71  Cancer of the Esophagus
Geoffrey Y. Ku and David H. Ilson
S UMMARY OF K EY
Classification
• Adenocarcinomas and squamous
cell carcinomas (SCCs) comprise
98% of esophageal tumors.
• The Siewert classification is now
commonly used to categorize
gastroesophageal junction (GEJ)
tumors, although many studies,
especially those for advanced
disease, have enrolled patients with
esophageal, GEJ, and gastric
cancers.
Incidence
• In the United States, approximately
17,290 patients will be diagnosed
with esophageal cancer in 2018, with
15,850 deaths.
• Historically and internationally, SCC
is the most common histologic type;
however, a dramatic increase in the
incidence of adenocarcinoma has
been documented in the United
States, the United Kingdom, and
Western Europe.
Pathogenesis
• Esophageal cancers arise as a result
of chronic irritation from a wide
variety of sources, including gastric
contents in chronic reflux and known
carcinogens.
• A strong association between Barrett
esophagus and adenocarcinoma is
seen, but a benefit for screening
endoscopy for those at risk for or
with known Barrett esophagus is
unknown because the overall risk of
cancer-related mortality is low.
Barrett esophagus arises confirmed a survival benefit with
from gastroesophageal reflux
disease (GERD) and other risk
factors, including obesity and
smoking.
• SCC is associated with smoking and
with alcohol use, and the declining
incidence has paralleled the decline
in smoking.
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P OI N T S
Diagnosis and Staging
• Symptoms and demographics will
strongly suggest the diagnosis.
• Endoscopy is the best screening
examination, with diagnosis made
with endoscopy with biopsy and
cytologic assessment of tumor.
• Endoscopic ultrasonography (EUS)
should be used to assess T and N
stage to guide optimal definitive
therapy.
• Computed tomography (CT) of the
chest and abdomen is useful in
screening for metastatic disease.
• Positron emission tomography (PET)
scan is useful to detect additional
cases of metastatic disease before
costly and toxic definitive therapy. It
may be superior to endoscopic EUS
in detecting intraabdominal lymph
nodes, but not periesophageal nodes
adjacent to the primary tumor.
• Additional studies include
laparoscopy, thoracoscopy, bone
scan, and CT of the brain when
indicated by clinical circumstances.
Treatment
• Treatment of premalignant dysplasia
is guided by grade of histology.
Low-grade dysplasia should be
treated with endoscopic ablative
techniques or observation.
High-grade dysplasia is treated
with endoscopic ablation or
esophagectomy, although close
follow-up may be appropriate for
selected patients.
• Selection of appropriate treatment
for carcinoma depends on tumor
stage and patient performance
status.
• Chemotherapy is now routinely used
in perioperative strategies and is the
mainstay of treatment for recurrent
or metastatic disease, in which
response rates and duration of
reserved.
response are modest for most
patients. The addition of targeted
therapies incrementally improves
outcomes. The evaluation of immune
checkpoint inhibitors reveals a
modest but notable benefit in the
metastatic setting and is of high
priority.
• Surgery is an accepted
single-modality therapy for patients
with early localized disease
(T1–2N0M0) or for patients who may
not tolerate combined modality
therapy. The selection of surgical
approach depends on location and
experience, but no approach has
been demonstrated to lead to
superior cure rates.
• Combined chemoradiation leads to
prolonged median survival and
long-term survival compared with
radiation alone when used as a
definitive nonoperative approach.
This represents a potentially curative
alternative to surgery for SCCs and
is appropriate for unresectable
lesions of either histologic type.
• There are now established data
showing that preoperative
chemoradiation followed by surgery
improves survival versus surgery
alone for both locally advanced
(clinically staged T2–T4 or
node-positive) adenocarcinoma and
SCC. There is less certainty about
the value of preoperative
chemotherapy alone.
• Randomized trials have not
surgery added to potentially curative
chemoradiation in SCC, but there is
a local control benefit. Therefore
definitive chemoradiation for patients
with SCC is an option, with surgery
reserved for locally persistent or
recurrent disease. There are limited
data regarding this approach for
 Cancer of the Esophagus  •  CHAPTER 71 1175

patients with adenocarcinomas, but
it can be considered in patients who
are borderline candidates for
esophagectomy.
• Postoperative adjuvant
chemotherapy or chemoradiation is
less well studied in locally advanced
esophageal cancer, but trials in
gastric cancer including GEJ
adenocarcinoma have demonstrated
a benefit.
• Endoscopic palliative therapy
includes laser or electrical
fulguration, mucosal resection,
photodynamic therapy (PDT), or
stenting. Excepting very superficial
lesions, these therapies are not
alternatives to surgery because they
do not address deeper disease or
lymphatic spread.
• Radiation and/or chemotherapy preoperative chemotherapy alone.
may be used to palliate local
symptoms.
Algorithm
• T1is or T1a Tumors
○ High-grade dysplasia or T1a
tumors are managed with
endoscopic ablation or
esophagectomy.
• T1b–2N0 Tumors
○ Surgery is an accepted
single-modality therapy for
patients with early localized
disease (T1–2N0M0) or for patients
who may not tolerate combined
modality therapy. The selection of
surgical approach depends on
location and experience, but no
approach has been demonstrated
to lead to superior cure rates.
• T2–4Nany or TanyN+ Tumors
○ Combined chemoradiation leads to
prolonged median survival and
long-term survival compared with
radiation alone when used as a
definitive nonoperative approach.
This represents a potentially
curative alternative to surgery for
SCCs and is appropriate for
unresectable lesions of either
histologic type.
○ There are also established data
that preoperative chemoradiation
followed by surgery improves
survival compared with surgery
alone for both locally advanced
adenocarcinoma and SCC. There
is less certainty about the value of
○ Randomized trials have not
confirmed a survival benefit with
surgery added to potentially
curative chemoradiation in SCC,
but there is a local control checkpoint inhibitors against the
benefit. Therefore definitive
chemoradiation for patients with
SCC is an option, with surgery
reserved for locally persistent or
recurrent disease. There are
limited data regarding this
approach for patients with
adenocarcinomas, but it can be
considered in patients who are
borderline candidates for
esophagectomy.
○ Postoperative adjuvant
chemotherapy or chemoradiation
is less well studied in locally
advanced esophageal cancer, but
trials in gastric cancer including
GEJ adenocarcinoma have
demonstrated a benefit.
Metastatic or Recurrent Disease
• Chemotherapy is the mainstay of
treatment for recurrent or metastatic
disease, where response rates and
duration of response are modest for
most patients. The standard doublet
consists of a fluoropyrimidine and a
platinum drug. Adding docetaxel to
this doublet slightly improves
outcomes, but at the expense of
significant additional toxicity.
• The addition of trastuzumab to
first-line chemotherapy for
HER2-positive disease incrementally
improves outcomes. Similarly,
ramucirumab with or without
paclitaxel in the second-line setting
is a validated strategy.
• The evaluation of immune
PD-1/PD-L1 axis reveals a modest
but notable benefit in the metastatic
setting and is of high priority.
• Endoscopic palliative therapy
includes laser or electrical
fulguration, mucosal resection, PDT,
or stenting. Excepting very
superficial lesions, these therapies
are not alternatives to surgery
because they do not address deeper
disease or lymphatic spread.
• Radiation and/or chemotherapy may
be used to palliate local symptoms.

Esophageal cancer is a devastating disease associated with poor
survival outcome and adverse effects on swallowing and quality of
life (QoL). Although it is an aggressive malignancy that usually
manifests in a locally advanced stage, significant progress has been
made in the treatment of this disease, including expanded treatment
options, decreased surgical morbidity and mortality, confirmation
of the benefit of combined modality therapy, and improvements in
identifying patients at risk. These advances are resulting in incremen-
tal but still quite meaningful improvements in outcome, but there
remains considerable controversy over the optimal management in
individual scenarios. The emphasis of this chapter is on selecting the
appropriate options in the curative and palliative management of
esophageal cancer.
The revised American Joint Committee on Cancer (AJCC) seventh
edition staging system refines the categorization of patients. In par-
ticular, there is now consideration of location within the esophagus,
number of positive lymph nodes, and histologic findings and a changed
categorization of extent of primary disease. Adenocarcinoma and
squamous cell carcinoma (SCC) histologic types are also considered
separately. Survival data based on this staging system are shown
in Fig. 71.1.
HISTOLOGIC AND MOLECULAR
CLASSIFICATION AND LOCATION
Esophageal cancer is classified based on histologic appearance and cell
of origin, as follows: (1) epithelial tumors, (2) metastatic tumors, (3)
lymphomas, and (4) sarcomas. Cancers of epithelial cell origin, pre-
dominantly SCC and adenocarcinoma, are the most common. Although
SCC and adenocarcinoma were previously treated as similar entities
and grouped together, there is increasing recognition that they should
be studied as separate entities whose optimal therapy may diverge in
the era of multimodality treatments.
There is now clear-cut molecular evidence that SCCs and adeno-
carcinomas are entirely distinct entities. Data from The Cancer Genome
Atlas showed different molecular aberrations between them.1 Specifically,
SCCs showed frequent genomic amplifications of CCND1 and SOX2
and/or TP63, whereas ERBB2, VEGFA. and GATA4 and GATA6 were
more commonly amplified in adenocarcinomas. Equally notable is
the fact that esophageal and gastroesophageal junction (GEJ) adeno-
carcinomas strongly resembled the chromosomally unstable variant
of gastric cancer (which is most commonly found in the cardia2),
suggesting that these tumors should be treated as a single entity.

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reserved.
1176 Part III: Specific Malignancies
Adenocarcinoma
100
Risk-adjusted survival (%)
80
60
40
20
0 of adenocarcinomas, which are now more common because of an
0 2 4 6
A Years
Squamous Cell Carcinoma
100
Risk-adjusted survival (%)
80
60
40
20
0
0 2 4 6
B Years
Figure 71.1  •  Survival according to American Joint Committee on Cancer/
International Union Against Cancer seventh edition staging system for an
international cohort of 4627 patients treated surgically for esophageal neoplasms,
including adenocarcinoma patients (A) and squamous cell carcinoma patients
(B). (From Rice TW, Rusch VW, Ishwaran H, et al. Worldwide Esophageal
Cancer Collaboration. Cancer of the esophagus and esophagogastric junction:
data-driven staging for the seventh edition of the American Joint Committee
on Cancer/International Union Against Cancer cancer staging manuals. Cancer.
2010;116[16]:3763–3773.)
SCC usually occurs in the middle third of the esophagus, whereas
adenocarcinomas are most common in the lower third of the esophagus.
The Siewert classification is now routinely used to further subtype
GEJ tumors based on their location.3 Siewert type I tumors arise from
the distal esophagus and infiltrate the GEJ from above, whereas type
III tumors are gastric cardia tumors that infiltrate the GEJ from below;
type II tumors are true tumors of the GEJ.
INCIDENCE
Because SCCs and adenocarcinomas account for 98% of all esophageal
tumors, this chapter focuses on these two histologic types. Epidemiologic
data show that the incidence of esophageal cancer varies considerably
from one country to another and often within a single country. This
geographic diversity underscores the multifactorial etiologies of
esophageal cancer worldwide, where more than 90% of tumors are
SCCs. The epidemiologic factors responsible for the geographic vari-
ability in incidence of esophageal cancer, including potential dietary
and environmental carcinogens, remain under active investigation.
Although cases of SCC have steadily declined in the United States
because of a decrease in tobacco and alcohol abuse,4 the incidence of
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adenocarcinoma of the distal esophagus, GEJ, and gastric cardia has
increased 4% to 10% per year among US men since 1976, so it now
comprises 75% of all esophageal tumors.5–7 The absolute incidence
in the United States has increased from 3.8 per million in 1973 to
1975 to 23.3 per million in 2001 based on the National Cancer
0 Institute’s Surveillance, Epidemiology, and End Results (SEER) database.
IA This rate of increase exceeds that of all other cancers, including lung,
breast, and prostate cancers and melanoma. Adenocarcinoma is much
IB
less common in African Americans but has increased from 0.4 per
IIA
100,000 to 0.9 per 100,000, and 0 to 0.2 per 100,000 in females.
IIB Even as it appears that the rate of increase may be slowing in the
IIIA United States,8 the incidence of esophageal adenocarcinoma globally
IIIB
IIIC continues to increase.9
Changing epidemiologic factors account for the increasing incidence
8 10 increased incidence of gastroesophageal reflux disease (GERD)10
and obesity.11 Helicobacter pylori, implicated in peptic ulcer disease
and associated with an increased risk of gastric cancer, has not been
implicated in the pathogenesis of esophageal adenocarcinoma. In
fact, because infection with H. pylori may lead to a reduction in
gastric acidity in association with atrophic gastritis, there has been
speculation that a decline in the prevalence of H. pylori infection may
predispose to an increase in GERD and therefore in the incidence
of GEJ adenocarcinomas.12,13 Similarly, infection with human papil-
lomavirus, while implicated in oropharyngeal SCC, has not been
IA
0 observed in esophageal SCC.1,14
IB
IIA
IIB
PATHOGENESIS
IIIA Data support the hypothesis that esophageal cancer arises as a result
IIIB
IIIC of chronic irritation and inflammation of the esophagus, leading to
a sequence of genetic alterations in the damaged epithelium and
histologic changes of dysplasia to carcinoma. Factors that are associated
8 10 with an increased risk of SCC include caustic lye ingestion and radiation
therapy, and the interval between injury and the development of
cancer may be considerable. In addition, a history of underlying
esophageal disease such as achalasia, Plummer-Vinson syndrome, and
tylosis is also linked to SCC. In adenocarcinoma, gastroesophageal
reflux of acid and bile are major risk factors that cause chronic inflam-
mation, which then leads to carcinogenesis.
There are important differences between the risk factors and
histologic progression that support the concept that SCC and adeno-
carcinoma are separate entities with the potential to respond differently
to newer treatment approaches.
Clinical Risk Factors
Two major risk factors for esophageal SCC are alcohol use and
tobacco smoking, according to epidemiologic studies from various
countries worldwide. This relationship is dose dependent, and there
is a multiplicative interaction with alcohol intake and tobacco use.
In a prospective cohort study from the Netherlands involving more
than 120,000 people with 16 years of follow-up, the strongest risk
factor for SCC was alcohol consumption with a 4.6-fold increased
risk, whereas combined exposure with smoking increased the risk more
than 8-fold. The risk of SCC decreased with smoking cessation and
alcohol abstinence, but only after one to two decades.15
In adenocarcinoma, smoking but not alcohol is associated with
increased risk. A prospective study of tobacco, alcohol, and the risk
of esophageal cancer in the United States found an increased risk of
SCC among current smokers compared with nonsmokers (hazard ratio
[HR] 9.27; 95% confidence interval [CI], 4.04–21.29) and also an
increased risk for adenocarcinoma (HR, 3.70; 95% CI, 2.20–6.22).
For people who consumed more than three alcoholic drinks a day
compared with one drink, there was increased risk of esophageal SCC
but not adenocarcinoma.16
reserved.

Nutritional and dietary factors have been found to contribute to
the risk of both SCC and adenocarcinoma. Pickled vegetables, processed
meat, and other foods containing nitrates have been linked to an
increased risk of SCC. Drinking very hot liquids or eating hot foods
such as stewed meat frequently is postulated to cause thermal injury
to the esophagus and has been found to be a risk factor for SCC.
Low consumption of fruits and vegetables is a risk factor for both
SCC and adenocarcinoma.17
Obesity, defined as a body mass index of 30 or higher, is a strong
risk factor for esophageal adenocarcinoma, as demonstrated in a meta-
analysis of epidemiologic studies (HR, 2.78; 95% CI, 1.85–4.16).11
This has clear implications regarding the increasing obesity rates in
the United States and could partly explain the rising incidence of
esophageal adenocarcinoma. The exact mechanism for this association
of obesity is not understood but might reflect an increased propensity
for gastroesophageal reflux. Obesity does not appear to be a risk
factor for SCC.
Adenocarcinoma: Role of Gastroesophageal Reflux
Disease and Barrett Esophagus
There is a clear relationship between GERD and the development of
Barrett esophagus. Esophageal adenocarcinoma frequently arises in
Barrett esophagus, a condition in which the normal stratified squamous
mucosa of the esophagus is replaced by a metaplastic columnar-lined
epithelium that extends upward from the GEJ, generally as a result
of injury from chronic reflux. Barrett esophagus may progress to
dysplasia and then malignancy as the dysplastic epithelial cells accu-
mulate genetic alterations.
GERD is a well-established risk factor for esophageal adenocarci-
noma. A population-based case-control study in Sweden demonstrated
an odds ratio (OR) of 7.7 (95% CI, 5.3–11.4) for the development
of esophageal cancer in patients with chronic GERD. With long-
standing, severe symptoms, the OR for esophageal adenocarcinoma
was 43.5 (95% CI, 18.3–103.5).18 There was no association seen
between reflux and SCC.
The prevalence of Barrett esophagus is estimated to be 1% to 2%
of the general population.19 The length of time for progression from
Barrett esophagus to dysplasia to adenocarcinoma is unknown, although
several reports of endoscopic surveillance programs have suggested that
progression of Barrett esophagus to adenocarcinoma is uncommon.
A nationwide population-based cohort study in Denmark followed
more than 11,000 patients with Barrett esophagus for a median of
5.2 years and found that the annual risk of adenocarcinoma was
0.12% (95% CI, 0.09–0.15).20 Meanwhile, a meta-analysis of 57
studies involving more than 11,000 patients with nondysplastic Barrett
esophagus found a pooled annual incidence rate of adenocarcinoma
of 0.33%.21 Patients with low-grade dysplasia had an incidence
rate of adenocarcinoma of 0.5% per year, whereas those with high-
grade dysplasia has an incidence rate of adenocarcinoma of 3% to
5% per year.
DIAGNOSTIC AND STAGING EVALUATION
The most common presentation of esophageal carcinoma is solid food
dysphagia and weight loss of several months’ duration. Other presenta-
tions that occur with esophageal adenocarcinoma in particular include
chest pain in the absence of myocardial ischemia and anemia from
chronic gastrointestinal bleeding from the mucosal lesion. These clinical
signs and symptoms should prompt endoscopic evaluation and
diagnostic imaging. The diagnosis is usually evident by the characteristic
narrowing of the esophagus on barium studies, but endoscopy and
biopsy are essential for histopathologic diagnosis. Endoscopic biopsies
and brushings of the lesion will yield the diagnosis in more than 90%
of patients. Multiple biopsies may be necessary for diagnosis of an
invasive malignancy that is submucosal or necrotic.22 A diagnosis of
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Cancer of the Esophagus  •  CHAPTER 71 1177
in situ carcinoma or dysplasia in the face of a large lesion seen on
endoscopic or radiographic studies should not be accepted, and biopsy
should be repeated to confirm the extent of invasion and guide optimal
management.
Once the pathologic diagnosis has been established, evaluation to
determine the extent of disease should include a computed tomog-
raphy (CT) scan of the chest and complete abdomen. The accuracy
of abdominal CT for identification of metastases to the liver and
celiac axis depends on the bulk of the disease. Small liver metastases,
peritoneal studding, and abdominal nodes will often be undetectable.
For the patient with an adenocarcinoma of the distal esophagus, GEJ,
or cardia, a complete abdominopelvic CT scan is recommended because
these tumors are more likely to metastasize early to periaortic lymph
nodes. A complaint of back pain may signal the presence of enlarged
retroperitoneal nodes.
Positron emission tomography (PET) scanning enables the
identification of metastatic disease in patients who might otherwise
inappropriately receive definitive local therapy and therefore is
now considered a standard staging test. Studies demonstrated that
PET will detect unsuspected metastatic disease in approximately
15% of patients after all other staging tests have been completed,
although it is not as useful as other techniques in identifying involved
regional nodes (based on uptake from the primary tumor obscuring
peritumoral lymph nodes). A prospective study of 79 patients found
that the specificity and sensitivity of PET for identifying stage IV
disease were 90% and 74% versus 47% and 78%, respectively, for
the combination of CT and endoscopic ultrasonography (EUS),
with an overall accuracy of identification of stage IV disease of 82%
versus 64% (P = .004).23 Furthermore, when PET was added to
CT and EUS, 22% of patients had a change in stage that altered
their planned treatment (15% upstaged to incurable stage IV disease
and 7% downstaged to a stage at which curative therapy would be
appropriate). A consensus panel has confirmed the recommendation for
PET imaging in possibly localized esophageal cancer to better detect
metastatic disease.24
Accurate determination of the extent of disease has a major impact
on therapeutic decision making for single-modality versus multimodal-
ity treatment or curative versus palliative intent, and therefore it is
essential that comprehensive staging be performed. A substantial body
of literature now also exists regarding EUS and laparoscopy. The
largest and earliest experience was with EUS.25,26 A pooled analysis
of the literature indicates a sensitivity and specificity, respectively,
for stage T1 of 81.6% and 99.4%, T2 of 81.4% and 96.3%, T3 of
91.4% and 94.4%, and T4 of 92.4% and 97.4%.26 EUS has not
been considered accurate in distinguishing in situ cancer from invasive
(T1) superficial lesions. For nodal staging based on morphologic
features (size, shape, border, and echo characteristics), the observed
sensitivity and specificity were 84.7% and 84.6%, respectively, which
with the addition of fine-needle aspiration improved to 96.7% and
95.5%. EUS is not a reliable technique for diagnosing liver and
peritoneal metastases because of the limited depth of penetration of
ultrasound waves.27
The indications for minimally invasive surgical staging techniques
are not fully defined. Laparoscopic evaluation of abdominal lymph
nodes can be achieved with minimal risks and can allow for the
identification of node-positive disease not detected with cross-sectional
imaging and EUS,28–30 although whether the presence of locoregional
lymphadenopathy will affect the overall management strategy is unclear.
Unsuspected findings such as liver metastases or peritoneal studding that
would clearly alter treatment occur in approximately 15% of patients.
However, there is not a consensus regarding the use of laparoscopy
as part of baseline staging. Whereas the Society of Thoracic Surgeons
recommends staging laparoscopy for locally advanced (T3 and T4)
GEJ adenocarcinoma that infiltrates the gastric cardia, National
Comprehensive Cancer Network guidelines consider laparoscopy an
optional part of the staging process in patients with GEJ tumors.31
1178 Part III: Specific Malignancies
CHOICE OF THERAPEUTIC OPTIONS:
BARRETT ESOPHAGUS AND DYSPLASIA
Because of the premalignant nature of Barrett esophagus, it has
been recommended that patients with this condition undergo
regular endoscopic surveillance, primarily to assess for dysplasia.
As mentioned in a previous section, it is estimated that the risk of
progression from Barrett esophagus to adenocarcinoma is 0.12%
to 0.33% annually.20,21 This relatively small risk calls into question
the value of routine endoscopic surveillance for Barrett metaplasia,
especially in the absence of dysplasia or specialized intestinal metaplasia,
given the significant cost and small risk of injury from the follow-up
endoscopies.
The focus in the future may be on better defining the risk of
progression for individual patients through use of biomarkers and
genetic and epigenetic abnormalities. For example, a retrospective
assessment of a large multicenter database of patients attempted to
develop a model of risk assessment based on age and methylation of
eight genes previously observed to be associated with progression of
Barrett esophagus: p16, HPP1, RUNX3, CDH13, TAC1, NELL1,
AKAP12, and SST.32 A model was developed with a sensitivity of 90%
and specificity of 50%, which could create a low-risk group with a
1.7% rate of progression to high-grade dysplasia or adenocarcinoma
over 5 years, a high-risk group with a 27% risk, and intermediate-risk
groups of patients who would also be good candidates for close
follow-up. Any study like this requires prospective validation.
The most recent American Gastroenterological Association medical
position statement on the topic recommends follow-up endoscopy
every 3 to 5 years for patients with Barrett esophagus without dysplasia.
If low-grade dysplasia is identified, both endoscopic ablative therapy
and endoscopic surveillance every 12 months are options. Endoscopic
ablation should be offered for patients with high-grade dysplasia.
Validated options include endomucosal resection (EMR), radiofrequency
ablation, or photodynamic therapy (PDT). The relative benefits and
disadvantages of these approaches in this context are beyond the scope
of this review.
Esophagectomy is the only treatment option that allows a patient
to safely stop periodic endoscopic biopsy surveillance. However, other
alternatives may be optimal for many patients. A meta-analysis including
1874 patients who underwent esophagectomy for high-grade dysplasia
suggested a risk of unsuspected lymph node involvement of only 1%
to 2%, further suggesting that more localized therapies are indeed
appropriate.33 However, the patients who choose endoscopic ablative
therapy must be willing to undergo endoscopic biopsy surveillance
indefinitely.
CHEMOTHERAPY
Single-Agent Chemotherapy
Up to one-half of patients with esophageal cancer have metastatic
disease at presentation, and, despite multimodality therapy in the
localized setting, the majority of patients will eventually develop
recurrence. Therefore most patients with esophageal cancer will receive
chemotherapy at some point during their disease course.
Until the early 1990s, chemotherapy drugs commonly used to treat
esophagogastric cancers (EGCs) included 5-fluorouracil (5-FU),34,35
cisplatin,36–38 and mitomycin,39–41 with single-agent response rates
(RRs) ranging from 10% to 25%. Newer drugs with single-agent
activity that have since been evaluated include the oral 5-FU pro-
drugs (capecitabine42,43 and S-144–46), the taxanes (paclitaxel47–49 and
docetaxel50–52), and irinotecan,53 with RRs of 15% to 45%.
A Cochrane meta-analysis by Wagner and colleagues that combined
three trials of chemotherapy versus best supportive care (BSC) revealed
a clear survival benefit for treatment (HR, 0.37; 95% CI, 0.24–0.55).54
This translates into an improvement in median overall survival (OS)
from 4.3 to 11 months with chemotherapy.
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Given the modest activity of single agents in esophageal cancer,
combination chemotherapy of two and even three drugs has been
extensively studied. A Cochrane meta-analysis of 13 trials including
1914 patients (which mostly evaluated older chemotherapy regimens)
did show modest improvements in RRs (35% versus 18%; OR, 2.91;
95% CI, 2.15–3.93), median time to progression (TTP; 5.6 versus
3.6 months; HR, 0.67; 95% CI, 0.49–0.93), and median OS (8.3
versus 6.8 months; HR, 0.82; 95% CI, 0.74–0.90) with combination
over single-agent chemotherapy.54
Despite incremental advances, the duration of response to both
modern single agents and combination regimens is only 4 to 6 months,
in general, with a median OS of 10 to 12 months.
Combination Chemotherapy
Fluoropyrimidine/Platinum Doublet
The combination of infusional 5-FU–cisplatin has been studied
extensively since the 1980s, and the doublet of a fluoropyrimidine
with a platinum compound remains a reference regimen in many
contemporary trials. Of note, contemporary studies have generally
enrolled patients with adenocarcinomatous histology, irrespec-
tive of whether the tumor is found in the lower esophagus, GEJ,
or stomach.
More contemporary trials have evaluated substitutions of both of
these drugs with either an oral 5-FU prodrug (capecitabine55 or S-156)
and/or the newer platinum compound oxaliplatin.55,57 Regimens such
as S-1–cisplatin,56 capecitabine-cisplatin,58 infusional 5-FU–oxaliplatin,57
and capecitabine-oxaliplatin (along with the anthracycline epirubicin)55
appear to have at least comparable efficacy compared with 5-FU–
cisplatin and are also mostly associated with decreased toxicity and
increased ease of administration. In fact, an individual patient data
meta-analysis of two randomized trials that compared capecitabine-based
with infusional 5-FU–based regimens—the capecitabine-cisplatin versus
5-FU–cisplatin trial58 and the REAL-2 study,55 mentioned earlier and
discussed in more detail later—suggested that capecitabine-based
treatments are associated with superior RR and OS than infusional
5-FU regimens.59
The other platinum analogue—carboplatin—has been associated
with low single-agent activity in esophagogastric (EG) adenocarcino-
mas.60 However, phase II trials of carboplatin combined with taxanes
have indicated promising activity,61,62 and the combination of
carboplatin-paclitaxel with concurrent radiation has emerged as an
international standard in locally advanced disease.63
One of the only studies that has shown a benefit for a fluoropy-
rimidine doublet compared with fluoropyrimidine alone, although
the former is routinely used, is the phase III SPIRITS (S-1 Plus
Cisplatin Versus S-1 in RCT in the Treatment for Stomach Cancer)
study. S-1 is a mixture of tegafur (an oral 5-FU prodrug), gimeracil
(a dihydropyrimidine dehydrogenate inhibitor that may potentiate
the effect of 5-FU), and oteracil (which may reduce the gastrointestinal
toxicity of 5-FU). In this Japanese trial in which 298 patients with
advanced gastric cancer were randomized to receive S-1 with or without
cisplatin, the doublet was associated with a higher RR (54% versus
31%; P = .002) and superior OS (13.0 versus 11.0 months; P = .04).64
Although this study helped to establish S-1–cisplatin as a standard
therapy in Japan, a trial performed in US and European patients
comparing S-1–cisplatin versus 5-FU–cisplatin failed to demonstrate
superiority of S-1 over infusional 5-FU.56 Accordingly, S-1 is not
widely used outside of East Asia.
Moving Beyond 5-Fluorouracil–Cisplatin
Despite the widespread use in the 1990s of high-dose cisplatin (100 mg/
m2) with a 4- or 5-day infusion of 5-FU (at 1000 mg/m2/day) as a
standard therapy, two seminal trials in the late 1990s directed the
development of chemotherapy regimens in EGC away from this
schedule of therapy. A European trial compared 5-FU–cisplatin
with the FAMTX (bolus 5-FU–doxorubicin-methotrexate) and ELF

(etoposide–leucovorin–5-FU) regimens.65 All regimens performed
poorly, with high rates of toxicity, RRs of 20% or lower, and median
OS of only approximately 7 months. These disappointing results
led investigators in continental Europe to pursue better-tolerated
colorectal cancer–like schedules of biweekly infusional 5-FU with a
platinum compound57 and to investigate taxane- and irinotecan-based
chemotherapy.
The second key trial was performed in the United Kingdom and
compared FAMTX and the ECF regimen, which combines epirubicin
with a lower dose of cisplatin (60 mg/m2) and a 21-day infusion of
low dose 5-FU (200 mg/m2/day).66 The ECF arm achieved superior
RRs (45% versus 21%; P = .0002), median OS (8.9 versus 5.7 months;
P = .0009), and QoL at 24 weeks compared with FAMTX. This trial
established ECF as the reference regimen in the United Kingdom.
Anthracyclines
After the validation of the ECF regimen, a subsequent study compared
it with the MCF regimen, in which mitomycin was substituted for
epirubicin (and the infusional 5-FU was administered at a higher dose
of 300 mg/m2/day).67 Although designed to test the superiority of
MCF, the study reported no significant differences in RR or median
survival but found that QoL was better maintained with ECF. Accord-
ingly, ECF remained the preferred regimen, even as some investigators
questioned whether either of these triplet regimens is actually superior
to the 5-FU–cisplatin doublet.
Subsequently, the REAL-2 (Randomized ECF for Advanced and
Locally Advanced Esophagogastric Cancer 2) study compared the
ECF regimen and the ECX regimen (which involves the substitution
of 5-FU with capecitabine), the EOF regimen (substitution of
oxaliplatin for cisplatin) and the EOX regimen (a double substitution
of both capecitabine and oxaliplatin) in patients with advanced EG
adenocarcinomas or SCCs.55 All the combinations had similar RRs
(40%–48%) and toxicities, and the EOX regimen was associated with
improved median OS compared with the ECF regimen (11.2 versus
9.9 months; P = .02), leading the authors to propose that the EOX
regimen could replace ECF in future trials.
Despite the standard use of ECF or one of its derivates in the
U.K., the clear superiority of this triplet over a fluoropyrimidine-
platinum doublet has never been demonstrated in a randomized fashion.
One piece of evidence frequently cited to support the incorporation
of an anthracycline comes from the previously cited Cochrane meta-
analysis, which analyzed three individually negative trials (including
the negative evaluation of ECF versus MCF described earlier).54
Combining all three trials revealed a survival benefit for the addition
of epirubicin (HR, 0.77; 95% CI, 0.62–0.91), which translates into
an approximate 2-month survival advantage. However, this conclusion
comes largely from the comparison of ECF versus MCF because that
trial contributed two-thirds of the patients to the meta-analysis. Given
the greater toxicity noted on the MCF arm and the fact that the
comparison is not purely between a 5-FU–cisplatin-only arm at identical
doses and ECF, a determination of the relative merits of adding
epirubicin remains difficult to make.
Continuing questions regarding the benefit of an anthracycline
were raised by the results of a randomized phase II trial performed
by the US Cancer and Leukemia Group B (CALGB) and Eastern
Cooperative Oncology Group (ECOG). The CALGB 80403/ECOG
1206 trial randomized 245 patients (222 with adenocarcinomas) to one
of three chemotherapy regimens—ECF, FOLFOX (biweekly bolus and
infusional 5-FU–leucovorin–oxaliplatin), or cisplatin-irinotecan—along
with cetuximab, a monoclonal antibody against the epidermal growth
factor receptor (EGFR), for patients with advanced esophagogastric
adenocarcinomas or SCCs.68 In the patients with adenocarcinomas,
both the ECF and FOLFOX regimens plus cetuximab produced RRs
of greater than 40% (61% and 54% respectively), which met the
primary objective of the trial. However, survival outcomes were very
similar between the cetuximab-ECF and cetuximab-FOLFOX arms.
Median progression-free survival (PFS) was 7.1 versus 6.8 months,
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Cancer of the Esophagus  •  CHAPTER 71 1179
and median OS was 11.6 versus 11.8 months, respectively. Overall,
cetuximab-FOLFOX appeared to be the least toxic of the three regimens.
Of course, the randomized phase II nature of this study was not
designed to detect a survival difference between these regimens, and
the contribution of cetuximab, now thought to be either neutral or
even detrimental, cannot be determined. Nevertheless, the results of
this trial do support the contention that any benefit of an anthra-
cycline, if there is any benefit at all, is likely to be small. Another
notable finding of this study is that cetuximab-cisplatin-irinotecan
had the lowest RRs and survival outcomes and the highest toxicity
rates, which has contributed to a significant decline in the use of
this chemotherapy regimen in the first-line setting. Correspondingly,
the favorable toxicity profile and activity of the FOLFOX arm have
reinforced its established role as the standard first-line regimen in the
United States.
Taxanes
In comparison to the unclear benefit of adding an anthracycline to a
fluoropyrimidine-platinum doublet, there are randomized data to
support the addition of a taxane. The phase III V325 randomized
trial in GEJ and gastric adenocarcinomas compared the DCF regimen
(docetaxel–cisplatin–infusional 5-FU) and infusional 5-FU–cisplatin.69
The addition of docetaxel improved RRs (37% versus 25%; P = .01)
and TTP (5.6 versus 3.7 months; P < .001), but OS was only slightly
improved (median OS 9.2 versus 8.6 months; 2-year OS, 18% versus
9%; P = .02). In addition, the three-drug regimen was associated with
significantly more toxicity, including a grade 3/4 neutropenia rate of
82% (versus 57%) and febrile neutropenia in 29% of patients (versus
12%). Fifty percent of patients came off treatment because of either
severe adverse events or consent withdrawal. Despite these significant
toxicities, the authors reported a slower decrement in QoL measure-
ments in the DCF arm.70 On the basis of this study, docetaxel was
approved by the US Food and Drug Administration (FDA) in 2006
for use with 5-FU–cisplatin in this context.
Because the toxicities seen with the parent DCF regimen are
significant and may outweigh its small survival advantage over
5-FU–cisplatin, it has not been widely adopted. It is also unclear if
similar survival benefits would be accrued by the sequential use of
first-line 5-FU–cisplatin followed by subsequent docetaxel (or paclitaxel)
at progression.
Several investigators have attempted to modify the regimen to
increase tolerability. For example, our group performed a randomized
phase II trial of parent DCF (with prophylactic growth factor support)
versus a modified DCF (mDCF) regimen (consisting of reduced doses
of docetaxel and cisplatin administered with bolus and 2-day infusional
5-FU and leucovorin every 14 days).71 mDCF was associated with
decreased toxicity compared with parent DCF (neutropenic fever rate,
9% versus 16%; grade 3/4 nausea/vomiting rate, 2% versus 23%),
and median OS appeared superior in the mDCF arm (18.8 versus
12.6 months; P = .007). Nevertheless, 22% of the patients receiving
mDCF (who had a median age of 59 years) required hospitalization
in the first 3 months, mostly for treatment-related toxicities (febrile
neutropenia and gastrointestinal toxicities), reinforcing the notion
that this remains a relatively difficult regimen to administer and is an
option only for healthy, motivated patients with frequent access to
medical evaluation.
Another extensively evaluated and commonly used modification
is the German FLOT regimen, which consists of the substitution of
oxaliplatin for cisplatin and is built around a 1-day infusion of 5-FU
every 14 days. Encouraging activity was noted in a phase II study of
59 patients, which reported an RR of 58% and a median OS of 11.1
months.72 The FLOT regimen was subsequently compared with the
5-FU–oxaliplatin doublet (FLO) in the randomized phase II FLOT65+
study, which enrolled patients who were 65 years of age or older and
had either locally advanced or metastatic disease.73 No benefit was
seen for the triplet combination in patients aged 65 years or older
with metastatic disease or in any patient aged 70 years or older. This
1180 Part III: Specific Malignancies
study again emphasizes the need for strict patient selection for such
three-drug regimens.
Irinotecan
Irinotecan is another active agent in EGC that has been combined
with mitomycin, 5-FU–leucovorin, and cisplatin with or without
docetaxel in phase II evaluations, with RRs ranging from 30% to
65%.74–81 Toxicities in some of these trials (e.g., with cisplatin-docetaxel-
irinotecan) have been substantial.
A randomized phase II trial compared the FUFIRI regimen (weekly
infusional 5-FU–leucovorin–irinotecan) with cisplatin-irinotecan in
patients with advanced GEJ and gastric adenocarcinomas.76 FUFIRI
was associated with superior outcomes and less neutropenia than
cisplatin-irinotecan. This led to a subsequent phase III trial of FUFIRI
versus 5-FU–cisplatin. Both regimens had comparable efficacy, but
there was less neutropenic fever and grade 3/4 stomatitis and nausea
in the FUFIRI arm.82 Only the incidence of grade 3/4 diarrhea was
increased in the FUFIRI arm, although more patients withdrew from
the 5-FU–cisplatin arm than the FUFIRI arm (22% versus 10%; P
= .004) for drug-related adverse events. Although there was no clear
benefit for FUFIRI over 5-FU–cisplatin, the favorable toxicity of this
combination supports its use as a front-line option, especially in patients
who are not candidates for a platinum compound.
The use of first-line 5-FU–irinotecan is now further supported by
the results of a phase III French Fédération Francophone de Can-
cérologie Digestive (FFCD) group study, in which 416 patients were
randomized to the FOLFIRI regimen (biweekly bolus and infusional
5-FU–leucovorin–irinotecan) versus ECX in patients with advanced
gastric cancer.83 At progression, patients received therapy with the
alternate regimen. This study revealed a superior time to treatment
failure for FOLFIRI versus ECX (5.1 versus 4.2 months; P = .008)
and comparable PFS (5.3 versus 5.8 months; P = .96) and OS (9.5
versus 9.7 months; P = .95). Toxicities were significantly less for
FOLFIRI (e.g., overall grade 3/4 toxicity rate of 69% versus 84%; P
< .001). Time to treatment failure was selected as the primary end
point because it captured discontinuation of a regimen for both efficacy
and toxicity reasons.
Finally, Boku and colleagues also performed a phase III trial in
which Japanese patients were randomized to infusional 5-FU versus
cisplatin-irinotecan (a third arm was designed to evaluate and did
confirm noninferiority of S-1 versus infusional 5-FU).44 When compared
with infusional 5-FU, cisplatin-irinotecan was associated with an
improved RR (38% versus 9%) but only a nonsignificant trend toward
improved median OS (12.3 versus 10.8 months; P = .055), at the
expense of significantly more grade 3/4 toxicities. As noted earlier,
results of the CALGB 80403/ECOG 1206 study, which randomized
patients to cetuximab plus ECF versus FOLFOX versus cisplatin-
irinotecan, revealed that the cisplatin-irinotecan arm had the lowest
RR and shortest median OS.68
Taken together, these results have led many oncologists to move
away from using cisplatin-irinotecan as a first-line regimen for advanced
EGCs, although FOLFIRI has recently emerged as a viable first-line
option. Some uncertainty about the superiority of irinotecan in the
first-line setting was reinforced by the Cochrane meta-analysis of four
clinical trials, which revealed a non–statistically significant trend toward
a small survival benefit for an irinotecan-containing regimen (HR,
0.86; 95% CI, 0.73–1.02).54 Notably, the FFCD study discussed
earlier was not included in this meta-analysis.
Second-Line Chemotherapy
Until recently, there were no large randomized studies to support a
survival benefit for second-line chemotherapy in EGCs. There are
now three randomized studies that were performed in patients with
gastric cancer to support such a benefit.
The first study involved 202 Korean patients with an ECOG
Performance Status score of 1 or lower who had previously received
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two or fewer prior regimens were randomized in a 2:1 ratio to further
treatment with either docetaxel or irinotecan versus BSC.84 The patients
who received chemotherapy had a superior OS (5.3 versus 3.8 months;
HR, 0.66; P = .007), and therapy was well tolerated, with manageable
hematologic toxicities and comparable rates of nonhematologic toxicities
in both groups. There were no significant differences between the
chemotherapy arms.
The West Japan Oncology Group (WJOG) 4007 study then
randomized 223 patients to second-line paclitaxel versus irinotecan.85
Median OS was comparable (9.5 versus 8.4 months; P = .38), although
there appeared to be less toxicity in the paclitaxel arm and more of
those patients went on to receive third-line chemotherapy than in the
irinotecan-arm. Finally, the UK COUGAR-2 study confirmed the
benefit for second-line docetaxel versus BSC in a Western population,
with a median OS of 5.2 versus 3.6 months (P = .01).86
Based on these results, patients with good performance statuses
should be offered additional non–cross-resistant treatment beyond
progression on first-line chemotherapy. As noted later, the combination
of paclitaxel with ramucirumab, an antibody against vascular endothelial
growth factor receptor–2 (VEGFR2) is now considered the standard
of care in the second-line setting.
Response Rates in Adenocarcinoma and Squamous
Cell Carcinoma
In general, it appears that adenocarcinoma and SCC tumors have
overlapping RRs to combination chemotherapy, similar to the experience
with non–small cell lung cancer. Few single agents have been tested
in both cell types, and the number of patients treated in such studies
has been small. Phase III studies in SCC patients are also lacking.
Accordingly, regimens that are active in adenocarcinoma of the
esophagus, GEJ, and stomach are routinely extrapolated and used to
treat patients with SCC tumors.
TARGETED THERAPY
Most investigators believe that the potential for making significant
progress lies in understanding and exploiting the molecular biology
of these tumors. The focus of recent study has shifted toward testing
newer agents that target specific molecular abnormalities known to
occur in EGCs.
Gene expression profiling of 296 EGCs from a Western population
by Dulak and colleagues found amplified genes in 37% of samples,
including in several of the therapeutically targetable kinases that are
discussed here (specifically, EGFR and HER2), along with fibroblast
growth factor receptor and K-ras.87 A similar analysis of 193 tumors
(mostly from Singapore and East Asia) also identified amplifications
of the same five targets.88 On the other hand, mutations in the K-ras
and B-raf oncogenes, which are common in some other solid tumors,
are rare in EGCs.89
Therefore the molecular targets of agents that are currently under
active clinical evaluation include HER2 and vascular endothelial growth
factor (VEGF). Therapies against EGFR were previously intensively
investigated, but completed phase III studies showed either no benefit
or even detriment for its addition to standard treatments. Therapies
against HER2 and VEGF have focused exclusively on GEJ and gastric
adenocarcinoma patients, whereas the studies of anti-EGFR therapies
have also enrolled esophageal SCC patients.
Anti-HER2 Therapy
HER2 is a member of the ERBB tyrosine kinase receptor family.
Ligand binding to these receptors leads to dimerization of a receptor
either with itself or another member of the ERBB family. At least
nine such homodimers and heterodimers exist. In this network, HER2
plays a major coordinating role because each receptor with a specific
ligand appears to prefer HER2 as its heterodimeric partner. This

preference is further biased by overexpression of HER2, as seen in
many types of human cancer cells.90
In EGCs, HER2 overexpression has been variably demonstrated
in esophageal SCC (mean, 23%; range, 0%–52%) and GEJ adeno-
carcinoma (mean, 22%; range, 0%–43%).91,92 The wide range of
expression reflects the differences in receptor testing based on
immunohistochemistry (IHC) or fluorescence in situ hybridization
(FISH), in addition to the varied cancer stages of patients.
The significance of HER2 expression as a prognostic or predictive
marker is unclear. In esophageal SCC, HER2 overexpression has been
correlated with extramural invasion and poor response to neoadjuvant
chemotherapy.92 Similarly, a meta-analysis of 14 studies involving
1464 patients with operable esophageal cancer also suggested inferior
5-year survival for patients with HER2-positive tumors.93 However,
a more recent study from the Mayo Clinic (which was not part of
this meta-analysis) suggested that HER2 overexpression is actually
associated with a lower tumor grade, fewer malignant lymph nodes,
and the presence of Barrett esophagus.94 In patients with esophageal
adenocarcinoma and Barrett esophagus, HER2 expression correlated
with improved disease-specific survival and OS.
In gastric and GEJ adenocarcinoma, some studies have demonstrated
a correlation between HER2 amplification as determined with FISH
and increasing depth of invasion, lymph node and distant organ
metastasis, and overall poor survival.95 The worse prognosis conveyed
by HER2 positivity appears to be confirmed by a meta-analysis of 49
studies involving 11,337 patients with localized and metastatic tumors.96
However, more recent studies not included in this meta-analysis
have suggested otherwise. A study by our group indicated that HER2
overexpression is more common in intestinal versus diffuse or mixed
histologic types (33% versus 8%; P = .001) but that it is not an
independent prognostic factor in the metastatic setting.97
In the locally advanced setting, large retrospective reviews also did
not show HER2 to be prognostic or predictive of benefit either from
perioperative chemotherapy (in the UK MAGIC study with epirubicin–
cisplatin–5-FU)98 or from adjuvant chemotherapy after up-front surgery
(in the Japanese ACTS-GC trial with the oral 5-FU prodrug S-1).99
Part of the discrepancy of these results may arise because of dif-
ferences in IHC staining and scoring for HER2. The more contemporary
studies cited here used IHC and FISH techniques similar to those
used in the ToGA study (discussed later), which may make their
conclusions more relevant.
Trastuzumab
Trastuzumab, a monoclonal antibody against HER2, was the first
targeted therapy approved by the FDA for EGCs. In the pivotal ToGA
(Trastuzumab for Gastric Cancer) trial, the addition of trastuzumab
to a fluoropyrimidine-cisplatin doublet for patients with GEJ and
gastric adenocarcinomas whose tumors were HER2 positive with IHC
(3+) or FISH (HER2/CEP17 ratio ≥2) improved outcomes.100 RRs
(47% versus 35%; P = .0017), median PFS (6.7 versus 5.5 months;
P = .0002), and OS (13.8 versus 11.1 months; P = .0046) were all
improved with the addition of trastuzumab. The greatest benefit seen
for the addition of trastuzumab was in high HER2 overexpressors
with IHC 3+ or FISH-positive/IHC 2+ patients. Based on this dif-
ferential benefit, trastuzumab is approved in the European Union
only for this subgroup of high HER2 overexpressors; in the United
States, it is approved for any patient who met the eligibility criteria
for the ToGA study, including patients with FISH-positive status only.
Other Anti-HER2 Therapies
Building on the results of the ToGA study and mirroring strategies
that have proven to be beneficial in HER2-positive breast cancer, an
anti-HER2 tyrosine kinase inhibitor (TKI) and other antibody strategies
have been evaluated. Unfortunately and somewhat unexpectedly, the
results that have been reported show no benefit for these drugs.
The first of these negative studies was the LOGiC study, a phase
III evaluation of lapatinib, an anti-HER2 TKI, in combination with
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Cancer of the Esophagus  •  CHAPTER 71 1181
capecitabine-oxaliplatin chemotherapy as first-line treatment in 545
patients whose tumors were HER2 amplified with FISH testing.101
Although RRs were higher in the lapatinib and chemotherapy arm
(53% versus 39%; P = .0031), there was not a statistically significant
improvement in OS, the primary end point (12.2 versus 10.5 months;
P = .35). In a preplanned subset analysis, there was a benefit for
lapatinib in Asian and younger (<60 years old) patients. There was
no correlation between HER2 positivity by IHC and benefit in this
HER2-amplified population.
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate
of trastuzumab and DM1 (a microtubule inhibitor derived from
maytansine) that has been approved by the FDA for use in HER2-
positive breast cancer that is refractory to trastuzumab and a taxane,
based on the phase III EMILIA study.102 T-DM1 binds to HER2,
releasing DM1 into the cytoplasm via receptor-mediated internalization
and resulting in apoptosis. The randomized phase II/III GATSBY
trial compared T-DM1 versus docetaxel-paclitaxel in the second-line
treatment of HER2-positive metastatic gastric cancer that progressed
on trastuzumab-based therapy. Results have been presented only in
abstract form but reveal no improvement in OS versus chemotherapy
(7.9 versus 8.6 months; P = .86).103
Finally, pertuzumab is a humanized monoclonal antibody that
binds to the domain II dimerization arm of HER2, leading to inhibition
of HER2 dimerization with other ERBB family members and antibody
dependent cell-mediated cytotoxicity.104,105 Pertuzumab was initially
FDA approved in combination with trastuzumab and docetaxel for
previously untreated HER2-positive breast cancer on the basis of the
CLEOPATRA study.106
In the phase II JOSHUA study, 30 HER2-positive EG adenocar-
cinoma patients were randomized to two different doses of pertuzumab
in combination with capecitabine-cisplatin and trastuzumab.107 Fifteen
patients received pertuzumab at a dose of 840 mg every 3 weeks for
six cycles, and the other 15 patients received 840 mg of pertuzumab
for cycle 1 followed by 420 mg every 3 weeks for the next five cycles.
Both doses reached the predefined trough concentrations of pertuzumab
on day 43. The disease-control rates (complete plus partial response
plus stable disease) at the end of six cycles were 82% and 100%,
respectively, in each arm. Toxicities appeared to be similar in both
arms, and diarrhea, mostly grade 1/2, was the most common toxicity.
The higher dose of 840 mg every 3 weeks was selected for the phase
III JACOB study (NCT01774786), which has completed accrual and
randomized 780 patients to fluoropyrimidine-cisplatin and trastuzumab
with or without pertuzumab. These results are eagerly awaited; this
is the one remaining phase III study that has the potential to further
improve treatment in HER2-positive EG adenocarcinoma.
Anti–Vascular Endothelial Growth Factor Therapy
Therapies directed against VEGF have been the focus of major ongoing
research in solid tumor malignancies. Folkman and others have provided
compelling evidence linking tumor growth and metastases with
angiogenesis.108
Of the identified angiogenic factors, VEGF is the most potent and
specific and has been identified as a crucial regulator of both normal
and pathologic angiogenesis. VEGF produces a number of biologic
effects, including endothelial cell mitogenesis and migration and
induction of proteinases, leading to remodeling of the extracellular
matrix, increased vascular permeability, and maintenance of survival
for newly formed blood vessels.109 VEGF exerts its angiogenic effects
by binding to several high-affinity transmembrane receptors, most
notably VEGFR types 1 (flt-1) and 2 (KDR, flk-1).110 In esophageal
cancer, VEGF is overexpressed in 30% to 60% of patients, with several
studies demonstrating a correlation among high levels of VEGF
expression, advanced stage, and poor survival in patients undergoing
esophagectomy.111–115 Studies in SCCs have indicated that expression
of VEGF in tumors correlates with more advanced tumor stage, the
presence of nodal and distant metastases, and a poorer survival
1182 Part III: Specific Malignancies
outcome.113,116 In esophageal adenocarcinoma, increasing expression
of VEGF correlates with the transition from Barrett esophagus to
high-grade dysplasia and with the transition from microinvasive to
locally advanced cancer.117,118 Similarly, increased VEGF expression
on tumors and increased serum VEGF levels have been correlated
with worse prognoses in gastric cancer.119,120
Bevacizumab
The phase III AVAGAST trial evaluated the addition of bevacizumab,
a monoclonal antibody against VEGF-A, to capecitabine-cisplatin as
first-line therapy for patients with advanced EG adenocarcinoma.121
Although RRs and PFS were improved, the primary end point of an
OS improvement was not met, although there was a non–statistically
significant trend toward benefit for the bevacizumab-containing arm
(12.1 versus 10.1 months; P = .1002). In a planned subset analysis,
there did appear to be more benefit for European and Pan-American
patients than Asian patients.
The contention that gastric cancer in East Asia is fundamentally
different from that in the rest of the world was bolstered by a biomarker
analysis of the AVAGAST study.122 Baseline VEGF-A levels and baseline
levels of neuropilin-1, transmembrane glycoproteins involved in
angiogenesis and tumor growth, were found to be prognostic and
predictive. In patients who received chemotherapy alone, higher
VEGF-A level and lower neuropilin-1 expression were associated with
shorter OS. In patients who received bevacizumab and chemotherapy,
this same pattern was associated with greater benefit from the addition
of bevacizumab. Noticeably, the relationship between baseline VEGF-A
levels and benefit from bevacizumab was seen only in non-Asian
patients. Additional evidence to suggest that bevacizumab may offer
greater benefits to a Western population comes from the two phase
II studies performed by our group that paved the way for the AVAGAST
study.123,124 In both of these studies, the addition of bevacizumab to
different chemotherapy regimens improved survival outcomes signifi-
cantly, compared with historical controls.
Ramucirumab
Momentum for the evaluation of anti-VEGF therapies in EGC was
halted after the AVAGAST trial until the results of the phase III
REGARD study were made available.125 Three hundred fifty-five
patients with EG adenocarcinoma with prior progression on first-line
fluoropyrimidine and/or platinum-based chemotherapy were random-
ized 2:1 to receive ramucirumab, an antibody against VEGFR2, versus
placebo. The patients who received ramucirumab had improvement
in PFS (2.1 versus 1.3 months; HR, 0.48; P < .0001) and OS (5.2
versus 3.8 months, HR, 0.78; P = .047). Responses were uncommon
(RR was 3% in both arms). The only toxicity more common in the
ramucirumab arm was grade 3 hypertension in 8% of patients. On
the basis of this study, the FDA approved ramucirumab as second-line
monotherapy in April 2014.
In addition, a subsequent phase III study of second-line paclitaxel
with or without ramucirumab (the RAINBOW study) showed benefit
for the combination.126 Median OS was superior for the ramucirumab-
paclitaxel arm (9.6 versus 7.4 months; P = .0169); RRs (28% versus
16%; P = .0001) and PFS (4.4 versus 2.9 months; P < .0001) were
also improved. When ramucirumab was combined with paclitaxel,
the only other toxicity observed in addition to hypertension was a
higher incidence of grade 3/4 neutropenia (41% versus 19%) but not
a higher rate of neutropenic fever (3.1% versus 2.4%). The activity
and tolerability of this regimen led to its approval in November 2014
and has established it as the standard of care in the second-line setting.
A subsequent subset analysis that compared 140 Japanese patients
in this study with 398 patients from Western countries showed that
the Japanese patients appeared to derive more benefit in terms of
improvements in RR and PFS with the addition of ramucirumab.127
In general, these patients had more favorable characteristics than
Western patients, including a higher proportion of patients with
ECOG Performance Status 0, a TTP on first-line chemotherapy of
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6 months or longer, and fewer metastatic sites. The RRs of Japanese
patients who received ramucirumab-paclitaxel versus paclitaxel were
41% versus 19%, respectively (P = .0035), compared with 27% versus
13%, respectively (P = .0004), for Western patients. Similarly, the
median PFS for Japanese patients who received ramucirumab-paclitaxel
versus paclitaxel was 5.6 versus 2.8 months (HR, 0.50; P = .0002)
compared with 4.2 versus 2.8 months in Western patients (HR,
0.63; P < .0001). However, there was no OS benefit in the Japanese
patients (11.4 versus 11.5 months; P = .51), whereas Western patients
did have improved OS (8.6 versus 5.9 months; P = .0050). This
may have been because of the increased use of postdiscontinuation
therapy in Japanese patients compared with Western patients (75%
versus 37%). When only Japanese patients who did not receive
additional therapy at progression were analyzed, those who received
ramucirumab did have superior OS (9.6 versus 4.3 months; HR,
0.338; 95% CI, 0.124–0.922). Whether Japanese patients were able
to receive more second-line and beyond therapy because of more
favorable tumor biologic features that led to a slower decline in
performance status, superior oncologic care, or some other factor is
not known.
Based on its activity in the second-line setting, a phase III study
evaluating first-line fluoropyrimidine-platinum with or without
ramucirumab has completed accrual (RAINFALL; ClinicalTrials.gov
NCT02314117).
Anti-Vascular Endothelial Growth Factor Receptor–2 Tyrosine
Kinase Inhibitors
Apatinib, an anti-VEGFR2 TKI, was evaluated in a phase III study
in 267 Chinese GEJ and gastric adenocarcinoma patients who had
received two or more prior chemotherapy regimens.128 They were
randomized to receive either apatinib or placebo. Median OS was
significantly improved in the apatinib group (6.5 versus 4.7 months;
HR, 0.71; P = .0149), as was PFS (2.6 versus 1.8 months; HR,
0.444; P < .001). Responses in the apatinib group were rare (2.84%
versus 0% for placebo-treated patients). Toxicities were consistent with
those of other anti-VEGFR TKIs and included hypertension (35.2%
all-grade, 4.5% grade 3/4), hand-foot syndrome (27.8% all-grade,
8.5% grade 3/4), and elevated liver transaminases (27.8% all-grade, 8%
grade 3/4). On the basis of this study, apatinib was approved in China
for this indication.
Additional evidence that anti-VEGFR TKIs are active in non-Asian
patients with EG adenocarcinoma comes from the randomized phase
II INTEGRATE study of regorafenib, another VEGFR2 TKI, in
which 152 GEJ and gastric adenocarcinoma patients from Australia,
New Zealand, South Korea, and Canada who had received two or
fewer prior regimens were randomized in a 2:1 fashion to receive
regorafenib versus placebo.129 The primary end point was PFS, which
was improved in the regorafenib arm (2.6 versus 0.9 months; HR,
0.40; P < .001). There was a trend toward improved OS (5.8 versus
4.5 months; HR, 0.74; P = .147) and an OS benefit may have been
obscured by the fact that the study permitted crossover to regorafenib
at the time of progression. The grade 3/4 toxicity rate appears to have
been similar to that of apatinib. Interesting to note, the benefit for
regorafenib seemed to be greater in the South Korean than in other
patients (HR, 0.12 versus 0.61; P < .001). On the basis of this study,
a phase III study (INTEGRATEII, ClinicalTrials.gov NCT02773524)
will shortly open.
It is worth noting that the HR for PFS and OS are virtually
identical for apatinib and regorafenib (and very similar for single-agent
second-line ramucirumab), suggesting a robust antiangiogenic class
effect for these drugs in EG adenocarcinoma. It is also important to
note that none of the patients in these studies received prior ramu-
cirumab, so it is unclear if VEGFR TKIs will have activity in this
increasingly common group of patients. INTEGRATEII will permit
prior use of ramucirumab and will, it is hoped, definitively answer
this question. For now, especially given its superior toxicity profile

relative to the VEGFR TKIs, ramucirumab in the second-line setting
remains standard.
Anti-Epidermal Growth Factor Receptor Therapy
EGFR or ERBB1 is another member of the ERBB transmembrane
growth factor receptor family. The known ligands of the EGFR are
epidermal growth factor and transforming growth factor-α. Binding
of a ligand to the EGFR causes it to dimerize either with itself or
with another member of the ERBB family. Dimerization then leads
to activation of the TK and the downstream phosphorylation and
activation of other effector signals.130
In EGCs, EGFR overexpression demonstrated by IHC or gene
amplification by FISH occurs in 30% to 90% of tumors and correlates
with increased invasion, a more advanced stage, more poorly differenti-
ated histologic features, and a worse prognosis.131–134
The findings of four completed phase III trials of the anti-EGFR
antibodies cetuximab and panitumumab have been published. Individu-
ally, each of these studies has been negative; collectively, they have
dampened enthusiasm for further evaluation of these drugs in an
unselected population.
In the metastatic setting, the results of two studies have been
published. In the REAL3 study 553 patients with advanced EG
adenocarcinoma were randomized to EOC (epirubicin-oxaliplatin-
capecitabine) chemotherapy alone or with the addition of panitu-
mumab.135 Unfortunately, the addition of panitumumab resulted in
a statistically significant inferior OS (11.3 versus 8.8 months; HR,
1.37; P = .013), which was the primary end point. The addition
of panitumumab also resulted in a trend toward inferior PFS (6.0
versus 7.4 months; HR, 1.22; P = .068) and did not improve RRs
(46% versus 42%; P = .42). Toxicities were also increased with the
addition of panitumumab and included higher rates of grade 3/4
diarrhea, mucositis, rash, and hypomagnesemia, all class effects of
anti-EGFR antibodies.
These disappointing results cannot be easily explained. One pos-
sibility is that increased toxicities seen when panitumumab was initially
added to full-dose EOC chemotherapy led to dose reductions in
oxaliplatin (by 23%) and capecitabine (by 20%). These dose reductions
in chemotherapy—coupled with a lack of biologic benefit or even
harm from the addition of panitumumab—could have resulted in the
inferior OS in the experimental arm.
A second possibility is that the combination of anti-EGFR therapy
with the 5-FU prodrug capecitabine may be associated with an
unsuspected and inexplicable negative interaction. We previously
performed a meta-analysis of anti-EGFR antibodies in the first-line
therapy of colorectal cancer and noted that the addition of these
antibodies to regimens containing capecitabine or bolus 5-FU is
associated with reduced or absent benefit compared with infusional
5-FU–based regimens.136 Although the biologic basis for such a proposed
negative interaction is not known, there are emerging data that anti-
EGFR therapy can reduce the expression of thymidylate synthase,
which is a main target for 5-FU.137–139 Such reduced expression may
mean that the choice of infusional 5-FU as opposed to capecitabine
is important when anti-EGFR therapies are being added.
Finally, the REAL3 investigators also published a companion
manuscript of biomarker analysis focusing on genes previously identified
to correlate with response or resistance. Consistent with other published
data, the rates of mutations in K-ras, B-raf, and PIK3CA and loss of
PTEN expression were low (5.7%, 0%, 2.5%, and 15.0%, respectively)
and did not predict response to panitumumab.140
Similarly, EXPAND, a phase III trial of 904 patients with advanced
EG adenocarcinoma treated with capecitabine-cisplatin with or without
cetuximab, also failed to show a benefit in PFS, the primary end point
(4.4 versus 5.6 months; HR, 1.09; P = .32).141 RRs (30% versus 29%;
P = .77) and OS (9.4 versus 10.7 months; P = .95) were also not
improved. There was no difference in the primary outcome based on
EGFR expression demonstrated with IHC. Again, toxicities were
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Cancer of the Esophagus  •  CHAPTER 71 1183
increased in the cetuximab arm, including grade 3/4 diarrhea, rash,
hand-foot syndrome, and hypomagnesemia.
Although all of these studies have focused on adenocarcinoma
histologic type, a German randomized phase II study evaluated
5-FU–cisplatin with or without cetuximab in 62 patients with
esophageal SCC.142 The RR rate was not improved with the addition
of cetuximab (19% versus 13%; P = .79), and there was only a trend
toward improved time to treatment failure (3.4 versus 1.6 months; P
= .25) and OS (9.5 versus 5.5 months; P = .32). Despite these equivocal
results, a phase III study in Germany in which patients were randomized
to receive 5-FU–cisplatin with or without panitumumab was initiated.
The study closed because of slow accrual, and results have yet to be
presented (ClinicalTrials.gov NCT01627379).
In the locally advanced setting, two studies have evaluated the
addition of cetuximab to chemoradiation for locally advanced esophageal
and GEJ tumors. The UK SCOPE-1 study treated 258 patients with
capecitabine-cisplatin and radiation with or without cetuximab.143
Seventy-three percent of patients had SCC histologic type, and 60%
had stage III disease. The original design of the study was to recruit
420 patients. However, it was stopped after a preplanned analysis of
the first 180 patients who had completed 24 weeks of follow-up
occurred because it met predetermined criteria for futility. The primary
end point of being free of treatment failure at 24 weeks was lower in
the cetuximab arm (66.4%; 90% CI, 58.6–73.6) versus the standard
arm (76.9%; 90% CI, 69.7–83.0). The patients who received cetuximab
also had inferior OS (22.1 versus 25.4 months; HR, 1.45; P = .035).
Patients who received cetuximab were less likely to receive or complete
standard chemoradiation and also had higher rates of dermatologic
and metabolic toxicities.
Finally and most recently, the results of the Radiation Therapy
Oncology Group (RTOG) 0436 study were presented in abstract
form.144 This study evaluated cisplatin-paclitaxel and radiation with
or without cetuximab in the nonoperative setting for locally advanced
esophageal adenocarcinomas and SCCs. There was no difference in
outcomes between both arms, confirming a lack of benefit for cetuximab
combined with chemoradiation.
Immunotherapy
There has been growing excitement among oncologists and patients
alike regarding the use of immunotherapy or, more specifically,
immune checkpoint inhibitors. Since the landmark approval by
the FDA of the anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4)
antibody ipilimumab in advanced melanoma,145,146 these and other
antibodies (namely, antagonists of the programmed death [PD]-1/
PD-ligand 1 [PD-L1] pathway) that derepress the immune system have
undergone extensive evaluation in multiple other solid tumors, includ-
ing EGC. These studies have led to the FDA approval of additional
immune checkpoint inhibitors in several solid tumor malignancies
and, in EGC, have culminated in one recently reported positive
phase III study.147
Immune Checkpoints
The generation of an effective cellular immune response by T cells
against a cancer cell requires a primary signal and cosignals.148 The
primary signal comes from recognition of a cancer-associated antigen
by a T-cell receptor with very high specificity for the antigen, presented
in the context of a class I/II major histocompatibility complex molecule,
which is expressed on so-called antigen-presenting cells (APCs) such
as dendritic cells or on the tumor cell itself. In addition to this primary
signal, a secondary signal is required, in the absence of which the T
cell may be rendered anergic or nonfunctional.
It is now well established that the interactions between multiple
molecules at the interface between the T cell and tumor cell create
multiple secondary signals, some of which are costimulatory and
some of which are inhibitory. The ultimate activation or quiescence
of the immune response depends on the complex interplay and net
1184 Part III: Specific Malignancies
signal—positive or negative—of these diverse interactions, which occur
at different times in the process of successful T-cell engagement and
activation.
Under normal physiologic conditions, immune checkpoints are
crucial for the maintenance of self-tolerance (and the avoidance
of autoimmunity) and also for protection of tissues from excessive
damage if the immune system were to respond too exuberantly to an
infection. However, many of these molecules have become co-opted
by cancer cells (in the process of achieving equilibrium and escape
from the immune system). Their identification and targeting with
neutralizing (or agonist) antibodies now form the basis of modern
era immunotherapy.
In 1995, James Allison and colleagues were one of two groups that
simultaneously characterized the function of CTLA-4, a protein that
has high homology with CD28, which was already known to be a
costimulatory molecule expressed on T cells necessary to provide the
secondary signal for T-cell activation.149 Just as CD28 does, CTLA-4
also binds cognate ligands, the B7 molecules (which are found on
APCs), but with much higher affinity. However, unlike with CD28,
CTLA-4 expression is induced only when a T cell becomes activated. It
then competes with CD28 for binding to the B7 molecules but leads
to downregulation and eventual abrogation of the immune response.
Subsequently, PD-1 was also identified as another negative immune
checkpoint molecule.150 PD-1 has two ligands, PD-L1 and PD-L2.
PD-L2 is mostly expressed on APCs, whereas PD-L1 is expressed on
numerous tissues, including immune and tumor cells. In the tumor
microenvironment, PD-L1 expressed on tumor cells binds to PD-1
on activated T cells reaching the tumor. This delivers an inhibitory
signal to those T cells, preventing them from killing target cancer
cells and protecting the tumor from immune elimination.151 Unlike
CTLA-4, which is thought to be necessary for T-cell activation, the
PD-1/PD-L1/2 pathway is thought to protect cells from T-cell attack.152
Anti-PD-1 Antibodies
A full discussion of immune checkpoint inhibitors is beyond the scope
of this chapter; the breathtaking pace at which studies are being
presented—and the existing data used to design the next generation
of studies—would also make this discussion rapidly outdated.
However, two pivotal studies warrant discussion. At this time, the
only study with results that have been published—and the first major
study to ignite enthusiasm for this field in EGC—is the KEYNOTE-012
study, a phase Ib dose-expansion study that evaluated 39 patients with
GEJ or gastric adenocarcinomas.153 All patients had tumors that were
found to be PD-L1 positive with an experimental IHC assay that
used the Merck 22C3 antibody. Based on the cutoff for positivity of
1% or greater membrane staining of tumor or peritumoral mono-
nuclear inflammatory cells, 40% of tumors were noted to be PD-L1
positive.
Nineteen patients were from Asia, and the rest were from the rest
of the world. Patients were heavily pretreated, and two-thirds had
received two or more prior therapies. The confirmed RR was 22%
for all patients; four of these eight patients had ongoing responses at
the time of data analysis, and the median duration of response was
40 weeks. Median PFS was 1.9 months, and median OS was 11.4
months; the 6- and 12-month OS rates were 66% and 42%, respectively.
Toxicities appeared to be in line with the known side effects of
pembrolizumab and included grade 3 or greater pneumonitis, pem-
phigoid, peripheral neuropathy, and hypothyroidism in one patient
(3%) each.
The benefit of anti-PD-1 therapy was confirmed by the presentation
of the results of a phase III study of nivolumab, another anti-PD-1
antibody, in 493 East Asian patients who had received two or more
prior chemotherapy regimens.147 They were randomized in a 2:1 fashion
to nivolumab versus placebo. The study revealed a very modest
improvement in PFS (1.65 versus 1.45 months; HR, 0.60; P < .0001)
and OS (5.32 versus 4.14 months; HR, 0.63; P < .0001) but a
landmark 12-month OS rate of 26.6% (versus 10.9%). The RR was
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11.2% (versus 0% for the placebo group) in this group, in which
patients were enrolled irrespective of PD-L1 status. Based on this
study, regulatory approval for the use of nivolumab in this setting is
pending in Japan.
Overall, these results confirm the notable but modest activity of
single-agent immune checkpoint inhibition in EGC. Ongoing and
future efforts are focused on combinatorial strategies—with chemo-
therapy, other immune checkpoint inhibitors, tumor vaccines, and
locoregional therapies such as radiation or chemoradiation—and will,
it is hoped, transform the treatment of this disease in the next decade.
CHOICE OF THERAPEUTIC OPTIONS:
LOCALIZED ESOPHAGEAL CANCER
Surgery Alone
Esophagectomy with reconstruction has a clear goal of both achieving
local tumor control and restoring swallowing function. Esophageal
surgical intraoperative risks, postoperative complications, and length
of hospitalization have all decreased to acceptable levels that are now
comparable with other major oncologic resections.154–156 Whether
surgical resection is performed as the sole therapy or as part of a
combined approach, the surgical principles and techniques are the
same, with the goal of achieving a gross total resection. Surgery as a
single modality is generally only appropriate for curable patients with
very early lesions or those who are medically unfit for combined
modality therapy. Cancer cure rates do not appear related to the surgical
technique used.
When surgery is used, an R0 resection—gross total resection with
negative margins—is critical for long-term outcome, even with the
availability of adjuvant or salvage chemoradiation. Results from a
data set of 1602 patients undergoing resection of distal esophageal
and GEJ adenocarcinoma demonstrated 5- and 10-year survival rates
for R0 resected patients of 43.2% and 32.7%, respectively, whereas
the corresponding figures for patients with microscopic or macro-
scopic residual disease (R1 and R2 resection) were 11.1% and 6.2%
(P < .0001).157
A so-called palliative esophagectomy to restore swallowing function
but with little or no change in long-term survival because of the extent
of disease is of highly uncertain benefit relative to the risks and morbid-
ity and any delay in administering systemic therapy and should be
contemplated only under very limited circumstances.
The standard operation in the United States includes resecting the
involved portion of esophagus, the proximal stomach, and the regional
lymph nodes, as illustrated in Fig. 71.2. The surgical resection is
therefore properly termed a partial esophagogastrectomy with regional
(or one field) lymphadenectomy. The resected esophagus is replaced
with a conduit, usually the stomach or segments of the small or large
intestine, which are, in turn, mobilized as a vascularized pedicle and
anastomosed to the remaining proximal esophagus.
A number of incisional approaches can be successfully used to
perform a partial esophagogastrectomy, including the transhiatal, Ivor
Lewis, left thoracoabdominal, and three-incision techniques (Fig. 71.3).
Less common techniques or modifications of the approaches are listed.
The specific incisional approach used generally determines how much
esophagus is removed and where the esophageal anastomosis will be
located (see Fig. 71.2). In the past, various surgeons have argued in
support of their preferred techniques, giving the impression that all
of these approaches were uniquely different procedures. It is now
accepted that all of these incisional techniques use partial esophago-
gastrectomy (except segmental esophagectomy with free jejunal grafting,
which is discussed separately), and outcomes are similar. Ultimately,
long-term disease-specific survival after esophagectomy is related to
pathologic tumor stage and is not dependent on the surgical esopha-
gectomy technique.156,158,159 The data continue to demonstrate no
difference in mortality or survival between transthoracic and transhiatal
esophagectomy (THE) approaches.160–162 The main variables when

Transhiatal
Ivor-Lewis
Left thoracoabdominal
Figure 71.2  •  Regardless of the surgical approach used, a partial esopha-
gogastrectomy is performed to resect esophageal tumors. Depending on the
approach, different lengths of esophagus are removed. (From Heitmiller RF.
Carcinoma of the esophagus. In: Bayless TM, ed. Current Therapy in Gastro-
enterology and Liver Disease. 4th ed. St. Louis: Mosby; 1994;81.)
performing a partial esophagogastrectomy are which incision(s) to
use, the length of esophagus to resect, what to use to replace the
esophagus, and which route through the chest this conduit will take.
CHOICE OF THERAPEUTIC OPTIONS: EARLY
ESOPHAGEAL CANCER
Early esophageal cancers (T1–2N0) may be managed with single-
modality therapy with the goal of curing the tumor while minimizing
morbidity of treatment. Endoscopic approaches should optimally be
considered only for tumors confirmed to invade no further than
one-third of the depth of the submucosa (Tis, Ia). When deeper
invasion has occurred, there is an otherwise high rate of undetected
nodal involvement that would necessitate esophagectomy and result
in a change to a combined modality approach. Single-modality therapy
is also appropriate for the rare group of patients with locally advanced
disease who are not medically appropriate candidates for combined
modality therapy.
Nonsurgical Management of Early-Stage (Tis, Ia)
Esophageal Cancer
EMR may be the optimal endoscopic minimally invasive approach
for early carcinoma. In contrast to PDT and radiofrequency ablation,
this approach allows pathologic confirmation of depth of invasion.
This confirmation is critical because the greater the depth of invasion,
the higher is the associated risk of nodal involvement, which requires
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Cancer of the Esophagus  •  CHAPTER 71 1185
Transhiatal approach Ivor Lewis approach
Left thoracoabdominal
Three-incision approach approach
Figure 71.3  •  Different incisions are used to perform partial esophago-
gastrectomy. (From Reichle RI, Fishman EK, Nison MS, et al. Evaluation of
the post-surgical esophagus after partial esophagogastrectomy for esophageal
cancer. Invest Radiol. 1993;28:247.)
more extensive therapy for adequate curative management. This is
appropriate therapy for disease confined to the mucosa, where there
is a probability of lymph node involvement that approaches 0%. This
approach may also be appropriate for submucosa involvement up to
one-third of the thickness: lymph node involvement is observed in
45% (23 of 51) of cases with deep submucosal invasion versus 10%
(3 of 29) of middle-third and 7.5% (3 of 40) of inner-third cancers.163
Therefore for lesions with invasion beyond the submucosa, standard
management including surgical resection is warranted, although
EMR may be appropriate under select circumstances with minimal
submucosal invasion.
Esophagectomy for Stage I and IIa Tumors
Esophagectomy is the standard therapy. The outcome is favorable,
especially for T1–2N0 disease, and is demonstrated in Fig. 71.1. This
procedure has the advantage of pathologic confirmation of the extent
of disease, which offers prognostic information and which may inform
adjuvant therapy. For patients with T3N0 or TanyN+ tumors, combined
modality therapy should be considered because the long-term survival
is less than 50% and clinical staging may frequently overlook involved
lymph nodes.
CHOICE OF THERAPEUTIC OPTIONS:
LOCALLY ADVANCED ESOPHAGEAL CANCER
Transhiatal Resection
THE is a frequently used approach, “rediscovered” in 1976 by Dr.
Mark Orringer, in which the intrathoracic esophagus is mobilized
1186 Part III: Specific Malignancies
distally through the esophageal hiatus and proximally through a cervical
incision. The increased prevalence of distal esophagus and GEJ adeno-
carcinoma has largely been responsible for the widespread popularity
amongst surgeons of the transhiatal approach. Because of their distal
esophageal location, these tumors are invariably near the GEJ and
readily accessible for direct-vision dissection through the hiatus.
Moreover, the regional lymph nodes for these distal tumors are in the
parahiatal and proximal lesser curvature regions, both accessible via
laparotomy. The resected esophagus is reconstructed by using the
greater curvature of the stomach, vascular pedicle based on the right
gastroepiploic artery, or long-segment colon, which is passed up into
the neck as vascularized graft to be anastomosed to the proximal
cervical esophagus. Although reports exist regarding the use of jejunum
for long-segment esophageal replacement, small bowel is generally
not an ideal option for esophageal replacement because of its mesenteric
vascular anatomy, unless specialized techniques with vascular augmenta-
tion are used. The esophageal replacement conduit is passed through
the chest into the neck by one of three routes: (1) subcutaneous, (2)
substernal, or (3) posterior mediastinum. The posterior mediastinum
is the preferred route when possible. The advantages of THE include
avoidance of postthoracotomy discomfort, wide proximal esophageal
margins to ensure complete resection of tumor and Barrett mucosa,
cervical anastomosis where the consequences of anastomotic leak are
minimized, and an esophageal reconstruction that results in an excellent
quality of swallowing.
The disadvantages of this approach include an inability to visualize
middle or proximal third tumors and to perform extensive intrathoracic
regional lymphadenectomy, the potential for injury to intrathoracic
and cervical structures, and the need for long-segment esophageal
replacement. Randomized trials have confirmed similar long-term
survival with the use of a transhiatal approach despite a more limited
mediastinal lymph node dissection than can be accomplished via
thoracotomy.
THE is safe, well tolerated, and associated with infrequent major
complications in experienced hands.161 In a large series of more than
2000 patients, the mortality rate was only 1% in those patients who
underwent surgery in 1998 and later; anastomotic leaks and pulmonary
complications occurred in 9% and 2% of patients, respectively.
A Dutch randomized trial evaluated the experimental arm of THE
with reconstruction with the gastric remnant compared with a right
thoracoabdominal approach.156 In this study, lymph node dissection
varied with the two surgical approaches. For all patients, periesophageal
lymph nodes were removed, as was the lymph node–bearing region
along the left gastric artery. However, in the right thoracoabdominal
group, a much more extensive dissection was performed, including
lower and middle mediastinal, subcarinal, and right-sided paratracheal
lymph nodes (dissected en bloc). Through a midline laparotomy, the
paracardial, lesser curvature, left gastric artery (along with lesser
curvature), celiac trunk, common hepatic artery, and splenic artery
nodes were dissected, and a gastric tube was constructed. Despite the
theoretical benefit of a more extensive nodal resection, the pattern of
recurrence was similar: locoregional recurrence occurred in 14% and
12% of patients, respectively; distant recurrence in 25% and 18%;
and both in 18% and 19% (P = .60). Perioperative morbidity was
substantially less with transhiatal resection, especially pulmonary
complications, but in-hospital mortality was similar.
Intriguingly, a subgroup analysis of long-term outcome suggested
a possible benefit based on lymph node status. Although 5-year OS
did not differ between the THE and transthoracic groups (34% versus
36%; P = .71), 5-year locoregional disease-free survival (DFS) was
improved in the transthoracic group for patients with one to eight
positive lymph nodes (23% versus 64%; P = .02).159
Ivor Lewis Approach
Partial esophagogastrectomy with an abdominal and right thoracotomy
approach was originally described by Welsh thoracic surgeon Ivor
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Lewis in 1945.164 This procedure was designed to optimize exposure
of the intrathoracic esophagus, which passes through the upper two-
thirds of the chest along the right posterior mediastinum. Once the
involved intrathoracic esophagus has been mobilized, a partial
esophagogastrectomy is performed and the esophagus is replaced with
stomach, colon, or (less frequently) jejunum, which is passed into the
chest along the esophageal bed and anastomosed to the proximal
esophagus, usually at or above the level of the azygos arch. The
advantages of the technique are the excellent exposure of the mid to
upper intrathoracic esophagus, dissection of esophageal pathologic
structures from the surrounding mediastinal structures, and the ability
to perform a mediastinal lymph node dissection. The disadvantages
are related to the use of a thoracotomy and its associated morbidity,
with limits on the proximal resection margin and the potential for
an intrathoracic esophageal anastomotic leak, which is a more difficult
management problem than a cervical anastomotic leak. Reported
complications include respiratory problems in 11% to 20%, anastomotic
leak in 3% to 7%, and wound infection in 5%. Operative mortality
ranges from none to 4%.165–167
Left Thoracoabdominal Approach
The left thoracoabdominal approach uses a single incision extending
from the left side of the chest onto the abdomen; it provides excellent
exposure of the lower third of the esophagus and left upper quadrant
of the abdomen.168 This technique is ideal for patients with limited
tumors near the GEJ, especially when the extent of gastric invasion
is unclear, because it yields superb exposure and maximizes reconstruc-
tive options of the lower third of the esophagus. Respiratory complica-
tions are the most common postoperative complications with this
approach. At least some degree of atelectasis, usually involving the
left lower lung, occurs in most patients. Pneumonia is reported to
occur in up to 24% of cases. Anastomotic leaks occur in as many as
12% of cases, leading to a higher mortality rate. Other complications
include atrial fibrillation in 10%, wound infection in 1.5% to 5.2%,
and (infrequently) empyema and subphrenic abscess. The reported
operative mortality is none to 6.2%.168,169
Multiple Incisions
Multiple-incision surgical approaches combine the incisional strategies
of the standard techniques. Of these, the three-incision approach
using a cervical incision (right or left), right thoracotomy, and midline
laparotomy, as described by McKeown, is the most common and is
also referred to as the three-incision, three-hole, total esophagectomy,
or modified McKeown approach.170 It combines the exposure of the
thoracotomy approach for esophageal mobilization or nodal dissection
with the advantages of a cervical esophageal anastomosis. Patient
outcome results with this technique are similar to those of other
approaches, with reported mortality of 3% to 4% and esophageal
anastomotic leak rates of 5% or less.171
Radical Resections
The majority of patients with esophageal cancer are first seen with
locally advanced disease (T3–4N0 or TanyN+ tumors). In these patients,
survival results are poor with surgery alone. An approach to improve
outcomes involves adding an en bloc, wide-field lymphadenectomy to
the standard esophagectomy technique. The esophagus has an extensive
regional lymphatic drainage. Arbitrarily, the lymphatic drainage has
been divided into three zones or fields—cervical, intrathoracic, and
abdominal. Standard esophagectomy techniques involve regional, or
one-field, lymphadenectomy. Radical approaches advocate two- or
three-field lymphadenectomy in conjunction with esophageal resection
and replacement. Hagen and colleagues believe that proximal hemigas-
trectomy should also be included as part of an en bloc approach, using
colon to replace the resected esophagus.172,173 Radical esophagectomy is

more complex surgery than standard techniques. Nonetheless, 30-day
mortality rates as low as 1.6% to 4.3% are reported.172,174–176 However,
survival data using radical esophagectomy techniques are conflicting,
and therefore it is unknown whether there is sufficient benefit to
outweigh the increased operative morbidity.
Minimally Invasive Esophagectomy
With the advent of minimally invasive surgical techniques, an interest
developed in applying thoracoscopic and laparoscopic techniques to
esophagectomy.177 Certainly, the techniques of gastric and esophageal
mobilization have been well established for other complex minimally
invasive surgeries. Minimally invasive esophagectomy (MIE) required
that these individual techniques be “spliced” together. Not unexpectedly,
a steep learning curve exists for these surgeries.
Approaches used have included laparoscopic transhiatal resec-
tion, combined laparoscopic–thoracoscopic procedures, and
laparoscopic creation of a gastric tube with thoracotomy and other
combinations. The need to convert to an open surgical procedure
has been uncommon. The number of lymph nodes removed also
appears similar to that achieved with open surgery.178 Luketich from
the University of Pittsburgh has described results for more than
a thousand patients, 76% with adenocarcinoma and 93% with
distal and GEJ tumors.179 In this group, 98% underwent resection
with negative margins, and nodal dissection recovered a median of
21 nodes.
There has been a single randomized trial examining the role of
MIE.155 In this randomized trial, 115 patients were randomized to
MIE versus standard approaches, with the primary objectives including
the short-term outcomes of pulmonary infections, pain, and QoL
end points.180 In this trial, 93% underwent preoperative therapy before
resection. The end points of infection, pain, and QoL were superior
in the group undergoing MIE. The R0 resection rates, number of
lymph nodes retrieved, and pathologic stage were similar in both
groups. Three-year survival data were recently published and show
no difference in DFS (37% versus 43%; P = .602) or OS (41% versus
43%; P = .633) for the open surgery versus MIE groups.
Overall, when comparing MIE with open procedures, anastomotic
leaks, stricture rates, and survival seem to be comparable; however,
MIE may be associated with a lower intraoperative blood loss, shorter
length of stay, and less morbidity, but offset by longer operative times
and costs.
SURVIVAL AFTER SURGERY ALONE
Cancer-related survival after surgical resection is discussed separately
from the description of individual techniques to emphasize the fact
that postesophagectomy survival is a function of stage and not of
surgical approach.
Regardless of whether a thoracotomy or nonthoracotomy technique
is used, long-term OS is similar, at approximately 20% to 25%. This
fact has been underscored most graphically by Muller and associates,
who reviewed the world literature to compare overall postesophagectomy
survival by technique and found no significant difference.155 Hulscher
and colleagues performed a meta-analysis of the English language
literature of transthoracic and transhiatal resection of esophageal cancer
and found a higher risk of pulmonary morbidity and mortality with
the transthoracic procedure but a similar 5-year OS of approximately
20%.181 These investigators also compared limited transhiatal resection
with an extended en bloc lymphadenectomy in 220 patients with
esophageal adenocarcinomas. No significant difference was found in
survival or operative mortality.
Although the surgical procedure does not affect outcome, large
retrospective series have suggested a modest improvement in long-term
outlook in recent years, probably the result of lower operative mortality.
For example, Gockel and colleagues found that for the periods 1985
to 1995 and 1995 to 2005, 5-year OS increased from 15% to 25%,
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Cancer of the Esophagus  •  CHAPTER 71 1187
and 30-day surgical mortality improved from 8.3% to 3.1%.182 In
addition, better patient selection may play an important role in
improved outcome. For example, Steyerberg and colleagues proposed
a simple scale based on important comorbidities, age, preoperative
therapies, and esophagectomy volume at the treating hospital, which
divided patients into groups with predicted 30-day mortality of under
4% to approximately 20%.183 It is also expected that more accurate
preoperative staging with PET scan and EUS may improve surgical
outcome by removing some patients with existing gross metastatic
disease.
Overall, despite advances in surgical techniques, postesophagectomy
survival has remained remarkably stable over time, emphasizing that
improvements would likely require effective combined modality
therapies.
PERIOPERATIVE CHEMOTHERAPY
AND SURGERY
A strategy of perioperative chemotherapy is the predominant approach
in Europe, based primarily on the phase III MAGIC (Medical Research
Council Adjuvant Gastric Infusional Chemotherapy) trial performed
in the United Kingdom.184 In this trial, 503 patients with gastric
cancer (26% of whom had tumors in the lower esophagus or GEJ)
were randomized to three cycles (9 weeks) each of preoperative and
postoperative ECF (epirubicin–cisplatin–5-FU) and surgery or surgery
alone. Perioperative chemotherapy resulted in significant improvement
in 5-year OS (36% versus 23%; P = .009), establishing this regimen
as a standard of care.
A similar degree of benefit was also noted in the contemporaneous
French FFCD 9703 trial of 224 patients with EG adenocarcinoma.185
Patients were randomized to six cycles (18 weeks) of perioperative
5-FU–cisplatin followed by surgery versus surgery alone. Perioperative
chemotherapy in this trial was associated with a significant improvement
in 5-year DFS (34% versus 19%; P = .003) and OS (38% versus
24%; P = .02). Although comparisons among different clinical trials
must be made cautiously, the survival benefit seen with 5-FU–cisplatin
in this trial appears to be nearly identical to that seen with ECF in
the MAGIC trial.
The benefit of anthracycline and the duration of preoperative
therapy have now been definitively disputed by the MRC OEO-5
study, which has so far been presented only in abstract form.186 In
this study, 897 patients with esophageal or GEJ adenocarcinomas
were randomized to preoperative chemotherapy with either 6 weeks of
5-FU–cisplatin or 12 weeks of ECX (epirubicin-cisplatin-capecitabine)
chemotherapy. Although the pathologic RR was improved in the
ECX group versus the 5-FU–cisplatin group (including a pathologic
complete response [pCR] rate of 11% versus 3% in the patients who
underwent surgery), there was no difference in median PFS (1.78 versus
1.53 years; P = .058) or OS (2.15 versus 2.02 years; P = .86) between
the groups.
The OEO-5 study has therefore also raised the provocative sug-
gestion that as little as 6 weeks of preoperative chemotherapy conveys
the same OS benefit as 12 weeks of chemotherapy. Although this
may be counterintuitive based on the findings of the MAGIC and
FFCD studies and other studies in gastric cancer in which 6 to 12
months of adjuvant chemotherapy have been administered,187,188
these results are not without precedent. As will be discussed later,
the CROSS study found benefit for preoperative chemoradiation in
which patients received only five weekly treatments of carboplatin-
paclitaxel as the entirety of their systemic chemotherapy.63,189 The
absolute improvement in OS seen in the CROSS study is also very much
in the range of 10% to 15% seen in other positive phase III studies
discussed here.
It is also important to remember that although the MAGIC and
FFCD studies aimed to deliver 18 weeks of perioperative chemotherapy,
in both studies only 50% of patients who underwent preoperative
chemotherapy and surgery were able to receive or complete adjuvant
1188 Part III: Specific Malignancies

chemotherapy, further suggesting that most patients derived the survival
benefit of chemotherapy from receiving significantly less than 18 weeks
of treatment. The generally poor ability to deliver therapy after surgery
was also seen in the recently presented Dutch CRITICS study (to be
discussed later) and would suggest, especially given the absence of a
biologic rationale to split up the same systemic treatment with surgery,
that future experimental strategies should focus on exclusively preopera-
tive approaches.
Aside from the MAGIC and FFCD studies, other contemporary
phase III evaluations of preoperative or perioperative chemotherapy
in esophagogastric adenocarcinomas have either been negative or had
more marginal benefit. The North American Intergroup 113 trial
failed to show a survival benefit for perioperative 5-FU–cisplatin in
440 patients with esophageal cancer (approximately half of whom
had adenocarcinomas; eligibility limited extension of the tumor to
2 cm beyond the GEJ into the stomach).190 The MRC OEO-2 trial,
in which 802 patients were randomized to surgery alone versus two
cycles of preoperative 5-FU–cisplatin, reported a modest improvement
in 5-year OS with chemotherapy (23% versus 17%; P = .03).191
Two-thirds of patients had adenocarcinomas and three-quarters of
tumors were in the lower esophagus or gastric cardia. Most recently,
the European EORTC 40954 trial evaluated a strategy of preoperative
5-FU–leucovorin-cisplatin in 144 patients with GE and gastric adeno-
carcinoma.192 The trial was stopped because of poor accrual, which
limited the power of the study, and no differences in survival were
detected.
These data are summarized in Table 71.1. An updated meta-analysis
by Sjoquist and colleagues of 10 randomized trials involving preoperative
chemotherapy for esophageal and GEJ cancers suggested a 13%
decreased risk of all-cause mortality for this approach in patients with
adenocarcinomas versus surgery alone (HR, 0.87; 95% CI, 0.79–0.96;
P < .005).193 In this meta-analysis, both the MAGIC and EORTC
40954 trials were excluded because outcomes were not stratified based
on gastric versus GEJ tumors.
In comparison with a benefit for adenocarcinoma tumors, there
was only a trend toward benefit for preoperative chemotherapy in
SCC tumors (HR, 0.92; 95% CI, 0.81–1.04; P = .18).
CHEMOTHERAPY AFTER SURGERY
In comparison to chemoradiation, trials in East Asia of resectable
gastric cancer have frequently focused on postoperative chemotherapy
alone. To date, two large phase III trials have demonstrated a benefit
for this approach. These data support the use of adjuvant fluoropy-
rimidines as monotherapy and combination chemotherapy with a
fluoropyrimidine plus a platinum agent. The results are summarized
in Table 71.2 but should be interpreted with caution because these
trials have exclusively enrolled patients with gastric adenocarcinoma.
In East Asia, less than 10% of tumors occur in the proximal stomach
or GEJ, making it unclear if they are applicable to patients with
esophageal or GEJ adenocarcinoma.
ACTS-GC (Adjuvant Chemotherapy Trial of TS-1 for Gastric
Cancer) was performed in Japan. In this study of 1059 patients with
stage II/III gastric cancer who had undergone D2 resections, patients
were randomized to 1 year of adjuvant S-1 versus observation.187
Five-year outcomes for this trial were updated in 2011, confirming
that adjuvant S-1 is associated with significant improvements in 5-year
relapse-free survival (RFS) (65.4% versus 53.1%; HR, 0.65; 95% CI,
0.54–0.79) and OS (71.7% versus 61.1%; HR, 0.67; 95% CI,
0.54–0.83) compared with observation alone.194 Subgroup analyses
revealed benefit for all groups, including by stage and histologic type.
The second of these trials is the CLASSIC trial (capecitabine and
oxaliplatin adjuvant study in stomach cancer), which was performed
in 1035 East Asian patients who had undergone a D2 resection of
stage II–IIIB gastric cancer.188 Patients were randomized to 6 months
of adjuvant capecitabine-oxaliplatin versus observation. Updated survival
data confirmed improved 5-year OS for patients who received che-
motherapy (78% versus 69%; HR, 0.66; P = .0015); 5-year DFS was
also improved (68% versus 53%; HR, 0.58; P < .0001).195
The possibility of benefit for an adjuvant chemotherapy-only
approach for esophageal or GEJ adenocarcinoma was suggested by
a phase II study performed by ECOG of four cycles of postopera-
tive cisplatin-paclitaxel in patients with pT3–4N+ adenocarcinomas
of the esophagus, GEJ, and cardia.196 The results confirmed the
feasibility of the approach. Comparison with historical controls

Table 71.1  Esophageal Cancer Preoperative Chemotherapy Phase III Trials

SURVIVAL
Histologic No. of R0 Resection Pathologic Local
Treatment Type Patients Rate CR Rate Median Overall Failure Reference
Perioperative ECF + surgery Adenocarcinoma 250 69% 0% 24 mo 5 yr, 36% 14% Cunningham
Surgery 253 66% N/A 20 mo 5 yr, 23% 21% et al184
Perioperative 5-FU/cisplatin Adenocarcinoma 109 87% NS NS 5 yr, 38% 24% Ychou et al185
+ surgery
Surgery 110 74% N/A NS 5 yr, 24% 26%
Preoperative ECX + surgery Adenocarcinoma 446 67% 11% 25.8 3 yr, 42% NS Alderson et al186
Preoperative 5-FU/cisplatin 451 60% 3% 24.2 3 yr, 39% NS
+ surgery
Perioperative 5-FU/cisplatin Adenocarcinoma 213 62% 2.5% 14.9 mo 3 yr, 23% 32% Kelsen et al190
+ surgery (54%) + SCC
Surgery 227 59% N/A 16.1 mo 3 yr, 26% 31%
Preoperative 5-FU/cisplatin Adenocarcinoma 400 60% NS 16.8 mo 5 yr, 23% 19% Medical Research
+ surgery (66%) + SCC Council,260 Allum
Surgery 402 54% N/A 13.3 mo 5 yr, 17% 17% et al191
Preoperative 5-FU/LV/ Adenocarcinoma 72 82% 7.1% 64.6 mo 2 yr, 73% NS Schuhmacher
cisplatin + surgery et al192
Surgery 72 66.7% N/A 52.5 mo 2 yr, 69.9% NS

Boldface indicates statistically significant difference.

CR, Complete response; ECF, epirubicin, cisplatin, 5-fluorouracil; ECX, epirubicin, cisplatin, capecitabine; 5-FU, 5-fluorouracil; LV, leucovorin; N/A, not applicable; NS, not stated;
SCC, squamous cell carcinoma.

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 Cancer of the Esophagus  •  CHAPTER 71 1189

Table 71.2  Results of Phase III Postoperative Chemotherapy Trials in Esophageal and Gastric Cancer
SURVIVAL
No. of Local
Treatment Histologic Type Patients Median Overall Failure Reference
Surgery Adenocarcinoma 530 NR 5 yr, 61% 2.8% Sakuramoto et al,187
Surgery + S-1 (gastric) 529 NR 5 yr, 72% 1.3% Sasako et al194
Surgery Adenocarcinoma 515 NRa 5 yr, 78% 44% Bang et al.188,195
Surgery + Capeox (gastric) 520 NRa 5 yr, 69% 21%
Surgery SCC 100 NS 5 yr, 45% 30% Ando et al197
Surgery + cisplatin/vindesine 105 NS 5 yr, 48% 30%
Surgery SCC 122 NS 5 yr, 52% 46% Ando et al198
Surgery + 5-FU/cisplatin 120 NS 5 yr, 61% 8%
5-FU/cisplatin + surgery SCC 164 NS 5 yr, 55% NS Ando et al199
Surgery + 5-FU/cisplatin 166 NS 5 yr, 43% NS

a
Disease-free survival. Numbers in bold indicate statistically significant differences.
Capeox, Capecitabine-oxaliplatin; CR, complete response; 5-FU, 5-fluorouracil; NR, not reached; NS, not stated; SCC, squamous cell carcinoma.

suggested an improved survival (60% versus 38% 2-year survival;
P = .0008).
In comparison, postoperative chemotherapy for resected esophageal
SCC has not clearly been shown to be beneficial. This approach was
studied in two Japanese randomized trials in which patients with SCC
histology were randomized to receive two cycles of chemotherapy
with cisplatin-vindesine197 or 5-FU–cisplatin,198 respectively. Although
the trial with cisplatin-vindesine did not show any survival benefit,
an unplanned subset analysis of the trial with 5-FU–cisplatin revealed
a survival benefit for patients with lymph node involvement (5-year
DFS of 52% versus 38%).
The possible benefit of postoperative therapy suggested by the
aforementioned trial led to a subsequent Japanese trial in which 330
patients with SCC histologic type were randomized to surgery and
either two cycles of preoperative or postoperative 5-FU–cisplatin.199 The
results showed improved 5-year OS for the preoperative chemotherapy
group (55% versus 43%; P = .04), further raising questions about
the value of adjuvant chemotherapy in these patients. However,
interpretation of these results is confounded by the fact that only
96 of the 166 patients randomized to postoperative chemotherapy
received any treatment; 38 patients who had pN0 disease were not
treated per protocol because of the prior observation that adjuvant
chemotherapy benefited only patients with lymph node involvement.
Furthermore, this study observed that a survival benefit for preoperative
chemotherapy was seen only in N0 patients, which contrasted with
the prior postoperative adjuvant study that claimed a benefit only in
N1 patients.
PREOPERATIVE CHEMORADIATION
AND SURGERY
Standard Approaches
The seminal phase III US RTOG 85-01 study demonstrated the
superiority of chemoradiation over radiation alone.200 This nonoperative
study compared standard fractionation radiation (64 Gy) versus
radiation (50 Gy) plus concurrent 5-FU–cisplatin. The trial was stopped
when data from 121 patients showed an improved median OS in
favor of chemoradiation (12.5 versus 8.9 months). Two-year survival
was also improved in the chemoradiation group (38% versus 10%),
as was 5-year survival (21% versus 0%).201 Although the majority of
patients treated in this trial had SCC, long-term survival was also
seen in the small number of adenocarcinoma patients in the trial,
with 13% of patients alive at 5 years. Based on this study,
chemoradiation was established as the standard of care in the nonsurgical
management of locally advanced esophageal SCC.
Since then, preoperative chemoradiation has been evaluated
extensively in trials of esophageal or GEJ cancer. Six contemporary
randomized trials have compared preoperative chemoradiation followed
by surgery versus surgery alone.63,202–206 Of these, three have been
positive and revealed a survival benefit for this approach. These results
are summarized in Table 71.3.
A potential new standard of care was established by the rigorously
conducted Dutch CROSS trial.63 In this study of 366 evaluable patients
with esophageal tumors (of which 75% and 65%, respectively, were
adenocarcinomas and lymph node positive at EUS), patients were
randomized to preoperative carboplatin-paclitaxel combined with
41.4 Gy of radiation versus surgery alone. Preoperative chemoradiation
resulted in an improvement in R0 resection rates (92% versus 67%;
P < .001), in a pCR rate of 29% (23% for adenocarcinoma and 49%
for SCC), and in improved OS compared with surgery alone (median
OS, 49.4 versus 24.0 months; 3-year OS, 58% versus 44%; P = .003).
Preoperative therapy was also relatively well tolerated, with mostly
grade 3 toxicities noted in only 20% of patients (13% nonhematologic,
7% hematologic). There did appear to be a greater degree of benefit
for patients with SCC versus adenocarcinoma histologic type (univariate
HR for death, 0.45 versus 0.73), but all patients derived benefit.
Long-term follow-up of this study confirmed an OS benefit for both
adenocarcinoma and SCC patients, and a 9% reduction in distant
metastases was reported for patients who received preoperative
chemoradiation.189
Although this study demonstrated a clear benefit for chemoradiation,
it is not possible to definitively conclude that carboplatin-paclitaxel
is the preferred regimen when combined with radiation relative to
standard 5-FU–cisplatin used in other trials. Nevertheless, the pCR
rate of 49% in SCC is the highest ever reported in a phase III trial,
and the pCR rate of 23% for adenocarcinomas compares favorably
with the findings of other phase II/III studies. Coupled with the ease
of administration and tolerability, carboplatin-paclitaxel has become
the new standard of care and has become the reference regimen for
future trial design. However, initial results of the CALGB 80803
study suggest that a 5-FU–platinum regimen may be comparable or
even possibly superior (see later).
Overall, many of the other randomized trials conducted were
associated with methodologic concerns (including the lack of rig-
orous pretherapy staging with EUS and/or laparoscopy) and were
significantly smaller than randomized preoperative chemotherapy trials
(e.g., the positive CALGB 9781 study enrolled only 56 patients).

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1190 Part III: Specific Malignancies

Table 71.3  Results of Phase III Preoperative Chemoradiation Trials in Esophageal Cancer
SURVIVAL
No. of R0 Resection Pathologic Local
Treatment Histologic Type Patients Rate CR Rate Median Overall Failure Reference
Preoperative CRT Adenocarcinoma (76%) 50 45% 24% 16.9 mo 3 yr, 30% 19% Urba et al204
Surgery + SCC 50 45% N/A 17.6 mo 3 yr, 16% 42%
Preoperative CRT Adenocarcinoma 58 NS 25% 16 mo 3 yr, 32% NS Walsh et al205
Surgery 55 N/A 11 mo 3 yr, 6%
Preoperative CRT SCC 143 81% 26% 18.6 m 5 yr, 26% NS Bosset et al.202
Surgery 139 69% N/A 18.6 mo 5 yr, 26%
Preoperative CRT Adenocarcinoma (63%) 128 80% 9% 22.2 mo NS 15% Burmeister et al203
Surgery + SCC + other 128 59% N/A 19.3 mo 26%
Preoperative CRT Adenocarcinoma (75%) 30 NS 40% 4.5 yr 5 yr, 39% NS Tepper et al206
Surgery + SCC 26 N/A 1.8 yr 5 yr, 16%
Preoperative CRT Adenocarcinoma (74%) 178 92% 29% 49.4 mo 3 yr, 58% NS van Hagen et al63
Surgery + SCC 188 69% N/A 24.0 mo 3 yr, 44%

CR, Complete response; CRT, chemoradiation; N/A, not applicable; NS, not stated; SCC, squamous cell carcinoma.

Although the results of these trials are conflicting, they do at a
minimum suggest improved curative resection rates and decreased local
recurrence.
A benefit for preoperative chemoradiation is supported by the
previously discussed meta-analysis in which 13 randomized trials of
preoperative chemoradiation (including the five aforementioned trials)
were analyzed.193 Preoperative chemoradiation was associated with a
decreased risk of all-cause mortality of 25% (HR, 0.75; 95% CI,
0.59–0.95; P = .02) in patients with adenocarcinoma histologic type
versus surgery alone. There also appeared to be benefit for SCC tumors
(HR, 0.80; 95% CI, 0.68–0.93; P = .004).
Intensification of Combined Modality Therapy
Neoadjuvant Chemotherapy
The administration of systemic chemotherapy before chemoradiation
has several theoretical benefits. In a disease that is moderately che-
mosensitive, more chemotherapy may better control micrometastatic
disease. The approximately 70% dysphagia improvement rates of
chemotherapy may also reduce the need for feeding tube placement
during chemoradiation.
Despite these theoretical benefits, there does not appear to be a
benefit to such an approach. To date, the largest study that has evaluated
this approach is a randomized phase II study performed at MD
Anderson Cancer Center.207 One hundred and twenty-six patients
were randomized to receive either induction infusional 5-FU–oxaliplatin
followed by chemoradiation with 5-FU–oxaliplatin or chemoradiation
alone, followed by surgery in both groups. There was a nonsignificant
trend toward an increased pCR rate in the patients who received
induction chemotherapy (13% versus 26%; P = .094) but absolutely
no difference in survival outcomes (median OS, 43.7 versus 45.6
months; P = .69).
Although induction chemotherapy may not be beneficial in
and of itself, it can allow for early assessment by PET scan, to be
discussed later.
radiation or chemoradiation.209 Although there are technical and
radiobiologic differences between high-dose and low-dose rates, there
are no clear therapeutic advantages.
In the RTOG 92-07 trial, 75 patients (92% with SCC) received
the RTOG 85-01 combined modality regimen (5-FU–cisplatin/50 Gy)
followed by a boost during cycle 3 of chemotherapy with either low–
dose rate or high–dose rate brachytherapy.210 Although the complete
RR was 73% with a median follow-up of only 11 months, local
failure as the first site of failure occurred in 27%. Acute toxicity
included 58% grade 3 toxicities, 26% grade 4 toxicities, and 8%
treatment-related deaths. The cumulative incidence of fistula was 18%
per year, and the crude incidence was 14%. Of the six treatment-related
fistulas, three were fatal. Given this significant toxicity and a lack
of clear improvement in outcomes, this approach has been largely
abandoned.
External-Beam Radiotherapy
INT 0123 (RTOG 94-05) was the follow-up trial to RTOG 85-01.
In this trial, patients with either SCCs (85%) or adenocarcinomas
(15%) who were selected for a nonsurgical approach were randomized
to a slightly modified RTOG 85-01 combined modality regimen with
50.4 Gy versus the same chemotherapy with 64.8 Gy.211
The study was closed when an interim analysis revealed that it was
unlikely that the high-dose arm would achieve a superior survival
compared with the standard-dose arm. For the 218 eligible patients,
there was no significant difference in median OS (13.0 versus 18.1
months) or 2-year survival (31% versus 40%) in the high-dose versus
standard-dose arm. Eleven treatment-related deaths occurred in the
high-dose arm compared with two in the standard-dose arm. However,
7 of the 11 deaths occurred in patients who had received less than
50.4 Gy, making it unclear if the higher dose of radiation was
responsible for the apparent increased mortality. Based on the findings
of the INT 123 trial, the standard dose of external-beam radiation
remains 50.4 Gy.

Intensification of the Radiation Dose Preoperative Chemoradiation for

Intraluminal Brachytherapy
Another approach to the dose intensification of chemoradiation is
increasing the radiation dose, through either intraluminal brachytherapy
and/or external beam radiotherapy.
Intraluminal brachytherapy has been used both as primary therapy
(usually as a palliative modality)208 and as a boost after external beam
Early-Stage Disease
Although the aforementioned studies focused on locally advanced
tumors (which, by contemporary standards, would include staging
with EUS and consist mostly of uT3–4N+ tumors), in the French
FFCD 9901 study, 195 patients with early-stage cT1–2Nany or cT3N0
tumors were treated with preoperative 5-FU–cisplatin and radiation

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and surgery versus surgery alone.212 Seventy-two percent of patients
in this study had SCCs, and 24% and 74%, respectively, had cT1
and cN0 tumors. This study revealed a strikingly high 93% R0 resection
rate in the surgery-alone arm, which was not improved with preoperative
chemoradiation. Similarly, median DFS and OS were not significantly
different in both arms, but in-hospital postoperative mortality was
significantly increased in the chemoradiation arm (11.1% versus 3.4%;
P = .049).
These results are somewhat surprising. Despite the lack of
improvement in R0 resection rates, locoregional recurrence was
reduced in the chemoradiation arm (22.1% versus 28.9%; P = .02);
on the other hand, the rate of distant recurrence was not signifi-
cantly different between both arms (22.5% versus 28.9%; P = .31).
In addition, the unexpectedly high postoperative mortality in the
chemoradiation arm, compared with 4% in both treatment arms of
the CROSS study, might have obscured a small survival benefit from
chemoradiation.
Nevertheless, these results are not necessarily inconsistent with
other published data. An accepted approach, discussed later, is definitive
chemoradiation without surgery for patients with SCC who achieve
a clinical complete response (CR). Because 72% of patients in this
study had SCC tumors, it suggests the complementary conclusion
that SCC patients who do undergo chemoradiation should not undergo
mandatory surgery. Similarly, these results are concordant with current
guidelines from the National Comprehensive Cancer Network, which
recommend surgery alone for patients with cT1N0 tumors.
Preoperative Chemoradiation Versus Chemotherapy
The possible superiority of preoperative chemoradiation over preopera-
tive chemotherapy was suggested by the German POET (Preoperative
Chemotherapy or Radiochemotherapy in Esophagogastric Adenocar-
cinoma Trial) study, in which patients with GEJ adenocarcinomas
were randomized to either 5-FU–leucovorin–cisplatin followed by
surgery or 5-FU–leucovorin–cisplatin followed by chemoradiation
with cisplatin-etoposide and then surgery.213 One hundred nineteen
eligible patients were randomized before the trial was closed because
of poor accrual, limiting the power of this study to detect a difference
between the treatment groups. Nevertheless, patients who received
preoperative chemoradiation had a higher pCR rate (15.6% versus
2%; P = .03) and tumor-free lymph node status (ypN0 64.4% versus
36.7%; P = .01) than those who received preoperative chemotherapy.
There were also trends toward an improvement in local control (76.5%
versus 59%; P = .06) and in 3-year OS (47.4% versus 27.7%; P =
.07) for the chemoradiation group that nearly approached statistical
significance.
A similar nonsignificant trend toward improved outcomes with
preoperative chemoradiation over chemotherapy for adenocarcinoma
histologic type was also suggested in the meta-analysis by Sjoquist
and colleagues, which revealed an all-cause mortality HR of 0.88
(95% CI, 0.76–1.01; P = .07) favoring chemoradiation.193
A major benefit of preoperative chemoradiation over chemotherapy
alone may stem from an improvement in R0 resection rates for tumors
that involve the GEJ. For example, the R0 resection rates in the 1400
patients treated in the contemporary MAGIC and OEO-5 studies
were consistently below 70%; in the OEO-5 study, the majority of
patients were assessed to be surgical candidates based on preoperative
EUS and PET scan. The addition of radiation to preoperative che-
motherapy in the CROSS study improved the R0 resection rate to
greater than 90%.
POSTOPERATIVE CHEMORADIATION
In the United States, a standard of care is postoperative chemoradiation
for GEJ and gastric cancers undergoing up-front resection, based
primarily on the results of the Intergroup 116 trial.214 In this trial,
556 patients (20% of whom had tumors that involved the GEJ) were
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Cancer of the Esophagus  •  CHAPTER 71 1191
randomized to adjuvant chemotherapy and chemoradiation with bolus
5-FU–leucovorin versus observation alone after surgery. Patients who
received adjuvant chemoradiation had an improvement in RFS (3-year
RFS, 48% versus 31%; P < .001; and 3-year OS, 51% versus 40%;
P = .005). Despite these positive results, this trial is frequently criticized
because of the relatively inadequate surgical resections that were
performed; 54% of patients had less than a D1 or D2 resection, which
is less than an optimal resection of the involved lymph nodes. It has
been argued that radiation in this setting potentially compensated for
inadequate surgery because the greatest impact of adjuvant chemoradia-
tion was a reduction in local recurrence of cancer. Such benefits may
not be seen for radiotherapy if a more complete D1 or D2 surgical
resection is undertaken.
Based on the results of the Intergroup trial, the CALGB launched
and completed the 80101 trial. A total of 546 gastric cancer patients
(30% of whom had tumors involving the GEJ and proximal stomach)
were enrolled. The standard arm consisted of systemic bolus 5-FU–
leucovorin preceding and following chemoradiation with infusional
5-FU; the experimental arm intensified the systemic chemotherapy
by replacing the bolus 5-FU–leucovorin with the ECF regimen.
Results have been presented in abstract form and reveal no improve-
ment in 3-year DFS (47% versus 46%) or OS (52% versus 50%)
with the addition of an anthracycline and platinum compound to
5-FU.215 These results are also virtually identical to the outcomes in
the adjuvant chemoradiation arm of the Intergroup 116 trial. These
results indicate that 5-FU monotherapy, combined with radiation,
remains a standard of care and that adding cisplatin and epirubicin
to adjuvant chemotherapy failed to improve survival. ECF should
not be used as an adjuvant chemotherapy regimen, although preop-
erative and postoperative ECF without radiation therapy remains a
care standard.
Finally, the Dutch CRITICS study evaluated an alternative to the
perioperative ECF approach by randomizing patients (38% of whom
had GEJ or proximal gastric adenocarcinomas) to perioperative ECX or
EOX (epirubicin-oxaliplatin-capecitabine) chemotherapy (the control
arm) versus preoperative ECX-EOX and adjuvant chemoradiation
with capecitabine. The results revealed no difference in PFS and
OS for either treatment arm.216 Although subgroup analyses are
planned, the nearly superimposable Kaplan-Meier survival curves
confirm, for now at least, that patients who have received preopera-
tive chemotherapy should not receive adjuvant chemoradiation in a
standard fashion.
These results are shown in Table 71.4.
IS SURGERY NECESSARY AFTER COMBINED
MODALITY THERAPY?
Two randomized European trials compared definitive chemoradiation
versus chemoradiation followed by surgery in (mostly) esophageal
SCC patients.217,218 Taken together, both studies suggest that local
control is improved by subsequent surgery but that there is no clear
improvement in survival.
In the setting of definitive chemoradiation, FOLFOX (5-FU–
leucovorin–oxaliplatin) also appears to be a comparable option to
5-FU–cisplatin based on the French PRODIGE5/ACCORD17
study, in which 267 patients were randomized to either regimen with
radiation as definitive therapy.219 Eighty-five percent of the patients
in this study had SCC. Survival and toxicities were comparable in
both arms.
An interesting question that arises from one of these studies (the
FFCD 9102 trial) is whether patients who do not respond to initial
therapy benefit from subsequent surgery. In this study, patients
received initial treatment with 5-FU–cisplatin and radiation; only
responders were subsequently randomized to surgery versus additional
chemoradiation. A total of 192 of the 451 registered patients were
not randomized to further protocol therapy after initial chemoradia-
tion, primarily because of a lack of response (111 patients) but also
1192 Part III: Specific Malignancies

Table 71.4  Results of Phase III Postoperative Chemoradiation Trials in Esophageal Cancer
DISEASE-FREE
SURVIVAL OVERALL SURVIVAL
No. of Local
Treatment Patients Median Overall Median Overall Failurea Reference
Surgery 275 19 mo 3 yr, 31% 27 mo 3 yr, 41% 29% MacDonald et al214
Postoperative 5FU/LV → 5-FU/RT → 5-FU/LV 281 30 mo 3 yr, 48% 36 mo 3 yr, 50% 19%
Postoperative 5-FU/LV → 5-FU/RT → 5-FU/LV 280 30 mo 3 yr, 46% 36.6 mo 3 yr, 50% NS Fuchs et al215
5 yr, 41%
Postoperative ECF → 5-FU/RT → ECF 266 28 mo 3 yr, 47% 37.8 mo 3 yr, 52% NS
5 yr, 44%
ECX/EOX → Surgery → ECX/EOX 393 27.6 mo 5 yr, 38.5% 42 mo 5 yr, 40.8% NS Verheij et al216
ECX/EOX → Surgery → Chemoradiation 395 30 mo 5 yr, 39.5% 39.6 mo 5 yr, 40.9% NS

a
Local failure with or without distant recurrence; entries in bold indicate statistically significant differences.
ECF, Epirubicin/cisplatin/infusional 5-fluorouracil; ECX, epirubicin/cisplatin/capecitabine; EOX, epirubicin/oxaliplatin/capecitabine; 5-FU, 5-fluorouracil; LV, leucovorin; NS, not
stated.

because of medical contraindication or patient refusal.220 Of these
nonrandomized patients, 112 subsequently underwent surgery. The
median OS for the nonresponding patients who underwent surgery
was significantly superior to the median OS of those who did not (17.0
versus 5.5 months; P < .0001) and was comparable to the median
OS of the patients who were randomized (18.9 months; P = .40).
Although there are clear limitations and potential strong confounders
to such an analysis, these data suggest that salvage esophagectomy may
be beneficial in a subset of patients who do not respond to initial
therapy.
On the other hand, there are no randomized data in patients with
adenocarcinomas to suggest that definitive chemoradiation is comparable
to chemoradiation and surgery. However, given the significant morbidity
and mortality associated with esophagectomy even at high-volume
institutions, one option is to closely follow adenocarcinoma patients
who achieve a clinical CR to preoperative chemoradiation—especially
those who are relatively frail—with repeat endoscopy and imaging.
Those patients who develop locoregional failure without distant
metastases may then be evaluated for salvage esophagectomy.
A major concern about such an approach is that postoperative
complications and deaths may significantly increase when surgery is
delayed beyond the standard 6- to 8-week break after chemoradiation.
The group at MD Anderson Cancer Center reported their experience
in 65 patients with esophageal adenocarcinoma who underwent salvage
esophagectomies a median of 216 days after chemoradiation.221 When
compared with matched patients who underwent planned esophagec-
tomy after chemoradiation, postoperative complications and survival
did not appear to be different.
Similar conclusions were drawn from a retrospective French
review, which examined this approach in 848 patients, 540 of whom
underwent esophagectomy after preoperative chemoradiation and
308 who underwent salvage surgery after chemoradiation for either
persistent cancer (234 patients) or recurrent cancer (74 patients).222
Although the rates of anastomotic leak and surgical infection were
increased in the salvage versus immediate surgery groups, in-hospital
mortality rates were similar and relatively high in both groups (8.4%
versus 9.3%; P = .688). Three-year DFS (39.2% versus 32.8%; P =
.232) and OS (43.3% versus 40.1%; P = .542) were also similar in
both groups.
In addition, the RTOG 0246 study evaluated induction che-
motherapy with 5-FU–cisplatin-paclitaxel and chemoradiation
with 5-FU–cisplatin in 43 patients with locally advanced esopha-
geal cancer; salvage surgery was reserved for patients with locally
persistent or recurrent disease.223 Although the study did not meet
its primary end point of improving 1-year survival to 77.5%, the
findings did suggest that postoperative mortality was not increased
by delaying surgery. Therefore such an approach can be considered
for select patients at institutions with significant experience with
this strategy.
POSITRON EMISSION TOMOGRAPHY–
DIRECTED THERAPY
Fluorodeoxyglucose–positron emission tomography (FDG-PET)
scanning is emerging as an important tool to investigate response to
therapy. Several studies in esophagogastric tumors have demonstrated
that the degree of response detected with PET after preoperative
chemoradiation224,225 or chemotherapy226,227 is highly correlated with
pathologic response at surgery and with patient survival.
The German MUNICON trial evaluated the strategy of taking
patients with locally advanced GEJ adenocarcinomas with a suboptimal
response to 2 weeks of induction chemotherapy with 5-FU–cisplatin,
as determined with serial PET scans, directly to surgery, instead of
continuing with presumably ineffective chemotherapy. Patients with
a metabolic response demonstrated with PET (defined as ≥35%
reduction in standard uptake value between baseline and repeat PET
scan) continued with an additional 12 weeks of chemotherapy before
surgery.228 This trial revealed a significantly improved R0 resection
rate (96% versus 74%; P = .002), major pathologic RR (58%
versus 0%; P = .001), median event-free survival (29.7 versus 14.1
months; P = .002), and median OS (median not reached versus 25.8
months; P = .015) for PET responders versus PET nonresponders.
The outcome for PET nonresponders referred for immediate surgery
was similar to the outcome of such patients in an earlier trial who
completed 3 months of preoperative chemotherapy,226 indicating
that nonresponding patients were not compromised by referral to
immediate surgery. These results therefore support the early discontinu-
ation of inactive preoperative chemotherapy in PET nonresponder
patients.
Building on the results of the MUNICON trial, the MUNICON-2
trial attempted to improve outcome in the PET nonresponders to the
same regimen of preoperative 5-FU–cisplatin by treating them with
“salvage” chemoradiation with cisplatin before surgery.229 When
compared with the PET responders who completed 3 months of
5-FU–cisplatin before surgery, the PET nonresponders had inferior
2-year PFS (64% versus 33%; P = .035) and a trend toward inferior
2-year OS (71% versus 42%; P = .10). These results likely speak to
the underlying unfavorable biologic features of the tumors of PET
nonresponders but do not rule out the possibility that such patients
can receive effective salvage therapy. In this trial, the chemotherapy

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administered with radiation (cisplatin) had already been assessed to
be associated with suboptimal outcomes at PET scanning when
administered as induction therapy.
Another possible strategy would be to use PET assessment after
induction chemotherapy to dictate subsequent chemotherapy during
concurrent radiation. Responding patients can continue with the same
chemotherapy regimen during concurrent radiation, whereas nonre-
sponding patients can be switched to alternative, non–cross-resistant
chemotherapy during radiation. Our group has reported long-term
DFS in patients whose disease progressed on induction chemotherapy
but who were changed to alternative chemotherapy during subsequent
chemoradiation.230
We have also since retrospectively reviewed our experience of
changing to alternative chemotherapy during radiation for some PET
nonresponders to induction chemotherapy in 201 patients with
esophageal or GEJ adenocarcinomas.231 Our data suggest that improve-
ments in pCR rate and PFS are possible and that there is also a trend
toward improved OS.
Based on this concept, the CALGB completed the 80803 trial,
which enrolled patients with esophageal or GEJ adenocarcinomas.
Participants were randomized to receive induction chemotherapy
with either carboplatin-paclitaxel or a modification of the FOLFOX6
regimen (infusional 5-FU–leucovorin–oxaliplatin). Responses to induc-
tion chemotherapy were then adjudicated with an early PET scan
performed after induction chemotherapy. Although PET responders
continued with the same regimen during concurrent radiation, PET
nonresponders were changed to the alternative regimen with radiation
before surgery. The primary end point was to improve the pCR rate
in PET nonresponder patients by changing chemotherapy during
combined chemoradiation.
Results have very recently been presented in abstract form and
indicate an improvement in the pCR rate in PET nonresponders who
change chemotherapy to 17% PET non-responders to carboplatin/
paclitaxel and 19% FOLFOX (compared with a historical rate of 3%
in our retrospective analysis), meeting the primary end point of the
study.232 It is also of significant interest that the pCR rate in the PET
responders to induction FOLFOX who received 5-FU–oxaliplatin
with radiation is 37.5%, whereas the pCR rate in the PET responders
to induction carboplatin-paclitaxel who received that regimen with
radiation is 12.5%. The number of patients in these two groups is
relatively small (64 and 56, respectively) and the study was not designed
to detect a difference in outcomes between the two induction regimens.
These results also seem to suggest the opposite conclusion of the
UK NEOSCOPE study, in which 85 patients were randomized to
induction capecitabine-oxaliplatin, followed by concurrent chemoradia-
tion with carboplatin-paclitaxel versus capecitabine-oxaliplatin. Results
presented in abstract form revealed a pCR rate of 28% versus 12%
for the carboplatin-paclitaxel versus capecitabine-oxaliplatin group.233
Of course, the lack of PET assessment in the NEOSCOPE study and
the administration of induction capecitabine-oxaliplatin to all patients
make it impossible to infer any conclusions.
The results of the CALGB 80803 study are hypothesis generat-
ing, and clinical equipoise continues to exist about what the optimal
chemotherapy regimen to combine with radiation is, especially
because treatment was well tolerated in both arms. Survival data
are pending.
MANAGEMENT OF TRACHEOESOPHAGEAL
FISTULA
In the United States, esophageal cancer with airway invasion is fairly
uncommon. In a series from the Washington, DC Veterans Affairs
hospital from 1985 to 1998, 20% of patients with established esophageal
cancer had airway involvement, with 9.4% having fistulous connec-
tions.234 The vast majority (88%) of these patients had SCC, consistent
with the location of these tumors in the cervical and proximal esophagus.
As the incidence of the SCC histology has steadily decreased, the
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Cancer of the Esophagus  •  CHAPTER 71 1193
incidence of airway invasion with or without fistulas also appears to
have decreased.
Irrespective of its incidence, the treatment of esophageal cancer
with airway invasion with or without fistula continues to present
difficult management decisions. Primary surgical resection is generally
considered inadvisable because of the substantial treatment-related
mortality and morbidity. In a series of 28 patients with known airway
invasion without fistulas who underwent surgical exploration with or
without esophagectomy, the operative mortality was 17%.235 Other
approaches have included palliative treatments, such as the placement
of endoesophageal stents to relieve malignant dysphagia or to occlude
a fistula or single-modality radiation therapy.236 Left untreated, patients
with airway fistulas have a median survival of only 1 to 6 weeks.236,237
Small Japanese studies have focused on the use of combined
chemoradiation to treat patients with T4 tumors with or without
fistulas.238–240 Although these studies have demonstrated long-term
survival in a minority of patients, they have also been associated with
the worsening or development of new fistulas and treatment-related
deaths in a significant proportion of patients. For example, in a phase
I/II evaluation, Nishimura and colleagues treated 28 patients with
esophageal squamous cell cancers with airway invasion with or without
fistulas.239 Patients received protracted infusion 5-FU–cisplatin, along
with split-dose radiation to a total dose of 60 Gy over 30 fractions.
This study reported an encouraging 2-year survival rate of 27% for
the patients with stage III (T4N+M0) disease.241 However, this was
at the expense of significant toxicity, including the development or
worsening of fistulas in 18% of patients and treatment-related deaths
in 7% of patients.
Given the significant potential toxicities associated with up-front
chemoradiation, one option is induction chemotherapy in an attempt
to downstage the primary tumor and to potentially reduce the risk
of fistula formation or progression with subsequent chemoradiation.
We previously published a case report of a patient with a T4 tumor
and tracheoesophageal fistula who underwent induction chemotherapy
and reassessment with PET scan and bronchoscopy.242 These revealed
significant response in the tumor and complete healing of the fistula.
He then received chemoradiation and achieved a prolonged clinical
complete response.
CERVICAL ESOPHAGEAL CANCER
Cervical esophageal cancer (almost always SCC) is a particular treatment
challenge. The surgery required is often quite extensive, requiring a
total laryngopharyngoesophagectomy, an operation associated with
significant dysfunction and morbidity. This has led to the use of
definitive chemoradiation as the preferred alternative in many patients.
Definitive radiation is fraught with technical difficulty in achieving
an adequate dose, given the complexity of treating a structure in
proximity to the spinal cord, the varying shape of the thorax and
upper neck, and the bilateral lymph nodes at risk. The optimal dose
is unknown, with some radiation oncologists advocating for a higher
dose (approximately 70 Gy versus the 50.4 Gy that was used in the
RTOG 85-01 study200) than commonly used for treatment of head
and neck SCCs in or bordering the cervical esophagus. Although
this seems reasonable given the similar biologic characteristics and
behavior that may underlie all aerodigestive SCCs and given that
tumors of the head and neck and cervical esophagus are in reality
separated by only several centimeters, enthusiasm for such an approach
is also dampened by the negative results of studies in esophageal
cancer in which the dose of radiation was augmented, namely
RTOG 94-05.211
Data for higher doses of radiation in this context are extremely
limited; a retrospective analysis of 44 patients has suggested a benefit
for higher doses of radiation (68.1 versus 60 Gy),243 although there
is always a concern that short- and long-term toxicity could be higher.
In another series, 34 patients were treated with 5-FU–cisplatin che-
motherapy and radiation to 61.2 Gy.244 The local control rate was
1194 Part III: Specific Malignancies
88%, and the 5-year OS estimate was 55%. Acute toxicity was
acceptable, but two patients died from complications of strictures.
In the absence of clear-cut data, treatment needs to be individualized
and based on multidisciplinary evaluation and consensus.
TREATMENT OF DYSPHAGIA
Chemotherapy and Radiation
Esophageal obstruction due to malignancy can lead to dysphagia that
can be the source of very significant morbidity. Therefore the restoration
of the ability to swallow is a key objective of both curative and palliative
treatments. The management of malignant esophageal obstruction
should not compromise or interfere with curative therapy. Placement
of a percutaneous gastric or jejunostomy feeding tube and esophageal
stents may be useful in temporizing symptoms, improving QoL, and
optimizing the patient’s nutritional status while curative therapy is
initiated. Other endoluminal treatments such as laser therapy, PDT,
or brachytherapy are generally not appropriate in situations in which
curative treatment is the goal. For patients who are not candidates
for curative therapy, the palliative treatment selected often depends
on the likelihood of success given the length and location of the lesion,
life expectancy, the burden of metastatic disease, and the expertise of
the treating team.
Chemotherapy trials have reported significant palliation of patient
dysphagia with chemotherapy alone.64,92,114,119 Spiridonidis and col-
leagues treated patients who had unresectable or metastatic esophageal
cancer with cisplatin and etoposide.261 Of 18 evaluable patients with
dysphagia, 89% experienced relief of dysphagia within 3 weeks of
initiating chemotherapy. Of 25 patients with dysphagia before therapy
with cisplatin and paclitaxel, 18 showed complete resolution (72%)
and 2 had partial resolution of dysphagia (8%) with chemotherapy.
In a trial using a combination of weekly irinotecan and cisplatin, 20
patients had evaluable dysphagia; 14 patients (70%) had complete
resolution; and 4 patients (20%) experienced improvement of dysphagia,
with improvement occurring after a median of one treatment cycle.119
In an older phase III trial, Ross and McKenna treated nearly 600
patients with esophageal or gastric cancer with either the ECF regimen
or mitomycin combined with cisplatin and 5-FU infusion.92 In patients
evaluable for dysphagia, in both treatment arms 77% of patients
reported improvement in dysphagia symptoms. The rate of dysphagia
relief reported in these trials correlated with antitumor RRs ranging
from 40% to 50%.
There are relatively limited data on the ability of chemoradiation
to improve dysphagia. Coia and colleagues reported a series of patients
treated in the 1980s; within 2 weeks after the start of chemoradiation,
45% had improvement in dysphagia, and by the completion of the
sixth week, 83% had improvement.245 Overall, 88% had an improve-
ment in dysphagia, with a median time to maximum improvement
of 4 weeks. Histologic features and stage had no impact on the rate
of palliation. In another series from the 1990s, 106 patients were
treated and 51% maintained improved swallowing until the time of
last follow-up or death.246
One of the few randomized studies to compare palliative radiation
to 30 to 35 Gy alone versus chemoradiation with cisplatin is the
TROG 03.01/NCIC CTG ES2 study performed in the United
Kingdom, Canada, Australia, and New Zealand.247 The abstract
presentation shows that there was only a nonsignificant trend in favor
of improvement in dysphagia at 9 weeks maintained at 13 weeks for
chemoradiation versus radiation (47% versus 41%; P = .42), at the
expense of increased toxicity.
Intraluminal brachytherapy is also an effective, albeit more
limited, method of achieving palliation of dysphagia in 40% to
90% of patients.248,249 In a randomized trial from the Dutch SIREC
Study Group of stent versus one 12-Gy fraction of brachytherapy,
dysphagia, as measured by a variety of QoL scales, improved more
rapidly after stent placement; however, long-term relief was superior
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after brachytherapy.208 One potential benefit is that brachytherapy
can be used in patients previously treated with external beam radio-
therapy.250 Such a situation may arise in a patient with medically
inoperable disease with local persistence or recurrence after definitive
chemoradiation.
The choice of palliative radiation and/or chemotherapy to treat
dysphagia has to be carefully made based on patient factors, including
the burden of metastatic disease. For patients with significant metastatic
disease, an initial trial of chemotherapy is warranted, given its significant
dysphagia improvement rates and the imperative to rapidly control
systemic disease and to stabilize the patient’s performance status. On
the other hand, initial treatment with palliative radiation is an option
for patients with small-volume metastatic disease and significant
dysphagia. The endoscopic procedures discussed in the following section
can also be incorporated into treatment decisions, hopefully offering
patients several different opportunities and modalities to reduce this
extremely debilitating symptom.
Endoscopic Techniques
The available endoscopic options for management of malignant
dysphagia have shifted from the use of rigid funnel-shaped tubes to
the use of expandable stents, laser fulguration, and PDT. Because
there are no large studies directly comparing the efficacy of the available
endoscopic treatment modalities, the treatment modality chosen for
each patient depends on the length, location, and angulation of the
stricture, the patient’s overall health status, the cost of the technique,
the experience of the endoscopist, and the presence or absence of a
tracheoesophageal (TE) fistula.
Because of the relatively high incidence of complications, rigid
funnel tubes have been replaced by self-expanding metallic stents
(SEMSs) and self-expanding plastic stents (SEPSs) that are compressible,
are easier to place, and have fewer complications.251–253 The first-
generation SEMSs were uncovered and were associated with rapid
tumor ingrowth, resulting in stent obstruction. Up to 78% of patients
who survived at least 4 months required repeat endoscopic intervention
for palliation from tumor ingrowth. Newer SEMSs are covered with
polyethylene, polyurethane, or silicone sheaths to delay or prevent
ingrowth of tumor, substantially reducing the need for repeat endoscopic
procedures. SEMSs require less tumor dilation for insertion, expand
to greater luminal diameter than rigid stents, and have thinner walls
to minimize erosion and hemorrhage. SEMSs may be “stacked” to
manage tumor growth over the top of a previously placed expandable
stent. Successful insertion of an SEMS is reported to occur in more
than 90% of patients. Initial complications are less frequent and less
morbid than those reported with the use of rigid tubes.
In a series of 127 stent placements in 100 patients, researchers
reported that no fatal complications occurred, 1.6% of patients had
severe pain necessitating removal, 3.1% of patients had inadequate
deployment, 0.8% of patients experienced perforation, 7.9% of patients
had a food impaction, 11% of patients reported severe reflux, and
8.7% of patients developed stent migration requiring removal. Two
of 16 patients who underwent subsequent chemotherapy after stent
placement developed stent erosion through the esophageal wall. Studies
suggest an increased rate of stent-related complications in patients
who have undergone prior chemoradiation.252
Patients will have severe reflux when the esophageal stent traverses
the GEJ, and this may result in life-threatening aspiration. There is
an SEMS with an antireflux valve that may reduce risk of reflux;
however, its success in clinical practice is muted, and widespread use
of the antireflux stent is not practiced.
Stents placed distally into the gastric lumen may be prone to
migration, and/or the distal end may cause gastric mucosal ulceration
resulting in hemorrhage. This can often be managed endoscopically.
SEMSs cannot be placed within 2 cm of the cricopharyngeal muscle
because patients cannot tolerate the SEMS because of severe pain and
the sensation of a foreign body in the upper esophagus.
 Cancer of the Esophagus  •  CHAPTER 71 1195

There is no difference in efficacy or complication rates among any
of the currently available SEMSs. SEPSs are also available and indicated
for malignant dysphagia, but there are no comparative studies between
SEPSs and SEMSs. SEPSs can be better tolerated if placed near the
cricopharyngeal muscle, and they are removable. However, the migration
rate may be increased when compared with SEMSs. Despite these
complications, placement of esophageal stents for malignant dysphagia
does improve swallowing in 88% to 100% of patients.
A clear indication for placement of an SEMS is the presence of a
TE fistula. As compared with other endoscopic options, placement
of an SEMS is often a successful palliative measure. In small series,
SEMSs were found effective in sealing a TE fistula, with low complica-
tion rates.250,254,255 Consideration should be given to placing a respiratory
stent as well.
Other endoscopic options for palliation of malignant dysphagia
include neodymium:yttrium-aluminum-garnet (Nd:YAG) laser,
electrofulguration with monopolar or bipolar (BICAP) coagulation,
and PDT.256–258
Electrofulguration techniques use either a monopolar probe or a
BICAP device. The monopolar probe directly coagulates the obstructing
endoluminal tumor under endoscopic control. The BICAP tumor
probe is passed through the narrowed esophageal lumen over a
guidewire. The mechanism of action of the BICAP probe includes
dilation of the narrowed lumen, tumor coagulation, hyperthermia,
and tissue necrosis with delayed sloughing. Because the BICAP probe
coagulates blindly and circumferentially, it is not recommended for
noncircumferential lesions, because injury to the normal esophageal
mucosa may result in perforation. Comparisons of electrocoagulation
(monopolar or bipolar) with Nd:YAG laser techniques have shown
comparable results in terms of morbidity, mortality, and relief of
dysphagia.
PDT is a technology that has generated a great deal of interest,
although it is not currently widely used (for reasons that will be
discussed shortly). This technique involves the administration of a
chemical sensitizer, usually hematoporphyrin derivative or dihemato-
porphyrin ethers, that accumulates preferentially in the target tumor.
The tumor is then exposed to a specific wavelength of low-power
laser light that activates the accumulated sensitizing chemical, resulting
in tumor necrosis mediated by production of singlet oxygen radicals.
The light penetrates only several millimeters, so this therapy is most
useful for palliative benefit because only superficial tumors would be
treated in their entirety.
Studies have documented that PDT is at least equally as effective
as laser therapy in palliation in patients with esophageal cancer and
is associated with a lower incidence of perforation.257,258 In a series of
215 patients undergoing palliative PDT, the mean dysphagia-free
interval was 66 days.259 Complications included perforation (2%),
stricture (2%), Candida esophagitis (2%), pleural effusions (4%), and
sunburn (6%). The procedure-related mortality rate was 1.8%.
Disadvantages of PDT relative to other methods of endoscopic pal-
liation, which have severely limited its use, include a prolonged period
of photosensitivity and significant cost (for both the laser and the
chemical agents).
The complete reference list is available online at
ExpertConsult.com.

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