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SCIENTIFIC REVIEW
Esophagectomy for End-Stage Achalasia: Systematic Reviewand Meta-analysis
Alberto Aiolfi1 • Emanuele Asti1 • Gianluca Bonitta1 • Luigi Bonavina1
Published online: 11 October 2017
� Societe Internationale de Chirurgie 2017
Abstract
Background Indications for surgery and clinical outcomes of esophagectomy in the management of end-stage
achalasia are not clearly defined. The aim of this systematic review and meta-analysis was to provide evidence-based
information to help in the decision-making and in the choice of surgical technique.
Methods An extensive literature search was conducted to identify all reports on esophagectomy for end-stage
achalasia patients over the past three decades. MEDLINE, Embase and Cochrane databases were thoroughly con-
sulted matching the terms ‘‘achalasia,’’ ‘‘end-stage achalasia,’’ ‘‘esophagectomy’’ and ‘‘esophageal resection’’ with
‘‘AND’’ and ‘‘OR.’’ Short- and long-term outcome data were extracted. Pooled prevalence of pneumonia, anasto-
motic leakage and mortality were calculated using Freeman–Tukey double arcsine transformation and DerSimonian–
Laird estimator in random effect meta-analysis. Heterogeneity among studies was evaluated using I2-index and
Cochrane Q test. Meta-regression was used to address the effect of potential confounders.
Results Eight papers published between 1989 and 2014 matched the inclusion criteria. In total, 1307 patients were
included. Esophagectomy was performed through a transthoracic (78.7%) or a transhiatal (21.3%) approach. The
stomach was used as an esophageal substitute in 95% of patients. Pooled prevalence of pneumonia, anastomotic
leakage and mortality were 10% (95% CI 4–18%), 7% (95% CI 4–10%) and 2% (95% CI 1–3%), respectively.
Conclusions Esophagectomy for end-stage achalasia is safe and effective. Based on the results of this study,
esophagectomy should be performed without hesitation in patients who are fit for major surgery and present with
disabling symptoms, poor quality of life and dolichomegaesophagus recalcitrant to multiple endoscopic dilatations
and/or surgical myotomies.
Introduction
Achalasia is a rare disease, with an estimated annual
incidence of 1 case per 100,000/year. It results from a
dysfunction of the esophageal myenteric plexus that causes
impaired lower esophageal sphincter (LES) relaxation and
loss of peristalsis [1]. Dysphagia, regurgitation, weight
loss, respiratory symptoms and aspiration pneumonia are
common. The incidence of squamous cell carcinoma in
achalasia is 312.4 cases per 100,000 patients/year [2].
Treatment of achalasia aims to reduce the pressure
gradient across the LES and improve gravitational eso-
phageal emptying in an effort to palliate symptoms and halt
the natural history of the disease [3]. Pneumatic dilatation
and surgical myotomy are the two most commonly used
first-line treatment modalities [4, 5]. While some patients
achieve excellent long-term symptom control with a single
& Luigi Bonavina
1 Division of General Surgery, Department of Biomedical
Sciences for Health, IRCCS Policlinico San Donato,
University of Milan, Piazza Edmondo Malan, 1,
20097 San Donato Milanese, MI, Italy
123
World J Surg (2018) 42:1469–1476
DOI 10.1007/s00268-017-4298-7
intervention, other patients will require multiple treatments
[6]. In the absence of therapy, or when therapy is inade-
quate, progressive dilatation and increasing tortuosity of
the esophagus lead to the end-stage disease in about 5% of
patients [7].
Esophagectomy may be required in patients with end-
stage achalasia to restore alimentary transit, reverse nutri-
tional deficiencies and decrease the risk of aspiration
pneumonia and carcinoma [8]. The aim of this systematic
review and meta-analysis was to examine the current evi-
dence on the therapeutic role and outcomes of
esophagectomy in the management of end-stage achalasia.
Methods
We conducted this study according to the Preferred
Reporting Items for Systematic Reviews and Meta-analy-
ses (PRISMA) statement [9]. An extensive literature search
between 1987 and 2017 was conducted by two independent
authors (AA and SS) to identify the English-written pub-
lished series on esophagectomy in end-stage achalasia
patients. MEDLINE, Embase and Cochrane databases were
consulted matching the terms ‘‘achalasia,’’ ‘‘end-stage
achalasia,’’ ‘‘esophagectomy’’ and ‘‘esophageal resection’’
with ‘‘AND’’ and ‘‘OR.’’ The search was completed by
consulting the listed references of each article.
Articles with sample size [15 were included in the
systematic review; abstracts, case reports, case series and
non-English-written articles were excluded (Fig. 1). Two
authors (AA and EA) independently extracted data from
eligible studies. Data extracted included study character-
istics (first author name, year and journal of publication),
number of patients included in the series, time frame,
clinical and demographic characteristics of patients’ pop-
ulation, type of surgical procedure and postoperative out-
comes. Disagreements between authors were resolved by
consensus; if no agreement could be reached, a third senior
author (LB) made the decision.
Three investigators independently assessed the
methodological quality of the papers using the Newcastle–
Ottawa Scale (NOS) [10]. Each study is judged on a ‘‘star
system’’ based on the selection of the study groups and the
ascertainment of outcome of interest. Each study could
earn a maximum of 9 stars. Studies with low-quality score
(NOS\6) were excluded.
Statistical analysis
Proportions were transformed via the Freeman–Tukey
double arcsine method [11] and with the corresponding
back-transformation equation [12]. Then an inverse-vari-
ance-weighted random effect meta-analysis was performed
by conventional methods using DerSimonian–Laird esti-
mator for estimate between-study variance (s2) [13].
Clopper–Pearson 95% confidence interval for individual
was computed [14]. Heterogeneity among the studies was
evaluated by I2-index, Cochran Q test and using visual
inspection of radial plot [15]. Small study and publication
bias effects were assessed by trim and fill funnel plot visual
inspection [16]. Egger tests were applied [17]. Prediction
interval for treatment effect of a new study is calculated
according to Borestein [15]. As sample size is not the same
in all studies, we gradually removed small sample size to
perform a sensitivity analysis to assess stability of results.
Two-sided p value were considered statistically significant
when\0.05. All analyses were carried out using R version
3.2.2 software [18].
Results
Systematic review
Eight studies published between 1989 and 2014 met the
inclusion criteria. The total number of patients was 1307;
the sample size of the individual studies ranged from 15 to
963. All reports were observational, cohort studies; each
study earned a NOS score of 6 or 7 (median 6.4), sug-
gesting a good quality level. Demographic, clinical and
operative variables of the patient sample are shown in
Table 1. The largest report included 963 patients registered
in a national administrative database. Five papers included
more than 30 patients. The age of the included patients
ranged from 41 to 54.6. Half of the patients were females
(50.5%), and the duration of symptoms before
esophagectomy ranged from 0.3 to 21 years.
The majority of patients had multiple previous endo-
scopic and/or surgical attempts to relieve long-lasting
achalasia symptoms. The indication for esophageal resec-
tion was mostly driven by recurrent and disabling symp-
toms and radiographic findings of sigmoid esophagus. All
patients were operated through an open surgical approach.
Overall, 1029 patients (78.7%) were managed through a
transthoracic approach while 278 (21.3%) underwent a
transhiatal esophagectomy. The stomach was most com-
monly (95.3%) used to replace the esophagus. The post-
operative morbidity ranged from 19 to 50%. Pneumonia
and anastomotic leaks were the two most commonly
reported complications. The mortality ranged from 0 to
5.4%. The hospital length of stay ranged from 10 to
16 days. Overall, 27.5% of the patients required endo-
scopic dilation of the anastomosis within 1 year. At a
follow-up ranging from 12 to 75 months, 7 of the 8 studies
reported that the proportion of patients on an unrestricted
diet ranged from 75 to 100%. One study reported a median
1470 World J Surg (2018) 42:1469–1476
123
weight gain of 6.3 kg at a mean follow-up of 72 months
[21]. No validated questionnaires for quality of life
assessment were used in any of the studies.
Meta-analysis
In addition to a systematic review, we performed a fre-
quentist meta-analysis. Considering random effect model,
the estimated pooled prevalence of pneumonia resulting
from 7 studies, which include a total of 1185 patients, is
10% (95% CI 4–18%). The prediction lower and upper
limits are 0 and 42%, respectively. The heterogeneity index
is high (I2 = 82%, 95% CI 64–91%; p\ 0.01). Funnel plot
shows that publication and small study bias should be
considered. The Egger test does not show evidence of
publication bias (p = 0.20). The meta-regression, using the
age as a covariate, does not significantly reduce the
heterogeneity of the study (I2 = 75%, p\ 0.01) (Fig. 2).
The estimated pooled prevalence of anastomotic leak
resulting from 7 studies, which include a total of 344
patients, is 7% (95% CI 4–10%). The prediction lower and
upper limits are 4 and 12%, respectively. The heterogeneity
index is zero (I2 = 0%, 95% CI 0–66%; p = 0.52). Funnel
plot shows that publication and small study bias effect
could be rejected according to Egger test (p = 0.63)
(Fig. 3).
The estimated pooled prevalence of mortality resulting
from 8 studies, which include a total of 1307 patients, is
Records iden�fied through MEDLINE searching
(n = 32)Screen
ing
Includ
edEligibility
Iden
�fica�o
n
Addi�onal records iden�fied through Embase, Cochrane
database and ar�cle’s references (n = 25 )
Records a�er duplicates removed (n = 43)
Records screened(n = 43)
Excluded (n = 27)
(treated by endoscopic dilata�on or Heller myotomy)
Full-text ar�cles assessed for eligibility
(n = 16) Excluded (n = 8)
• Case report/case series with <15pa�ents (n = 6)
• Abstract (n = 1)• Not English-wri�en (n = 1)
Studies included in qualita�ve synthesis
(n = 8)
Studies included in quan�ta�ve synthesis
(meta-analysis)(n = 8)
Fig. 1 PRISMA diagram
World J Surg (2018) 42:1469–1476 1471
123
Table
1D
emo
gra
ph
ican
dcl
inic
ald
ata
of
13
07
pat
ien
tsu
nd
erg
oin
ges
op
hag
ecto
my
for
end
-sta
ge
ach
alas
ia
Ref
eren
ces
No
.
pat
ien
ts
Mea
n
age
M/F
Mea
nd
ura
tio
no
f
sym
pto
ms
(yea
rs)
Su
rgic
al
app
roac
h
Co
nd
uit
Pn
eum
on
ia
(%)
An
asto
mo
tic
leak
age
(%)
Ov
eral
l
mo
rbid
ity
(%)
Mo
rtal
ity
(%)
Mea
nfo
llo
w-u
p
(mo
nth
s)
Orr
ing
eran
d
Sti
rlin
g[1
9]
26
49
10
/16
21
TH
(24
)S
tom
ach
3.8
41
93
.83
0
TT
(2)
Pin
ott
iet
al.
[20]
12
24
56
3/5
9N
RT
H(1
22
)S
tom
ach
NR
8.2
19
4.1
60
Pet
ers
[21]
19
44
13
/61
0T
T(1
9)
Co
lon
5.3
02
10
72
Mil
ler
etal
.[2
2]
37
56
20
/17
0.3
TH
(9)
Sto
mac
h(3
1)
colo
n(6
)
5.4
5.4
32
.45
.47
5
TT
(28
)
Ban
bu
ryet
al.
[23]
32
48
15
/17
13
TH
(21
)S
tom
ach
22
13
NR
34
2
TT
(11
)
Dev
aney
etal
.
[24]
93
51
43
/50
NR
TH
(87
)S
tom
ach
(91
)
colo
n(2
)
21
03
02
38
TT
(6)
Tan
ket
al.
[25]
15
41
10
/56
.5T
H(1
5)
Sto
mac
h2
6.6
13
.35
05
12
Mo
len
aet
al.
[26]
96
35
4.6
47
2/
49
1
NR
TT
(96
3)
Sto
mac
h(9
29
)
colo
n(3
4)
17
NR
NR
2.7
NR
TH
tran
shia
tal,TT
tran
sth
ora
cic,
NR
no
tre
po
rted
1472 World J Surg (2018) 42:1469–1476
123
2% (95% CI 1–3%). The prediction lower and upper limits
are 1 and 3%, respectively. The heterogeneity index is zero
(I2 = 0%, 95% CI 0–43%; p = 0.78). Funnel plot shows
that publication and small study bias effect could not be
rejected. The Egger test do not show evidence of publi-
cation bias (p = 0.09) (Fig. 4).
The Galbraith plot confirmed the level of heterogeneity
for each outcome (Fig. 5). The sensitivity analysis showed
the robustness of the results. In particular, regarding
pneumonia complications, we removed the study by
Devaney et al. [24], without alteration, where I2 value
decreased (I2 = 58.9%), indicating that the result was
stable.
Discussion
The systematic review presented in this study shows that
73% of esophagectomies for end-stage achalasia were
performed in patients with a mean age around 55 years.
However, there is lack of information regarding the natural
history and progression of the disease, and one-third of the
studies did not report the age of onset and the time that
elapsed to reach the end-stage disease phenotype. In most
circumstances, dysphagia, regurgitation and weight loss
were present, combined with massive dilatation and tor-
tuosity of the esophagus, and the disease was unresolved
despite multiple endoscopic and/or surgical treatments.
Whether possible reluctance by the patient or the surgeon
Fig. 3 Forest (a) and funnel (b) plot of anastomotic leakage
Fig. 2 Forest (a) and funnel (b) plot of pneumonia
World J Surg (2018) 42:1469–1476 1473
123
to undertake such a radical surgical intervention may have
delayed the date of operation remains unspecified.
Although we have excluded from our search papers
focused on concomitant achalasia and esophagectomy
cancer, we found two patients with incidental diagnosis of
squamous cell carcinoma in the resected specimen and 3
more patients with preoperative diagnosis of squamous cell
carcinoma. In addition, an emergency esophagectomy was
performed in eight patients due to bleeding or to esopha-
geal perforation secondary to endoscopic dilatation
[19, 21–23]. For the above reasons, the pooled incidence of
postoperative complications, namely pneumonia, anasto-
motic leaks and deaths, may have been overestimated by
including in the analysis patients with a potentially higher-
risk profile.
The heterogeneity of pooled pneumonia prevalence was
high in the meta-analysis. The meta-regression, adjusted
for the age, does not explain this heterogeneity. Other
possible sources of heterogeneity may be the generic
definition of pneumonia, the unknown patients’ smoking
habit and the unspecified effect of surgical approach
(transhiatal vs. transthoracic). This does not allow a sub-
group analysis. Despite the heterogeneity, the prevalence
of pneumonia was 9% with a upper limit of the prediction
interval reaching 42%. This is in accordance with the lit-
erature data indicating that pneumonia is a major compli-
cation of esophagectomy. Apparently, the incidence of
postoperative respiratory complications in achalasia
patients was similar compared to that of patients under-
going esophagectomy for cancer. Although this may be
surprising, since one would have expected a chronic pul-
monary damage from repetitive aspiration in achalasia,
outcomes of esophagectomy were not influenced by the
disease.
On the other hand, the heterogeneity of pooled anasto-
motic leakage and mortality prevalence were low. The
pooled prevalence of anastomotic leak and mortality was
7% (95% CI 4–10%) and 2% (95% CI 1–3%), respectively,
Fig. 4 Forest (a) and funnel (b) plot of mortality
Fig. 5 Galbraith plot of pneumonia (a), anastomotic leakage (b) and mortality (c)
1474 World J Surg (2018) 42:1469–1476
123
which is comparable with the mean incidence of anasto-
motic leak and mortality after esophagectomy for carci-
noma. Although there was no heterogeneity, it was not
possible to analyze more in depth the outcomes stratified
by type of surgical approach and type of esophageal sub-
stitute because of lack of comparative data.
Unfortunately, functional outcomes such as dietary
changes were not reported in a standardized manner. For
this reason, we were unable to calculate a pooled preva-
lence with meta-analysis; it was only possible to describe
these results in a qualitative manner observing that the
majority of patients were able to eat a normal diet. It is also
unfortunate that no formal assessment of quality of life was
provided by any of the included studies.
From the present study, no recommendations can be
made regarding the ideal method of surgical approach and
reconstruction for end-stage achalasia because of the lack
of direct comparative data. All patients in this analysis
have been operated through an open surgical approach.
However, surgical mobilization of the esophagus can be
successfully accomplished also by a thoracoscopic or a
laparoscopic transhiatal route. There are only two small
published case series reporting the results of thoracoscopic
and transhiatal esophagectomy, respectively, in patients
with end-stage achalasia. Unfortunately, these reports did
not meet the criteria of inclusion in our meta-analysis
because of the limited number of patients included. The
thoracoscopic approach resulted in zero operative mortal-
ity, one anastomotic leak and no pneumonia [27]. The
laparoscopic transhiatal approach resulted in 9% mortality,
anastomotic leak 18% and no pneumonia [28]. There is
further recent evidence showing that the risk of respiratory
infection after esophagectomy can be reduced by threefold
if a minimally invasive approach is used [29, 30].
Regarding the choice of the esophageal substitute, some
authors argue that gastric interposition is the procedure of
choice because a single anastomosis is needed and because
of the more constant pattern of blood supply of the stomach
compared to the colon [31, 32]. Use of small-sized gastric
tubes and long-term therapy with proton pump inhibitors
may reduce the risk of reflux esophagitis and Barrett’s
esophagus. Other authors argue that the colon is the best
replacement conduit [21]. Colon interposition is more
complex compared to gastroplasty and requires three
anastomoses. For long interpositions, ischemia at the distal
extremity of the graft is perceived as a risk factor for fistula
and stricture formation. In addition, redundancy of the
conduit may cause mechanical dysfunction and reinter-
vention [33]. Again, no conclusive evidence can be drawn
from our review because no comparative studies are
reported.
Conclusions
The main finding of this meta-analysis is that esophagec-
tomy for end-stage achalasia can be safely performed with
acceptable morbidity, low mortality and satisfactory long-
term alimentary function. It is likely that such results can
be obtained only in specialized centers. Due to the lack of
conclusive evidence, the choice of the operative approach
and the type of reconstruction should be based on a tailored
patient evaluation and surgeon’s preference. Esophagec-
tomy should probably be performed without hesitation in
patients who are fit for major surgery, complain of long-
lasting disabling symptoms and present with sigmoid
esophagus recalcitrant to multiple endoscopic and laparo-
scopic interventions. The role of minimally invasive
esophagectomy in the management of end-stage achalasia
should be further investigated. Future studies should
address patients’ quality of life assessment with validated,
generic and disease-specific questionnaires, in order to
provide patients, surgeons and payers with more compre-
hensive outcome data for a better decision-making.
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