Introduction
Endoscopic resection (ER) including endoscopic mucosal resection (EMR) and endoscopic
submucosal dissection (ESD) is a standard treatment for superficial esophageal squamous
cell carcinoma (ESCC) [1]
[2]
[3]. In particular, ESD has recently been widely adopted for the treatment of superficial
ESCC because en bloc complete resection can be achieved, even in large lesions, without
organ resection. However, esophageal strictures are one of the major complications
of ER for large superficial ESCC [4]
[5]. This complication is usually associated with dysphagia, which is followed by declining
quality of life. In our previous study, mucosal defects due to ER that were larger
than 3/4 of the circumference of the esophagus were significantly associated with
the occurrence rate of esophageal strictures when no prophylactic treatment was performed
[6]. Endoscopic balloon dilation (EBD) is performed with tandem repeats as a general
treatment worldwide for esophageal strictures. As we previously reported, more than
6 EBD procedures were required for 66 % of patients with mucosal defects larger than
3/4 of the circumference of the esophageal lumen [7]. There has been a report regarding the efficacy of scheduled preventive EBD for
esophageal strictures; however, the benefit of EBD for wide mucosal defects was limited
[7]
[8].
Recently, steroid administration has been reported as a prophylactic treatment to
reduce esophageal strictures due to ER [9]
[10]. In these studies, promising efficacy was demonstrated; however, the studies involved
a small number of subjects, and the efficacy of the combination of local steroid injection
and oral steroid administration was not compared with the efficacy of local steroid
injection alone [9]
[11]. Moreover, these reports did not focus on the stricture rate according to the degree
of mucosal defect lumen circumference after ER. Therefore, little is known about what
width of mucosal defect should indicate prophylactic steroid treatment or what would
be an appropriate method of administration to prevent stricture formation. There is
also little data on populations at high risk of stenosis after ER even with prophylactic
steroid treatment.
The aim of this study was to retrospectively evaluate the esophageal stricture rate
among individual Groups classified according to prophylactic methods for various sized
lesions of large superficial ESCC. We compared patients receiving no prophylactic
treatment, steroid injection, or steroid injection followed by oral steroid according
to the different widths of their mucosal defects. In addition, we analyzed the factors
related to EBD for those patients whose mucosal defects were larger than 7/8 of the
circumference of the esophagus, which seemed to put them at high risk for stricture
even with prophylactic steroid administration.
Patients and methods
Patients
Between June 2007 and December 2013, 699 patients with 1123 superficial ESCC lesions
were treated with ER at the National Cancer Center Hospital East. Of these, 149 patients
with widespread mucosal defects due to ER for a solitary lesion involving 3/4 or larger
than the circumference of the esophageal lumen were enrolled. The indication criteria
of ER for ESCC were as follows: 1) depth invasion was limited to within SM1 in pretreatment
endoscopic findings; 2) absence of lymph node or distant metastasis; 3) histologically
confirmed ESCC with biopsy specimens prior to ER; and 4) provision of written informed
consent. The following patients were excluded from the study: 1) those who could not
be followed up for 6 months or longer; 2) those who already had a stricture due to
prior ER for esophageal cancer; 3) those who had a history of chemoradiotherapy (CRT)
for prior esophageal cancer; and 4) those who had received additional CRT or surgery
after non-curative ER.
Study design
In this study, we classified all enrolled patients into 3 groups according to the
width of the mucosal defect (Group A, ≥ 3/4 and < 7/8; Group B, ≥ 7/8 and less than
the entire circumference; Group C, the entire circumference), as shown in [Fig. 1]. The circumference of the mucosal defect was retrospectively estimated with endoscopic
pictures immediately after ER. The primary outcome of this study was to evaluate the
occurrence of esophageal strictures within 6 months among individual groups classified
according to mucosal defect or by the prophylactic methods in each Group. A stricture
was defined as cases where an ordinary sized endoscope (GIF Q260, GIF 1T240; Olympus
Optical Co. Ltd., Tokyo, Japan) could not pass through the post-ER site. The other
outcomes were the number of EBD procedures, time to achieve EBD success, and refractory
stricture rate, which are all related to EBD, so these analyses were performed for
patients who received EBD in Groups B and C. The time to achieve EBD success was defined
as the period from the initial EBD to the last EBD session. We evaluated the necessity
of EBD among the individual steroid treatment groups (no treatment, steroid injection,
and steroid injection followed by oral steroid).
Fig. 1 Groups classified according to width of mucosal defect. Patients who underwent endoscopic
resection (ER) for large superficial esophageal squamous cell carcinoma (ESCC): Group
A, ≥ 3/4 and < 7/8; Group B, ≥ 7/8 and less than the entire circumference; Group C,
the entire circumference.
ER procedure
The method of ER use in this study was strip biopsy [12] as EMR and ESD [13]. We used a single-channel upper gastrointestinal endoscope (GIF Q260J; Olympus,
Tokyo, Japan), with an electrosurgical unit (ICC-200; ERBE, Tubingen, Germany) and
electrosurgical knife (Dual knife KD-650 L/IT knife nano KD-612; Olympus, Tokyo, Japan).
We identified the tumor outlines with iodine staining and placed marker dots circumferentially
outside the tumor margins using the electrosurgical knife. We injected a 0.4 % sodium
hyaluronic acid solution (Mucoup®; Johnson and Johnson, Tokyo, Japan) into the submucosal
layer and then performed mucosal incision and submucosal dissection using the electrosurgical
knife.
Management after ESD for stricture prevention
Starting in December 2009 at our institution, steroid injections into the ulcer bed
due to ER were introduced for all patients with 3/4 or larger mucosal defects. Furthermore,
beginning in November 2012, we commenced oral steroid administration in addition to
local injections in all cases of a mucosal defect due to ER 7/8 or larger than the
circumference.
For steroid injections, 1 part triamcinolone acetonide (Kenacort®; 50 mg/5 mL; Bristol-Meyers Squibb Co., Tokyo, Japan) was diluted with 2 parts saline
and injected into the residual submucosal tissue of the ulcer bed, using between 0.5 mL
and 1.0 mL until all 50 mg of triamcinolone acetonide was injected. From December
2009, the sessions were performed at 3, 7, and 10 days after ER, and all 50 mg of
triamcinolone acetonide was used each time, as described previously [10]. Beginning in March 2011, a single session was undertaken at 1 day after ER, and
from October 2011, immediately after ER, according to the literature report [14].
For oral steroid administration, prednisolone was started at a dose of 30 mg/day on
the third day post-ESD, tapered gradually (30, 30, 25, 25, 20, 15, 10, and 5 mg for
7 days each), and then discontinued 8 weeks later, as Yamaguchi reported [9].
Follow up
Initial endoscopic examination was planned about 7 to 14 days after ESD to evaluate
patients’ post-ESD ulcer or stricture status. Then, regular endoscopic examination
was performed at 1, 3, 6, and 12 months after ER. However, whenever patients felt
dysphagia, endoscopic examination was performed on demand. When we found an esophageal
stricture, EBD was subsequently performed. We used an esophageal balloon dilation
catheter (CRE Fixed Wire 12 – 15 mm/15 – 18 mm, Boston Scientific Co, Boston, Ma)
according to the severity of the stricture. EBD was carried out using direct visualization
and fluorographic monitoring [7].The EBD procedure was repeated every 2 weeks until relief of the dysphagia and improvement
of the stricture; it was then defined as a successful dilation treatment. Cases that
required 6 or more EBD procedures were defined as having refractory strictures [15].
For patients with steroid injection followed by oral steroid administration, a physical
examination and blood examination was performed at each regular endoscopic examination
for the purpose of evaluating the side effects of the steroid.
Ethical considerations
This study was retrospective and performed at a single institution, and the protocol
was approved by the institutional review board of the National Cancer Center (2013 – 356).
All data were collected from medical records. All procedures were carried out after
provision of written informed consent from the patients.
Statistical Analysis
The main focus of the current study was evaluation of 2 possible comparisons within
treatment groups (no treatment vs. steroid injection, no treatment vs. steroid injection
followed by oral steroid, and steroid injection vs. steroid injection followed by
oral steroid). Fisher’s exact test was applied to compare the stricture rate and the
refractory stricture rate among each group. The time to stricture, the number of EBD
procedures, and the time to achieve EBD success were compared by using the 2-sample
t-test (variance unknown). All variables were deemed to be significant if P ≤ 0.05. Data were analyzed using SPSS software (version 22.0 for Mac).
Results
Background characteristics of patients
Of 149 patients with 3/4 circumference or larger mucosal defects after ER, 12 patients
who received an additional CRT, 8 who received an additional surgery, 4 who had a
history of CRT for prior esophageal cancer, 4 who had a stricture because of prior
ER and 6 who had not been followed up for 6 months were excluded. Finally, a total
of 115 patients met the selection criteria. Patient and tumor characteristics are
shown in [Table 1]. Male patients were predominant with a median age of 70 years. Six patients had
received ER treatments for prior esophageal cancer and 10 other patients had a history
of radiation therapy (RT) for head and neck cancer, including pharynx, larynx, and
tongue cancer. However, they did not have any strictures or dysphasia after prior
treatments. ESD and EMR were performed in 103 and 12 patients, respectively. The median
resection size was 50 mm and the interquartile range (IQR) was 43.5 to 60 mm in diameter.
The longitudinal extension of the mucosal defect were < 50 mm in 17 patients and ≥ 50 mm
in 98 patients.
Table 1
Background characteristics of patients with large superficial ESCC.
|
|
Total
|
n = 115
|
|
Sex
|
|
|
|
|
Men
|
|
99
|
(86 %)
|
|
Women
|
|
16
|
(14 %)
|
|
Age (years)
|
median, IQR
|
70
|
(64 – 73)
|
|
History of ER for prior esophageal cancer
|
6
|
(5 %)
|
|
History of radiation therapy for head and neck cancer
|
12
|
(10 %)
|
|
Tumor location
|
|
|
|
|
Upper thoracic
|
|
9
|
(8 %)
|
|
Middle thoracic
|
|
57
|
(50 %)
|
|
Lower thoracic
|
|
46
|
(40 %)
|
|
Abdominal
|
|
3
|
(3 %)
|
|
Macroscopic type
|
|
|
|
0-IIa
|
|
1
|
(1 %)
|
|
0-IIc
|
|
114
|
(99 %)
|
|
Endoscopic resection
|
|
|
|
EMR
|
|
12
|
(10 %)
|
|
ESD
|
|
103
|
(90 %)
|
|
Tumor size (mm)
|
median, IQR
|
40
|
(32 – 52)
|
|
Resection size (mm)
|
median, IQR
|
50
|
(43.5 – 60)
|
|
Longitudinal extension of the mucosal defect
|
|
|
|
< 50 mm
|
|
17
|
(15 %)
|
|
≥ 50 mm
|
|
98
|
(85 %)
|
|
Depth of tumor invasion
|
|
|
|
Epithelium
|
|
26
|
(23 %)
|
|
Lamina propria mucosa
|
|
55
|
(48 %)
|
|
Muscularis mucosa
|
|
28
|
(24 %)
|
|
SM1
|
|
1
|
(1 %)
|
|
SM2
|
|
5
|
(4 %)
|
IQR, interquartile range; EMR, endoscopic resection; ESCC, esophageal squamous cell
carcinoma.
In 109 lesions, the depth of invasion was histologically limited within the mucosal
layer. Of them, 2 were diagnosed as muscularis mucosa (MM) accompanied with lymphovascular
infiltration. Moreover, 6 other lesions reached the submucosal layer. Finally, although
a total of 8 patients required additional treatments due to non-curative resection,
they received no additional therapy because of their poor physical condition.
There were 45 patients in Group A (≥ 3/4 and < 7/8 of lumen mucosal defect), 45 in
Group B (≥ 7/8 and less than the entire circumference mucosal defect), and 25 in Group
C (the entire circumference mucosal defect) according to classification of their esophageal
mucosal defects. The relationships between the groups and the prophylactic treatment
for esophageal strictures are summarized in [Table 2]. There were a total of 33 patients with no treatment, a total of 53 patients with
steroid injection, and a total of 29 patients with steroid injection followed by oral
steroid administration. Of 53 patients with steroid injection, 12 patients received
steroid injections at several days, and the other 41 patients received it once at
1 day after ER or immediately after ER. There were 5 patients with steroid injection
followed by oral steroid in Group A. The mucosal defects of them were evaluated as
7/8 circumference or larger by the operator just after ER, but were judged as less
than 7/8 circumference with review and classified in Group A. In Groups B and C, approximately
80 % of patients received prophylactic treatments. Steroid injection alone was a major
treatment in Groups A and B, whereas steroid injection followed by oral steroid was
predominant in Group C.
Table 2
Prophylactic treatment of each mucosal defect group.
|
Prophylactic treatment
|
|
|
No treatment
|
Steroid injection
|
Steroid injection followed by oral steroid
|
|
Group A (n = 45)
|
18
|
(40 %)
|
22
|
(49 %)
|
5
|
(11 %)
|
|
Group B (n = 45)
|
10
|
(22 %)
|
25
|
(56 %)
|
10
|
(22 %)
|
|
Group C (n = 25)
|
5
|
(20 %)
|
6
|
(24 %)
|
14
|
(56 %)
|
|
Total (n = 115)
|
33
|
(29 %)
|
53
|
(46 %)
|
29
|
(25 %)
|
Patients were categorized by size of lesion in reference to the esophageal lumen into
Group A (> 3/4 and < 7/8), Group B (> 7/8 and less than the entire circumference),
and Group C (the entire circumference). Treatment type was determined by the time
period.
Stricture rate
Finally, esophageal stricture was diagnosed in 57 patients. Strictures were discovered
in 36 patients with planned follow-up endoscopic examination, and in the other 21
with endoscopy, on demand after the trigger symptom of dysphagia. For patients with
steroid injection, the stricture rate in patients who received steroid injection over
several days was 50 % (6/12), and for those who received it once was 41 % (17/41).
There was no statistical difference between stricture rates with each steroid technique.
As shown in [Table 3], the stricture rate gradually increased as the width of the mucosal defect became
larger. The stricture rates for Groups A, B, and C were 22 % (10/45), 58 % (26/45)
(vs. Group A, P = 0.001), and 84 % (21/25) (vs. Group A, P < 0.001 and vs. Group B, P = 0.034), respectively. In both Groups A and B, the stricture rate was lower in patients
with steroid injection (Group A, 14 % P = 0.14; Group B, 56 % P = 0.015) compared to patients with no treatment (Group A, 39 %; Group B, 100 %).
Furthermore, the stricture rate was lower in patients with steroid injection followed
by oral steroid (Group A, 0 % P = 1.0; Group B, 20 % P = 0.071) compared to patients with steroid injection alone. Conversely, a high stricture
rate was found in Group C regardless of prophylactic treatment (no treatment, 100 %
[5/5]; steroid injection, 100 % [6/6]; steroid injection followed by oral steroid,
71 % [10/14]). The median duration to stricture was 15.5 days (IQR: 12 – 25.5) in
patients with no treatment, 33 days (IQR: 14.5 – 47.5) in patients with steroid injection
(vs no treatment, P = 0.005), and 66.5 days (IQR: 40 – 76.5) in patients with steroid injection followed
by oral steroid (vs. no treatment, P < 0.001 and vs. steroid injection, P = 0.083). As shown in [Table 4], there was no significant difference in stricture rate according to the longitudinal
extension of the mucosal defect (< 50 mm vs. ≥ 50 mm). Representative cases in Groups
B and C are shown in [Fig. 2] and [Fig. 3].
Table 3
Stricture rate and time to stricture of each group.
|
Prophylactic treatment
|
Total
|
P value
|
|
No treatment
|
Steroid injection
|
Steroid injection followed by oral steroid
|
No treatment vs. steroid injection
|
No treatment vs. steroid injection followed by oral steroid
|
Steroid injection vs. steroid injection followed by oral steroid
|
|
n = 33
|
n = 53
|
n = 29
|
n = 115
|
|
Group A
|
39 %
|
(7/18)
|
14 %
|
(3/22)
|
0 %
|
(0/5)
|
22 %
|
(10/45)
|
0.14
|
0.27
|
1.0
|
|
|
|
|
|
|
|
(95 %CI: 11 – 37 %)
|
|
|
|
|
Group B
|
100 %
|
(10/10)
|
56 %
|
(14/25)
|
20 %
|
(2/10)
|
58 %
|
(26/45)
|
0.015
|
< 0.001
|
0.071
|
|
|
|
|
|
|
|
(95 %CI: 42 – 72 %)
|
|
|
|
|
Group C
|
100 %
|
(5/5)
|
100 %
|
(6/6)
|
71 %
|
(10/14)
|
84 %
|
(21/25)
|
1.0
|
0.53
|
0.27
|
|
|
|
|
|
|
|
(95 %CI: 64 – 95 %)
|
|
|
|
|
Total
|
67 %
|
(22/33)
|
43 %
|
(23/53)
|
41 %
|
(12/29)
|
50 %
|
(57/115)
|
0.046
|
0.073
|
1.0
|
|
(95 %CI: 48 – 82 %)
|
(95 %CI: 30 – 58 %)
|
(95 %CI: 24 – 61 %)
|
(95 %CI: 40 – 59 %)
|
|
|
|
|
Time to stricture (days) median (IQR)
|
15.5
|
(12 – 25.5)
|
33
|
(14.5 – 47.5)
|
66.5
|
(40 – 76.5)
|
27
|
(14 – 42)
|
0.005
|
< 0.001
|
0.083
|
95 %CI, 95 % confidence interval. Groups are described in [Table 1].
Table 4
Stricture rate of each group according to the longitudinal extension of the mucosal
defect.
|
Prophylactic treatment
|
Total
|
|
|
No treatment
|
Steroid injection
|
Steroid injection followed by oral steroid
|
|
|
n = 33
|
n = 53
|
n = 29
|
n = 115
|
|
Longitudinal extension
|
|
< 50 mm
|
75 %
|
(6/8)
|
14 %
|
(1/7)
|
50 %
|
(1/2)
|
47 %
|
(8/17)
|
|
≥ 50 mm
|
64 %
|
(16/25)
|
48 %
|
(22/46)
|
41 %
|
(11/27)
|
50 %
|
(49/98)
|
|
Total
|
67 %
|
(22/33)
|
43 %
|
(23/53)
|
41 %
|
(12/29)
|
50 %
|
(57/115)
|
|
P value < 50 mm vs. ≥ 50 mm
|
0.69
|
0.12
|
1.0
|
1.0
|
Fig. 2 Representative case (case 1). 59-year-old male who underwent endoscopic resection
for large superficial esophageal squamous cell carcinoma: a Endoscopic view of the tumor after Lugol’s staining. The tumor spread to about 3/4
of the circumference of the esophageal lumen. b Endoscopic view of the ulcer bed immediately after ESD. The width of the mucosal
defect was ≥ 7/8 and less than the entire circumference (Group B). Then, steroid injection
alone was performed as a prophylactic treatment. c The esophageal stricture occurred at 42 days after ESD and subsequently endoscopic
balloon dilation (EBD) was performed.
Fig. 3 Representative case (case 2). 76-year-old male who underwent endoscopic resection
for large superficial esophageal squamous cell carcinoma: a Endoscopic view of the tumor after Lugol’s staining. The tumor spread to about 7/8ths
of the circumference of the esophageal lumen. b Endoscopic view of the ulcer bed immediately after ESD. The width of the mucosal
defect was the entire lumen circumference (Group C). Then, steroid injection followed
by oral steroid was administered as a prophylactic treatment. c Endoscopic view on the 35th day. The mucosal defect was still undergoing re-epithelialization,
and an ordinary sized endoscope could pass. d Endoscopic view on the 120th day. The complete epithelialization is shown and an
ordinary sized endoscope could pass without dysphagia.
EBD for strictures due to ER
We evaluated the patients in Groups B and C for the following items that were related
to EBD: number of EBD procedures, time to achieve EBD success, and refractory stricture
rate. Of 70 patients in Groups B and C, 2 patients (1 with no treatment and the other
with steroid injection) were excluded from statistical analysis because EBD had not
been performed due to surgery for pancreatic cancer or death from another disease.
Finally, 68 patients were analyzed. As shown in [Table 5], the median time to achieve EBD success and number of required EBD procedures was
92 days (IQR: 66 – 176) and 7 times (IQR: 5 – 12), respectively. There were significantly
higher numbers of required EBD procedures in patients treated with no treatment compared
with steroid injection (P = 0.046) and steroid injection followed by oral steroid (P = 0.002). Finally, 28 patients developed refractory strictures, with a refractory
stricture rate of 41 % (28/68). The refractory stricture rates among individual treatments
were as follows: no treatment, 86 % (12/14); steroid injection, 33 % (10/30); and
steroid injection followed by oral steroid, 25 % (6/24). Significant differences were
seen between no treatment and steroid injection (P = 0.002) or steroid injection followed by oral steroid (P < 0.001).
Table 5
Duration and number of EBD sessions.
|
Prophylactic treatment
|
|
P value
|
|
No treatment
|
Steroid injection
|
Steroid injection followed by oral steroid
|
Total
|
No treatment vs. steroid injection
|
No treatment vs. steroid injection followed by oral steroid
|
Steroid injection vs. steroid injection followed by oral steroid
|
|
n = 14
|
n = 30
|
n = 24
|
n = 68
|
|
Case of stricture
|
14
|
19
|
12
|
45
|
|
|
|
|
Time to achieve EBD success (days) median (IQR)
|
173 (85.8 – 230)
|
84 (53.5 – 123)
|
92.5 (64.3 – 129)
|
92 (66 – 176)
|
0.58
|
0.053
|
0.26
|
|
Number of EBD sessions median (IQR)
|
12.5 (7.5 – 16)
|
6 (4.5 – 10.5)
|
5.5 (4 – 8.3)
|
7 (5 – 12)
|
0.046
|
0.002
|
0.51
|
|
1~2
|
0
|
4
|
2
|
6
|
|
|
|
|
3~5
|
2
|
5
|
4
|
11
|
|
|
|
|
≥ 6
|
12
|
10
|
6
|
28
|
|
|
|
|
Refractory stricture rate
|
12/14 (86 %)
(95 %CI: 57 – 98 %)
|
10/30 (33 %)
(95 %CI: 17 – 53 %)
|
6/24 (25 %)
(95 %CI: 10 – 47 %)
|
28/68 (41 %)
(95 %CI: 29 – 54 %)
|
0.002
|
< 0.001
|
0.56
|
EBD, endoscopic balloon dilation; IQR, interquartile range; 95 %CI, 95 % confidence
interval. We analyzed data for Groups B and C without Group A, and excluded the 2
cases that could not be evaluated for whether they had refractory strictures.
Finally, 5 patients in Group C could not recover from dysphagia despite tandem repeat
EBD procedures. Of them, 4 patients were treated with other modalities, such as the
radial incision and cutting method [16]
[17] or biodegradable stents [18]
[19] for their refractory strictures. The remaining patient died from advanced cancer
of the tongue.
Side effects of oral steroid administration, such as diabetes mellitus, peptic ulcer,
adrenal insufficiency, esophagitis, and corticosteroid psychosis were not found. Although
the direct relationship between infection and opportunistic infection as a side effect
was unclear, 1 patient in Group C with steroid injection followed by oral steroid
was diagnosed as acute pneumonia. While he had a fever of over 38 °C and displayed
wheezing at 25 days after ESD, the pneumonia was successfully cured with medical treatment
at our hospital.
Regarding complications for EBD, perforation was found in 2 patients, with a perforation
rate of 0.43 % (2/460) in all EBD sessions. These 2 patients had been classified into
Group C, and were administered steroid injections alone as prophylactic treatment.
The onsets of their perforations were at 68 days and 84 days after ESD, and in the
third and 11th EBD procedures, respectively. They recovered with only conservative
treatment including antibiotics.
Discussion
In the current study, steroid injection alone and steroid injection followed by oral
steroid administration were demonstrated to be significantly effective in preventing
strictures, compared with no treatment, in patients with mucosal defects after ER
of 7/8 circumferences to nearly the entire lumen. However, the efficacy of steroid
treatments was limited in cases with a lesion extending to the whole circumference
of the esophageal lumen. In addition, prophylactic treatments, especially steroid
injection followed by oral steroid, significantly led to a reduction in the required
number of interventions with EBD to treat stricture in patients who had experienced
post-ER esophageal strictures.
Fibrosis and scar formation occurring during the healing process is generally found
in the condition of esophageal stricture [4]
[6]
[20]. This process is classified into 3 phases: the acute inflammation phase, proliferation
phase, and remodeling phase. It has been reported that stricture formation due to
ER is hypothesized to be caused by a decrease of the esophageal wall elasticity due
to fibrosis, or layers of regular horizontal arrangements of spindle-shaped myoblasts
[20]
[21]. Some clinical studies have shown that esophageal strictures occur approximately
2 to 4 weeks after ER procedures [4]
[5]. The mechanism of the prophylactic efficacy of steroid injection has been reported
as a reduction in the appearance and proliferation of the spindle-shaped myofibroblastic
cells and normalized epithelialization [21]
[22]. In our study, the median time to stricture was prolonged significantly in the prophylactic
treatment groups. Based on these results, we suggest that systemic steroid administration
may prolong the duration to stricture formation by an additional effect of delaying
epithelialization.
In the current study, the stricture rate in patients with no treatment was 67 % (22/33).
In contrast, the stricture rate in patients with 3/4 diameter or larger mucosal defects
due to ER was 68 % (13/19) in our previous report [6]. This result from the current study was similar to that in the previous study despite
completely different patients. Furthermore, the subjects in our previous study evaluating
the efficacy of scheduled preventive EBD [8] included many patients with ER defects as large as the entire circumference of the
lumen. Scheduled preventive EBD was so effective that it decreased the stricture rate
from 92 % (no treatment) to 59 % (with scheduled preventive EBD). Therefore, prophylactic
steroid administration appears to be a more favorable treatment compared to scheduled
preventive EBD only, because the stricture rate with any steroid administration and
no preventive EBD was 43 % (35/82) in the current study.
There are several reports of the efficacy of prophylactic steroid administration after
ER for large ESCC. Hanaoka et al. conducted a prospective study to evaluate the efficacy
of steroid injection in patients with mucosal defects ≥ 3/4 diameter to nearly the
entire circumference of the esophageal lumen [14]. In their study, significant differences in the frequency of strictures were represented,
and steroid treatment was quite effective for esophageal stricture due to ER. In contrast,
because patients with whole-circumference mucosal defects were excluded from their
study, the efficacy of steroid treatment for whole-circumference lesions is unclear.
Yamaguchi et al. reported initially the efficacy of oral prednisolone administration
after ER [9]. Stricture rates in semicircular ESD (≥ 3/4 diameter to less than the entire circumference)
and in complete circular ESD were 6.3 % (1/16) and 0 % (0/3), respectively [9]. The stricture rate of patients with mucosal defects of less than the entire circumference
and with oral steroid administration in their study was similar to our current results.
In contrast, no esophageal strictures were found in patients with entire-circumference
resections in their study. In our study, patients with entire-circumference resections
showed high stricture rates in spite of the additional local steroid injection. Because
the number of subjects with an entire-circumference resection was quite small, there
would be some limitations to their study. Therefore, we believe that the efficacy
of prophylactic steroid treatment for entire-circumference defects eventually will
be elucidated. At present, we routinely performed local steroid injection for the
mucosal defect after ESD that larger than 3/4ths of the circumference of the esophagus,
and subsequently, oral steroid administration was added for the patients with the
mucosal defect larger than 7/8ths in our practice. Furthermore, alternative effective
prophylactic modalities for whole circumference defects are expected to be investigated
in the near future. In the cases that were regarded as the high risk of esophageal
stricture after ESD even with prophylactic treatment, CRT could be a primary treatment.
And if local residual lesion was found, salvage ESD could be performed in some cases
[23].
There have been explorations into other treatments for strictures as well. There was
a report that showed the efficacy of scheduled EBD combined with the oral anti-allergic
agent tranilast (stricture rate: 33 % [5/15]) [24], the preliminary results of tissue-engineered cell sheets (stricture rate: 10 %
[1/10]) [25], and polyglycolic acid sheet (stricture rate: 7.7 % [1/13]) [26]. As for prophylactic esophageal stent placement after ER, results with a fully-covered
metallic stent (stricture rate: 18 % [2/11]) [27] and a biodegradable stent (for porcine) [19] have been previously published. For prophylactic treatment with a steroid over a
short period, there was a report about low-dose oral prednisolone (30, 20, and 10 mg/day
in weeks 1, 2, and 3) that showed a stricture rate of 18 % (3/17) for lesions more
than 3/4 circumferences including 3 cases with complete circumference [28].
Finally, this study has several limitations. First, it was a retrospective historical
comparison in a single institution. Beginning in December 2009, we introduced steroid
injection, and oral steroid administration in addition to steroid injection was commenced
beginning in November 2012. Therefore, prophylactic steroid treatments, either steroid
injection alone or steroid injection followed by oral steroid administration, were
not performed during the same time periods. In addition, the number of subjects in
each Group was small; therefore, the study was statistically underpowered when comparing
the efficacy of each prophylactic treatment in each subgroup. Second, the efficacy
of steroid injection alone was not compared with that of oral steroid administration
alone. Third, patients’ symptoms were not taken into the definition of esophageal
stricture because we did not completely document their degree of dysphagia at every
visit. Therefore, we defined the esophageal stricture only with the ability of endoscope
passage in this study. Because of these limitations, prospective randomized controlled
studies will be required to evaluate the efficacy of prophylactic steroid treatment
and to clarify the adequate method for each width of mucosal defect.
Conclusion
In conclusion, prophylactic steroid administration is effective for patients with
7/8 circumference or larger but not whole-diameter mucosal defects after ER. This
Group may be the true target population who will benefit the most from prophylactic
steroid administration. However, a higher stricture rate was found in entire-circumference
defect cases regardless of prophylactic treatment. The most important next step is
to clarify the factors limiting prophylactic steroid treatments in entire-circumference
defect cases. If the serious complication of esophageal strictures can be avoided,
patients with entire-circumference mucosal defects due to ER will have a greatly improved
quality of life.
