The

Oncologist

Meet The Professor

Multimodality Therapy for Esophageal Cancer
J.R. SIEWERT, H.J. STEIN, U. FINK
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar der TU Mnchen, Mnchen, Germany
Key Words. Esophageal cancer Multimodality therapy Neoadjuvant therapy Adjuvant therapy Additive therapy

A BSTRACT
Adjuvant and neoadjuvant therapeutic principles
have in recent years received increasing attention in the
management of patients with esophageal cancer. A
series of randomized prospective trials has convincingly
demonstrated that adjuvant postoperative radiation or
chemotherapy does not result in a survival advantage
after a complete tumor resection. The available data on
the role of neoadjuvant preoperative therapy in patients
with adenocarcinoma or squamous cell carcinoma of
the esophagus are not yet conclusive. While neoadjuvant therapy may undoubtedly reduce the tumor mass
in a substantial portion of patients, a series of randomized controlled trials has shown that compared with primary resection, a multimodal approach does not result
in a survival benefit in patients with locoregional, i.e.,
potentially resectable, tumors. In contrast, in patients
with locally advanced tumors, i.e., tumors in which a
complete tumor removal with primary surgery appears

unlikely, neoadjuvant therapy allows a marked downstaging of the primary tumor and thus significantly
increases the chance for complete tumor removal on
subsequent surgery. However, only patients with objective clinical or histopathological response to preoperative therapy appear to benefit from this approach.
Compared with preoperative chemotherapy alone, combined radiochemotherapy increases the rate of response
but may also increase postoperative morbidity and mortality. Neoadjuvant therapy should therefore currently
be performed only in experienced centers within the
context of clinical trials. The identification of factors
which would facilitate prediction of the response to
neoadjuvant therapy is currently the focus of several
studies. Furthermore, more effective and less toxic preoperative therapy regimens are required to increase
the response rates and combat systemic recurrences.
The Oncologist 1996;1:210-218

INTRODUCTION
In past decades, there have been marked advances in
the surgical management of patients with esophageal
cancer. Detailed preoperative risk analysis, standardized resection and reconstruction techniques and aggressive perioperative management have reduced postoperative mortality of en bloc esophagectomy with systematic
lymph node dissection to below 5% in experienced centers [1-5]. The majority of patients with early esophageal
carcinoma limited to the mucosa or submucosa can be
cured with this approach. Even in patients with more
advanced tumors or early stages of lymphatic spread, the

five-year survival rate after surgical resection

approaches 40% provided that a complete macroscopic
and microscopic tumor resection is performed with sufficient margins in the area of the primary tumor and the
lymphatic
drainage, i.e., an Meet The Professor
R0-resection in The Oncologist encourages you to
the International pose questions or comments to the
Union Against authors. To use this interactive jourCancer (UICC) nalism, please see details on how you
classification [6], can M EET T HE P ROFESSOR on page 218.
is achieved [1, 2].

Correspondence: Dr. med. H.J. Stein, Chirurgische Klinik und Poliklinik der TU Mnchen, Klinikum rechts der Isar, Ismaninger
Str. 22, D-81675 Mnchen, Germany. Telephone: 49-89-41-402-037; Fax: 49-89-41-404-940. Accepted for publication May 20,
1996. AlphaMed Press 1083-7159/96/$5.00/0

The Oncologist 1996;1:210-218

211

Figure 1. Prevalence of lymph node metastases in patients with esophageal cancer in relationship to the T stage and histologic tumor type (constructed based
on data given by Roder et al. [1] and Hlscher et al. [2]).

Despite these advances, the overall prognosis of patients

with esophageal carcinoma has not improved markedly [7].
This is due to the usually late diagnosis of squamous cell or
adenocarcinoma of the esophagus. At the time of presentation, the tumor has usually grown beyond the esophageal
wall and extensive lymph node or distant metastases are present. Furthermore, lymph node metastases can already be
documented in up to 30% of the patients with early tumors
(Fig. 1). Finally, the close anatomic relationship between the
proximal esophagus and the tracheobronchial tree frequently
prohibits an extensive resection with adequate safety margins
in the affected patients [8]. A complete macroscopic and
microscopic tumor resection is consequently not possible in
the majority of patients presenting with esophageal cancer.
Even extended surgical resection usually remains palliative
in these patients.
This situation has resulted in an increased interest in
neoadjuvant and adjuvant therapeutic modalities, i.e.,
radiation, chemotherapy or combined radiochemotherapy
before or after surgical resection, in the management of
patients with esophageal cancer [9-11]. In the following
review, the clinical role of these multimodal therapeutic
approaches is critically analyzed based on the original published data. Whenever possible, randomized phase III trials
were considered. Only where randomized trials were not
available were phase II studies also included in the analysis.
Despite the large number of available studies, no firm
conclusions can be drawn in most instances. This is because
of a series of shortcomings in many studies which have to be
taken into account when interpreting the data. In most studies, tumor length is used to stratify the patients, rather than
the prognostically more important factor of depth-of-wall
penetration. Endoscopic ultrasound, the most accurate tool

Multimodality Therapy for Esophageal Cancer

for assessing wall penetration, is usually not used in the
pretherapeutic assessment. Furthermore, adenocarcinoma
and squamous cell carcinoma, which biologically represent
different tumor entities, are often not separated. In addition,
the extent of resection and lymphadenectomy, both of which
may influence the prognosis of the patient [1, 2, 4, 5], is usually not standardized, and the postoperative histopathological
evaluation of the resected specimen is often not performed
according to the criteria of the American Joint Committee on
Cancer (AJCC)/UICC [6]. This makes comparison of data
between various centers difficult. Despite these shortcomings, a critical evaluation of the available data clearly shows
that the tumor type, the pretherapeutic estimation of the
resectability of the primary tumor (i.e., locoregional and
well-resectable tumors versus locally advanced tumors with
doubtful resectability), the clinical response to neoadjuvant
therapy and the presence of residual tumor after resection are
the major factors that need to be considered when critically
evaluating the clinical role of multimodal therapy for
esophageal cancer [12, 13].
ADJUVANT AND ADDITIVE THERAPY
Postoperative radiation and/or chemotherapy are frequently employed after incomplete tumor resection (R1- or
R2-resection [6]) and are also advocated after complete
tumor resection (R0-resection). The advantage of postoperative therapy in contrast to preoperative radiation or
chemotherapy is that it can be guided by the intraoperative
and histopathological findings. Disadvantages of postoperative therapy include the presence of the radiation-sensitive
esophageal substitute and the low activity of chemotherapy
in postoperative tissue.
The role of postoperative radiation was evaluated in
two randomized prospective trials. Both studies failed to
show an increase in survival time with postoperative radiation in patients with or without residual tumor after surgical
resection [14, 15]. The only benefit from postoperative
radiation was improved local tumor control with a 10%40% reduction in mediastinal recurrences and tracheobronchial fistulae after palliative resections. This was
achieved at the expense of significant morbidity and early
systemic metastasis in one of these trials. Postoperative
radiation should consequently be considered only in
patients with residual mediastinal disease after surgical
resection in whom the risk of mediastinal recurrence and
tracheobronchial fistula is high.
Postoperative chemotherapy is frequently employed to
prevent, delay or treat systemic metastases in patients with
squamous cell esophageal carcinoma who had a local R0resection. Controlled trials supporting the use of adjuvant
chemotherapy are, however, scarce. In a randomized trial

Siewert, Stein, Fink

by the Japanese Oncology Group, postoperative chemotherapy had no beneficial effect compared to postoperative
radiation, but was associated with significant side effects
and morbidity [16]. This was also confirmed in a recent
randomized multicenter study from France. This trial
showed no survival difference with or without postoperative chemotherapy in patients who had a curative or
palliative resection of squamous cell esophageal carcinoma,
while side effects were common and severe in those who
received postoperative chemotherapy [17].
Consequently, there is currently no firm scientific basis for
adjuvant or additive postoperative radiation or chemotherapy in
patients who have undergone resection for esophageal cancer.
Palliative postoperative radiation may only be considered in those
with macroscopic or microscopic residual tumor (R1- or R2resection) in whom the risk for a tracheobronchial fistula is high.
THEORETICAL AND EXPERIMENTAL BASIS OF
NEOADJUVANT THERAPY
Due to the lack of effective postoperative protocols, a
variety of neoadjuvant preoperative therapeutic modalities
has been extensively investigated in recent years in an effort
to induce downstaging of the primary tumor, increase the rate
of complete tumor resections, eliminate potential systemic
micrometastasis and ultimately prolong survival in patients
with esophageal carcinoma. There are several theoretical considerations and experimental data that support the use of radiation and/or chemotherapy prior to, rather than after, surgical
resection. Experimental studies showed that surgery may
induce a growth stimulus for tumor cells left behind after
resection [18]. This was manifested by an increased proliferation rate, a marked shortening of tumor doubling time and
rapid increase of the size and number of distant metastases
[19-21]. The proliferation stimulus may also be associated
with an increased rate of spontaneous mutations resulting in
clones of chemotherapy-resistant tumor cells [22]. Reduction
of the tumor cell mass prior to surgical intervention by
chemotherapy or radiation inhibited this proliferation stimulus and markedly prolonged survival in these experimental
models [23]. An additional argument supporting the preoperative use of chemotherapy is the altered vascular supply in the
surgical field. In contrast to the preoperative situation, postoperative systemic therapy may not reach residual tumor in
sufficiently high concentrations.
NEOADJUVANT THERAPY FOR SQUAMOUS CELL
ESOPHAGEAL CANCER
The available data on neoadjuvant treatment in patients
with esophageal cancer can be classified into studies assessing
preoperative radiation, preoperative chemotherapy or combined preoperative radiochemotherapy, either applied

212

consecutively or simultaneously. Because of the markedly different prognosis and different available therapeutic alternatives,
patients with locoregional or potentially resectable tumors must
be assessed separately from patients with locally advanced
tumors in whom the chance for a complete tumor resection is
questionable based on pretherapeutic staging [12, 13]. In
patients with potentially resectable tumors, the results of neoadjuvant therapy followed by resection have to be compared with
the current gold standard of primary resection. In contrast, the
results of primary surgical resection in patients with locally
advanced tumors are dismal. Any therapeutic modality which
offers the chance for long-term survival in these patients must
be considered a significant benefit.
Preoperative Radiotherapy
The use of neoadjuvant radiation is based on the premise of
preoperative devitalization, reduction of the tumor bulk and
eradication of lymph node metastases. Theoretically, this
should increase the resectability, particularly for tumors located
in the proximal half of the esophagus, and diminish intraoperative spread of tumor cells. The possible increase of the resection
rate and reduction of local recurrences with this approach, however, have to be balanced against a potentially increased perioperative morbidity, and in patients who do not respond to
radiation, an unjustifiable delay of potentially curative surgery.
Earlier uncontrolled and retrospective studies suggested a
prognostic benefit with preoperative radiation in patients with
squamous cell esophageal cancer. Five randomized prospective trials comparing preoperative radiation followed by surgical resection with surgical resection alone have been published
(Table 1) [24-28]. Four of these trials could not confirm an
increase in the resection rate or effect on survival with preoperative radiation as compared to results for patients who had
surgical resection alone [24-27]. The only benefit from preoperative radiation in these studies appeared to be an improvement in local tumor control. Unfortunately, in these studies,
patients were not stratified into those with locoregional or
locally advanced tumors. In contrast, a Scandinavian randomized multicenter study showed improvement in the prognosis
after preoperative radiation as compared to primary resection
in patients with locoregional esophageal cancer [28]. The latter study was, however, severely criticized because of low
patient numbers in the various treatment arms and grave weaknesses in the study design and data analysis. Consequently, the
clinical use of preoperative radiation therapy in patients with
esophageal carcinoma cannot currently be justified by randomized trials. Because of recent advances in timing, dosage
and delivery of radiation and the supportive effect of radiosensitizing chemotherapeutic agents, additional studies are
required to define the role of preoperative radiation in patients
with squamous cell esophageal carcinoma.

Multimodality Therapy for Esophageal Cancer

213

Table 1. Randomized prospective studies comparing preoperative radiation (RTx) followed by surgical resection with primary resection in patients with
potentially resectable squamous cell esophageal carcinoma
Treatment
modality

Number
of patients

Locoregional
relapse

Distant
relapse

Median
survival

2-year
survival

5-year
survival

EORTC/Gignoux [24]

Surgery alone
Preop RTx (33Gy) + Surgery

106
102

67%
46%

46%
52%

11 months
11 months

30%
28%

10%
10%

Launois [25]

Surgery alone
Preop RTx (40Gy) + Surgery

57
67

12 months
11 months

35%
20%

12%
10%

Arnott [26]

Surgery alone
Preop RTx (20Gy) + Surgery

86
90

10 months
10 months

30%
25%

17%
9%

Wang [27]

Surgery alone
Preop RTx (40Gy) + Surgery

102
104

52%
48%

50%
50%

30%
35%

Nygaard [28]

Surgery alone
Preop RTx (35Gy) + Surgery

41
48

9%
21%

Author

Preoperative Chemotherapy
At least theoretically, the preoperative use of chemotherapy offers several advantages. In addition to an increase in the
resectability by downstaging of the primary tumor, preoperative chemotherapy allows early systemic treatment of distant
micrometastases which may be present even in patients with
less-advanced disease. Furthermore, the efficacy of various
cytotoxic agents can be tested in the individual patient. The
results of these tests can be used as a guide for the selection
of postoperative additive or adjuvant therapy.
The vast majority of studies on preoperative chemotherapy in patients with potentially resectable tumors have been
single-arm uncontrolled phase II trials. Taken together, these
studies indicate that preoperative chemotherapy in patients
with potentially resectable esophageal carcinoma is feasible
and does not appear to increase postoperative morbidity and
mortality. Depending on the preoperative chemotherapy protocol employed, a complete or partial clinical response was

observed in 14%-71% of the patients, with subsequent R0resection in 36%-83%. A complete histopathological
response after preoperative chemotherapy was rare. When
compared to results on a series of patients with equally
advanced esophageal carcinoma who had primary resection
at our institution, preoperative chemotherapy does not appear
to improve overall survival [9, 12]. This was confirmed in six
prospective randomized trials (Table 2) [29-33]. Compared
to primary surgical resection, preoperative chemotherapy did
not increase the resection rate, rate of R0-resections or survival time in these studies. In none of the phase III trials did
the rate of complete pathological responses to preoperative
chemotherapy exceed 10%. A survival advantage with preoperative chemotherapy could only be demonstrated in the
subgroup of patients who responded to preoperative
chemotherapy. Preoperative chemotherapy in patients with
potentially resectable tumors must therefore be considered
investigational.

Table 2. Randomized prospective studies comparing preoperative chemotherapy followed by surgical resection with primary resection in patients with
potentially resectable esophageal carcinoma
Author

Treatment
modality

Number
of patients

Clinical
response

Complete histopathological response

Postop
mortality

Median
survival

Long-term
survival

Roth et al. [29]

Surgery alone
CDDP-BL-VDS + Surgery

19
17

47%

6%

0%
12%

9 months
9 months

5% (3-year)
25% (3-year)

Schlag et al. [30]

Surgery alone
CDDP-5-FU + Surgery

41
34

41%

6%

10%
19%

9 months
8 months

Nygaard et al. [28]

Surgery alone
CDDP-BL + Surgery

41
50

13%
15%

3% (5-year)
9% (5-year)

Kok et al. [31]

Surgery alone
CDDP-5-FU + Surgery

80
80

51%

7%

4%
2%

12 months
12 months

Fok et al. [32]

Surgery alone
CDDP-Etop + Surgery

26
48

42%

10 months
14 months

Ancona et al. [33]

Surgery alone
CDDP-5-FU + Surgery

38
36

8%

3%
9%

Siewert, Stein, Fink

Despite the usually late presentation of patients with
squamous cell carcinoma, randomized trials comparing
preoperative chemotherapy to primary resection in
patients with locally advanced squamous cell
esophageal cancer are still lacking. Taken together, the
data from the available phase II studies show that as in
patients with potentially resectable tumors, preoperative
chemotherapy is also feasible in patients with locally
advanced esophageal carcinoma, but appears to improve
the prognosis only in those patients who respond to preoperative treatment.
Preoperative Combined Radiochemotherapy
The low rate of complete pathological responses with
preoperative chemotherapy alone prompted several groups
to assess a combination of preoperative chemotherapy with
radiation. A review of the literature shows several initial
studies using a variety of chemotherapeutic agents in combination with a wide range of radiation doses, while most of
the recent studies are based on a combination of cisplatinum with 5-fluorouracil (5-FU) and 30-40 Gy of radiation
[9, 12]. In these studies, the concurrent use of preoperative
radiation and chemotherapy resulted in complete pathological response rates ranging between 20% and 42%. These
were, however, achieved at the expense of an increase in
morbidity and postoperative mortality which exceeded 20%
in some of the studies.
Despite the impressive response with combined
radiochemotherapy, the results of the available randomized phase III studies comparing preoperative combined
radiochemotherapy with primary surgical resection in
patients with potentially resectable tumors do not show
an increase in the R0-resection rate or a clear overall survival benefit with preoperative therapy [34-36]. Any
beneficial effect of neoadjuvant radiochemotherapy in
patients with potentially resectable tumors appears to
exist only in the subgroup of patients with clinical or
complete histopathological response to preoperative
therapy. Since clinical and histopathological responses
cannot currently be reliably predicted based on pretherapeutic parameters, preoperative radiochemotherapy in
patients with potentially resectable tumors should not be
performed outside the context of clinical studies.
The experience with studies assessing preoperative
radiochemotherapy in patients with locally advanced
squamous cell esophageal carcinoma is limited. The few
available phase II studies indicate that preoperative combined radiochemotherapy may lead to a marked downstaging of the tumor in a significant number of patients
and thus allow subsequent complete tumor resection [9].
In our experience, a three-week course with 5-FU

214

chemotherapy given as continuous infusion simultaneously with 30 Gy radiation allowed subsequent complete
resection in over 80% of 55 patients who had a locally
advanced squamous cell esophageal carcinoma located
at or above the level of the tracheal bifurcation [37].
Compared to primary resection for similarly advanced
tumors, neoadjuvant radiochemotherapy significantly
improved the prognosis in this study (Fig. 2). Detailed
analysis, however, showed that the prognostic gain was
limited to those who had an objective tumor remission
and subsequent complete resection. In all other patients,
this neoadjuvant approach was associated with significant morbidity and mortality but no prognostic benefit.
NEOADJUVANT THERAPY FOR ADENOCARCINOMA OF
THE ESOPHAGUS
The prevalence and incidence of adenocarcinoma of the
distal esophagus has shown a marked rise in past decades; in
some centers of the Western world, this adenocarcinoma
now equals or outnumbers squamous cell esophageal carcinoma. Although esophageal adenocarcinoma and squamous
cell carcinoma are different tumor entities epidemiologically
and biologically, they are not separated in most neoadjuvant
treatment trials. Studies solely investigating neoadjuvant
therapy in patients with adenocarcinoma of the esophagus
are scarce and their results contradictory [38-41]. The single
available randomized phase III study in patients with adenocarcinoma of the esophagus compares preoperative combined
radiochemotherapy with primary resection in patients having potentially resectable tumors [42]. The results of this

Figure 2. Cumulative survival rate with primary resection versus neoadjuvant radio-chemotherapy (RCTx) with subsequent resection in patients with
locally advanced squamous cell carcinoma of the esophagus located at or
above the level of the tracheal bifurcation (data from ongoing study at TU
Mnchen) [37].

215

study are available as interim analysis in abstract form only.

This analysis demonstrates a marked downstaging and a significant survival benefit with combined neoadjuvant
radiochemotherapy as compared to primary resection.
However, until the final results of this study are available
and confirmed by other investigators, primary resection
remains the treatment of choice for patients with potentially
resectable adenocarcinoma of the distal esophagus.
In our practice, neoadjuvant therapy in patients with adenocarcinoma of the esophagus is restricted to those with locally

Figure 3. Cumulative survival rate with primary resection versus neoadjuvant

chemotherapy (CTx) with subsequent resection in patients with locally advanced
adenocarcinoma of the distal esophagus (data from ongoing study at TU
Mnchen) [44].

advanced tumors in whom, based on preoperative staging, an

R0-resection appears questionable. The neoadjuvant therapy
regimen used is derived from studies assessing combined
modality treatment of gastric cancers rather than squamous cell
esophageal carcinoma [43]. Our experience with this approach
shows that neoadjuvant therapy with a cisplatin-based polychemotherapy regimen followed by surgical resection
markedly improves survival in patients with locally advanced
adenocarcinoma of the esophagus as compared to patients in
similarly advanced tumor stages who had a primary resection
(Figure 3) [44]. Follow-up of these patients, however, showed
a rather high rate of locoregional tumor recurrences, suggesting
that a combination of preoperative chemotherapy with radiation must be considered in future studies.
Patient Selection for Neoadjuvant Therapy
Based on this analysis, the choice of therapy for
esophageal cancer should be guided by the resectability
of the tumor and the physiological status of the patient [13, 45]. Resectability can best be assessed by

Multimodality Therapy for Esophageal Cancer

endoscopic ultrasonography. Estimation of the risk
requires a detailed analysis of cardiac, pulmonary,
hepatic and renal functions and an assessment of the
cooperation of the patient. In patients with tumors confined to the esophageal wall on endoscopic ultrasonography, i.e., patients in whom an R0-resection can be
anticipated with a high degree of certainty, primary
resection is the treatment of choice, provided that their
physiological status permits an extensive surgical procedure. In patients with locally advanced tumors, i.e.,
patients in whom an R0-resection is questionable, neoadjuvant therapy should be initiated with the aim of downstaging the primary tumor and increasing the chance for a
complete tumor resection on subsequent surgery. Due to
the potential for increased mortality and morbidity with
this approach, however, surgical resection after preoperative neoadjuvant therapy should be restricted to those
who respond to preoperative therapy and who have sufficient physiological reserve to withstand a potentially prolonged and complicated postoperative course. In patients
with a locoregional or locally advanced esophageal carcinoma and poor physiological status, the expected high
perioperative mortality does not justify combined modality therapy or primary resection. Conservative measures,
e.g., combined definitive radiochemotherapy, should
therefore be initiated in these patients.
OPEN QUESTIONS IN NEOADJUVANT THERAPY
Selection of the Neoadjuvant Therapeutic Modality
Careful long-term follow-up of patients who had
neoadjuvant therapy followed by surgical resection shows
that control of distant disease remains a major problem.
Even patients with no viable tumor in the resected specimen
may die from systemic disease three years or longer after
surgical resection. Current neoadjuvant modalities, therefore, appear to delay the occurrence of distant metastasis
rather than cure systemic disease. Consequently, more
effective and less toxic preoperative chemotherapy regimens are needed to combat systemic sites of esophageal
cancer. Improvement in the control of distant tumor growth
may in the future be achieved by intensifying the chemotherapy component in the combined modality approach. Supportive use of G-CSF or GM-CSF to increase the dose
intensity per treatment time and an alteration in the sequence
of radiation and chemotherapy with the aim of delivering
more systemic chemotherapy prior to combined radiochemotherapy are the most promising approaches for achieving this goal. One such study assessed whether the
development of systemic metastases can be prevented or
delayed without a loss in local tumor control by the use of

Siewert, Stein, Fink

intensive primary chemotherapy followed by radiochemotherapy and subsequent resection. Initial results with this
sequential approach are promising [46]. Because of the
excessively long preoperative treatment phase and the
associated burden for the patient, the long-term results of
this study must be awaited before this approach can be
recommended.
Assessment of Response to Neoadjuvant Therapy
Most available studies show that a prognostic benefit from
multimodal therapy can be expected only in patients who
respond to preoperative therapy and who have a subsequent
complete tumor resection. Treatment-related morbidity and
mortality are excessive, and the prognosis is dismal in those
who do not respond to neoadjuvant therapy. Consequently, a
surgical resection after neoadjuvant therapy should only be
performed if a complete tumor resection can be anticipated.
Parameters that would facilitate prediction of the response to
neoadjuvant therapy and subsequent R0-resection are, therefore, clearly needed to avoid the morbidity and mortality associated with combined modality treatment in patients who may
not receive any benefit from this approach.
The matter is complicated, however, by the observation that none of the commonly available pretherapeutic
data allow prediction of clinical or histopathological
response to neoadjuvant therapy. In addition, clinical
response frequently does not relate to histopathological
response. Residual tumor is often found in the resected
specimen in patients who had a complete clinical
response, while up to 20% of patients with only partial or
no clinical remission may have a sterilized specimen.
Endoscopic ultrasonography does not aid in the assessment of response to neoadjuvant therapy either because
the echo pattern of residual tumor cannot be differentiated

216

from the sequelae of radiation and chemotherapy [47].

Consequently, additional research must focus on parameters that facilitate the identification of patients who might
benefit from neoadjuvant therapy and that improve the
assessment of response prior to resection. Potential markers that are currently under investigation include the endoscopic growth pattern of the tumor and several subcellular
and molecular markers of the tumor cells. Positron emission tomography is currently also under investigation as a
tool for assessing response to neoadjuvant therapy.
Role and Extent of Surgical Resection after Neoadjuvant
Therapy
The potentially increased risk of esophageal resection after neoadjuvant therapy has prompted several
investigators to question the role of surgical resection
after chemotherapy or radiochemotherapy. Several
recent studies show that in contrast to patients who had
neoadjuvant therapy followed by resection, patients who
have radiochemotherapy alone commonly exhibit local
tumor recurrences [48, 49]. Surgical resection therefore
remains an essential component of the combined-modality approach to treating esophageal cancer. However, at
the present time it is unclear whether a surgical resection
should be performed on all patients receiving neoadjuvant therapy or only on those who respond to neoadjuvant therapy. The optimal timing of surgical resection,
i.e., immediate surgery after recovery of neoadjuvant
therapy or surgery as salvage therapy, has not been properly assessed. Furthermore, the extent of resection and
lymphadenectomy after neoadjuvant therapy remains
controversial. In order to definitely answer these questions, carefully designed further-randomized prospective
trials are essential.

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