ORIGINAL ARTICLE
Predictive factors for early recurrence in patients with esophagealsquamous cell carcinoma after curative esophagectomy
Hiroki Shimizu • Atsushi Shiozaki • Hitoshi Fujiwara • Shuhei Komatsu • Daisuke Ichikawa •
Kazuma Okamoto • Yasutoshi Murayama • Yoshiaki Kuriu • Hisashi Ikoma •
Masayoshi Nakanishi • Toshiya Ochiai • Yukihito Kokuba • Eigo Otsuji
Received: 3 October 2011 / Accepted: 26 December 2011 / Published online: 21 January 2012
� The Japan Esophageal Society and Springer 2012
Abstract
Background Even after curative resection with combined
modality treatment by chemotherapy and radiation, esopha-
geal cancer has remained a disease with poor prognosis upon
early recurrence. In this study, the clinicopathological pre-
dictive factors for early recurrence in patients with curative
resected esophageal cancer were retrospectively evaluated.
Methods Eighty-one consecutive patients who had recur-
rence of primary esophageal squamous cell carcinoma after
curative resection were analyzed. The patients were clas-
sified into two subgroups by time of recurrence (within
180 days of surgery or later): an early group and a late
group.
Results Twenty-seven (33.3%) and 54 (66.7%) patients
were classified into the early and late groups, respectively.
Patients in the early group had significantly deeper tumors
than those in the late group. The initial recurrence patterns
were not significantly different between the two groups,
and distant recurrences were found in two-thirds of patients
in both groups. The 1-year survival rates of patients in the
early and late groups were 11 and 62%, respectively. The
survival rate after recurrence of patients in the early group
was significantly poorer than that of patients in the late
group (p \ 0.0001). Multivariate logistic regression anal-
ysis revealed that the presence of three or more patholog-
ical lymph node metastases was an independent risk factor
associated with early recurrence.
Conclusions Early distant recurrences of esophageal
cancer frequently occurred even after curative surgery. The
number of pathological lymph node metastases (three or
more) was the independent risk factor for early recurrence
in patients with esophageal cancer after curative resection.
Keywords Esophageal cancer � Surgery �Early recurrence � Lymph node metastasis
Introduction
Esophageal cancer is one of the most aggressive malig-
nancies globally [1]. In Japan, the predominant pathologi-
cal type of esophageal cancer is squamous cell carcinoma
(SCC). Recent advances in surgical methods combined
with perioperative treatment have led to better prognosis
for esophageal cancer; however, the tumor recurrence rate
is still high, and the prognosis is worse than that for other
gastrointestinal malignancies, even if curative resection
with radical lymph node dissection is completed [2–4].
Furthermore, recurrence in esophageal cancer presents
earlier than that in other types of cancer [5–8]. Symptoms
of esophageal cancer recurrence, such as obstruction or
recurrent nerve paralysis, have a tremendous influence on
the patient’s quality of life, and time of recurrence was
reported as one of the factors affecting treatment response
[9]. Therefore, it is important to predict groups of patients
at high risk of early recurrence in order to implement an
intensive follow-up or treatment strategy. There are many
reports regarding the factors that affect survival and
recurrence in patients with esophageal cancer [10–14].
Little, however, is known about the predictors for early
recurrence in esophageal cancer after curative resection
[15]. Regarding a disadvantage of invasive surgery for
H. Shimizu � A. Shiozaki � H. Fujiwara (&) � S. Komatsu �D. Ichikawa � K. Okamoto � Y. Murayama � Y. Kuriu �H. Ikoma � M. Nakanishi � T. Ochiai � Y. Kokuba � E. Otsuji
Division of Digestive Surgery, Department of Surgery,
Kyoto Prefectural University of Medicine, 465 Kajii-cho,
Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
e-mail: [email protected]
123
Esophagus (2012) 9:17–24
DOI 10.1007/s10388-011-0308-2
esophageal cancer, a disease-free survival (DFS) time
within 180 days of operation is hard to accept. Further-
more, the achievement of preoperative prediction for high-
risk patients with such an early recurrence within 180 days
of operation would have a great influence on treatment
strategies to avoid an unnecessary surgery and consider an
induction chemotherapy. In the present study, we examined
patients with esophageal SCC who had recurrence after
curative resection and then investigated prognostic factors
for early recurrence in these patients.
Materials and methods
Patients
The records of 253 consecutive patients with esophageal
SCC who had undergone esophagectomy with extensive
lymph node dissection (curative R0 resection) at the
Department of Surgery, Division of Digestive Surgery,
Kyoto Prefectural University of Medicine, between Janu-
ary 1998 and August 2010 were reviewed. Of these, we
examined 81 patients (30.8%) who had recurrence of pri-
mary esophageal SCC in this study. Then, the patients were
classified into two subgroups according to the initial time
of recurrence of primary tumor after surgery; in detail, we
defined the patients with initial recurrence within 180 days
of operation as the early group and those later than
180 days after operation as the late group. Of all 81
patients, 27 (33.3%) and 54 (66.7%) patients were classi-
fied into the early and late groups, respectively.
Treatment for primary tumor
At our institute, patients with thoracic esophageal cancer
underwent cervical lymph node dissection according to the
presence or absence of laryngeal nerve nodal metastasis
detected on intraoperative pathological examination [16].
We routinely performed three-field (cervical, mediastinum,
and abdomen) lymph node dissection in patients with
cervical esophageal cancer, and two-field (mediastinum
and abdomen) lymph node dissection in those with
abdominal esophageal cancer. Of the 27 and 54 patients in
the early and late groups, 16 and 43 patients underwent
two-field lymph node dissection, and 11 and 11 patients
underwent three-field lymph node dissection, respectively.
The criteria for indication for perioperative treatment at
our institute changed as of 2008 according to the results of
the randomized clinical trial [17]. Postoperative chemo-
therapy was routinely performed even after curative
resection before 2008. However, since 2008, preopera-
tive chemotherapy has been performed for patients with
stage II or III esophageal cancer without postoperative
chemotherapy. A concurrent preoperative chemotherapy
regimen was high-dose FP [5-FU (800 mg/body/day, days
1–5) plus cisplatin (80 mg/body/day, day 1)]. Preoperative
therapy was undergone by 18 of 27 patients in the early
group and 18 of 54 patients in the late group. In detail, of
18 patients in the early group, 7 underwent chemoradio-
therapy (40 Gy, 2 Gy/day), 10 underwent chemotherapy
alone, and 1 underwent radiotherapy (RT) (60 Gy, 2 Gy/
day) alone. Of 18 patients in the late group, 7 underwent
chemoradiotherapy and 11 underwent chemotherapy alone.
Postoperative chemotherapy regimens were high-dose FP
or low-dose FP [5-FU (250–500 mg/body/day) plus cis-
platin (10 mg/body/day)] plus oral fluoropyrimidine [5-FU
(150–200 mg/body/day) or UFT (300–400 mg/body/day)]
for 3 years [18]. Postoperative therapy was undergone by 7
of 27 patients in the early group and 34 of 54 patients in the
late group. In detail, of 7 patients in the early group, all
patients underwent chemotherapy alone, and of 34 patients
in the late group, 2 underwent chemoradiotherapy and 32
underwent chemotherapy alone.
Clinicopathological features
Gender, age, size, location, macroscopic type, region, and
number of lymph node metastasis were analyzed as pre-
operative characteristics. Presence of lymphatic and venous
invasion, depth of tumor invasion, number of lymph node
metastasis, and presence of intramural metastasis were also
analyzed as pathological characteristics. The resected
specimens were fixed in formalin, embedded in paraffin,
stained with hematoxylin and eosin, and examined rou-
tinely by experienced pathologists at our hospital after
surgery. In general, the tumor had been sectioned in its
entirety parallel to the reference line. In addition, immu-
nohistochemical detection of the nuclear Ki-67 antigen,
which is expressed in proliferating cells, was performed in
18 patients (4 in the early group and 14 in the late group).
All 18 patients did not receive any preoperative treatments.
To evaluate the proliferation index, the number of Ki-67
stained cells was quantified in five randomly selected fields
at 4009 magnification.
Tumor location, tumor macroscopic type, depth of
tumor invasion, region of lymph node metastasis, presence
of intramural metastasis, clinical response, and pathological
grade of preoperative treatment, and curability of surgery
were classified according to the Japanese Classification of
Esophageal Cancer, 10th edition [19, 20].
Follow-up programs and definition of recurrence
The patients were followed at our outpatient department
every 3 months for the first 2 years, and thereafter every
6 months. Physical examination and blood examination,
18 Esophagus (2012) 9:17–24
123
including for tumor markers (SCC antigen and cytokeratin
19 fragment), were performed at each follow-up, and a
multislice CT scan was performed every 6 months. Since
2007, positron emission tomography (PET) has been
introduced in screening for recurrence [21]. The median
follow-up period after esophagectomy was 496 days (range
49–4,278).
The initial recurrence pattern detected by imaging
studies was classified as locoregional or distant. In detail,
recurrences within the area of initial esophagectomy and
nodal dissection were defined as locoregional recurrence,
and hematogenous metastasis, non-regional lymph node
metastasis, and pleural dissemination were defined as dis-
tant recurrences.
Statistical analysis
Cause-specific death of a patient was defined as when the
cause of death was specified as a recurrence of primary
esophageal SCC. Chi-square test and Fisher’s exact test
were used to evaluate differences in proportions, and
Student’s t test was used to evaluate continuous variables.
Cumulative survival rates were calculated by the Kaplan-
Meier method, and the statistical significance of differences
was examined by the log-rank test. Multivariate logistic
regression was used to identify risk factors associated with
early recurrence. A p value less than 0.05 was considered
significant.
Results
Of all 81 patients, the mean age was 62 years (range
43–82), and the male:female ratio was 5.75. The preoper-
ative characteristics of patients in each group are shown in
Table 1. There were no significant differences in gender,
age, tumor size, tumor location, tumor macroscopic type,
regions, and number of lymph node metastases between the
two groups. However, clinical lymph node metastases at
multiple regions were found in nine patients (33%) in the
early group, which was significantly frequent compared
with six patients (11%) in the late group. FDG-PET
Table 1 Preoperative
characteristics of two groups
SD standard deviation, SUVstandardized uptake valuea p values were statistically
significant at 0.05b Japanese Classification of
Esophageal Cancer
Variable n Recurrence time after surgery p valuea
Early (within
6 months)
Late (6 months
and later)
Total 81 27 54
Gender
Male 69 22 (81%) 47 (87%) 0.522
Female 12 5 (19%) 7 (13%)
Age (years)
Mean (±SD) 62.2 ± 8.2 63.9 ± 8.7 0.263
Size (mm)
Mean (±SD) 40.9 ± 30.1 41.7 ± 25.0 0.464
Location
Ce/Ut 13 5 (19%) 8 (15%) 0.751
Mt/Lt/Ae 68 22 (81%) 46 (85%)
Macroscopic type
Type 0/scar 21 5 (19%) 16 (30%) 0.420
Non-type 0 60 22 (81%) 38 (70%)
Region of lymph node metastasisb
None 30 6 (22%) 24 (44%) 0.063
One region 36 12 (44%) 24 (44%)
Two/three regions 15 9 (33%) 6 (11%)
Number of lymph node metastases
None 31 7 (26%) 24 (44%) 0.331
Single node 23 8 (30%) 15 (28%)
Multiple nodes 27 12 (44%) 15 (28%)
Maximum SUV of FDG-PET
Total 23 9 14
Mean (±SD) 8.6 ± 6.0 6.1 ± 3.6 0.223
Esophagus (2012) 9:17–24 19
123
examination was performed preoperatively in 23 patients
(9 in the early group and 14 in the late group), and there
was no significant difference in the mean of maximum
standardized uptake value (SUV) at the primary tumor
between the two groups.
The treatment outcomes for the primary tumor are
summarized in Table 2. Among all the patients, 89 and
80% in the early and late groups received perioperative
therapy, respectively. There was no significant difference
in clinical response of preoperative treatment, extent, and
curability surgery.
The pathological characteristics of patients in each
group are shown in Table 3. Patients in the early group had
significantly deeper tumors (p = 0.043) than those in the
late group. However, the univariate analysis did not show a
statistical difference in the number of lymph node metas-
tases between the two groups; presence of lymph node
metastasis was found in 25 patients (93%) in the early
group, which was significantly frequent compared with 36
patients (67%) in the late group. The Ki-67 index showed
no difference between the two groups.
The median DFS time of all patients was 264 days. The
initial recurrence pattern and the treatment after recurrence
are summarized in Table 4. The patterns were not signifi-
cantly different between the two groups, and distant
recurrence was detected in 17 of 27 (63%) and 36 of 54
(67%) patients in the early and late groups, respectively.
Regional lymph node recurrence occurred in 14 and 27
patients in the early and late groups, respectively. Among
them, regarding the location of recurrent regional lymph
nodes, 9 (64%) and 17 (63%) of patients in the early and
late groups had recurrence within the area of initial lymph
node dissection, respectively.
Multivariate logistic regression analysis, which was
performed for the factors of depth of tumor invasion,
number of pathological lymph node metastases, presence
of intramural metastasis, and region of clinical lymph node
metastasis, revealed that the presence of three or more
lymph nodes was an independent risk factor associated
with early recurrence (Table 5).
Figure 1 shows the survival curves after esophagectomy
for patients in the two groups. The survival rate after
esophagectomy of patients in the early group was signifi-
cantly poorer than that of the late group (p \ 0.0001).
Figure 2 shows the survival curves after recurrence for
patients in the two groups. The 1-year survival rates of
patients in the early and late groups were 11 and 62%,
respectively. The 2-year survival rate of patients in the late
group was 25%, while none of the patients in the early
group survived more than 2 years. The survival rate after
recurrence of patients in the early group was significantly
poorer than that of patients in the late group (p \ 0.0001).
Discussion
Little is known about the risk factors for early recurrence in
patients with esophageal cancer after curative resection
[15]. The present study revealed that the presence of three
or more lymph node metastases was an independent risk
factor for early (within 180 days) recurrence. The survival
rate after recurrence in patients in the early group was
Table 2 Treatment outcomes
of two groups
CR complete response, PRpartial response, SD stable
disease, PD progressive diseasea Japanese Classification of
Esophageal Cancer
Variable n Recurrence time after surgery p value
Early (within
6 months)
Late (6 months
and later)
Total 81 27 54
Perioperative therapy
Negative 14 3 (11%) 11 (20%) 0.365
Positive 67 24 (89%) 43 (80%)
Clinical response to preoperative treatmenta
Total 36 18 18
CR/PR 23 12 (67%) 11 (61%) 1
SD/PD 13 6 (33%) 7 (39%)
Extent of esophagectomy
Subtotal 72 24 (89%) 48 (89%) 0.749
Middle and lower 6 1 (4%) 5 (9%)
Total with laryngectomy 3 2 (7%) 1 (2%)
Curability of surgerya
A 45 13 (48%) 32 (59%) 0.343
B 36 14 (52%) 22 (41%)
20 Esophagus (2012) 9:17–24
123
significantly poorer than that in patients in the late group.
These results might indicate that it is necessary to recon-
sider treatment strategies especially for esophageal cancer
patients with three or more lymph node metastases.
Despite recent advances in surgical techniques, postop-
erative management, and perioperative treatment strategies,
the prognosis of esophageal cancer is still poor, and the
postoperative 5-year survival rate has been reported as
29–56.8% even if curative resection is performed [7, 8, 11,
22]. Furthermore, recurrence of esophageal cancer was
shown to occur much more frequently and earlier than in
gastric cancer or colorectal cancer [4], and more than half
of tumor recurrences occur within 12 months of curative
resection [5–8]. Osugi et al. [23] reported that 83% of
recurrences in esophageal cancer patients were found
within 24 months of curative resection, and the survival
time after recurrence correlated with the time of recur-
rence. In this study, recurrences occurred in 30.8% of
esophageal SCC patients even after R0 resection, and it
was noteworthy that recurrences occurred within only
180 days in one-third of these patients. The later the
recurrence was, the longer the survival period after recur-
rence. In this study, the 2-year survival rate of patients in
the late group was 25%, while none of the patients in the
early group survived more than 2 years. The period
between esophagectomy and recurrence was reported as
one of the independent factors related to length of survival
after recurrence [9, 23]; furthermore, nonsurgical treatment
response in patients with recurrence within 1 year was
Table 3 Pathological
characteristics of two groups
a Japanese Classification of
Esophageal Cancer
Variable n Recurrence time after surgery p value
Early (within
6 months)
Late (6 months
and later)
Total 81 27 54
Lymphatic invasion
Negative 25 8 (30%) 17 (31%) 1
Positive 56 19 (70%) 37 (69%)
Venous invasion
Negative 37 14 (52%) 23 (43%) 0.430
Positive 44 13 (48%) 31 (57%)
T stage
T0/1a/1b 17 2 (7%) 15 (28%) 0.043
T2/3/4 64 25 (93%) 39 (72%)
Number of lymph node metastases
0 20 2 (7%) 18 (33%) 0.072
1–2 27 10 (37%) 17 (31%)
C3 34 15 (56%) 19 (35%)
Intramural metastasisa
Negative 75 23 (85%) 52 (96%) 0.092
Positive 6 4 (15%) 2 (4%)
Response grade of preoperative treatmenta
Total 36 18 18
0/1a/1b 24 11 (61%) 13 (72%) 0.725
2/3 12 7 (39%) 5 (28%)
Ki-67 index
Total 18 4 14
Mean (±SD) 0.31 ± 0.06 0.34 ± 0.03 0.764
Table 4 Initial recurrence pattern and treatment after recurrence of
two groups
Pattern of recurrence Type of treatment
CRT/RT or Op Chemotherapy BSC
Early group
Locoregional site only 7 3 0
Distant site only 2 2 9
Both sites 2 2 0
Late group
Locoregional site only 16 2 0
Distant site only 13 9 1
Both sites 7 4 2
CRT chemoradiotherapy, RT radiotherapy, Op operation, BSC best
supportive care
Esophagus (2012) 9:17–24 21
123
significantly worse than in those with recurrence after 1 year
or later [9]. Regarding these results, we must reconsider
treatment strategies to avoid these early recurrences.
Was the radicality of accurate surgery insufficient to
prevent recurrences? Indeed, surgical resection remains the
primary treatment for esophageal cancer as it provides the
best chance of cure. The effect of radical surgery with
three-field lymph node dissection for thoracic esophageal
cancer has been controversial. At our institute, the indica-
tion of cervical lymph node dissection for thoracic esoph-
ageal cancer was determined according to the presence or
absence of laryngeal nerve nodal metastasis by intraoper-
ative pathological examination. Ueda et al. [16] reported
that 31 patients with thoracic esophageal cancer who had
no recurrent nerve nodal metastasis on intraoperative
pathological examination did not undergo cervical lymph
node dissection, and none of them had cervical lymph node
recurrence. Furthermore, our study showed that distant
recurrences occurred in two-thirds of patients of both
groups, which was similar to the results in previous reports
[22–24]. These findings suggested that small distant
metastases, which could not be detected by current imaging
techniques, have already occurred by the time of operation,
and further radicality of surgery might not contribute to
improving the recurrence rate or time.
Some previous studies reported that not only the pres-
ence, but also the number of lymph node metastases was
one of the independent prognostic factors in patients with
esophageal cancer after curative resection [11, 12, 25, 26].
Despite recently developed imaging techniques, it might be
difficult to accurately estimate the number of metastatic
lymph nodes before surgery. This study showed that 93%
of patients in the early recurrence group had pathological
lymph node metastasis, and the presence of three or more
pathological lymph node metastases was an independent
risk factor for early recurrence after curative resection.
However we analyzed some clinical data to find patients
with a high risk for early recurrence preoperatively; no
clinical factors, including the region and number of clinical
lymph node metastases, were selected as an independent
risk factor. Regarding these results, more accurate preop-
erative diagnosis of lymph node metastasis is important to
Table 5 Logistic regression
analysis of early recurrence
after curative esophagectomy
HR hazard ratio, CI confidence
interval
Variable HR 95% CI p value
T stage
T2/3/4 versus T0/1a/1b 3.612 0.680 – 19.194 0.132
Lymph node metastasis
1–2 versus none 5.352 0.961 – 29.788 0.055
C3 versus none 6.276 1.127 – 34.945 0.036
Intramural metastasis
Positive versus negative 3.096 0.484 – 19.792 0.232
Region of preoperative lymph node metastasis
1 region versus none 2.041 0.597 – 6.993 0.256
2–3 regions versus none 1.016 0.234 – 4.425 0.983
Fig. 1 The survival rate after esophagectomy of patients in the early
group was significantly poorer than that of the late group
(p \ 0.0001)
Fig. 2 The survival rate after recurrence of patients in the early group
was significantly poorer than that of patients in the late group
(p \ 0.0001)
22 Esophagus (2012) 9:17–24
123
clear up the discrepancy. In addition to multi-detector-row
computed tomography (MDCT) and PET, transesophageal
or transbronchial ultrasound with needle biopsy have
contributed to progress in diagnosing mediastinal lymph
node metastasis [27].
In patients with resectable esophageal cancer, periop-
erative chemotherapy has an effective role in controlling
small distant metastases, and some randomized trials of this
have been reported [17, 28–30]. In Japan, in two phase III
studies that compared surgery with or without pre- or
postoperative chemotherapy, preoperative chemotherapy
followed by surgery emerged as standard treatment for
patients with stage II or III esophageal cancer [17, 30].
Some studies reported the efficacy of chemotherapy with
docetaxel, cisplatin, and 5-FU (DCF) [31]. In this study,
despite the fact that the chemotherapy regimen was FP and
most patients received perioperative treatments, early
recurrence occurred at a high rate. Dose, regimen, and
timing of chemotherapy have to be discussed, especially
for the prevention of early distant recurrences. Regarding
the result in this study, we considered adding adjuvant
chemotherapy for patients who have three or more patho-
logical lymph node metastases, even if preoperative
chemotherapy and curative resection were performed.
In conclusion, distant recurrences of esophageal cancer
frequently occurred in patients with recurrence within
180 days of curative surgery, and regardless of detailed
analysis with many clinicopathological variables, the
presence of three or more pathological lymph node
metastases was the only independent risk factor for early
recurrence in patients with esophageal cancer after curative
resection. Concerning these results, it might be possible to
classify esophageal cancer patients with three or more
pathological lymph node metastases as being at high risk of
early recurrence, and thus treatment strategies for this
group, especially the presence, regimen, and timing of
perioperative treatments, should be reconsidered. Further
research is needed to predict and prevent early recurrence
of esophageal cancer.
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