 3 years) for patients with
resectable adenocarcinoma of the esophagus and the
gastroesophageal junction who receive chemotherapy
or chemoradiation followed by surgery as compared
with surgery alone [60]. Rates of complete pathologic
response ranged from 2.5 to 26%. Responders had
longer survival thannonresponders.
related mortality increased by 1.7% with neoadjuvant
chemotherapy and by 3.4% with chemoradiation com-
pared with surgery alone.
The prognosis of patients with locally advanced (T4
or T3 N positive), presumably not completely resect-
able, adenocarcinoma of the esophagus or esophago-
gastric junction is very poor [5, 39, 63, 65, 66]. Evidence
from recent trials indicates that in these patients, the
Treatment-
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use of preoperative chemoradiation is effective in in-
creasing the chance for a curative resection and in
prolonging survival in responding patients [5]; there-
fore, the use of multimodal treatments has become
routine in many institutions.
THE PADOVA EXPERIENCE
We recently evaluated the presence of invasive can-
cer in patients with Barrett’s HGD who underwent
prophylactic esophagectomy [67]. Our updated data
are as follows: from 1983 to 2002, 28 patients with
Barrett’s HGD were observed. Nine patients were not
operated because of medical contraindications or re-
fusal of surgery, and 19 patients underwent esopha-
gectomy. Invasive carcinoma (pT1N0) was detected in
7 (37%) of 19 surgical specimens. There were no oper-
ative deaths. During a mean follow-up period of 42
months, no recurrence of the disease was observed.
In a previous surgical study we compared adenocar-
cinoma in Barrett’s esophagus with adenocarcinoma of
the esophagogastric junction. Fifteen (27%) of 56 Bar-
rett’s cancers had an early-stage tumor compared to
only 11 (3.7%) of 294 cancers of the cardia, probably
thanks to endoscopic biopsy surveillance which pa-
tients with known benign Barrett’s esophagus had
been subjected to. However, stratifying patients who
underwent resection surgery by pathologic tumor
stage, the prognosis of Barrett’s adenocarcinoma and
that of cancer of the cardia were comparable [68].
From 1980 to 2002, we observed 3813 primary can-
cers of the esophagus or esophagogastric junction: the
prevalence of adenocarcinomas rose from 21% in the
1980s to 36% during the last two years. Of 911 patients
with adenocarcinoma of the esophagus or esophagogas-
tric junction, 623 (68%) underwent surgery. Postoper-
ative in-hospital mortality declined from 4.2% at the
beginning of the 1980s to 0.6% during the last eight
years. Thirty-two (30%) of 107 patients with adenocar-
cinoma arising in Barrett’s esophagus had an early
stage (pT0–Ia) tumor compared to only 24 (4.6%) of 516
patients with adenocarcinoma of the esophagus or
esophagogastric junction without evidence of Barrett’s
metaplasia. The overall 5-year survival after complete
R0 resection was 33%. Prognosis was strictly related to
pathological tumor stage: the 5-year survival rate was
88% for pStage 0–Ia tumors (i.e., pT0–T1/N0/M0), 65%
for pStage Ib tumors (i.e., pT1/N1/M0 or pT2/N0/M0),
44% for pStage II tumors (i.e., pT1/N2/M0 or pT2/
N1/M0 or pT3/N0/M0), and 16% for pStage III–IV tu-
mors.
CONCLUSIONS
Novel diagnostic modalities such as chromoendos-
copy, magnification endoscopy, and fluorescence endos-
copy may help to better recognize patients with lesions
that are progressing to cancer. In the near future,
molecular and genetic markers in biopsied tissue will
also help to identify patients with an increased risk of
cancer progression.
Esophagectomy remains the treatment of choice for
the appropriate patient with Barrett’s adenocarcinoma
invading beyond the mucosa, without evidence of dis-
tant metastasis or invasion of adjacent organs. On the
other hand, there is extensive investigation directed
toward better defining the therapeutic approach to pa-
tients with Barrett’s HGD or mucosal adenocarcinoma.
Therapeutic management of these patients should be
individualized, taking into account patient’s prefer-
ences, willingness to return for frequent endoscopic
biopsies, and medical fitness to undergo esophagec-
tomy. Surgery has to be considered the best treatment
for HGD or early carcinoma, unless contraindicated by
severe comorbidities, because it has proven to be the
only treatment that is successful in curing the condi-
tion and preventing recurrent HGD or the develop-
ment of invasive cancer. Nonsurgical treatment by
PDT or EMR may be a less invasive and organ-sparing
option for elderly, poor-risk patients with HGD, or
early carcinoma, but it is still to be considered an
investigational therapy that should only be conducted
under a clinical trial protocol. Finally, intensive endo-
scopic biopsy surveillance of patients with HGD, the
“watching and waiting” attitude [69], is another inves-
tigational option that may allow prompt treatment of
cancer if it develops. However, few data document the
safety of this observational approach. Since the diag-
nostic accuracy and treatment-related morbidity and
mortality rates are better in institutions where a high
number of patients with Barrett’s HGD or cancer are
observed, consideration should be given to referral of
these patients to specialty centers.
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