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372 Part III Esophagus
FIGURE 17-10 Infracarinal mediastinal dissection. A, aorta; C,
carinal lymph node on esophagus; E, esophagus; LMB, left main
Perhaps based on the realization that such an extensive
operation carries with it substantial morbidity and that
not all patients can benet, the recent focus of research in
this area is to further rene the indications for extended
lymphadenectomy. A survival advantage was only evident
for upper- and middle-third cancers in some studies.
164,167,168
C
FIGURE 17-9 Continued—C. Total mediastinal lymphadenectomy
includes an extended mediastinal lymphadenectomy plus the left
recurrent laryngeal and paratracheal nodes.
does not lie with the addition of a cervical phase, but the
completeness of the superior mediastinal dissection along the
recurrent laryngeal nerves to the neck.
ree-eld lymphadenectomy as practiced in Japan shows
an overall hospital mortality rate of 4%. Although this very
low mortality rate is achieved, most of these results come
from experienced and specialized institutions and such
extensive surgery is expected to carry with it a more unfavorable outcome if it were more widely and unselectively
applied. In addition, morbidity rates are substantial; septic
complications were the most common at 26.8%, followed
165
by pulmonary ones at 21.3%.
injury can occur in more than 50% of patients, which predisposes to pulmonary complications and impairs long-term
quality of life.
166
FIGURE 17-11 Superior mediastinal dissection. Large metal
retractor retracting the trachea anteriorly to expose the left recurrent
right main bronchus; T, trachea.
Chapter 17 Cancer of the Esophagus 373
FIGURE 17-12
V, vagus nerve.
Other poor prognostic factors include (1) when all three
elds have metastatic nodes; (2) when a lower-third tumor
has positive cervical nodes; and (3) when ve or more lymph
169
nodes are involved.
ese situations suggest advanced
FIGURE 17-14 For cervical lymphadenectomy, the cranial
landmark is the cricoid cartilage and the caudal border is the upper
margin of the clavicle. e most important nodes are the paratracheal
nodes along the recurrent laryngeal nerves. Left neck dissection. CA,
recurrent laryngeal nerve; S, stomach; T, trachea. e esophagogastric
anastomosis is seen, constructed with a one-layer continuous suturing
technique.
metastatic disease and three-eld lymphadenectomy may
not be justied. Other suggested strategies include using
intraoperative polymerase chain reaction to examine recurrent
laryngeal nerve lymph nodes to predict the need for cervical
170
dissection,
metastasis,
select patients suitable for cervical lymphadenectomy.
similar to the concept of sentinel lymph node
171
and taking a two-stage operative approach to
172
173
adjuvant, or intraoperative radiotherapy
are alternatives,
but their roles remain controversial.
Another major criticism of three-eld dissection is that the
prognostic superiority over conventional resection is only a
result of stage migration. While retrospective studies provide
174,175
evidence for benets of three-eld dissection,
the more
robust evidence of a well-performed randomized controlled
trial is lacking. Two small randomized trials could not demonstrate convincing survival advantage, and, in both, the
patient groups appeared to be highly selected and not wellmatched, and adjuvant therapies were not controlled for.
176,177
FIGURE 17-13 Abdominal lymphadenectomy involves dissection
around the celiac trifurcation. HA, hepatic artery; LG, left gastric
artery stump ligated; SA, splenic artery.
Barrett’s Adenocarcinoma and Gastric Cardia Cancers.
For Barrett’s adenocarcinomas of the lower esophagus and
cancer of the gastric cardia, data suggest that nodal spread
tends to occur later than for squamous cell cancers. Positive
nodes are found in approximately 10% of patients with squamous cell cancers for T1a lesions, while in Barrett’s cancer
this is only 0–6%. In T1b cancers, the respective gures are
30–50% for squamous cell and 20% for adenocarcinomas. In
addition, the pattern of lymphatic spread also diers; more
than 85% of all positive nodes in early adenocarcinoma are
located in close proximity to the primary tumor in contrast
178
to fewer than 60% in squamous cell cancers.
Nodes are
not commonly found in the superior mediastinum and, when
179
present, probably indicate very widespread disease.
us
lymphadenectomy is generally performed using a standard
two-eld approach. e advent of transhiatal esophagectomy
came at a time when esophagectomy was a high-risk operation with high mortality rates, and this less invasive method
374 Part III Esophagus
probably contributed to reducing overall death rates. With
improvement in surgical techniques and perioperative care,
it seems that, in most experienced centers, when selected
appropriately, both procedures can be carried out safely and
the margin of benet in reducing morbidity for most patients
with the transhiatal operation is not overwhelming. ere is
also increasing evidence of the benets of radical lymphadenectomy in recent years.
e concept of en bloc resection has been discussed in
a previous section; this enhances lateral margin clearance,
results in a complete lymphadenectomy within a facial
108,163
envelop surrounding the primary tumor,
and is especially
advocated for adenocarcinoma of the lower esophagus. In
dedicated centers, en bloc resection has a morbidity rate of
40%, a mortality rate of less than 5%, and a 5-year survival
163,180,181
rate of 37–52%.
It has been suggested that local recurrence can be reduced to an impressive 5% within the eld
of dissection,
163,182–184
and nodal recurrences are mostly found
outside the limits of dissection in the superior mediastinum or
aortopulmonary window, in areas along the recurrent laryngeal nerves that are not routinely removed. Taking en bloc
resection further, in selected centers in the United States and
Europe, three-eld lymphadenectomy has been tested and
interestingly also yielded similar incidences of positive cervi-
109,184
cal lymph nodes of around 30%.
is type of resection,
however, is not commonly performed in the West.
For tumor of the gastric cardia (Siewert types II and III
tumors), most surgeons would perform a total gastrectomy
would prefer to preserve the distal stomach for anastomosis.
An upper abdominal compartment nodal dissection around
the celiac axis seems routine for all, but complete lower mediastinal nodal dissection is somewhat controversial. Some
and this is only possible with the addition of a thoracotomy;
others believe that this is unnecessary, and mediastinal nodal
involvement could indicate advanced disease for which survival is poor regardless of the extent of lymphadenectomy.
e Japanese Oncology Group trial 9502 addressed this question. Patients whose tumors were Siewert II or III adenocarcinomas and which have inltrated into the esophagus for
less than 3 cm were randomly assigned to a transabdominal
(n = 82) or left thoracoabdominal approach (n = 85). A more
thorough mediastinal dissection was deemed only possible
with the later approach. e trial was closed prematurely
after the rst interim analysis, when the predicted probability of left thoracoabdominal approach having a signicantly
better overall survival than transabdominal route at the nal
analysis was only 3.65%. e morbidity rate was worse after
the left thoracoabdominal approach. us a transabdominal
approach seems adequate, though the surgeon must be prepared to add a thoracotomy when frozen section indicates a
positive proximal resection margin.
emerging to show that extended lymphadenectomy is related
to survival, from single and multi-institutional studies,
187,188
as well as from population data.
e number of nodes
185,186
removed correlates signicantly with long-term survival. One
international multicenter study showed that the number of
nodes removed was an independent prognostic factor, in addition to age, gender, cell type, presence of nodal metastases,
number of nodes involved, and depth of tumor invasion.
e optimal number of nodes removed was identied as 23,
though this number varies among studies. From a Worldwide
Esophageal Cancer Collaboration including institutions from
the United States, Europe, and Asia, the number of nodes that
must be removed to maximize survival depends on the pT classication: for pT1, approximately 10 nodes must be resected;
for pT2, 20 nodes; and for pT3 or pT4, 30 nodes or more.
us, one should resect as many regional nodes as possible,
balancing the extent of lymphadenectomy with morbidity.
RECONSTRUCTION AFTER ESOPHAGECTOMY
e reconstruction phase of an esophagectomy determines
to a signicant extent the postoperative morbidity and longterm quality of life. e most commonly used conduit is
the gastric tube, and of the many congurations, a tailored
isoperistaltic tube based on the greater curvature with preservation of the right gastric and right gastroepiploic vessels
is most reliable. A 4-cm gastric tube on the greater curvature
190
gives the best blood supply.
e simplicity of preparation,
adequate length, and robust blood supply makes it the rst
choice as the esophageal substitute (Fig. 17-15). Disadvantages of the gastric conduit include the fact that patients who
have an intrathoracic stomach often experience postprandial discomfort and early satiety related to loss of normal
gastric functions such as receptive relaxation. Patients can
also suer from acid reux, possible gastric ulceration, and
191
dysfunctional propulsion.
In addition, Barrett’s esophagus
has been reported to develop in the esophageal remnant,
although the clinical relevance of this nding is at present
unknown. ese are important considerations though, in our
experience, serious problems are uncommon. e level of the
esophagogastric anastomosis has a bearing on the severity
of reux. Patients who have a low intrathoracic anastomosis tend to have more severe reux and esophagitis compared
with the high intrathoracic or cervical anastomosis. Preserving a longer length of esophagus, on the other hand, theoretically may enhance swallowing function. Inadequate gastric
emptying can be a problem. A pyloric drainage procedure
is not universally practiced. In a randomized trial, 13% of
patients who did not have a pyloroplasty had problems with
193
gastric emptying.
A meta- analysis suggested that a drainage procedure lessens the chance of early postoperative gastric
stasis, but long-term function is not aected.
194
Many other factors contribute to emptying of the intra-
thoracic gastric conduit. A smaller stomach enhances postop-
195
erative emptying.
e straighter position of the stomach,
when delivered to the neck via the posterior mediastinal or
the retrosternal route, may make the stomach empty more
eciently compared to one placed in the right pleural cavity, where the angulation at the diaphragmatic hiatus as the
stomach continues from the right paravertebral gutter into the
186
189
192
Chapter 17 Cancer of the Esophagus 375
FIGURE 17-15 Gastric conduit prepared for transposition to the neck
for pharyngoesophagostomy after pharyngolaryngoesophagectomy.
Ample length is evident.
stomach at the hiatus should be avoided. With a gastric conduit, diet modications and the use of acid suppressive and
prokinetic drugs such as erythromycin may be useful.
196,197
ere are instances when the stomach cannot be used, such
as after previous gastric resection, and tumor involvement of
a substantial part of the stomach dictating its removal. In
these situations the use of the colon is preferred. For most,
colonic interposition remains an infrequently performed
198
procedure and has the potential for more complications.
Mobilization of the colonic loop is more complex; its blood
supply is less reliable than the gastric conduit; three anastomoses are required; when the colon becomes ischemic, the
choice of alternative conduit is restricted. In our experience,
use of a colon loop is associated with more blood loss, a longer operating time, and a higher anastomotic leak rate. Colon
ischemia occurs in 1 of 42 patients (2.4%), which compares
favorably to a rate of 3–10% reported in the literature.
199
A colonic conduit provides good long-term swallowing
function; it seems to have active peristalsis, and this is cited
as an explanation for its superior function as an esophageal
200,201
substitute when compared with a passive gastric conduit.
Although peristalsis can be demonstrated immediately
202
following surgery,
203
gravity.
When the distal stomach is retained in the abdomen
long-term emptying likely relies on
after a colon interposition with a cologastric anastomosis, the
latter provides additional reservoir function.
204
e jejunum is used most frequently after distal esophagec-
tomy and total gastrectomy for cancer of the lower esophagus
it prevents bile reux to the esophagus. A jejunal loop used
in a modied Merendino procedure to interpose between
the esophagus and proximal stomach after limited resection
205
of the distal esophagus and GEJ has also been advocated.
Excellent postoperative quality of life and function is claimed.
Along jejunal loop is sometimes used to reach the neck, but
preparation is tedious and the vasculature may not be reliable; a “supercharge” using a microvascular anastomosis to
206
cervical vessels may be required.
A free jejunal graft is used
for reconstructing the defect after resection of the pharyngoesophageal segment in the neck.
127
e method of reconstruction is in part related to the
surgical approach for resection. When a cervical anastomosis is
chosen, one must decide whether to place the conduit via the
orthotopic, retrosternal, or subcutaneous route. e subcutaneous route is rarely used because it is cosmetically unsightly.
e retrosternal route has variably been shown to be associated with increased or similar cardiopulmonary morbidity and
207–209
mortality rates.
compared to the orthotopic route,
e retrosternal route is 2–3 cm longer
210
but this is rarely of relevance because the esophageal replacement conduit is usually
of sucient length. Some suggest that the tight space at the
thoracic inlet in the neck could cause potential constriction
on the conduit and recommend partial manubrial, clavicular
211
head and rst rib resection
; we have found this unnecessary.
Functionally, although it was shown that there is a higher rate
of gastric retention when the retrosternal route is used, quality
of life is not adversely aected.
208,212
When palliative resection is carried out for advanced tumor,
recurrent tumor could inltrate into the conduit placed in the
posterior mediastinum. In a retrospective study of 209 patients
who had undergone curative resection and orthotopic reconstruction, or 73 patients (35%) who had locoregional tumor
recurrence, 46 (22%) had secondary dysphagia as a result.
e authors concluded that in 27 patients (13%) dysphagia would likely have been prevented by using a retrosternal
213
reconstruction route.
However, the site of the obstruction
that produced dysphagia was not clearly stated. e stomach
is usually spacious and tumor inltration will not readily result
in dysphagia. Only at the thoracic inlet and in the cervical
region, where there is limited space, can tumor involvement
lead to obstruction. Using the retrosternal route will eliminate tumor involvement in the posterior mediastinum, but
inltration from tumors in the neck cannot be avoided. e
benets of choosing the retrosternal route in reducing secondary dysphagia from recurrent tumor inltration may be
overemphasized. In our own study, only 4 out of 28 patients
(14%) developed tumor inltration into the gastric conduit in
the posterior mediastinum. e main symptom was bleeding
376 Part III Esophagus
in two patients and none had dysphagia.
214
It is our policy
therefore to only use the retrosternal route for reconstruction
when resection is palliative, especially when postoperative
radiotherapy is planned, or when the reconstructive phase of
the operation precedes tumor resection.
PERIOPERATIVE CARE AND POSTOPERATIVE
MORBIDITY AND MORTALITY
With adequate preoperative workup, serious cardiac events
like myocardial infarction should be rare. Atrial arrhythmia
is common, aecting about 20% of patients. In itself, atrial
brillation is benign; rather it serves as a marker for more
serious underlying pulmonary and septic surgical compli-
215
cations.
Occurrence of atrial arrhythmia should prompt
thorough search for a more ominous underlying cause.
Pulmonary complications remain the most common and
serious postoperative morbidity. Major complications can
aect 30% of patients; most series report a rate of about
216
20%.
Pneumonia and respiratory failure occurred in 15.9%
of our patients and were responsible for 55% of hospital
deaths. Predictive factors include advanced age, supracarinal
tumor location (in part related to recurrent laryngeal nerve
injury), and lengthy operating time. Neoadjuvant therapy
112
did not lead to increased morbidity.
Measures to improve
respiratory outcome include cessation of smoking preoperatively, chest physiotherapy, avoidance of recurrent laryngeal
nerve injury, cautious uid administration to avoid uid
217
overload, use of smaller chest tubes,
early ambulation,
regular bronchoscopy, and early tracheostomy for sputum
218
retention.
pain relief and has been shown to improve outcomes.
Epidural analgesia is invaluable in postoperative
153
e most common surgical complication after esophagec-
219
tomy is still anastomotic leak and can reach 30%,
although
in experienced centers leak rates of below 5% can be achieved.
118,220
Most leaks are probably related to technical errors,
such as
tension between the conduit and the esophageal stump, ischemia of the conduit because of rough handling and poor preparation, and suboptimal technique. e intrinsic vascular perfusion of the stomach can be enhanced by certain methods, such
as “ischemic preconditioning,” whereby partial mobilization of
the gastric conduit is followed by a second stage-anastomosis
later. e perfusion of the stomach could be shown to improve
221
in the interim period.
Although an interesting concept and
potentially useful, the existing wide range of reported leak rates
(from 2–3 to 30%) suggests that much improvement is possible by other means, even without ischemic conditioning. It
would be ideal if one could identify the right patients on whom
to perform ischemic conditioning pre- or intraoperatively, so
that such elaborate preparation can be selectively applied.
e actual method of anastomosis is perhaps less important than its proper application. Stapled anastomosis is
popular for intrathoracic anastomosis while the hand-sewn
technique is preferred in the neck. ere is no evidence from
randomized trials that leak rates dier between stapled and
hand-sewn anastomoses, but the circular stapler may give
222
rise to more strictures.
e linear stapler has also been
advocated in the neck. One group reduced their cervical leak
rate from 10 to 15% using a hand-sewn technique to 2.7%
223
using linear staples with a side-to-side anastomosis.
With
experience, however, the hand-sewn method is as safe, if not
more so, and certainly less expensive.
As mentioned already, technical variables play an important
role in the genesis of postoperative complications. Anastomotic
leaks (largely technical) and recurrent laryngeal nerve injury, for
instance, are related to higher incidences of postoperative pulmonary morbidities. At the author’s center, pulmonary complications occurred in 10% of patients without technical complications, and in 38% of patients who developed such morbidities,
224
and mortality rates were 3.3 and 9.2%, respectively.
Multivariate analyses also demonstrated that a long operating time was
related to pulmonary complications, and increasing intraopera-
112
tive blood loss was related to postoperative mortality.
In sum,
the meticulous and expeditious execution of an esophagectomy
and its subsequent reconstruction are of paramount importance
in lessening complication and mortality rates.
Vigilant and aggressive treatment of complications is
important for good outcomes. Management of complications
has improved with time. At the author’s unit, anastomotic
leak rate was 16% in the 1960s to 1970s, 61% of whom died,
225
resulting in a leak-related mortality of 9.8%.
In the 1980s
the leak rate was 3.5%, of whom 35% died, a leak-related
220
mortality of 1.2%,
3.2% of patients and none died as a result.
while in the late 1990s leak occurred in
226
Other surgical complications like chylothorax and herniation of bowel through the diaphragmatic hiatus are rare
but should be recognized early; both are corrected by surgical
reexploration.
Combined Multimodal
Treatment Strategies
e past two decades have seen a proliferation of additional
treatments for esophageal cancer. e rationale is based on the
suboptimal long-term results of surgery or radiotherapy. Both
the spatial and synergistic actions of chemotherapeutic agents
and radiotherapy are explored in multimodality treatments.
How surgical resection and these new combinations should be
integrated into treatment programs is an active area of research.
NEOADJUVANT RADIOTHERAPY
Trials of neoadjuvant radiotherapy have failed to show increased
resection rate or improved survival compared with surgery
227–232
alone.
ease control but no better long-term outcome.
which also involved chemotherapy, suggested a survival advantage imparted by preoperative radiotherapy but only in the
pooled groups of patients receiving radiotherapy.
meta-analysis showed that if preoperative radiotherapy regimens do improve survival, the eect is likely to be modest with
-
229
One study,
232
A Cochrane
Chapter 17 Cancer of the Esophagus 377
an absolute survival bene t of 3% at 2 years and 4% at 5 years
233
that was not statistically signi cant ( p = .062).
ADJUVANT RADIOTHERAPY
Postoperative radiotherapy was studied in three randomized tri-
234–236
; all three demonstrated improved local disease control.
als
e largest study randomized 495 patients with intrathoracic
squamous cell cancers. Postoperative radiotherapy of 50–60
Gy was given in 220 patients to the entire mediastinum and
bilateral supraclavicular fossae. Per protocol, analysis showed no
overall di erence in 5-year survival at 31.7% for the surgery
alone group and 41.3% for the radiotherapy group. A bene t in
the radiotherapy group was observed in stage III patients; 5-year
survival rates were 13.1 and 35.1%, respectively. In patients
with node-positive disease, the di erence in survival was of borderline signi cance. e chance of mediastinal, cervical lymph
236
node and anastomotic recurrence was also reduced.
Survival
bene t was not demonstrated for the other trials. From these
studies it seems reasonable to give postoperative radiotherapy to
subgroups of patients, especially those who have palliative resections, to enhance local disease control.
NEOADJUVANT CHEMOTHERAPY
Eleven randomized trials studied the role of preoperative che-
232,
237–246
motherapy.
e two largest trials were the Intergroup
rst study randomized patients to undergo surgery alone, or to
have three cycles of cisplatin and 5- uouracil before surgery, and
in those who had stable or responsive disease, two additional
postoperative courses.
245
Of 440 eligible patients, 213 were
assigned to the neoadjuvant group. e median survival was
14.9 months for the chemotherapy group compared with 16.1
months for the surgery group. Two-year survival rates were no
involved 802 patients and similar preoperative regimens with
246
two courses of cisplatin and 5- uouracil.
Overall survival
was better in the chemotherapy group. Median survival was
16.8 versus 13.3 months, and 2-year survival rates were 43 and
with a median follow-up is of 6 years and 93% of patients
followed to 5 years or death, 5-year survival rates were 23%
in the chemotherapy group compared with 17% in surgery
group. Bene ts were evident for both squamous cell cancer and
247
Many di erences between the two studies could explain
the di erent outcomes, including the chemotherapy regimen,
distribution of histologic cell types (66% adenocarcinoma in
went resection, time to resection, type of surgery performed,
and number of patients who also had radiotherapy. e larger
detection of a small improvement with chemotherapy.
A Japanese study conducted by the Japanese Clinical
Oncology Group (JCOG 9907) randomized 330 patients
with stage II/III squamous cell cancers (excluding T4 disease) comparing two courses of preoperative cisplatin and
5- uorouracil to a similar regimen given after esophagectomy. Overall 5-year survival was signi cantly better at 60%
in thepreoperative chemotherapy group compared to 38% in
248
the postoperative group.
Although this trial did not speci -
cally compare preoperative chemotherapy to surgical resection
TABLE 17-9: SELECTED RANDOMIZED TRIALS ON NEOADJUVANT ± ADJUVANT CHEMOTHERAPY
VERSUS SURGICAL RESECTION
N Histology (%) Chemotherapy
246,
a
Chemo + surgery
Surgery 402 Adeno (66) 5-FU 10 Cardia: 10 13.3 2 y (34) (sig)
245, b
Kelsen et al
Chemo + surgery
Surgery 227 Adeno (56) 5-FU 6
Cunningham et al
Chemo + surgery
Surgery 253 5.9 GEJ: 12 20
Adeno, adenocarcinoma; ECF, epirubicin, cisplatin, uorouracil; ESO, esophageal cancer; 5-FU, 5- uorouracil; GEJ, gastroesophageal junction; SCC, squamous cell
carcinoma.
a
Preoperative chemotherapy only.
b
ree courses preoperatively, two courses postoperatively.
c
ree courses preoperatively and three courses postoperatively.
d
Extrapolated from graphs.
400 SCC (31) Cisplatin 10 ESO: 90 16.8 2 y (43)
213 SCC (46) Cisplatin 6 14.9 2 y (35)
249, c
250 Adeno (100) ECF 5.6 Stomach: 74 26
Post-op
Mortality (%)
Tumor
Location (%)
ESO + cardia
(% not indicated)
Lower ESO: 14
Median
Survival (mo) Survival (%)
16.1 2 y (37)
5-y
d
5 y (36)
d
5 y (23) (sig)
378 Part III Esophagus
alone, this has quickly become a standard-of-care treatment
also established preoperative chemotherapy as a widely practiced strategy. Another ongoing trial (OE05) compares the
OE02 preoperative chemotherapy regimen with four courses
of preoperative epirubicin, cisplatin, and capecitabine (ECX)
in treating patients with adenocarcinoma of the esophagus
and GEJ. Accrual was planned for 1300 patients.
sional Chemotherapy (MAGIC) trial, a randomized study,
included 503 patients with adenocarcinoma of the stomach,
GEJ, and the lower esophagus. Initially planned for gastric
cancers, eligibility criteria were extended to include lower
esophageal adenocarcinoma coinciding with termination of
OE02. us 14% of patients had lower esophageal tumors,
and another 12% had GEJ tumors. ree courses of epirubicin, cisplatin, and infused uorouracil (ECF) were given to
patients before surgery, and three courses were repeated afterward, comparing this to patients undergoing surgical resection alone. Both progressive-free and overall survival rates
were improved in the chemotherapy group.
249
A recent individual patient data-based meta-analysis on
nine randomized trials (2102 patients) showed a statistically
signicant overall survival benet in favor of preoperative
chemotherapy translating into a 5-year absolute increase
of 4% (from 16 to 20%). Disease-free survival and curative
250
resection rates were also improved.
Similar benets were
demonstrated by another meta-analysis, with a 2-year absolute survival benet of 7%. However, adenocarcinomas may
benet more than squamous cell cancers.
251
ADJUVANT CHEMOTHERAPY
is is an area perhaps least well studied, and trials on
pure postoperative chemotherapy are limited. JCOG
9907, mentioned in the previous section, was in fact a
follow-up study on JCOG 9204, which randomized 242
patients comparing surgical resection with the addition of
two courses of postoperative cisplatin and 5-uouracil.
252
e 5-year disease-free survival rate was signicantly different at 45% with surgery alone and 55% with surgery
plus chemotherapy. e overall 5-year survival rates were
not signicantly dierent at 52 and 61%, respectively. e
eect was more marked in the subgroup with lymph nodes
252
metastases.
However, another small French study also
using cisplatin and 5-uouracil as adjuvant therapy did not
show any advantage with chemotherapy.
253
NEOADJUVANT CHEMORADIATION
Several groups have explored chemoradiation as neoadjuvant
therapy (Table 17-10).
232,254–261
e radiation dose ranged
from 20 to 45.6 Gy. In ve trials, only squamous cell cancers
were recruited
cinomas
259–261
232,254,255,257,258
and one treated adenocarcinomas only.
; three included mostly adenocar-
256
A sur-
vival advantage with neoadjuvant chemoradiation over surgery
256,260
alone was demonstrated only in two trials.
e trial
reported by Walsh and colleagues on adenocarcinomas only
has been criticized because of inadequate preoperative staging,
unclear surgical procedures, and the large number of protocol
violations, and survival from the surgery group was exceptionally poor (3-year survival rates were 32 and 6% for the preoperative treatment group compared to surgery alone).
CALGB 9781, 475 patients were planned, but the trial was
terminated after 56 patients because of poor accrual. Nevertheless, a survival advantage was seen in the chemoradiation
group; median survival was 4.5 versus 1.8 years and 5-year
260
survival was 39 versus 16%.
of the trial were much criticized.
However, the statistical analyses
262
e results from these studies are conicting and thus
inconclusive. Several meta-analyses have addressed the
role of neoadjuvant chemoradiation.
251,263–267
e latest
published meta-analysis included the randomized trials
comprehensively; 10 studies included 1209 patients. e
hazard ratio for all-cause mortality with neoadjuvant
chemoradiation versus surgery alone was 0.81 (95% CI
0.70–0.93; p = .002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for dierent
histological tumor types: 0.84 (0.71–0.99; p = .04) for
SCC and 0.75 (0.59–0.95; p = .02) for adenocarcinoma.
Although it cannot be said conclusively that neoadjuvant
chemoradiation therapy is superior to surgery alone in the
treatment of localized esophageal cancer, it is widely practiced,
especially in the United States. Neoadjuvant chemoradiation
therapy does result in more pathological complete responses
compared with chemotherapy (25–30% vs <10%). One
recent trial compared preoperative chemotherapy with preoperative chemoradiation therapy in advanced adenocarcinoma
of the lower esophagus and GEJ. More pathological complete
responses were observed in the chemoradiation group (16 vs
2%), and more patients had negative nodal involvement (64
vs 38%). A trend toward improved median survival (32.8 vs
21.1 months) and 3-year survival (47.4 vs 27.7%) were also
seen, though these did not reach statistical signicance.
DEFINITIVE CHEMORADIATION
trial of chemoradiation versus radiotherapy provided convincing evidence of the superiority of chemoradiation.
e 5-year survival rate reported for the combined therapy
group was 26% compared to 0% following radiotherapy
(median survival 14 vs 9 months). Data on recurrence
patterns showed that both local and distant disease control
were superior with combined treatment. Local persistence of
disease and recurrence were 47% compared to 65%. Intensication of radiation dose to beyond 50.4 Gy, whether by
external beam
270
or by brachytherapy,
271
did not yield further
advantage but potentially added complications.
A Cochrane meta-analysis on 13 randomized trials that compared chemoradiation with radiation conrmed the superiority
of chemoradiation. Concurrent chemoradiation provides a signicant overall reduction in mortality at 1–2 years, an absolute
268
256
In
269
.
Chapter 17 Cancer of the Esophagus 379
TABLE 17-10: RANDOMIZED TRIALS ON NEOADJUVANT CHEMORADIATION VERSUS
SURGERY ALONE
No. Histology
Nygaard et al
S
C + S
Apinop et al
S
C + S
Le Prise et al
S
C + S
Walsh et al
S
C + S
Bosset et al
S
C + S
Burmeister et al
S
C + S
232
41
SCC Cisplatin, bleomycin
47
255
34
SCC Cisplatin, uorouracil
35
254
41
SCC Cisplatin, uorouracil
45
256
55
Adeno Cisplatin, uorouracil
58
257
139
SCC Cisplatin
143
261
128
SCC (39%)
128
Adeno (61%)
Chemotherapy
Dose of RT(cGy) CR Rate Mortality (%)
NA 13
3500
24
NA 15
4000
14
12.5 a 7
2000
8.5
25% 8
4500
4
26% 4
3700
Cisplatin, uorouracil
3500
15%
SCC (26%)
12.3
b
4.6
22
Median
Survival (mo) 3-y Survival (%)
7.5
7.5
7.4
9.7
10
10
11
16
19
19
19
Adeno (9%)
259
Urba et al
S
C + S
50
50
SCC (25%)
Adeno (75%)
Cisplatin, vinblastine,
uorouracil
28% 2
17
7
17
4500
258
Lee et al
S
C + S
Tepper et al
S
C + S
a
In patients who had resection.
b
Treatment-related mortality.
c
Extrapolated from graphs.
50
SCC Cisplatin, uorouracil
260
52
26
SCC (25%)
30
Adeno (75%)
4560
Cisplatin, uorouracil
5040
21% (43%
40% (out of
25 patients)
a
) NA 27
4
0
28
22
54
9
17
20
26
14
19
6
32
c
34
37
32 c
34
16
30
2 y (51)
2 y (49)
5 y (16)
5 y (39)
reduction in death rate by 7%, and a reduction in local persistence/recurrence rate by 12%. e downside is a 17% increase
in grades 3–4 toxicities. Sequential chemoradiation provides
no bene t, perhaps demonstrating the need to maximize the
272
radiosensitizing properties of chemotherapy.
THE ROLE OF SURGERY
M0 disease a 14–26% 5-year survival can be expected. It has
been suggested that surgery may be of no additional value to
chemoradiation and should be relegated to use as an adjuvant
treatment.
Two clinical trials attempted to examine whether surgical resection was necessary after chemoradiation. A French
study (FFCD 9102) treated 444 patients with both squamous cell cancers and adenocarcinomas of stage T3-4 N0-1
M0 with two cycles of 5- uouracil, cisplatin, and concurrent
radiation (46 Gy at 2 Gy/d or split course 15 Gy weeks 1 and
3). Only 259 patients who had at least a partial response were
randomized to undergo immediate surgery or to have three
more cycles of chemotherapy with 20 Gy at 2 Gy/d or split
course 15 Gy. e death rate within 3 months after starting induction treatment was 9% for surgery group compared
with 1% in the chemoradiation group. Two-year survival rates
were not di erent at 34 and 40%, so were median survival at
17.7 and 19.3 months for surgical and nonsurgical groups,
respectively. Patients in the surgical arm, however, required
stenting less often (13 vs 27%) or dilations (22 vs 32%).
273
ere was no di erence in the long-term quality of life, but
the surgery arm had transient deterioration in the immediate
274
postoperative period.
A German multicenter trial recruited 172 patients with
squamous cell cancers (T3-4 N0-1 M0). ree cycles of
380 Part III Esophagus
5-uouracil/leucovorin/etoposide/cisplatin were given followed
by chemoradiation (cisplatin/etoposide +
was then performed. is was compared to a control group with
the same chemotherapy, followed by denitive chemoradiation
275
(cisplatin/etoposide + >60 Gy).
trial were presented recently.
Long-term data from this
276
A nonsignicant trend toward
better overall survival at 5 and 10 years was observed: 27.9 and
19.2% in the resection group, compared to 17.0 and 12.2% in
the chemoradiation alone group. Local tumor control was signicantly worse in the nonsurgical arm. ree-year survival rate
was 35% in nonresponders undergoing complete tumor resection compared to 11% in nonresponders who did not undergo
resection. Both the French and German studies concluded that
surgical resection may not be necessary after chemoradiation
therapy.
It may be premature to negate the value of surgical resection. First, chemoradiation is by no means harmless, and surgical resection may not be as morbid as described. Treatment
duration of chemoradiation is often long and compliance is
269
trial could complete the planned treatment.
In the control
arm of INT 0123, acute grades 3 and 4 toxicity aected 43
and 26%, respectively, and long-term grades 3 and 4 toxicity
270
aected 24 and 13% of patients, respectively.
Treatment-
related mortality was 5–9% as reported by the INT
270,277
trials.
In studies that showed a benet for chemoradiation or questioned the value of surgical resection, the results
of the surgical arm were often suboptimal. In the FFCD 9102
trial, death rate within 3 months in the surgical arm was 9%
273
compared to 1% in the nonsurgical arm
; in the German
trial again the mortality rates were 10 and 3.5%, respec-
276
tively.
e early surgical deaths likely biased the long-term
survival results. Comparisons with nonoperative treatments
will only be valid when better results from high-volume centers are integrated into clinical trials.
Second, local disease control with chemoradiation alone
is less than satisfactory. It can be shown that with increasing
extent of lymphadenectomy, better local control is achieved
with surgery; by comparison, nonoperative chemoradiation
has a much higher local persistence/recurrence rate of over
270
50%.
e relief of dysphagia, the main symptom requiring
palliation, is much more certain with surgical resection; the
need to treat dysphagia with a stent was twice in the nonsurgical group in the FFCD 9102 trial.
273
ird, residual disease exists for the majority of patients
treated by chemoradiation. e pathological complete
response rate for most trials is in the region of 25%. us it is
logical to assume that surgical resection would enhance cure at
least in the remaining 75%, who did not completely respond.
In the German trial, the 3-year survival of nonresponding
patients who underwent resection was 35% compared with
276
11% in those who did not.
In the FFCD 9102 trial, 192
patients were not randomized primarily because of lack of
objective response but also because of medical contraindications or patient refusal. Out of these, 112 patients had opera-
survival for the patients who underwent surgery was 17.3 ver-
sus 6.1 months for those who did not, and was comparable for
those who were randomized. e data suggest that salvage surgery could benet a subset of patients who do not respond to
278
initial therapy.
Conversely, the role of surgery is less obvious
in those with a complete response. However, ascertaining true
complete response is dicult, whether by endoscopy, EUS, or
279,280
CT scanning.
show promise,
82,281
but, while PET scan can more reliably
distinguish responders and nonresponders, it is not accurate
enough to pinpoint the complete pathological responders.
282
PREDICTION OF RESPONSE AND
RESPONSE-DIRECTED THERAPY
be useful, because multimodality treatments are toxic, time
consuming, and costly. Various markers have been explored,
283
such as simple histology,
proliferative cell nuclear antigen
thymidylate synthase, and microvessel density, both in tissue
and serum. To date none have been proven to help clinical
decision making.
284
Metabolic imaging with PET scan has some promise. e
degree of response detected by PET imaging has been shown
by many studies to correlate with pathological response after
chemotherapy or chemoradiation therapy (Fig. 17-16).
82,281
e MUNICON (the Metabolic response evalUatioN for
Individualization of neoadjuvant Chemotherapy in oesOphageal and oesophagogastric adeNocarcinoma) trial evaluated
patients with locally advanced adenocarcinoma of the distal
esophagus or type II cardia tumors undergoing neoadjuvant
chemotherapy. Early metabolic response was dened as a reduction of 35% or more in the mean glucose standard uptake value
(SUV) measured by serial PET scans at the beginning and at 2
chemotherapy for an additional 12weeks before resection, while
nonresponders went directly to immediate surgery. Out of 119
patients, 110 were evaluable for metabolic responses, of whom 54
(96 vs 74%), major pathological response rate (dened as <10%
residual tumor) (96 vs 0%), longer median event-free survival
(29.7 vs 14.1 months), and median overall survival (median not
reached versus 25.8 months) were found for metabolic responders versus nonresponders. More importantly, the outcomes for
nonresponders were not dierent from previous results in such
patients who completed 3 months of chemotherapy, indicating
that such a strategy did not compromise these patients and could
save them from suboptimal chemotherapy.
285
e same investigators reported on their MUNICON-2 trial
recently. Metabolic nonresponders as dened in MUNICON
were switched to chemoradiotherapy (both chemotherapy and
chemoradiotherapy were cisplatin-based). Out of 32 patients
recruited, 13 (41%) were metabolic nonresponders. Subtotal
histologic response (<10% residual tumor) following chemoradiotherapy was reported in three patients (23%), but no complete responses was observed. In contrast, complete histological
response rate in metabolic responders were seen in 16%. Higher
Chapter 17 Cancer of the Esophagus 381
A B
FIGURE 17-16 PET/CT before (A) and after (B) chemoradiation therapy; the tumor has become completely eumetabolic.
vs 16%). One-year progressive-free survival was also inferior (46
vs 63%). e study suggested that merely adding radiotherapy
to the same cisplatin-based chemotherapy in nonresponders was
286
only marginally better.
Another strategy may be to switch to
alternative, non– cross-resistant chemotherapy during radiation.
It seems that cisplatin and 5-uouracil–based chemoradiation therapy has reached its therapeutic limit in treating esophageal cancer. More novel chemotherapeutic agents are being
explored, including paclitaxel, docetaxel, the topoisomerase I
inhibitor irinotecan (CPT-11), vinorelbine, gemcitabine, Herceptin (trastuzumab), oxaliplatin, and biomodulators such as
interferon or targeted therapies with bevacizumab or cetuximab.
is remains a very active area of research. In addition, advances
in techniques in radiation delivery, such as intensity-modulated
radiotherapy, may further reduce radiation toxicity.
287
Endoscopic Palliation
Endoscopic palliative treatments for more advanced tumors
include placement of an esophageal prosthesis, laser therapy, intralesional injection of various substances, and PDT.
e most commonly employed technique is perhaps insertion of a prosthesis, especially self-expanding metallic stents
(SEMS) (Fig. 17-17). e smaller diameter of the delivery
mechanism makes aggressive dilation of the tumor before
insertion unnecessary. ese stents are more exible than
conventional plastic prostheses; membrane-covered versions
FIGURE 17-17 A self-expanding metallic stent (SEMS) in situ.