Systematic Review of Anastomotic Leakage Rate According to an International Grading System Following Anterior Resection for Rectal Cancer
et al. (2013) Systematic Review of Anastomotic Leakage Rate According to an International
Grading System Following Anterior Resection for Rectal Cancer. PLoS ONE 8(9): e75519. doi:10.1371/journal.pone.0075519
Systematic Review of Anastomotic Leakage Rate According to an International Grading System Following Anterior Resection for Rectal Cancer
Zhi-Jie Cong 0
Liang-Hao Hu 0
Zheng-Qian Bian 0
Guang-Yao Ye 0
Min-Hao Yu 0
Yun-He Gao 0
Shen Li 0
En-Da Yu 0
Ming Zhong 0
Georgina L Hold, University of Aberdeen, United Kingdom
0 1 Department of Colorectal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China , 2 Digestive Endoscopy Center, Changhai Hospital, Second Military Medical University , Shanghai , China
Background: A generally acceptable definition and a severity grading system for anastomotic leakages (ALs) following rectal resection were not available until 2010, when the International Study Group of Rectal Cancer (ISGRC) proposed a definition and a grading system for AL. Methods: A search for published data was performed using the MEDLINE database (2000 to December 5, 2012) to perform a systematic review of the studies that described AL, grade AL according to the grading system, pool data, and determine the average rate of AL for each grade after anterior resection (AR) for rectal cancer. Results: A total of 930 abstracts were retrieved; 40 articles on AR, 25 articles on low AR (LAR), and 5 articles on ultralow AR (ULAR) were included in the review and analysis. The pooled overall AL rate of AR was 8.58% (2,085/24,288); the rate of the asymptomatic leakage (Grade A) was 2.57%, that of AL that required active intervention without relaparotomy (Grade B) was 2.37%, and that of AL that required relaparotomy (Grade C) was 5.40%. The pooled rate of AL that required relaparotomy was higher in AR (5.40%) than in LAR (4.70%) and in ULAR (1.81%), which could be attributed to the higher rate of protective defunctioning stoma in LAR (40.72%) and ULAR (63.44%) compared with that in AR (30.11%). Conclusions: The new grading system is simple that the ALs of each grade can be easily extracted from past publications, therefore likely to be accepted and applied in future studies.
These authors contributed equally to this work.
Anastomotic leakage (AL) is the
complication after rectal cancer surgery and can result in the
need for additional surgery, prolonged hospital stays, increased
morbidity and mortality and possibly a poorer oncological
prognosis . AL occurred in 1% to 21% of individuals with
anterior resection (AR) for rectal cancer, as reported in several
clinical trials [2-4]. However, the reported rate of AL varies
worldwide. This variation can in part be attributed to the lack of
a generally acceptable definition and grading of the severity of
AL until 2010. This definition and grading system for AL was
proposed by the International Study Group of Rectal Cancer
(ISGRC) . This system has since been used by some groups
to describe AL in the current literature [6,7]. Our study aims to
review systematically the studies that describe AL, grade AL
according to the grading system proposed by ISGRC. We will
then pool the data and determine the average rate of AL for
each grade after AR for rectal cancer surgery. Given the impact
that total mesorectal excision and stapling devices have had on
AL, only studies using these techniques after the year 2000 will
be included in this review. In the absence of evidence based on
prospective trials of grading AL, this pooled systematic analysis
could underpin the current evidence base and thus provide
relatively definitive information on this common and potentially
life threatening complication.
Definition and severity grading of AL
ISGRC defined AL as a defect in the intestinal wall integrity
at the colorectal or coloanal anastomotic site (including suture
and staple lines of neorectal reservoirs), which leads to
communication between the intra- and extraluminal
compartments. A pelvic abscess close to the anastomosis is
also considered as AL. The group suggested grading the
severity of AL based on its effect on the patients clinical
management. Grade A was defined as a leakage that requires
no active therapeutic intervention. Grade B was defined as a
leakage that requires active therapeutic intervention but can be
managed without relaparotomy. Grade C was defined as a
leakage that requires relaparotomy .
Literature search and selection strategy
Relevant studies published between January 2000 and
December 2012 were identified from the search of the Medline
databases. The following search terms were used: (rectum OR
rectal OR proctectomy) AND (leakage OR failure OR integrity
OR insufficiency OR breakdown OR defect OR separation OR
dehiscence). Additional relevant articles were then obtained
using the citations in the publications identified by the initial
Publications in English language that met the following
inclusion criteriaeither (i, ii, and iii) or (i, ii, and iv)were
selected: (i) availability of laparotomic or laparoscopic
sphincter-saving resection for rectal cancer; (ii) availability of
data and an incidence rate of AL; (iii) subsequent management
of AL, including conservative treatment or relaparotomy
reported; and (iv) data on patients with routine imaging studies
such as contrast enema after the initial operation or before the
DS was closed.
Studies that considered preoperative chemoradiation therapy
as the study object were excluded from the analysis, as well as
those that used experimental surgical techniques such as
single-access laparoscopic or robot-assisted surgery. Two
authors (C.ZJ, and H.LH) independently reviewed each of the
included studies and extracted data from them. Any
discrepancies were resolved by discussion. To increase the
sensitivity of the search strategy, the reference lists of the
retrieved literature were cross searched manually for additional
Data extraction and analysis strategy
We used the number of ALs based on their definition in the
studies. Patients with AL were divided into three grades
Figure 2. AL rates reported by the included studies on AR ranked by volume.
according to the definition of the grading proposed by ISGRC.
The selected studies were divided into three groups: AR, low
AR (LAR), and ultralow AR (ULAR). Because the studies on
AR are the most common and representative in the current
literature, which also include patients with LAR and ULAR, we
chose the AR studies as the main part for the analysis and
discussion in our research. The pooled rates for each grade of
AL extracted from the studies on AR were presented. Then, the
data from AR were compared with the data from LAR and
ULAR. The data of the AR studies from different countries were
also compared. When available, the rate of defunctioning
ileostomy/colostomy was also extracted from the studies for
Statistical analysis of the relative frequencies was conducted
with the chi-squared test using the Statistical Package for
Windows, version 13.0 (SPSS, Chicago, Illinois, USA). A
twosided P value of <0.05 was considered as statistically
A total of 930 abstracts were retrieved from Medline from
2000 to December 5, 2012. Among these, 106 non-English
articles and 289 non-relevant English articles with no or
minimal association with AL were excluded. Some additional
201 articles were excluded after further examination of the
downloaded abstracts based on the criteria shown in Figure 1.
Thus, 334 full papers were examined. Among these, 258 were
rejected as irrelevant, which left 43 studies on AR, 28 studies
on LAR, and 5 studies on ULAR. Further review of the full
papers revealed that three studies on AR patients [8-10] and
one study on LAR patients  were conducted in the same
hospital and duplicated the time of the patients in the other four
studies; two other studies did not provide a conclusion whether
their patients all underwent LAR [12,13]. Thus, the final
analysis included 70 studies: 40 on AR patients [2-4,6,14-49],
25 on LAR patients [7, 50-73], and 5 on ULAR patients with AL
[74-78] (Figure 1).
Pooled rate of AL for each grade in patients with AR
Incidence of reported AL. A total of 40 studies that
addressed the rate of AL after AR were analyzed. Four
randomized controlled trials were performed, and the numbers
of non-randomized prospective and retrospective clinical trials
were 13 and 23, respectively. The included studies had a total
population of 24,288 patients. The sample sizes of the studies
varied from 56 to 2,729 patients.
AL was described in 32 of the 40 (80%) studies.
Twentyseven studies provided a detailed description of the definition
of AL, most of which consisted of a clinical suspicion based on
the patients clinical symptoms, which were subsequently
confirmed by endoscopy or imaging studies. Only one author
described AL according to the definition proposed by ISGRC
. The remaining five studies provided only a limited
In the 40 studies, the number of patients confirmed to have
anastomotic leaks ranged from 1 to 390, with a total of 2,085.
The pooled overall rate of AL was 8.58%. A large variation in
the AL rates was observed in the studies; the highest reported
AL rate was 20.50%, whereas the lowest was 1.22% (Figure
Incidence of Grade A leakage. Grade A AL was defined as
an asymptomatic/radiologic leakage, which was usually not
considered as the object of the study by almost all authors
because it required no change in the patient management.
Only five studies [3,31,39,45,49] reported that imaging studies
such as contrast enema were routinely performed after the
initial operation or before the stoma revision to detect a
radiological AL, where we obtained the number of events with
Grade A leakage. Since the guideline of routine imaging after
rectal resection was not available, the timing of imaging among
studies was different from each other. So we didnt give a
pooled data of the timing of imaging in this systematic review.
The studies showed that 30 out of 1,167 patients with routine
imaging studies had a Grade A leakage, and the pooled rate
was 2.57%, which varied from 0% to 7.37% (Figure 3).
Incidence of Grade B leakage. Based on non-surgical
interventions (such as antibiotics) or interventional drainage or
transanal lavage described in 33 studies, we extracted the
rates of Grade B leakage in these studies. A total of 442 out of
18,647 patients had subsequent Grade B leakage after AR for
rectal cancer. The pooled incidence rate of the Grade B
leakage was 2.37%, which varied from 0% to 8.99% (Figure 4).
Incidence of Grade C leakage. The number of Grade C
leakage was extracted from 39 studies. A total of 1,309 Grade
C leakage cases were confirmed in this review, which means
that 63.08% (1,309/2,075) of the reported ALs after AR for
rectal cancer required operative re-intervention. The pooled
incidence rate of Grade C leakage was 5.40% (1,309/24,232);
the highest was 11.97%, and the lowest was 0% (Figure 5).
Twenty-three authors reported surgical procedure of
reintervention for Grade C leakage in their studies. A total of 536
Grade C leakage cases were found in these specific studies,
and 480 (89.55%) needed temporary or permanent
AL in patients with LAR and ULAR compared with AR
The ALs reported in the studies on LAR and ULAR were also
reviewed. Twenty-five studies on LAR matched the inclusion
criteria, which had a total population of 4,664 patients. The
LAR definition was described in 11 of 25 (44%) studies. Most of
the description of the definition consisted of the level of
anastomosis or tumor margin, which should be below the
peritoneal reflection or from lower than 6 cm to 8 cm from the
anal verge. A total of 414 leaks were confirmed; the pooled
overall rate of AL was 8.88% (which ranged from 1.89% to
20.59%). The pooled rates of Grades A, B, and C leakages
were 1.14% (8/701 from 3 studies), 3.75% (151/4,022 from 22
studies), and 4.70% (219/4,664 from all 25 studies),
Five studies on ULAR matched the inclusion criteria, which
had a total population of 551 patients. ULAR was described as
intersphincteric resection or resection in the ultralow rectal
cancer in these studies. A total of 41 leaks were confirmed; the
pooled overall rate of AL was 7.44% (which ranged from 4.65%
to 12.50%). The pooled rates of Grades A, B, and C leakages
were 7.41% (2/27 from one study), 5.26% (29/551 from all five
studies), and 1.81% (10/551 from all five studies), respectively.
The pooled overall rates of AL in AR and LAR were similar
(8.58% versus 8.88%) and were both a little higher than that in
ULAR (7.41%). The pooled rates of AL for each grade in AR,
LAR, and ULAR are shown in Figure 6. Unfortunately, only very
few studies (only nine studies in all the three groups) provided
data for the Grade A leakage; thus, we could not make a
substantial analysis of the trend of AL in the three groups from
the few available data. However, the data for Grades B and C
were sufficient to be credible. The pooled rate of Grade C
leakage in the AR studies was the highest (AR > LAR > ULAR).
On the other hand, the pooled rate of Grade B was the lowest
in AR (AR < LAR < ULAR).
The data of the temporary DS in the initial operation were
also extracted and compared. The pooled rates of DS in the 29
AR studies, 21 LAR studies, and 4 ULAR studies were 30.11%
(6,024/20,006), 40.72% (1,643/4,035), and 63.44% (295/465),
respectively. The three results (AR < LAR < ULAR) also
showed the same trend as that of the Grade B leakage and an
opposite trend with that of the Grade C leakage.
Hong Kong(1) N/A
0 (1) 0
Pooled rate of AL with each grade after AR in different
The included AR reports consisted of 18 reports from Asia
[2,14-30], 21 from Europe [3, 4, 6, 31-48], and 1 from the US
. The pooled regional AL rates were 5.43% in Asia
(511/9,406), 11.09% in Europe (1,526/13,755), and 4.26% in
the US (48/1,127). The difference between the US and Asia in
the overall AL rate after AR was not significant (P = 0.097).
However, the rate was significantly higher in Europe than in the
US and Asia (both P < 0.001). The same situation was true for
the regional rate of Grades B and C leakages (Table 1).
0 (1) 0
AL has been well known as a predominant cause of
morbidity and mortality after AR [33,53]. In addition, some
authors also reported that leakage impaired long-term
prognosis of patients with rectal cancer, in addition to the
adverse effect on late functional results, particularly when
operative re-intervention was required [12,68,79-81]. The
administration of adjuvant chemotherapy may be prevented or
delayed for the occurrence of AL in these patients, which is
probably associated with poor oncological outcome. Therefore,
the incidence of AL after AR was considered an essential
measure to evaluate the clinical value of the different operative
and perioperative interventions and, hence, is selected
frequently as a primary end point in clinical trials. However,
because of the lack of objective and easily applicable
definitions of AL, the results among studies did not allow simple
comparison and, therefore, clear conclusions as to which type
of operative and perioperative management should be
preferred in daily practice were hindered.
To standardize the reporting of clinical studies, ISGRC
proposed a generally acceptable definition and grading of the
severity for AL in 2010 , which have been adopted by
clinicians in reporting their studies and helped readers compare
the results of different reports. This definition comprised all
types of leakages ranging from an asymptomatic leakage to a
leakage resulting in life-threatening conditions, and the grading
system was defined according to the clinical management of
AL, which can be applied easily within the routine clinical care
and is likely to be accepted and applied in future studies.
AL is classified as Grade A when not associated with clinical
symptoms, which is commonly detected by contrast enema
studies during routine diagnostic workup before the closure of a
temporary ileostomy/colostomy . We regret to find that
Grade A leakage cases were only extracted from five reports
on AR in our review. Because of the almost harmless character
of this type of AL, most authors in the literature may not have
required routine imaging studies, which made the radiologic AL
difficult to discover. Moreover, when occasionally found by
imaging, conservative treatment such as prophylactic antibiotic
therapy might be needed instead of simple fasting and
observation, even when no symptom is observed in the patient.
AL is classified as Grade B when the patients clinical
condition requires an active therapeutic intervention that can be
managed without operative re-intervention. Patients suffer from
mild to moderate distress, characterized by abdominal and/or
pelvic pain and possible abdominal distension. Pelvic drains
may discharge turbid/purulent or fecal fluid, although the
presence of this finding depends on the size of the leakage and
is alleviated in patients with DS. Moreover, patients with Grade
B leakage may complain of turbid/purulent rectal or vaginal
AL is classified as Grade C when the patient is quite ill and
requires operative relaparotomy. These patients usually have
abdominal pain and fever and subsequently develop signs of
peritonitis (tenderness to palpation, abdominal wall rigidity, and
tachycardia). If operative re-intervention to control the septic
source is delayed or not performed, the clinical condition of
these patients could deteriorate and ultimately results in sepsis
with clinical signs of hypothermia, leukopenia, and organ
failure. In this thorough overview of the studies, we extracted a
considerable pooled rate of 5.40% for Grade C leakage, which
means that 63.08% of AL patients needed operative
reintervention. Moreover, 89.55% of these patients with Grade C
leakage needed temporary or permanent diverting-stoma
Interestingly, although the difference in the overall rates of
AL among the reports on AR, LAR, and ULAR was not very
large, an opposite trend of the pooled rate of Grades B and C
leakages was observed in these three groups, as revealed in
the present systematic review (Grade C rate in AR > Grade C
rate in LAR > Grade C rate in ULAR and Grade B rate in AR <
Grade B rate in LAR < Grade B rate in ULAR). This results
means that more ALs required operative re-intervention in the
reports on AR than those on LAR and ULAR. We believed that
the difference in the rate of protective DS in the initial operation
among the reports on AR, LAR, and ULAR could explain this
interesting situation because primary DS can effectively reduce
the risk of AL that requires relaparotomy, as reported by other
authors [3,43,83,84]. Our findings in this review revealed the
following: the pooled rate of primary DS in AR < the pooled rate
of DS in LAR < the pooled rate of DS in ULAR.
The pooled rate of AL in the European countries was much
higher than those in the Asian countries and the US (P <
0.001). We cannot determine whether any ethnic or regional
differences exist in the actual incidence of AL in these
populations. Of course, the differences in the language
background and the indications for neoadjuvant
chemoradiation therapy between the European and Asian
countries cannot be ignored [85,86].
It would be informative to know, what proportion of surgery
was performed by colorectal surgical specialists. We failed to
give this data because most of our selected publications didnt
give the proportion of colorectal surgical specialists except for
those involve influencing factors analyzing. But many studies in
current literature demonstrated that leak rates were thought to
be lower in specialist, rather than general surgical hands. Our
previous work also supported this point, which showed that the
rate of leak in colorectal surgical specialists group and general
surgeons group were 3.9% and 11.3% (P=0.031), respectively
The other limitation of this article is the sourcing of the
publications. All abstracts were retrieved from Medline, and
non-English language papers were excluded in the final
analysis. A formal meta-analysis will provide more powerful
evidence. The methodology used in the present study was not
as powerful as a meta-analysis. However, our systematic
review provides the summarized data directly from the original
This new grading system is simple that ALs of each grade
publications on the AL rate and on grading.
We have extracted a significant pooled rate of AL that
required relaparotomy following AR for rectal cancer, which
was higher than those in LAR and ULAR. The higher rate of
protective DS in LAR and ULAR might be the cause of this
difference. Compared with past situations when authors used
their own definitions and grading in the studies, we now have a
generally accepted definition and grading of the severity of AL.
could be easily extracted from past publications. Therefore, this
simple classification is likely to be accepted and applied in
Conceived and designed the experiments: MZ EY. Performed
the experiments: ZC GY. Analyzed the data: LH MY ZL.
Contributed reagents/materials/analysis tools: ZB YG. Wrote
the manuscript: ZC ZB.
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