nodal metastasis from locally advanced esophageal cancer: how neoadjuvant therapy modifies their...
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ORIGINAL ARTICLE – THORACIC ONCOLOGY
Nodal Metastasis From Locally Advanced Esophageal Cancer:How Neoadjuvant Therapy Modifies Their Frequencyand Distribution
Carlo Castoro, MD1, Marco Scarpa, MD1, Matteo Cagol, MD1, Alberto Ruol, MD2, Francesco Cavallin, MSc1,
Rita Alfieri, MD1, Gianpietro Zanchettin, MD2, Massimo Rugge, MD3, and Ermanno Ancona, MD1,2
1Oncological Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy; 2Department of Surgical and
Gastroenterological Sciences, University of Padova, Padova, Italy; 3Department of Pathology, University of Padova,
Padova, Italy
ABSTRACT
Background. Neoadjuvant chemoradiotherapy (CT-RT)
before esophagectomy seems to affect the number of nodal
metastasis and to alter the distribution of those that remain.
The aim of this study was to define how neoadjuvant
chemoradiotherapy changes nodal metastasis patterns in
locally advanced esophageal cancer.
Methods. A total of 402 consecutive patients with cancer
of the esophagus or esophagogastric junction (181 adeno-
carcinoma [AC] and 221 squamous cell carcinoma [SCC])
(evaluated at clinical stage T1N1, T2N1, T3N0, or T3N1
and pathological stage M0) presenting in our Department
between 1992 and 2007 and who underwent complete
resection (R0) were included in this retrospective study on
a prospectively collected database. All dissected lymph
nodes were retrieved and microscopically analyzed. Nodal
metastasis patterns in patients who underwent chemother-
apy (CT) or chemoradiotherapy (CT-RT) neoadjuvant
therapy were compared with those in patients who under-
went surgery alone.
Results. Almost 30% of the adenocarcinoma patients and
approximately 40% of the SCC patients showed effective
tumor downstaging after neoadjuvant therapy. There were
fewer paracardial node metastases (P = .002) in the AC
patients who underwent CT-RT neoadjuvant therapy.
There were, likewise, significantly fewer paraesophageal,
paracardial, and subcarinal node metastases in the SCC
patients in whom the perigastric nodes became the second-
most frequent site of metastasis.
Conclusion. Not only was frequency of lymph node
metastases decreased after neoadjuvant therapy, but nodal
localization and pattern were also significantly modified.
Esophagectomy with lymphadenectomy remains the
mainstay of curative therapy in patients with esophageal
cancer without systemic metastases.1–3 Nodal stage clas-
sification is considered the most useful predictor of
survival and an indicator of risk for disease recurrence.4 In
a recent multicenter study, the number of lymph nodes
removed as well as tumor depth and the pattern of lymph
node distribution were found to be independent predictors
of survival.1
Recent studies suggest that neoadjuvant therapy can
effectively downstage locally advanced esophageal cancer
and consequently enhance survival rate following radical
esophagectomy resection (R0 resection).5–8 Achieving a
node-negative status (N0) is the major determinant of
outcome following neoadjuvant chemoradiotherapy and
surgery.9 Therefore, after neoadjuvant therapy, lymphade-
nectomy is still necessary at least for staging purposes, and
a recent authoritative study concluded that lymphadenec-
tomy is optimized when the surgeon can identify individual
lymph node stations and can submit lymph node packets
separately.10 However, we hypothesize that neoadjuvant
chemoradiotherapy (CT-RT) not only reduces the number
of affected lymph nodes, but it also modifies the frequency
of nodes sites involvement and a postneoadjuvant therapy
map of nodal metastasis is not currently available.
Carlo Castoro and Marco Scarpa contributed equally to this study.
� Society of Surgical Oncology 2011
First Received: 29 September 2010;
Published Online: 10 May 2011
C. Castoro, MD
e-mail: [email protected]
Ann Surg Oncol (2011) 18:3743–3754
DOI 10.1245/s10434-011-1753-9
In fact, several important studies have investigated and
described nodal metastasis distribution in esophageal can-
cer to provide surgeons with definite indications for
lymphadenectomy, but none has attempted to assess lymph
nodal metastatic distribution after neoadjuvant ther-
apy.11–15 Moreover, in the last years minimally invasive
surgery gained consensus in esophageal surgery, and the
distribution of nodal metastasis after neoadjuvant therapy
could be useful information in planning the operative
techniques. Although the clinical relevance of the sentinel
node concept in the current treatment of esophageal cancer
seems now limited because of the high false-negative rate
and the high frequency of sentinel nodes in more than 1
nodal station, further studies could combine the findings of
the sentinel nodes with the postneoadjuvant nodal distri-
bution patterns.16–18 Moreover, some authors performing
minimally invasive esophageal surgery suggest reducing
the extent of nodal dissection according to tumor site.19
Finally, Orringer et al. in 2007 admitted that when per-
forming a transhiatal esophagectomy for cancer after
preoperative chemoradiotherapy they counted on preoper-
ative staging of esophageal cancer to know with fair
accuracy that they were ‘‘not leaving a lot of involved
lymph nodes behind in the mediastinum.’’20 The findings of
positive nodes on restaging would suggest performing a
transthoracic resection and mediastinal lymph dissection
instead of a transhiatal approach.20 Clearly, a map of nodal
metastasis after neoadjuvant therapy could be helpful in the
decision-making process.
Therefore, the aim of the present study is to define how
neoadjuvant chemoradiotherapy can affect lymph node
distribution and frequency in order to provide surgeons
with a more precise map in preparation for adequate
lymphadenectomy.
PATIENTS AND METHODS
Patients
A total of 1328 patients with esophageal cancer were
treated at the Regional Center for Esophageal Diseases
located in Padova, Italy, between January 1, 1992 and
December 31, 2007. Their data were recorded in a pro-
spectively collected database. Of these, 402 consecutive
patients presenting with cancer of the thoracic esophagus or
esophagogastric junction, evaluated at clinical stages T1N1,
T2N1, T3N0, or T3N1 and pathological stage M0, and who
underwent a complete R0 resection, were included in the
current study. Patients operated on with minimally invasive
or transhiatal approaches were excluded from this analysis.
Clinical staging was based on results from barium
swallow examination, endoscopic ultrasound, and computed
tomography of chest and abdomen. Endoscopy and endo-
scopic ultrasound were performed by an experienced team
for all patients. Since 2005 most patients were also evaluated
with fluorodeoxyglucose positron emission tomography-
computed tomography (FDG PET-CT) scan both as an initial
workup and as restaging tool before surgery (after neoadju-
vant therapy). In recent years, patients with locally advanced
tumors (T2N1/T3) were frequently offered the option of
neoadjuvant CT-RT, while in the early years covered by this
retrospective study, surgery alone was the standard treat-
ment. Tumor node metastasis (TNM) staging was performed
according to the criteria of the International Union Against
Cancer (UICC).21 Of these patients, 221 had squamous cell
carcinoma (SCC), and 181 had AC (Table 1). Informed
consent was obtained from all the patients who participated
in this study, which was performed in accordance with the
principles of the Declaration of Helsinki.
Surgical Resection Details on surgical techniques have
already been published elsewhere.22 Briefly,
esophagectomy was performed using an Ivor-Lewis
procedure, via a laparotomy and right thoracotomy, for
tumors of the mid-lower esophagus and esophagogastric
junction. A 3-stage McKeown’s procedure, with an
additional left cervical incision, was reserved for tumors
in the upper third of the esophagus. At least 6–8 cm of
healthy esophagus was resected above the proximal edge of
the tumor to avoid neoplastic involvement of the resection
margins. In this group of patients en bloc lymph node
dissection was performed, including the paraesophageal,
subcarinal, posterior mediastinal, and paracardial lymph
nodes, as well as those located along the lesser gastric
curvature, the origin of the left gastric artery, the celiac
trunk, the common hepatic artery, and the splenic artery. In
2001, prophylactic ligation of thoracic duct was introduced
to reduce the incidence of chylothorax.23 Since 2000,
epidural analgesia has been routinely used intraoperatively
and postoperatively. Intraoperative fluid restriction and
early postoperative extubation was introduced in 1995 to
reduce intensive care unit (ICU) stay. The alimentary tract
was reconstructed using the gastric pull-up technique; if the
stomach was unavailable, either a jejunal loop or the left
colon was used.24 The site of the nodes was identified by
the operating surgeons during the operation, and, at the end
of it, the different groups of lymph nodes were separately
sent for histology. Patients were examined at regularly
scheduled intervals by members of the surgical team after
1, 3, 6, and 12 months and every 6–12 months thereafter.
Neoadjuvant Therapy During the study period the
number of patients who had neoadjuvant therapy
progressively increased from the 30% in the first 3 years
to more than the 50% in the last 3 years. The most
3744 C. Castoro et al.
common preoperative chemotherapy regimen consisted of
5-fluorouracil and a platinum agent (standard regimen was
100 mg/m2 DDP on day 1, and 5-FU 1000 mg/m2 per day
in continuous infusion from day 1–5 for 3–4 cycles), but
taxanes were also prescribed as part of the treatment
regimen in some of the patients. Chemotherapy was usually
administered concurrently with radiation therapy, but the
exact sequence depended on the clinical protocol or on the
physician’s preference.
Standard radiotherapy was usually performed in 1.8 Gy
daily fractions for a total dose of 45–50 Gy. The planned
target volume for carcinomas of the upper or middle third
of the esophagus included the primary tumor with 5-cm
longitudinal margins, metastatic nodes with 2-cm margins,
supraclavear fovea and mediastinum. For carcinomas of the
lower third of the esophagus, the field was extended to
include both the perigastric and celiac nodes. This involved
an initial phase using anteroposterior-posteroanterior fields
to a total dose of 30.6 Gy in 1.8 fractions. The radiation
portals were then modified to encompass the primary tumor
and metastatic nodes with 2-cm margins up to a dose of
45 Gy.
In all patients, surgery was performed 4–8 weeks after
the last cycle of chemotherapy.25 Only 16% patients
received postoperative adjuvant chemotherapy and/or
radiotherapy.
Pathology Histopathological examination of all resected
specimens consisted in evaluation of: tumor stage, residual
tumor, grading, and number of lymph nodes involved. The
specimens were fixed in 5% formaldehyde and set in
paraffin. The lymph nodes were counted and assessed by a
pathologist. A series of sections from each node were
selected and stained with hematoxylin and eosin (H&E) as
well as with periodic acid-Schiff (PAS). All dissected
lymph nodes were microscopically analyzed for metastatic
disease. Nodal status (N0, N1) was evaluated in accordance
with the 6th edition of the TNM classification, but for the
purpose of this study the number of metastatic lymph nodes
and their site were also analyzed.21
Statistical Analysis Data were collected prospectively in
accordance with a standardized prospective protocol that
began in 1980. All statistical analyses were performed
using the SAS for Windows version 9.1 (SAS Institute,
Cary, NC). A median (interquartile [IQ] range) or
frequency (%) was used for descriptive statistics, as
appropriate. Categorical data were compared using Fisher
exact test and McNemar test, as appropriate; continuous
data were compared using the Mann-Whitney U test and
the Kruskal-Wallis test, as appropriate. Survival estimates
were calculated using the Kaplan-Meier method, and a
comparison of survival rates was performed using log-rank
TABLE 1 Demographic and clinical characteristics of 402 patients
enrolled between 1992 and 2007 with locally advanced esophageal
cancer and R0 resection
Patients 402
Gender: M/F 327/75
Age: median (IQR) 63 (55.5–69.9)
Histotype
Adenocarcinoma 181 (45)
Squamous cell carcinoma 221 (55)
Tumor site
Upper thoracic 58 (14.4)
Mid thoracic 100 (24.9)
Lower thoracic 96 (23.9)
Esophagogastric junction 148 (36.8)
Clinical TN stage
T1N1 10 (2.5)
T2N1 55 (13.7)
T3N0 132 (32.8)
T3N1 205 (51)
Treatment
Surgery alone 248 (61.7)
Surgery ? neoadjuvant therapy 154 (38.3)
Neoadjuvant therapy
CT 48
CT-RT 106
Pathological TN stage
T0/Tis N0 45 (11.2)
T0N1 14 (3.5)
T1N0 12 (3)
T1N1 7 (1.7)
T2N0 55 (13.7)
T2N1 27 (6.7)
T3N0 74 (18.4)
T3N1 153 (38.1)
T4N0 8 (2)
T4N1 7 (1.7)
Number of examined lymph nodes: Median (IQR) 18 (14–25)
Number of metastatic lymph nodes: Median (IQR) 1 (0–3)
Site of metastatic lymph nodes:
Laterocervical 2 (0.5)
Supraclavicular 2 (0.5)
Paraesophageal 98 (24.4)
Paratracheal 15 (3.7)
Subcarinal 27 (6.7)
Recurrent nerve nodes 13 (3.2)
Inferior pulmonary vein nodes 8 (2)
Paracardial 91 (22.6)
Perigastric 86 (21.4)
Celiac axis 31 (7.7)
Post operative CT-RT 67 (16.7)
Data expressed as n (%)
Nodal Metastasis From Locally Advanced Esophageal Cancer 3745
test. All tests were 2-sided and P values less than .05 were
considered significant.
RESULTS
Patients
A total of 446 patients with locally advanced esophageal
tumors were eligible for inclusion in the study (Table 1).
However, 33 of these were excluded because their resec-
tion was not radical and 11 were excluded because they
received only neoadjuvant therapy.
There were 181 patients who underwent R0 resection for
locally advanced esophageal adenocarcinoma (AC)
(Table 2). One hundred thirty-two underwent surgery
alone, 32 underwent surgery ? CT-RT neoadjuvant ther-
apy, and 17 underwent surgery ? chemotherapy (CT)
neoadjuvant therapy. The gender rate was similarly dis-
tributed in the 3 groups, while the patients who underwent
surgery alone were significantly older (P = .002). All but
seven patients (who had a 3-field lymphadenectomy) had a
2-field lymphadenectomy. Tumor site distribution was
significantly different in the three groups: the patients who
underwent surgery and neoadjuvant therapy presented more
often with a low esophageal localization than those who had
surgery alone. A significant number of patients who
underwent neoadjuvant therapy presented with T0/T1-N0
stages at the pathological examination compared with those
who had surgery alone (P = .02).
A total of 221 patients underwent R0 resection for
locally advanced esophageal SCC. Of these, 116 under-
went surgery alone, 74 underwent surgery ? CT-RT
neoadjuvant therapy while 31 underwent surgery ? CT
neoadjuvant therapy. Tumor site distribution and gender
rate were similar in the three groups, and the median age
was not significantly different (P = .08). Patients who had
surgery alone presented more frequently with stage T3N0
and less frequently with stage T3N1 than the other groups
TABLE 2 Clinical characteristics of patients with adenocarcinoma
Surgery alone Surgery ? neoadjuvant therapy Surgery ? neoadjuvant CT-RT Surgery ? neoadjuvant CT
Patients 132 49 32 17
Sex: M/F 114/18 47/2 31/1 16/1
Age: median (IQR)a,b 66.6 (57.8–72.7) 59.9 (53.1–67.2) 60.4 (52.2–66.8) 59.7 (53.3–70.2)
Tumor sitea,b
Lower thoracic 15 (11.4) 20 (40.8) 15 (46.9) 5 (29.4)
Esophagogastric junction 117 (88.6) 29 (59.2) 17 (53.1) 12 (70.6)
Clinical stage
T1N1 3 (2.3) 1 (2) 0 1 (5.9)
T2N1 19 (14.4) 3 (6.1) 2 (6.3) 1 (5.9)
T3N0 54 (40.9) 5 (10.2) 4 (12.5) 1 (5.9)
T3N1 56 (42.4) 40 (81.7) 26 (81.2) 14 (82.3)
Clinical stage N 1a,b 78 (59.1) 44 (89.8) 28 (87.5) 16 (94.1)
Pathological TN stagea,b,c
T0/Tis N0 0 6 (12.2) 5 (15.6) 1 (5.9)
T0N1 0 5 (10.2) 5 (15.6) 0
T1N0 2 (1.5) 1 (2) 1 (3.1) 0
T1N1 2 (1.5) 1 (2) 1 (3.1) 0
T2N0 14 (10.6) 8 (16.3) 4 (12.5) 4 (23.5)
T2N1 10 (7.6) 6 (12.2) 5 (15.6) 1 (5.9)
T3N0 27 (20.5) 5 (10.2) 5 (15.6) 0
T3N1 73 (55.3) 15 (30.6) 5 (15.6) 10 (58.8)
T4N0 1 (0.8) 1 (2) 1 (3.1) 0
T4N1 3 (2.3) 1 (2) 0 1 (5.9)
Pathological stage N1 88 (66.7) 21 (42.9) 16 (50) 5 (29.4)
Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CTc Pathological stage: T0-1 vs T2-3-4
Clinical stage N1 versus pathological stage N1:surgery alone P = .22, surgery ? neoadjuvant therapy P = .0004
3746 C. Castoro et al.
(P \ .001). A significant number of patients who under-
went neoadjuvant therapy presented with T0/T1-N0 stages
at the pathological examination compared with those who
had surgery alone (P \ .001). The characteristics of
patients who were operated on for SCC are outlined in
Table 3.
The survival rate of the 402 patients who underwent R0
section ± neoadjuvant therapy for locally advanced
esophageal cancer is shown in Fig. 1a and b. In the group
of 154 patients who had neoadjuvant therapy, 41 patients
obtained a complete response (27%), 88 had a partial
response (57%), and 25 were classified as nonresponder
(16%). The overall survival of these patients correlated
with the response: 5-year survival was 67.5% in patients
with complete response, 49.2% in patients with partial
response, and 20.4% in nonresponders (P = .0003). Uni-
variate analysis for predictors of survival after treatment of
locally advanced esophageal adenocarcinoma and SCC
included, as possible predictors, treatment modality, age,
tumor site, clinical stage, pathological stage, number of
examined lymph nodes, number of nodal metastasis,
metastasis at the paraesophageal, subcarinal, paracardial
perigastric, or celiac trunk stations. With multivariate
analysis, only metastasis at paracardial (around the cardias)
and celiac trunk stations were revealed to be independent
predictors of survival in patients with locally advanced
esophageal adenocarcinoma. Moreover, multivariate anal-
ysis showed that only neoadjuvant therapy and pathologic
N0 status were independent predictors of better survival in
patients with esophageal SCC. Survival analysis in locally
advanced adenocarcinoma and SCC of the esophagus is
shown in Tables 4 and 5.
Metastatic Lymph Node Distribution Almost 30% of the
patients with AC and approximately 40% of the SCC
patients were found to have effective T downstaging
TABLE 3 Clinical characteristics of patients with SCC
Surgery alone Surgery ? neoadjuvant therapy Surgery ? neoadjuvant CT-RT Surgery ? neoadjuvant CT
Patients 116 105 74 31
Sex: M/F 88/28 78/27 53/21 25/6
Age: median (IQR)a 62.4 (55–70.1) 59.9 (53–66) 59.8 (53.7–66.6) 60 (50.6– 65.8)
Tumor site
Upper thoracic 25 (21.6) 33 (31.4) 19 (25.7) 14 (45.2)
Mid thoracic 50 (43.1) 50 (47.6) 39 (52.7) 11 (35.5)
Lower thoracic 41 (35.3) 22 (21) 16 (21.6) 6 (19.3)
Clinical stage
T1N1 2 (1.7) 4 (3.8) 4 (5.4) 0
T2N1 23 (19.8) 10 (9.5) 4 (5.4) 6 (19.4)
T3N0 53 (45.7) 20 (19.1) 7 (9.5) 13 (41.9)
T3N1 38 (32.8) 71 (67.6) 59 (38.7) 12 (38.7)
Clinical stage N1a,b 63 (54.3) 85 (81) 67 (90.5) 18 (58.1)
Pathological TN stagea,b,c
T0/ Tis N0 1 (0.9) 38 (36.2) 29 (39.2) 9 (29)
T0N1 0 9 (8.6) 8 (10.8) 1 (3.2)
T1N0 5 (4.3) 4 (3.8) 3 (4.1) 1 (3.2)
T1N1 2 81.7) 2 (1.9) 1 (1.4) 1 (3.2)
T2N0 12 (10.3) 21 (20) 16 (21.6) 5 (16.1)
T2N1 8 (6.9) 3 (2.9) 2 (2.7) 1 (3.2)
T3N0 31 (26.7) 11 (10.5) 6 (8.1) 5 (16.1)
T3N1 50 (43.1) 15 (14.3) 8 (10.8) 7 (22.6)
T4N0 4 (3.5) 2 81.9) 1 (1.4) 1 (3.29
T4N1 3 (2.6) 0 0 0
Pathological stage N1a,b 63 (54.3) 29 (27.6) 19 (25.7) 10 (32.3)
Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CTc Pathological stage: T0-1 versus T2-3-4
Clinical stage N1 versus pathological stage N1: surgery alone P = .99, surgery ? neoadjuvant therapy P \ .0001
Nodal Metastasis From Locally Advanced Esophageal Cancer 3747
(regression score 1 or 2 assessed using Mandard scoring)
after neoadjuvant therapy. In fact, a significantly higher
number of patients with pathological stage 0 or 1 had
undergone neoadjuvant therapy.
The median number of lymph nodes examined was 18
(IQ range 14–25). In the AC group the median number of
lymph nodes retrieved from the surgical specimens was
similar in the surgery-alone and in the surgery ? neoad-
juvant therapy groups. Those who underwent neoadjuvant
therapy had, instead, a significantly lower number of
metastatic lymph nodes (P = .03). This was particularly
evident in the patients who underwent CT-RT therapy.
100
80
60
40
20
Patients at risk
Surgery alone, pN0Surgery alone, pN1Surgery + Neoadjuvant therapy, pN0Surgery + Neoadjuvant therapy, pN1
600
Months
aPercentsurvival
Survival analysis afteresophagectomy for adenocarcinoma P = 0.0002
48362412
1410
4–
2319
64
3027
77
36381011
41591719
100
80
60
40
20
Patients at risk
Surgery alone, pN0Surgery alone, pN1Surgery + Neoadjuvant therapy, pN0Surgery + Neoadjuvant therapy, pN1
600
Months
Survival analysis afteresophagectomy for SCC
bPercentsurvival
48362412
95
192
171034
3
201240
5
252252
9
40466417
FIG. 1 Survival analysis after
esophagectomy for
a adenocarcinoma, b SCC
TABLE 4 Univariate and
multivariate survival analysis
after radical resection of locally
advanced esophageal
adenocarcinoma
Adenocarcinoma Univariate: log-rank test Cox regression model
Cumulative % 5 years surviving P value OR (95% CI) P value
Age group .09 .08
\65 years 42
[65 years 36.8
Treatment .19 .62
Surgery alone 36.9
Surgery ? neoadjuvant therapy 49.3
Pathological stage \.0001 .22
0–1–2 55
3–4 25.3
Pathological stage N .0002 .37
0 58.2
1 28
Paraesophageal nodes .03 .82
Nonmetastatic 43.8
Metastatic 27.1
Subcarinal nodes .01 .31
Nonmetastatic 40.6
Metastatic 17.4
Paracardial nodes \.0001 2.79 (1.86–4.18) \.0001
Nonmetastatic 52
Metastatic 12.5
Celiac axis nodes .003 1.77 (1.05–3.00) .03
Nonmetastatic 42.2
Metastatic 25.5
3748 C. Castoro et al.
There was no significant difference in the proportion of
clinical and pathological N1 patients (P = .22) in the
surgery-alone group. In the patients who underwent neo-
adjuvant therapy, however, 89% were clinical node
positive while the percent of pathological node positive
patients dropped to 42% (P = .0004). The distribution of
lymph node metastasis in the different stations was similar
in the surgery-alone and surgery ? neoadjuvant therapy
groups. There were, nevertheless, less frequent metastases
at the paracardial nodes (P = .002) in the group of patients
who underwent CT-RT therapy. Nodal metastasis distri-
bution in locally advanced AC is outlined in Table 6.
In the SCC patients, the median number of lymph nodes
retrieved from the surgical specimens was similar in the
surgery-alone and surgery ? neoadjuvant therapy patients.
Those who underwent neoadjuvant therapy had a signifi-
cantly lower number of metastatic lymph nodes (P \ .001).
In fact, in the surgery-alone patients there was no signifi-
cant difference in the proportion of clinical and
pathological N1 patients (54% were both clinical node
positive and pathological node positive P = .99). In the
group of patients who underwent neoadjuvant therapy,
instead, 81% were clinical node positive, while the number
of pathological node positive patients dramatically dropped
to 28% (P \ .0001). This was even more evident with
regard to the patients who underwent neoadjuvant CT-RT:
more than 75% were staged as N0 after therapy. The fre-
quency of metastasis in the various nodal stations was
different in the subgroups. While the periesophageal nodes
remained the most frequent site of metastasis after neoad-
juvant therapy, their frequency dropped significantly
(P \ .001), and the difference was even more evident in
the CT-RT group. The frequency of subcarinal node
metastasis was, likewise, significantly lower in the patients
who had neoadjuvant therapy (P = .007), and no patients
in the CT-RT group showed metastasis at that site. Para-
cardial nodes were the 2nd most frequent site of metastasis
in the patients who had surgery alone, while they were the
3rd site in patients who had neoadjuvant therapy
(P \ .001). Perigastric nodes became the 2nd most fre-
quent site of metastasis in that group. Nodal metastasis
distribution in locally advanced SCC after surgery alone
and after neoadjuvant therapy is outlined in Table 7.
In the group of patients with esophageal SCC originat-
ing from the superior or middle thoracic esophagus, the
frequency of metastasis at the periesophageal and subcar-
inal stations and at lymph nodes along the pulmonary vein
were significantly reduced in patients who had neoadjuvant
therapy. The periesophageal nodes were still the most
frequent site of metastasis in these patients, but the
TABLE 5 Multivariate
survival analysis after radical
resection of locally advanced
esophageal SCC
Squamous cell carcinoma Univariate: log rank test Cox regression model
Cumulative %
5 years surviving
P value OR (95% CI) P value
Age group .05 .11
\65 years 40.3
[65 years 31.9
Treatment .0004 (0.68 (0.47–0.98) .04
Surgery alone 26.7
Surgery ? neoadjuvant therapy 49.8
Pathological stage .0004 .69
0–1–2 45.1
3–4 22
Pathological stage N \.0001 2 (1.4–2.9) .0002
0 51.2
1 17.1
Paraesophageal nodes .0005 .93
Nonmetastatic 43.6
Metastatic 16.1
Subcarinal nodes .001 .18
Nonmetastatic 39.2
Metastatic 10
Perigastric nodes .0003 .18
Nonmetastatic 41
Metastatic 11.5
Nodal Metastasis From Locally Advanced Esophageal Cancer 3749
subcarinal station shifted from second to fourth place and
the paracardial nodes were completely free of metastasis.
Nodal metastasis distribution in locally advanced SCC
originating from the superior or middle thoracic esophagus
is outlined in Table 8.
The frequency of metastasis at the periesophageal and
paracardial nodes in the patients with esophageal SCC
originating from the lower third of the esophagus was
significantly lower in patients who had neoadjuvant ther-
apy compared with those who had surgery alone. Nodal
TABLE 6 Metastatic lymph node distribution in esophageal adenocarcinoma
Surgery
alone
Surgery ? neoadjuvant
therapy
Surgery ? neoadjuvant
CT-RT
Surgery ? neoadjuvant
CT
Patients 132 49 32 17
Number of examined lymph nodes:
median (IQR)
19.5 (15–27) 20 (15–25) 17 (14–24.5) 22 (18–26)
Number of metastatic lymph nodes:a,b
median (IQR)
2 (0–5.5) 1 (0–2) 0.5 (0–1) 2 (0–4)
Site of metastatic lymph nodes:
Laterocervical 0 0 0 0
Supraclavicular 0 0 0 0
Periesophageal 39 (29.6) 10 (20.4) 7 (21.9) 3 (17.7)
Paratracheal 4 (3) 2 (4.1) 1 (3.1) 1 (5.9)
Subcarinal 7 (5.3) 5 (10.2) 3 (9.4) 2 (11.8)
Recurrent nerve nodes 1 (0.8) 0 0 0
Inferior pulmonary vein 3 (2.3) 0 0 0
Paracardialb 49 (37.1) 14 (28.6) 4 (12.5) 10 (58.8)
Perigastric 47 (35.6) 12 (24.5) 6 (18.8) 6 (35.3)
Celiac axis 19 (14.4) 8 (16.3) 6 (18.8) 2 (11.8
Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CT
TABLE 7 Metastatic lymph node distribution in esophageal SCC
Surgery
alone
Surgery ? neoadjuvant
therapy
Surgery ? neoadjuvant
CT-RT
Surgery ? neoadjuvant
CT
Patients 116 105 74 31
Number of examined lymph nodes: median (IQR) 16 (12–21) 18 (13–23) 18 (15–24) 18 (12–19)
Number of metastatic lymph nodes:a,b median (IQR) 1 (0–3) 0 (0–1) 0 (0–0) 0 (0–1)
Site of metastatic lymph nodes:
Laterocervical 2 (1.7) 0 0 0
Supraclavicular 0 2 (1.9) 2 (2.7) 0
Periesophageala,b 37 (31.9) 12 (11.4) 7 (9.5) 5 (16.1)
Paratracheal 5 (4.3) 4 (3.8) 3 (4.1) 1 (3.2)
Subcarinala,b 13 (11.2) 2 (1.9) 0 2 (6.5)
Recurrent nerve nodes 7 (6) 5 (4.8) 3 (4.1) 2 (6.5)
Inferior pulmonary vein n 5 (4.3) 0 0 0
Paracardiala,b 23 (19.8) 5 (4.8) 4 (5.4) 1 (3.2)
Perigastric 19 (16.4) 8 (7.6) 6 (8.1) 2 (6.5)
Celiac axis 2 (1.7) 2 (1.9) 2 (2.7) 0
Data expressed as n (%)a P \ .05, surgery alone versus surgery ? neoadjuvant therapyb P \ .05, surgery alone versus surgery ? neoadjuvant CT-RT versus surgery ? neoadjuvant CT
3750 C. Castoro et al.
metastasis distribution in locally advanced SCC originating
from the lower esophagus is outlined in Table 9.
DISCUSSION
Nodal stage is considered the most reliable predictor of
survival after esophagectomy with lymphadenectomy in
esophageal cancer patients without systemic metastases, and
the presence of nodal metastases is indicative of high risk for
disease recurrence.2–4 Our data (Fig. 1a, b) have confirmed
these hypotheses. The number of lymph nodes removed, in
addition to tumor depth and the number of lymph nodes
involved, have recently been found to be independent pre-
dictors of survival.1 Several investigators, in fact, consider
the current AJCC staging system for esophageal cancer,
largely based on depth of invasion, inadequate when applied
to patients receiving neoadjuvant therapy.10,26 In fact,
despite conflicting results concerning neoadjuvant CT
before surgical resection, multimodal neoadjuvant therapy
has emerged as a potential paradigm for the management of
locally advanced esophageal cancer.27–32 Achieving a
pathologic complete response and a node-negative status are
the major determinant of outcome following neoadjuvant
CT-RT.9 In those cases in which pathologic response is not
complete, distribution and frequency of nodal metastasis
have been found to be extensively modified by CT-RT. The
aim of this study is to define how neoadjuvant chemoradio-
therapy can affect distribution of nodal metastasis in order to
provide surgeons with a more precise map in preparation for
adequate lymphadenectomy.
TABLE 8 Metastatic lymph
node distribution in esophageal
SCC originating from the
superior or middle esophagus
Data expressed as n (%)a P \ .05, surgery alone vs
surgery ? neoadjuvant therapy
Surgery alone Surgery ? neoadjuvant
therapy
N 75 83
Number of examined lymph nodes: median (IQR) 15.5 (12–21) 18 (12.5–23)
Number of metastatic lymph nodes:a median (IQR) 0 (0–2) 0 (0–1)
Site of metastatic lymph nodes:
Laterocervical 2 (6.7) 0
Supraclavicular 0 2 (2.4)
Periesophageala 21 (28) 10 (12.1)
Paratracheal 4 (5.3) 2 (2.4)
Subcarinala 9 (12) 2 (2.4)
Recurrent nerve nodes 7 (9.3) 5 (6)
Inferior pulmonary veina 4 (5.3) 0
Paracardial 10 (13.3) 4 (4.8)
Perigastric 7 (9.3) 6 (7.2)
Celiac axis 0 1 (1.2)
TABLE 9 Metastatic lymph
node distribution in esophageal
SCC originating from the lower
esophagus and the
esophagogastric junction
Data expressed as n (%)a P \ .05, surgery alone vs
surgery ? neoadjuvant therapy
Surgery alone Surgery ? neoadjuvant
therapy
N 41 22
Number of examined lymph nodes: median (IQR) 17 (12–20) 18 (14–21)
Number of metastatic lymph nodes:a Median (IQR) 1 (0–3) 0 (0–0)
Site of metastatic lymph nodes:
Laterocervical 0 0
Supraclavicular 0 0
Periesophageala 16 (39) 2 (9.1)
Paratracheal 1 (2.4) 2 (9.1)
Subcarinal 4 (9.8) 0
Recurrent nerve nodes 0 0
Inferior pulmonary vein 1 (2.4) 0
Paracardiala 13 (31.7) 1 (4.6)
Perigastric 12 (29.3) 2 (9.1)
Celiac axis 2 (4.9) 1 (4.6)
Nodal Metastasis From Locally Advanced Esophageal Cancer 3751
The impact of neoadjuvant therapy on the number of
metastatic nodes has been described by several studies
and has been confirmed by the present one.5–9 The
frequency of metastatic lymph nodes was lower in the
neoadjuvant therapy ? R0 resection patients than in
those who had surgery alone. This data is even more
remarkable considering that neoadjuvant therapy did not
decrease the number of lymph nodes retrieved. In fact,
although the number of examined lymph nodes was
lower than that reported by Hulsher et al. it was similar
in all the groups and more than 75% of the patients had
15 or more lymph nodes removed, indicating that the
extent of lymphadenectomy had been adequate.3,33 This
was true regardless of the histotype, but it was more
pronounced in the SCC patients. In fact, while in the AC
patients the overall survival of those staged N0 after
neoadjuvant therapy was similar to that in the patients
with the same stage who had surgery alone, in the SCC
patients the improvement in terms of overall survival was
significantly greater in the patients who staged N0 after
neoadjuvant therapy than in those who had surgery alone.
The frequency of nodal metastasis in the various stations
in the AC patients who had surgery alone was similar to
what reported by Dresner et al. and by Van de Val
et al.11,12 On the contrary, the AC patients who underwent
CT-RT neoadjuvant therapy had less frequent metastasis
at the paracardial nodes. The most frequently involved
nodal stations in patients who had surgery alone was the
paracardial, while in patients who underwent neoadjuvant
CT-RT the most frequent metastatic nodal station was
the periesophageal followed by the perigastric. Postneo-
adjuvant therapy nodal metastasis map could help define
the prognosis of AC. In fact, some authors reported that
metastases at the celiac nodes were one of most important
parameters of a new nomogram to assess the prognosis of
esophageal adenocarcinoma.34 Figure 2a illustrates the
modifications in the patterns of lymph node metastasis in
patients with AC who underwent CT-RT neoadjuvant
therapy.
In our SCC patients who had surgery alone the nodal
metastatic distribution was quite similar to what was
reported by Akiyama et al. in 1981 and 1994.13,14 On the
other hand, in the group of patients with esophageal SCC
originating in the superior or middle thoracic esophagus
who underwent neoadjuvant therapy, metastasis at the
periesophageal nodes was less frequent than that reported
by Altorki et al. and by Kato et al.15,35 The frequency of
metastasis at the subcarinal station and at the lymph nodes
along the pulmonary vein was significantly lower in the
patients with upper or middle esophagus SCC who
underwent neoadjuvant therapy. Periesophageal nodes
were still the most frequent site of metastasis in this group
of patients, but the subcarinal station was less frequently
involved and the paracardial nodes were completely free of
metastasis. The frequency of metastasis to the periesoph-
ageal and paracardial nodes in SCC originating from the
29.6%
p = 0.49
Adenocarcinoma
Neoadjuvant CT-RT therapySurgery alone
p = 0.002
p = 0.20
21.9%
12.5%
18.8%
37.1%
35.6%
31.7%
29.3%
9.8%
39.0% 9.8%
4.8%
9.1%
0%p = 0.29
p = 0.05
SCC
Neoadjuvant therapySurgery alone
p = 0.02
p = 0.11
5.3%
13.3% 4.8%
12.0%
28.0%
2.4%
0%
12.1%
p = 0.02
p = 0.03
p = 0.05
SCC
Neoadjuvant therapySurgery alone
p = 0.09
a
b
c
FIG. 2 a Main metastatic lymph nodes sites in esophageal adeno-
carcinoma. The area of the circles is proportional to the frequency of
nodal metastasis. b Main metastatic lymph nodes sites in esophageal
SCC originating from upper or mid esophagus. The area of the circles
is proportional to the frequency of nodal metastasis. c Main metastatic
lymph nodes sites in esophageal SCC originating from lower
esophagus and esophagogastric junction. The area of the circles is
proportional to the frequency of nodal metastasis
3752 C. Castoro et al.
lower third of the esophagus was significantly lower in
patients who had neoadjuvant therapy compared with those
who did not. As suggested by several investigators, these
findings indicate that the probability of finding metastatic
nodes in a particular nodal station can change significantly
not only in relation to the tumor’s histotype or to its pri-
mary localization, but also depending on neoadjuvant
therapy.13–15,35 Changes in nodal metastasis sites in
patients with upper and middle thoracic esophagus and
in those with lower thoracic esophagus SCC are illustrated
in Fig. 2b and c.
The present study is based on data recorded in a
prospectively collected database, but nevertheless it is a
retrospective study and patient selection bias could have
an impact on the results obtained. One of the limits of
this study is that the distribution of tumor sites and
clinical stages were not identical in the surgery-alone and
surgery ? neoadjuvant therapy groups of patients both
for SCC and AC. The fact that there were more T3N0
patients in the surgery-alone group could indicate a
selection bias. Nonetheless, in our opinion, the decrease
in the proportion of N ? patients in the neoadjuvant
therapy groups was so marked that a possible selection
bias could be considered not relevant. Moreover, only
SCC patients who had neoadjuvant therapy seemed to
have benefitted, while in the AC group the number of
nodal metastasis was similar to that observed in patients
who had surgery alone. These patients were, nonetheless,
equally distributed in the two groups receiving neoadju-
vant therapy, but to impede influencing data concerning
the distribution of nodal metastasis they were considered
apart. Secondly, the number of patients who were
excluded from this study because they had incomplete
resection (R1, R2) or only neoadjuvant therapy without
surgery was quite small (33 and 11 patients, respec-
tively), and excluding them from the study did not, we
feel, affect our analysis. In fact, their inclusion would
add patients for whom nodal situation could not be
completely assessed since part of the tumor was neces-
sarily left behind. However, we are conscious that this
might cause a selection bias as neoadjuvant therapy
increases R0 rate. Another limit concerns the lack of
information about the radiation field in our prospective
database. Information on positive lymph node basins
inside and outside the field of radiation could have been
very useful.
In conclusion, this study shows that not only did nodal
metastasis frequency decrease but even nodal metastasis
localization was altered after neoadjuvant therapy. The
map of the distribution of nodal metastasis after neoadju-
vant therapy might be useful information to plan the
operative technique and adequate lymphadenectomy.
ACKNOWLEDGMENT The authors are extremely grateful to
Linda Inverso for her kind help in the revision of the English language
and for editing the final version of the paper.
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