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: hfuji@koto.kpu-m.ac.jp

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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