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REVIEW ARTICLE – THORACIC ONCOLOGY
Assessment of Short-Term Clinical Outcomes following Salvage
Esophagectomy for the Treatment of Esophageal Malignancy:
Systematic Review and Pooled Analysis
Sheraz R. Markar, MRCS, MSc, MA
1
, Alan Karthikesalingam, MRCS, MSc, MA
2
, Marta Penna, MRCS, BSc
1
,
and Donald E. Low, FRCS, FACS
1
1
Department of Thoracic Surgery, Virginia Mason Medical Center, Seattle, WA;
2
Department of Outcomes Research, St
George’s Vascular Institute, St George’s Hospital, London, UK
ABSTRACT
Background. Combined chemoradiotherapy is increas-
ingly being used as definitive treatment for locoregional
esophageal malignancy. Patients with residual or recurrent
localized cancer are often selectively considered for sal-
vage esophagectomy (SALV). The aim of this pooled
analysis was to compare short-term clinical outcomes from
SALV following definitive chemoradiotherapy with those
from planned esophagectomy following neoadjuvant che-
moradiotherapy (NCRS).
Methods. MEDLINE, EMBASE, Cochrane, trial regis-
tries, conference proceedings and reference lists were
searched for relevant comparative studies. Primary out-
come measures were in-hospital mortality, anastomotic
leak and pulmonary complications. Secondary outcomes
were length of hospital stay, negative (R0) resection mar-
gin, and estimated blood loss.
Results. Eight studies comprising 954 patients; 242 (SALV)
and 712 (NCRS) were included. SALV was associated with a
significantly increased incidence of post-operative mortality
(9.50 vs. 4.07 %; pooled odds ratio [POR] =3.02; p\
0.001), anastomotic leak (23.97 vs. 14.47 %; POR =1.99;
p=0.005), pulmonary complications (29.75 vs. 16.99 %;
POR =2.12; p\0.001), and an increased length of hospital
stay (weighted mean difference =8.29 days; 95 % CI 7.08–
9.5; p\0.001). There were no significant differences
between the groups in the incidence of negative resection
margins or estimated blood loss.
Conclusions. SALV has poorer short-term outcomes when
compared with planned esophagectomy following neoad-
juvant chemoradiotherapy. Patients and multidisciplinary
tumor boards should be made aware of these differences in
outcomes and SALV should be reserved for practice in
high-volume institutions.
The incidence of esophageal malignancy is increasing
annually, representing 7 % of all gastrointestinal malig-
nancies internationally, and now represents the seventh
leading cause of all cancer-related deaths in the US male
population.
1–3
Despite improvements in staging modalities,
surgical techniques and perioperative care, cure rates fol-
lowing surgical resection alone for locoregional cancer
remain low.
4
Multimodality therapy in the form of neo-
adjuvant chemoradiation (NCR) was introduced in the
early 1980s for the treatment of esophageal cancer.
5
Several previous studies have shown benefit in terms of
survival following the use of neoadjuvant chemoradio-
therapy when compared with surgery alone.
6,7
More
recently, a randomized controlled trial
8
demonstrated clear
survival benefit to the use of neoadjuvant chemoradio-
therapy in resectable esophageal cancer (a difference in 3-
and 5-year survival of 14 and 13 %, respectively). Fur-
thermore, current National Care Cancer Network (NCCN)
guidelines recommend the use of NCR in clinical stage III
esophageal cancer.
9
Most surgeons recommend proceeding
to surgical resection 4–8 weeks after NCR, to allow suffi-
cient time for patient recovery and to avoid radiation-
induced changes to peri-esophageal tissue planes and pul-
monary and cardiac tissues.
Definitive combination chemoradiotherapy (DCR)
without surgical resection has been an option in patients
with poor performance status and thus high risk for surgical
ÓSociety of Surgical Oncology 2013
First Received: 11 July 2013;
Published Online: 9 November 2013
D. E. Low, FRCS, FACS
e-mail: donald.low@vmmc.org
Ann Surg Oncol (2014) 21:922–931
DOI 10.1245/s10434-013-3364-0
resection, or those patients who prefer to avoid esophagec-
tomy. Current NCCN guidelines state that DCR is an
alternative to surgical resection for local or regional esoph-
ageal cancer. Previous randomized controlled trials have
demonstrated that surgical resection does not improve sur-
vival when compared with definitive chemoradiotherapy for
the treatment of esophageal squamous cell carcinoma.
10–12
Despite the benefit of avoiding esophagectomy, elderly
patients selected for DCR due to a poor performance
status may experience treatment mortality rates of up to
18 %.
13
Furthermore, local recurrence rates following
DCR for esophageal cancer have been seen in 40–75 %
of patients,
14–16
and it is this group of patients who are
selectively considered for salvage esophagectomy. The
performance status of these patients can be seen to decrease
following DCR,
17
and together with the effects of high-dose
radiation on thoracic tissue planes as well as the potential
effects of radiation on cardiac and pulmonary function, this
can make salvage esophagectomy a challenging prospect.
These challenges are reflected by the single institutional
reports of high mortality and morbidity associated with sal-
vage esophagectomy.
18–20
The aim of this present systematic
review and pooled analysis is to assess the impact of salvage
esophagectomy following definitive chemoradiotherapy on
short-term clinical outcomes in comparison to neoadjuvant
chemoradiotherapy followed by planned esophagectomy.
METHODS
A systematic literature search of MEDLINE (January
1950–June 2013), EMBASE (January 1974–June 2013),
Web of Science (January 1990–June 2013) and the Coch-
rane Library (2013 Issue 1) databases was performed. The
search terms ‘(o)esophagectomy’, ‘salvage’, ‘definitive’,
‘neoadjuvant’, ‘(o)esophageal cancer’ and ‘chemoradio-
therapy’ and the medical subject headings (MeSH)
‘(o)esophagectomy’, ‘(o)esophageal neoplasm’, ‘chemora-
diotherapy’, ‘salvage therapy’, ‘evidence-based medicine’
and ‘evidence-based practice’ were used in combination
with the Boolean operators AND or OR. The electronic
search was supplemented by a hand search of published
abstracts from relevant conference proceedings (2010–
2013). Reference lists of all relevant studies and the search
included the Current Controlled Trials Register (http://
www.controlled-trials.com).
Abstracts of citations identified by the search were
scrutinized by two independent observers (MP and SM) to
determine eligibility for inclusion in this pooled analysis.
Publications were included if they met all of the following
criteria:
1. The subject of the study was the surgical treatment of
esophageal cancer
2. Surgical treatment was utilized with a curative intent
3. The study compared clinical outcome from esopha-
gectomy after definitive chemoradiotherapy (Salvage)
to esophagectomy planned after neoadjuvant chemo-
radiotherapy (NCRS).
4. Only articles published from 1995 onwards were
included in this analysis (this was to ensure that the
studies included reflected current surgical and peri-
operative management of esophageal cancer)
5. The study used only primary data and was not an
editorial or systematic review
Primary outcomes were the incidence of post-operative
mortality (defined as death during hospital admission
[in-hospital] or within 30 days of surgery [30-day]), anas-
tomotic leak and pulmonary complications (including
pneumonia, pneumothorax and respiratory failure). Sec-
ondary outcomes were length of hospital stay (days),
negative (R0) resection margin status, and estimated blood
loss.
Statistical Analysis
Data from eligible trials were entered into a computer-
ized spreadsheet for analysis. The quality of each trial was
assessed using the Oxford Centre for Evidence-based
Medicine criteria.
21
Statistical analysis was performed
using StatsDirect 2.5.7 (StatsDirect, Altrincham, UK).
Weighted mean differences (WMD), with 95 % confidence
intervals (CI) were calculated to assess the size of the effect
of salvage esophagectomy on continuous variables (length
of hospital stay and estimated blood loss). Pooled odds
ratios (POR), with 95 % CI, were calculated for the effect
of salvage esophagectomy on discrete variables (post-
operative mortality and anastomotic leak, pulmonary
complications, and incidence of negative [R0] resection
margin). Pooled outcome measures were determined using
random-effects models as described by DerSimonian and
Laird.
22
Heterogeneity among trials was assessed by means
of the I
2
inconsistency test and Cochran’s Q statistic, a null
hypothesis in which p\0.05 is taken to indicate the pre-
sence of significant heterogeneity.
23
The Egger test was
used to assess the funnel plot for significant asymmetry,
indicating possible publication or other biases.
RESULTS
The initial search identified nine articles (Fig. 1).
24–32
After screening, one further publication
24
was excluded as
this institution published their outcomes in a follow-up
publication, which was included in the analysis.
26
There-
fore, eight comparative studies were included in this pooled
analysis.
25–32
In total, 954 patients were included; 242
Salvage Esophagectomy 923
patients had salvage esophagectomy following definitive
chemoradiotherapy and 712 patients had neoadjuvant
chemoradiotherapy followed by planned esophagectomy
(NCRS). The majority of patients included in this analysis
were treated for esophageal squamous cell carcinoma
(82.9 %), and there was varied distribution of tumor
location and clinical stage (Table 1). There was a great
deal of heterogeneity between the studies observed in the
type of surgical resection, total radiation dose described as
DCR (range 30–76 Gy), and the timing of surgery fol-
lowing DCR (range 25–1,377 days) (Table 2). The
outcome measures from each individual trial along with the
pooled results are described in Table 3. There was no clear
difference in 5-year survival between the groups, as shown
in Table 3. The majority of studies failed to provide data
regarding the loss of patients to follow-up during the 5-year
period, and this lack of data prevented pooled analysis of
this important outcome measure.
PRIMARY OUTCOME MEASURES
Post-operative Mortality
All eight studies reported the incidence of post-operative
mortality,
25–32
six studies reported in-hospital mortal-
ity,
25,27–29,31,32
and two studies reported 30-day mortality
(Fig. 2a).
26,30
Post-operative mortality was greater in
patients undergoing salvage esophagectomy after definitive
chemoradiotherapy (23 patients [9.50 %]) compared with
those undergoing planned esophagectomy after neoadju-
vant chemoradiotherapy (29 patients [4.07 %]). Pooled
analysis confirmed the incidence of post-operative mor-
tality was significantly increased in the salvage esoph-
agectomy group (POR =3.02; 95 % CI 1.64–5.58;
p\0.001). There was no evidence of statistical hetero-
geneity (Cochran Q =4.82; p=0.682, I
2
=0 %) or bias
(Egger =0.14; p=0.881).
Anastomotic Leak
All eight studies reported the incidence of anastomotic
leak,
25–32
which was greater in patients undergoing salvage
esophagectomy after definitive chemoradiotherapy (58
patients [23.97 %]) compared with those undergoing plan-
ned esophagectomy after neoadjuvant chemoradiotherapy
(103 patients [14.47 %]) (Fig. 2b). Pooled analysis con-
firmed the incidence of anastomotic leak was significantly
increased in the salvage esophagectomy group (POR =
1.99; 95 % CI 1.24–3.22; p=0.005). There was no evi-
dence of statistical heterogeneity (Cochran Q =9.16;
p=0.242; I
2
=23.6 %) or bias (Egger =1.7; p=0.223).
Pulmonary Complications
All eight studies reported the incidence of pulmonary
complications,
25–32
which was greater in patients under-
going salvage esophagectomy after definitive chemo-
radiotherapy (72 patients [29.75 %]) compared with those
undergoing planned esophagectomy after neoadjuvant
chemoradiotherapy (121 patients [16.99 %]) (Fig. 2c).
Pooled analysis confirmed the incidence of pulmonary
complications was significantly increased in the salvage
esophagectomy group (POR =2.12; 95 % CI 1.47–3.05;
p\0.001). There was no evidence of statistical hetero-
geneity (Cochran Q =3.98; p=0.782; I
2
=0%) or
statistical bias (Egger =0.55; p=0.715).
SECONDARY OUTCOME MEASURES
Length of Hospital Stay
Three studies reported the length of hospital stay with
standard deviation to permit analysis.
26,29,30
Average
length of hospital stay ranged from 12 to 43 days in the
salvage esophagectomy group and 11–31.9 days in the
NCRS group. Salvage esophagectomy was associated
with a significantly increased length of hospital stay
(WMD =8.29 days; 95 % CI 7.08–9.5 days; pB0.001).
There was evidence of significant statistical heterogeneity
(Cochran Q =286.31; p\0.001; I
2
=99.3 %), and
unfortunately there were insufficient data to allow calcu-
lation of statistical bias.
Studies identified from
initial search (n = 266)
Duplicate records and records
excluded after review of title
and abstracts (n = 212)
Studies selected based on
abstract and title search for full
text article assessment (n = 42)
Full text articles excluded as
not controlled studies (n = 33)
Full text articles included
in study (n = 9)
Total studies included in
data meta-analysis (n = 8)
Studies excluded as previous
report of an updated series
already included (n = 1)
FIG. 1 PRISMA flowchart—systematic search and selection
strategy
924 S. R. Markar et al.
TABLE 1 Description of tumor location, histology, and clinical stage
Publication
(year)
Patient
number
(SALV)
Patient
number
(NCRS)
Tumor location SCC
(n)
Adenocar-
cinoma
(n)
Clinical stage
Upper
third
(SALV)
Upper
third
(NCRS)
Middle
third
(SALV)
Middle
third
(NCRS)
Lower
third
(SALV)
Lower
third
(NCRS)
II
(SALV)
II
(NCRS)
III
(SALV)
III
(NCRS)
IV
(SALV)
IV
(NCRS)
Chao et al.
25
27 191 7 36 14 104 5 47 218 0 11 74 14 92 2 25
Marks et al.
26
65 65 3
a
4
a
3
a
4
a
62 61 0 130 31 31 26 24 8 10
Miyata et al.
27
33 112 10 47 18 48 5 17 145 0 7 23 13 70 7 29
Morita et al.
28
27 197 9 53 9 95 9 49 439
b
17
b
–– –– ––
Nakamura et al.
29
27 28 4 5 17 17 6 6 55 0 – – – – – –
Smithers et al.
30
145310456411056––––––
Takeuchi et al.
31
25 40 8 6 15 29 2 5 65 0 1 3 18 30 1 7
Tomimaru et al.
32
24 26 5 8 13 11 6 6 50 0 7 5 11 15 2 6
Total (%) 242 712 47 (19.4) 159 (22.3) 93 (38.4) 313 (44) 101 (41.7) 232 (32.6) 982 203 57 (32.8) 136 (31.3) 82 (47.1) 231 (53.2) 20 (11.5) 77 (17.7)
SALV salvage esophagectomy, NCRS neoadjuvant chemoradiotherapy followed by planned esophagectomy, SCC squamous cell carcinoma
a
Upper and middle third tumors presented together
b
Total description of cohort included patients undergoing surgery alone; however, in this analysis these were filtered so the outcomes presented only refer to patients undergoing salvage esophagectomy or
neoadjuvant chemoradiotherapy followed by planned surgery were included
Salvage Esophagectomy 925
TABLE 2 Description of patient demographics and treatment allocation of surgical resection and radiotherapy
Publication Oxford level
of evidence
Age, years (median) Male:female ratio Type of surgery Total radiation dose Time to surgery (median)
SALV NCRS SALV NCRS SALV NCRS SALV NCRS
Chao et al.
25
3b 62.4 54.5 26:1 188:3 ILE: 170
Mackeown: 43
30 Gy in 200 Cgy
daily fractions—
two courses
30 Gy in 200 Cgy
daily fractions—
one course
– 30 days
Marks et al.
26
2b 63 63 59:6 60:5 ILE: 92
Mackeown: 14
MIE: 16
Transhiatal: 8
50 ±4Gy 50±4 Gy 216 ±237 days 50 ±27 days
Miyata et al.
27
3b 63.4 (38–78) 60.3 (36–77) 28:5 97:15 ILE: 41
Mackeown: 71
Transhiatal: 30
[50 (50–68) Gy \40 (34–40) Gy 249 (25–1,377) days 38.3 (19–60) days
Morita et al.
8
3b 63 ±9.2
a
62.1 ±9
a
23:4 170:27 CRTA: 140
ILE: 69
Transhiatal: 4
Cervical: 11
60–90 Gy 30–45 Gy 1–5 months (residual) ?
6–34 months (recurrent)
–
Nakamura et al.
29
3b 63 (36–79) 62 (50–74) 21:6 25:3 Right: 40
Left: 9
Transhiatal: 6
60 (50–76) Gy 39 (30–46) Gy 111 (39–462) days 28 (19–45) days
Smithers et al.
30
3b 66 (40–77) 60 (41–76) 7:7 49:4 ILE: 19
Mckeown: 47
60 Gy 35 Gy 28 (14–59) weeks 4 (3–7) weeks
Takeuchi et al.
31
3b 61 ±8
a
59 ±7
a
25:0 37:3 Right: 64
Transhiatal: 1
60 (50–60) Gy 46 (30–48) Gy 288 (183–347) days 46 days
Tomimaru et al.
32
3b 63 ±10
a
65 ±9
a
22:2 22:4 1 stage: 46
2 stage: 4
62 ±6Gy 40±0 Gy 6.1 (1–25) months 1.3 (1–4) months
ILE Ivor Lewis esophagectomy, CRTA cervical right thoracoabdominal approach, MIE minimally invasive esophagectomy, SALV salvage oesophagectomy, NCRS neoadjuvant chemoradio-
therapy followed by planned oesophagectomy
a
Data presented as mean ±standard deviation
926 S. R. Markar et al.
Negative Resection Margin (R0) Status
All eight studies reported the incidence of negative
resection margins.
25–32
A total of 188 patients (77.69 %) in
the salvage esophagectomy group and 510 patients
(71.63 %) in the NCRS group had negative resection (R0)
margins. There was no significant difference between the
groups in the incidence of negative resection margins
(POR =0.80; 95 % CI 0.44–1.44; p=0.458). There was
no evidence of significant statistical heterogeneity (Coch-
ran Q =13.54; p=0.060; I
2
=48.3 %) but there was
evidence of bias (Egger =-3.75; p=0.030).
Estimated Blood Loss
Six studies reported estimated blood loss following
esophagectomy.
26,27,29–32
Pooled analysis demonstrated no
significant difference between the groups in estimated
blood loss (WMD =-77.05 ml; 95 % CI -163.92 to
–9.82 ml; p=0.082). There was evidence of significant
statistical heterogeneity (Cochran Q =616.31; p\0.001;
I
2
=99.2 %), but no evidence of statistical bias (Egger =
-2.93; p=0.584).
DISCUSSION
Meta-analysis of randomized controlled trials has
demonstrated survival benefit associated with the use of
neoadjuvant chemoradiotherapy followed by surgery
compared with surgery alone.
33
However, esophagectomy
remains a complex surgical procedure with an associated
mortality and morbidity rate, and has the potential to
adversely impact long-term quality of life.
34,35
Oncologists
have evaluated the use of definitive chemoradiotherapy
(DCR) avoiding esophagectomy for the treatment of
locoregional disease, especially in patients with poor per-
formance status.
36,37
It is important to note that direct
comparison of DCR with surgical resection for esophageal
squamous cell carcinoma has failed to demonstrate any
long-term differences in quality of life, and, furthermore,
DCR is associated with a progressive deterioration in
pulmonary function.
38
Residual or recurrent malignancy
following DCR has been shown in 40–75 % of
patients,
14–16
who are selectively considered for salvage
treatment most commonly in the form of esophagectomy.
Recurrence is local in the majority of cases following
DCR, with salvage esophagectomy being the only poten-
tially curative option in these cases.
39,40
The aim of this present systematic review and pooled
analysis was to assess the impact of salvage esophagec-
tomy following definitive chemoradiotherapy on short-
term clinical outcomes in comparison to standard treatment
of neoadjuvant chemoradiotherapy followed by planned
TABLE 3 Description of outcome measures for salvage esophagectomy following definitive chemoradiotherapy and planned esophagectomy following neoadjuvant chemoradiotherapy
Publication Post-operative
mortality
R0 margin Length of hospital
stay (days)
a
Anastomotic leak Pulmonary
complications
Estimated blood loss (ml)
a
5-year survival
SALV NCRS SALV NCRS SALV NCRS SALV NCRS SALV NCRS SALV NCRS SALV (%) NCRS (%)
Chao et al.
25
6 15 17 130 22.4 20.1 4 2 9 22 335 330 25.4 20
Marks et al.
26
2 3 59 64 12 ±511±3.5 12 12 15 12 473 ±286 593 ±367 32 45
Miyata et al.
27
5 4 29 99 – – 13 25 10 25 1109 ±19.7 1249 ±28.1 35 31
Morita et al.
28
2 4 19 98 – – 10 46 8 29 – – 50.6 40.7
Nakamura et al.
29
2 1 18 17 39.9 ±25.4 31.9 ±22.8 6 3 6 4 679 ±414 975 ±861 30 38
Smithers et al.
30
1 0 10 48 43 ±3.9 19.5 ±2.4 2 4 8 16 293.5 ±5.9 316.3 ±7.9
Takeuchi et al.
31
2 2 20 31 – – 6 10 11 10 522 ±368 520 ±357 43 28
Tomimaru et al.
32
3 0 16 23 – – 5 2 5 3 1109 ±614 967 ±618
Total (%) 23 (9.5) 29 (4.1) 188 (77.7) 510 (71.6) – – 58 (24.0) 103 (14.5) 72 (29.8) 121 (17.0) – – – –
SALV salvage esophagectomy, NCRS neoadjuvant chemoradiotherapy followed by planned esophagectomy
a
Continuous variables are reported as mean ±standard deviation
Salvage Esophagectomy 927
esophagectomy. Salvage esophagectomy was associated
with significantly increased incidence of post-operative
mortality, anastomotic leak, pulmonary complications
and an increased length of hospital stay. There were no
significant differences between the groups in the incidence
of negative resection margins or estimated blood loss.
The incidence of post-operative mortality in the salvage
esophagectomy group (9.5 %) was more than twice than
that seen in the NCRS group (4.07 %), with a POR of 3.02.
This increase in post-operative mortality may be due to the
combination of several factors seen in patients undergoing
salvage esophagectomy. Currently in the US, total radia-
tion dosage in DCR and neoadjuvant situations is quite
similar, typically ranging between 4,500 and 5,040 CGy.
However, definitive chemoradiotherapy has historically
involved a greater total dose of radiation (range 30–76 Gy
in this series) to that seen with neoadjuvant chemoradio-
therapy. This increased radiation dose and delay in
operative therapy beyond 2–3 months following radio-
therapy can lead to increased mediastinal scarring that
makes resection more challenging, with greater potential
for complications and mortality. Secondly, allocation of
patients to DCR may have been based upon poor perfor-
mance status and a greater perceived operative risk.
Furthermore, during DCR, there may be an additional
decline in performance status in particular cardiac and
pulmonary function
38
due to the toxic side effects of this
regime. There were insufficient data presented in the
publications included in this pooled analysis to allow a
meta-regression analysis that may have accounted for any
discrepancies in patient medical co-morbidities or perfor-
mance status between the groups (only four of eight studies
provided any information regarding patient pre-operative
performance status). Marks et al.
26
used a propensity-
matched analysis to produce two comparable groups in
terms of medical co-morbidities, and were the only study to
demonstrate similar post-operative morbidity and mortality
for patients undergoing salvage esophagectomy and plan-
ned resection. This was also the only study in which the
majority of patients had adenocarcinoma. It provides some
evidence that these discrepancies in outcomes in previous
studies may be due to heterogeneity in patient surgical
fitness seen between the groups. However, it is important to
note that as part of the matching analysis, the total dose of
radiation was the same between the propensity-matched
salvage group and the NCRS group (50 ±4 Gy), which is
not the case for previous studies on this subject (Table 2).
As described above, only half of the papers included in
this analysis provided any data regarding patient pre-
operative fitness or medical co-morbidities, which pre-
cluded assessment of the potential effects of these
confounding variables on the outcomes from this study.
There are other important potential confounding variables
that are often poorly described in the surgical literature,
especially in the studies included in this review, that may
affect outcome following esophagectomy, including frailty,
mobility, nutritional status, and immunosuppression.
41,42
(a) Odds ratio meta-analysis plot [random effects]
Chao 2008
Marks 2012
Miyata 2009
Morita 2011
Nakamura 2005
Smithers 2007
Takouchi 2010
Tomimanu 2006
Combined [random]
3.35 (0.95, 10.37)
0.66 (0.05, 5.95)
4.82 (0.55, 25.62)
3.86 (0.33, 28.29)
2.16 (0.10, 132.07)
11.89 (0.10, infinity)
1.55 (0.11, 24.05)
8.63 (0.46, infinity)
3.02 (1.64, 5.58)
10000.001 0.1 100101
Odds ratio (95% confidence interval)
(b) Odds ratio meta-analysis plot [random effects]
Chao 2008
Marks 2012
Miyata 2009
Morita 2011
Nakamura 2005
Smithers 2007
Takouchi 2010
Tomimanu 2006
Combined [random]
16.43 (2.15, 136.25)
1.11 (0.41, 3.05)
2.26 (0.90, 5.55)
1.93 (0.73, 4.82)
2.36 (0.44 15.26)
2.04 (0.16, 16.10)
0.55 (0.24, 3.46)
3.16 (0.44, 35.63)
1.59 (1.24, 3.22)
10000.1 100101
Odds ratio (95% confidence interval)
(c) Odds ratio meta-analysis plot [random effects]
Chao 2008
Marks 2012
Miyata 2009
Morita 2011
Nakamura 2005
Smithers 2007
Takouchi 2010
Tomimanu 2006
Combined [random]
3.84 (1.34, 10.32)
1.33 (0.52, 3.43)
1.51 (0.55, 3.84)
2.44 (0.84, 6.50)
1.71 (0.35, 9.35)
3.08 (0.78, 12.52)
2.35 (0.71, 7.81)
2.02 (0.34, 14.49)
2.12 (1.47, 3.05)
1000.2 0.5 1052
1
Odds ratio (95% confidence interval)
FIG. 2 a Forrest plot demonstrating a significant increase in post-
operative mortality associated with salvage esophagectomy (pooled
odds ratio =3.02; 95 % CI 1.64–5.58; p\0.001). bForrest plot
demonstrating a significant increase in anastomotic leak associated
with salvage esophagectomy (pooled odds ratio =1.99; 95 % CI
1.24–3.22; p=0.005). cForrest plot demonstrating a significant
increase in pulmonary complications associated with salvage esoph-
agectomy (pooled odds ratio =2.12; 95 % CI 1.47–3.05; p\0.001)
928 S. R. Markar et al.
Furthermore, as reflected in Table 2, there was heteroge-
neity in treatment approach between the studies. This
includes surgical variation such as differences in technique
employed, extent of lymphadenectomy and aspects of peri-
operative care, which can all affect the results observed in
this pooled analysis. There was also a great deal of heter-
ogeneity between the studies observed in the total radiation
dose described as DCR (range 30–76 Gy), and the timing
of surgery following DCR (range 25–1,377 days). The
differences seen in timing of salvage esophagectomy may
reflect the different patterns of residual vs. recurrent dis-
ease following DCR, and the potential for differences in
reassessment and surveillance following DCR. Assessment
of complete response to chemoradiation based on clinical
staging by biopsy, positron emission tomography (PET) or
endoscopic ultrasound (EUS) has been shown to be poorly
correlated with pathological complete response, with a
specificity of only 29.8 %
43
. At present there is no rec-
ommended or validated follow-up methodology for
detecting tumor recurrence and referral to surgical services
following DCR.
44
A further limitation inherent to an analysis of this type is
the lack of a standardized definition of post-operative
complications following esophagectomy. For example, the
definition of anastomotic leakage varied from no definition,
minor/major leak, and leakage that required surgical
intervention. The use of surgical intervention to define
anastomotic leakage underestimates actual leak rate, as less
than half of leaks in the chest require surgery.
45,46
There
are other important complications, including cardiac and
renal complications and delirium, that may be responsible
for the increased length of hospital stay seen in the salvage
esophagectomy group, which were not commonly assessed.
The incidence of anastomotic leak was significantly
increased in the salvage esophagectomy group (23.97 vs.
14.47 %), which may be due to poor gastric perfusion as a
result of high exposure of the proximal stomach to radia-
tion.
25
Tumor location was similarly represented amongst
the groups, (Tables 1and 2) and therefore it is unlikely that
this difference in anastomotic leak is due to a difference in
anastomotic location. Intra-thoracic anastomotic leakage is
associated with mediastinitis, which in turn is associated
with increased mortality.
47
Therefore, the increased anas-
tomotic leak rate seen in the salvage esophagectomy group
may in part explain the differences in post-operative mor-
tality observed in this pooled analysis. The incidence of
pulmonary complications was also increased in the salvage
esophagectomy group (29.75 vs. 16.99 %). Previous
authors have suggested the importance of an R0 resection
but with a relatively less extensive mediastinal dissection
to reduce the incidence of post-operative pneumonia and
tracheobronchial necrosis.
18
There was significant hetero-
geneity in the follow-up methodology employed by the
studies included in this review that precluded analysis of
long-term outcomes, including survival and recurrence,
which are both important areas for future study.
CONCLUSIONS
This current systematic review and pooled analysis
demonstrates salvage esophagectomy following definitive
chemoradiotherapy is associated with an increase in
post-operative mortality, anastomotic leak, pulmonary
complications, and length of hospital stay. Patients with
locoregional esophageal malignancy should be evaluated at
a multidisciplinary tumor board prior to treatment allocation
of definitive chemoradiotherapy, given the challenges
associated with the surgical management of recurrent disease
shown in this analysis. Furthermore, patients with recurrent
or residual disease following definitive chemoradiotherapy
must be assessed again at a multidisciplinary tumor board,
with salvage esophagectomy reserved for cases where sur-
gical resection may be curative and undertaken in high-
volume esophageal centers by experienced esophageal sur-
geons. This current analysis provides strong evidence
indicating that salvage esophagectomy is associated with
increased morbidity and mortality. This information should
be applied in tumor board discussions regarding the primary
treatment of locoregional esophageal cancer, and made
available to patients during treatment planning.
ACKNOWLEDGMENT This study was supported by Ryan Hill
Research Foundation.
DISCLOSURES No sources of funding were used in the prepara-
tion of this manuscript and the authors have no conflicts of interest to
declare.
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