Introduction
Large (≥ 20 mm) non-pedunculated colorectal polyps are prevalent in current endoscopy
practice, and when considered benign, the primary approach for these lesions is endoscopic
mucosal resection [1]. Endoscopic mucosal resection (EMR) is associated with fewer complications than
more invasive resection techniques such as endoscopic submucosal dissection (ESD)
or surgery [2]
[3]. However, the pitfall in EMR of large colorectal polyps remains the higher risk
of recurrence, mostly reported between 15 % to 20 % at 6 months [1]
[4]. Risk factors for recurrence after endoscopic resection are widely studied and the
most important factors include piecemeal resection, lesion size ≥ 4 cm and intraprocedural
bleeding [5].
In the search for effective measures to lower the recurrence rates after (piecemeal)
EMR of large colorectal lesions, experience is gained with regard to adjuvant treatment
measures. Adjuvant treatment refers to additional treatment of the mucosal defect
after all visible neoplastic tissue has been removed. Argon plasma coagulation (APC)
and snare tip soft coagulation (STSC) are techniques that are often used in this setting.
Ablation of mucosal defect margins with APC or STSC is increasingly performed in order
to prevent local recurrence [6]
[7].
With thermal ablation of mucosal defect margins only recently emerging, not all current
guidelines incorporated firm statements regarding this adjuvant measure. The European
Society of Gastrointestinal Endoscopy (ESGE) clinical guideline for colorectal polypectomy
and endoscopic mucosal resection (2017) stated that the role of adjuvant thermal ablation
of the EMR resection margins to prevent recurrence requires further study [8]. However, the American Society for Gastrointestinal Endoscopy (ASGE) recently published
a renewed guideline about endoscopic removal of colorectal lesions, in which the use
of adjuvant thermal ablation of the post-EMR margin is incorporated as a conditional
recommendation with moderate-quality evidence [7].
To investigate and summarize current evidence on thermal ablation of mucosal defect
margins, we set out to perform a systematic review and a meta-analysis assessing the
effect of adjuvant thermal ablation, compared to no adjuvant treatment, of mucosal
defect margins on recurrence of large colorectal polyps removed by EMR.
Materials and methods
This systematic review was conducted according to a predefined protocol that has been
registered in the international prospective registry for systematic reviews (PROSPERO):
CRD42020189860. Our study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis
(PRISMA) statement [9].
Search strategy and inclusion criteria
The electronic databases of PubMed, EMBASE and Cochrane were searched for articles
published between January 1990 and July 19, 2021. The search terms comprised synonyms
for “colon” or “rectum”, “colonoscopy”, “colorectal polyps” as domain and “adjuvant
or additional treatment” or “argon plasma coagulation” or “snare tip soft coagulation”
as intervention. The search was performed after consultation of a search expert. The
full search can be found in Supplementary Material 1. Studies for inclusion were selected after removing duplicates. Studies were eligible
for inclusion if they were written in English, published in peer-reviewed journals
and reported original data from randomized clinical trials or observational studies.
Studies were included if thermal ablation was used as an adjuvant treatment, meaning
that all neoplastic tissue was removed during the EMR and no residual tissue was detected
during careful inspection of the EMR-defect. Studies were excluded if thermal ablation
was used as an adjunctive treatment on residual neoplastic tissue after EMR.
Study selection
Two authors (LWTM and RMMB) independently screened titles and abstracts identified
by our search. Subsequently, independent assessment of full-text articles for final
inclusion was performed. We cross-checked reference lists of included studies and
screened references that cited the included articles. Consensus was reached by discussion
and in case of disagreement or uncertainty about eligibility by consultation with
senior authors (AAMM and LMGM).
Data collection
A predesigned data extraction form was used to extract relevant data of included studies.
Two authors (LWTM and RMMB) independently extracted the data. Disagreement was resolved
by discussion between the two authors. If no agreement could be reached, this was
discussed with senior authors (AAMM and LMGM). Data were extracted based on the 6-month
follow-up interval. When a study did not report outcomes at 6 months, data were extracted
based on the 12-month follow-up interval. This follow-up interval of 6 months is in
line with current surveillance guidelines stating that first surveillance colonoscopy
should be performed at 6 months.
We extracted the following data: author, year of publication, country, study design,
randomization, blinding, number of participating centers, number of patients, number
of included lesions, size in mm, % proximal location, type of ablative therapy, follow-up
interval, and outcome.
Local recurrence and risk difference
The main goal was to identify local recurrence (at 6–12 months) after endoscopic resection.
Local recurrence was assessed for all adjuvant treatment modalities, as well as separately
for STSC and APC.
As a secondary goal, pooled recurrence rates for STSC and APC were calculated for
comparison.
Sensitivity analysis was performed to evaluate the recurrence and risk difference
in studies only including lesions from a size of ≥ 20 mm, thus leaving out two studies
that included lesions from a size of ≥ 10 mm or ≥ 15 mm. Furthermore, a second sensitivity
analysis was performed to account for potential case overlap in STSC studies from
one research group (Australia). For this analysis, pooled estimates were calculated
with only one study of this specific research group included.
Assessment of methodological quality
Two authors (LWTM and RMMB) independently evaluated the methodologic quality and potential
risk of bias in included studies. We used the Quality in Prognostic Studies (QUIPS)
tool for randomized studies, as recommended by the Cochrane Prognosis Methods Group
[10]. In addition, the Newcastle-Ottawa Scale (NOS) was used for quality assessment of
both non-randomized and randomized studies. We defined the components of the NOS according
to our research question. For “representativeness of the exposed cohort” we evaluated
whether there was no selection based on location, size or complexity of the lesions.
For “selection of the non-exposed cohort” we evaluated whether the controls were derived
from the same population as the exposed group, and whether there were reasons to believe
that the non-exposed group did not receive adjuvant treatment for a specific reason
(e. g. other resection technique used, inexperienced endoscopist). “Representativeness
of the exposed cohort” and “selection of the non-exposed cohort” together composed
the evaluation of possible selection bias. For “ascertainment of cohort” we evaluated
whether it was clear that adjuvant treatment methods were applied fully and correctly.
For “demonstration that outcome of interest was not present at the start of the study”
we evaluated whether the study described no visible residue present at the first resection.
For “comparability” we evaluated the study controlling for exposure vs. non-exposure,
baseline characteristics and both cohorts being samples of the same general population.
Hence, potential confounding bias was evaluated. For “assessment of outcome” definition
of recurrence had to be described and documented in the studies. For “follow-up long
enough for outcome to occur” we used a minimal follow-up period of 6 months. Finally,
“adequacy of follow-up” was defined by description of loss-to-follow-up by the different
studies, where < 15 % loss-to-follow-up, evenly distributed over groups, was acceptable
[11].
Disagreement was resolved through discussion and consensus was reached by coordination
with senior authors (AAMM and LMGM).
Statistical analysis
Pooled risk differences (RDs) along with 95 % confidence intervals (CIs) were calculated
using random-effect models with Mantel-Haenszel method. R statistical program version
4.0.5 was used to process all collected data [12]. The Metafor package version 3.0.2 was used for calculations and plotting [13].
Secondary, pooled recurrence rates after STSC and APC treatment were calculated by
applying generalized linear mixed models with a logit link to the raw data (recurrence
yes/no), where a random intercept on study level was included to account for the study
effect.
Heterogeneity was assessed with the Q test for significance and with the inconsistency
index (I2), where a value of > 50 % was considered as substantial heterogeneity between studies.
Funnel plots with Egger’s test for asymmetry were constructed to test the possible
effect of publication bias [14]. Crude estimates were used for statistical analysis. A two-sided P ≤ 0.05 was considered statistically significant.
Results
Included studies
Our search identified 2979 papers, of which ten met our inclusion and exclusion criteria
([Fig. 1]). Study characteristics are shown in [Table 1]. APC was evaluated as adjuvant treatment modality in three studies, while STSC was
evaluated in six studies. One additional study retrospectively compared both treatment
modalities, with 50 patients receiving APC and 51 patients receiving STSC. The ten
included studies represented a total of 316 APC cases and 1598 STSC cases.
Fig. 1 Study flowchart.
Table 1
Baseline study characteristics.
|
Author, year
|
Country
|
Study design
|
Randomization
|
Blinding
|
No. of participating centers
|
No. of patients
|
No. of lesions
|
Size in mm (mean±SD or median + IQR)
|
Proximal location (%)
|
Type of ablative therapy
(settings)
|
Follow-up interval
|
Outcome – local recurrence
|
P value
|
|
Intervention group
|
Control group
|
|
Albuquerque, 2013 [19]
|
Brazil
|
RCT
|
Yes
|
No
|
1
|
20
|
21
|
34 (± 13)
|
43 %
|
APC 60 W
Gasflow 2.0 L/min
|
3 and 12 months
|
2/10
(20 %)
|
2/11 (18.2 %)
|
NR
|
|
Brooker, 2002 [18]
|
UK
|
RCT
|
Yes
|
No
|
1
|
21
|
21
|
26 (± 10)
|
62 %
|
APC
45–55 W right, 65 W left colon
Gasflow 2.0 L/min
|
3 and 12 months
|
1/10
(10 %)
|
7/11
(63.6 %)
|
0.02
|
|
Kandel, 2019 [16]
|
USA
|
Prospective cohort
|
No
|
No
|
1
|
120
|
120
|
28 (± 11)
|
82 %
|
STSC 20–80 W
Soft coag mode
|
6 months
|
7/60
(12 %)
|
18/60
(30 %)
|
0.01
|
|
Katsinelos, 2019[1]
[24]
|
Greece
|
Retrospective cohort
|
No
|
No
|
1
|
101
|
101
|
41 (± 13)
|
16 %
|
STSC 20 W
Soft coag mode
APC 50 W right, 70 W left
Gasflow 1.5 L/min
|
3, 6 and 12 months
|
7/51
(13.7 %)
|
8/50
(16 %)
|
0.34
|
|
Klein, 2019 [6]
|
Australia
|
RCT
|
Yes
|
No
|
4
|
416
|
416
|
30 (IQR 25–45)
|
52 %
|
STSC 80 W
Soft coag mode
Erbe effect 4
|
6 and 18 months
|
10/192 (5.2 %)
|
37/176
(21.0 %)
|
< 0.001
|
|
Park, 2019 [21]
|
South Korea
|
Retrospective cohort
|
No
|
No
|
1
|
156
|
176
|
22 (± 10)[2]
|
NR
|
STSC 80 W
Soft coag mode
Erbe effect 4
|
3–12 months
|
8/171
(4.8 %)
|
3/5
(60 %)
|
0.002
|
|
Raju, 2020 [25]
|
USA
|
Retrospective cohort, no control group
|
No
|
No
|
1
|
246
|
246
|
35 (IQR 30–45)
|
80 %
|
APC 30–35 W
Gasflow 0.8 L/min
|
6 and 18 months
|
11/246 (4.5 %)
|
NA
|
NA
|
|
Shahidi, 2020 [22]
|
Australia
|
Prospective cohort
|
No
|
No
|
2
|
413
|
413
|
40 (IQR 30–60)
|
NA
|
STSC 80 W
Soft coag mode
Erbe effect 4
|
6 months
|
0/30 (0 %)
3/51 (5.9 %)
|
12/48 (25 %)
28/160 (17.5 %)
|
0.002
0.041
|
|
Shahidi, 2021 [23]
|
Australia
|
Prospective cohort
|
No
|
No
|
1
|
817
|
817
|
35 (IQR 30–50)
|
72 %
|
STSC 80 W
Soft coag mode
Erbe effect 4
|
6 months
|
2/336 (0.6 %)
|
82/481 (17.0 %)
|
< 0.001
|
|
Sidhu, 2021 [15]
|
Australia
|
Prospective cohort, no control group
|
No
|
No
|
6
|
1049
|
1049
|
35 (IQR 25–45)
|
54 %
|
STSC 80 W
Soft coag mode
Erbe effect 4
|
6 months
|
10/707 (1.4 %)
|
NA
|
NA
|
APC, argon plasma coagulation; STSC, snare tip soft coagulation; NR, not reported;
NA, not applicable.
1 Comparison between APC and STSC. STSC reported as intervention group (IG) and APC
as control group (CG)
2 Estimated mean + SD, calculated from reported size categories with frequencies
All studies included large colorectal polyps, but inclusion criteria differed between
studies, with the size of lesions suitable for inclusion ranging from ≥ 10 mm to ≥ 20 mm.
Mean age and gender distribution between groups in the included studies were comparable.
Furthermore, the included studies reported comparable size and location of lesions
between intervention and control groups.
Quality assessment
Quality and risk of bias assessment according to the QUIPS tool for randomized trials
is presented in Supplementary Material, Table 1. In addition, quality and risk of bias assessment according to the NOS for all included
studies is presented in Supplementary Material, Table 2.
Adjuvant thermal ablative treatment
The main results of the effect of adjuvant STSC and APC on recurrence are presented
in [Fig. 2]. Pooled estimates of the effect of any adjuvant treatment modality on recurrence
yielded a statistically significant risk difference of –0.17 (95 % CI –0.22 to –0.12)
compared to no adjuvant treatment. Pooled estimates of the effect of STSC on recurrence
yielded a statistically significant risk difference of –0.16 (95 % CI –0.19 to –0.14),
while the pooled effect of APC on recurrence yielded a non-significant risk difference
of –0.26 (95 % CI –0.80 to 0.28).
Fig. 2 Pooled data from included studies. IG, intervention group; CG, control group; RD,
risk difference; STSC, snare tip soft coagulation; APC, argon plasma coagulation.
*Not all included lesions in this study are ≥ 20 mm in size.
Risk of publication bias is presented in [Fig. 3]
. The funnel plot shows two studies being outliers, but this was not significant (Egger’s
test P = 0.112).
Fig. 3 Funnel plot of included studies.
Sensitivity analysis without the two studies including lesions from a size of ≥ 10
and ≥ 15 mm showed no difference in outcome, with an overall risk difference of –0.16
(95 % CI –0.19 to –0.13).
Sensitivity analysis to account for possible case overlap in studies from the same
research group did also not show any significant difference in outcome, with an STSC-specific
risk difference ranging from –0.18 to –0.22 (95 %-CI lower bound ranging from –0.25
to –0.34 and upper bound ranging from –0.09 to –0.12).
Comparing thermal ablation modalities
Pooled estimates of the recurrence rates after STSC and APC are presented in [Fig. 4]. Pooling studies reporting on STSC yielded a recurrence rate of 4 % (95 % CI 2 %
to 8 %), while a recurrence rate of 9 % (95 % CI 4 % to 19 %) was seen for APC.
Fig. 4 Pooled recurrence rates for STSC and APC after 6 to 12 months. *Not all included
lesions in this study are ≥ 20 mm in size.
One of 10 included studies directly compared APC (n = 50) and STSC (n = 51) in a retrospective
manner, and showed no significant difference in recurrence after APC vs. STSC (16 %
vs. 13.7 %; P = 0.34).
Discussion
This systematic review and meta-analysis of 10 studies shows that adjuvant thermal
ablative treatment of mucosal defect margins reduces recurrence rate after endoscopic
resection of large colorectal polyps (RD –17 %; 95 % CI –22 % to –12 %). STSC showed
a significantly reduced recurrence rate, while APC did not lead to a significant reduction
in recurrence. Pooled recurrence rates showed 4 % and 9 % recurrence after STSC and
APC, respectively.
Our findings are in accordance with recent studies on thermal ablation of mucosal
defect margins that concluded that thermal ablation after endoscopic resection, also
described as EMR-T, is an effective measure to reduce recurrence in large colorectal
polyps [6]
[15]
[16]. In addition, a recent meta-analysis about endoscopic techniques to reduce recurrence
rates after colorectal EMR also showed that treatment of the EMR resection margins
significantly reduces recurrence [17]. However, this meta-analysis by Kemper et al. harbors some concerns. First, it did
not include all currently available evidence regarding thermal ablation of resection
margins. Kemper et al. evaluated thermal ablation in only four studies, together accounting
for 529 lesions, whereas we evaluated thermal ablation in ten studies, together accounting
for 3380 lesions. Second, in the effect analysis, they also included studies in which
extended EMR and precutting was performed. This may have influenced the results. Third,
they did not perform sensitivity analysis for size and case overlaps. Fourth, using
only randomized controlled trials (RCTs) for their comparison between APC and STSC
ruled out important observational studies. Especially for APC, the original RCTs are
of questionable quality and applicability to current practice. Based on the data of
this systematic review and meta-analysis, evaluating all currently available evidence
on this subject, it can be concluded that thermal ablation of mucosal defect margins
should be incorporated for all large (≥ 20 mm) colorectal polyps removed by piecemeal
approach.
Two treatment modalities are available for thermal ablation, which both seem to reduce
the risk of recurrence. However, in this meta-analysis, APC did not show a significant
reduction when pooling studies, in contrast to STSC, which significantly reduced recurrence
risk. While pooled data are presented for STSC and APC separately, this information
should be interpreted with caution. A couple of recent high-quality studies have been
published on STSC, but the evidence on APC is of moderate quality. The number of lesions
included in the APC studies is very small (Brooker et al. n = 21; Albuquerque et al.
n = 21). Furthermore, the study by Brooker et al. showed a recurrence rate of 63.6 %
in the control group, which raises the question whether these data are representative
for current practice [18]
[19]. In addition to the studies by Brooker et al. and Albuquerque et al., an abstract
by Chattree and Rutter (2015) also reported data on the effect of APC on recurrence.
In this abstract, a total of 153 piecemeal EMR procedures were retrospectively analyzed,
with 18 % vs. 31 % recurrence in APC group vs. non-APC group respectively (P = 0.064) [20]. Sensitivity analysis, including these abstract data, did not lead to a significant
effect of APC. Consequently, at this point, the evidence on the effect of APC to reduce
recurrence is of insufficient quantity and quality to make any firm statements.
In addition to risk reduction analysis, all available evidence (including observational
studies without control group) was pooled to estimate recurrence rate after APC and
STSC. The difference in pooled recurrence rate after APC and STSC was not statistically
significant, given the overlapping CIs. Therefore, superiority of one of these modalities
remains unknown at this time.
Settings used during thermal ablation of mucosal defect margins sometimes differ between
operators. However, our data showed that operators in general agree about the settings
for STSC. For STSC, universally, the soft coagulation mode is used with a current
of 80 Watts and effect mode 4 on Erbe ENDO CUT Q [6]
[15]
[21]
[22]
[23].
Settings for APC show more variation between operators, with currents between 30–70
Watts and a gasflow of 0.8–2.0 liters per min [18]
[19]
[24]
[25]. A recent study in porcine models evaluating the effects of STSC and APC showed
that APC applied at 1.0 L/min, 30 W, was associated with islands of preserved mucosa
[26]. Therefore, it appears that higher power in APC is necessary to achieve deeper thermal
ablation. We advise using forced coag 60 Watts when applying APC.
En bloc EMR is associated with lower recurrence rates compared with piecemeal EMR
(3 % vs. 20 %) [27]. However, en bloc resection by EMR is difficult for lesions ≥ 20 mm. Therefore,
most large colorectal polyps are resected piecemeal when there is no suspicion for
submucosal invasion. Of the included studies in this meta-analysis, only three made
the distinction between en bloc and piecemeal resection [6]
[21]
[25], and only one of these three performed post-hoc analysis to evaluate the specific
effects of EMR-T after en bloc and piecemeal resection separately [6]. In this study, there was no significant difference in recurrence rate after traditional
en bloc EMR (0/23; 0 %) compared to en bloc EMR-T (1/25; 4 %). Therefore, it appears
that the positive effects of EMR-T seen after piecemeal resection, are not seen in
en bloc resections. Combining these data with the fact that recurrence rates after
en bloc resection are already low, the added value of thermal ablation remains questionable.
Prospective studies, with larger numbers are needed to make firm statements about
the value of thermal ablation after en bloc resection.
While large colorectal polyps without suspicion of submucosal invasion could be treated
by EMR, the discussion remains ongoing whether some of these lesions should be removed
en bloc by ESD [28]
[29]. The main argument for non-selective ESD on large colorectal polyps, is the fact
that it is associated with lower recurrence rates compared to EMR [27]
[30]
[31]. In a systematic review and meta-analysis by Fuccio et al., recurrence rate after
ESD was only 2.0 % (95 % CI 1.3 % to 3.0 %) [3]. However, with the emergence of EMR-T, recurrence rates after EMR can be significantly
reduced to percentages as low as 1.3 % [15], waiving this advantage of ESD over EMR. As thermal ablation of mucosal defect margins
is not associated with a higher frequency of adverse events [15], it should be preferred over ESD for treatment of large colorectal polyps without
suspicion for submucosal invasion. However, it is of utmost importance to perform
a thorough selection of cases suitable for EMR. When there is any suspicion for submucosal
invasion, one needs to perform an en bloc resection to obtain free resection margins
(R0 resection), which enables pathologists to perform detailed pathological analysis
[32]
[33]. EMR on superficially invasive colorectal cancers leads to suboptimal treatment
outcomes, with low R0-resection rates [34]. Therefore, in case there is any doubt about potential submucosal invasion being
present, an en bloc resection technique such as ESD is preferred.
Alternatives to EMR-T are present, such as (extra-)wide-field EMR (also known as extended
EMR) or marking of the lesion prior to EMR. In (extra-)wide-field EMR, a wider excision
is performed to excise at least 5 mm of normal-appearing tissue around the edges of
the lesion. However, a large cohort study, comparing extended EMR with standard EMR
did not show a reduction of recurrence after extended EMR [35]. Furthermore, a recent retrospective observational study by Emmanuel et al. showed
that microscopic residual adenoma was detected at the apparently normal defect margins
in 19 % of cases after wide-field EMR [36]. These studies suggest that wide-field EMR is not the appropriate technique to secure
that all microscopic adenomatous tissue is being resected and prevent recurrence.
Another recently evaluated alternative to EMR-T is margin marking before EMR. A single-center
historical control study, performed by Yang et al., showed that margin marking before
EMR reduced recurrence rates with 80 % when compared with conventional EMR [37]. This technique may therefore provide an alternative to margin ablation. However,
larger prospective or randomized studies might be desired to validate these outcomes.
In the future, expanding the scope to not only treating defect margins, but also the
base of resection, might be important to further reduce recurrence [36]
[38].
Our study has some limitations. First, some studies included in this meta-analysis
were performed on a small number of patients. Especially in the studies concerning
APC, the numbers of patients were limited, which leads to a higher heterogeneity when
pooling studies and wider CIs. Heterogeneity was also caused by different duration
of follow-up between studies. Therefore, especially the data concerning APC should
be interpreted with caution.
Second, this study does not allow us to perform sub-analyses based on specific risk
profiles (e. g. piecemeal vs. en bloc; number of pieces; high-grade dysplasia; experience
of endoscopist, local access to the lesion). Unfortunately, none of the included studies
evaluated the relationship between the number of pieces and the additional value of
thermal ablation. In other words, might thermal ablation only be of added value from
a specific number of pieces onwards. This question therefore remains unanswered. Consequently,
we are unable to make any firm statement about which specific lesions could benefit
the most from thermal ablation.
Third, while it was not the primary goal of this systematic review, we could not detect
a significant difference in effectivity between APC and STSC to reduce recurrence.
However, only one comparative study of both treatment modalities exists, of which
reliability and generalizability could be questioned because of the retrospective,
single endoscopist design, small numbers and long time period of inclusion [24]. Because of these concerns, a prospective randomized controlled trial should be
performed to determine whether there is a difference between APC and STSC in reducing
the risk of recurrence. Despite the lack of evidence, one could argue that STSC is
preferred over APC because of standard availability with EMR and the fact that for
APC an additional APC probe is needed, which leads to additional costs [15]. Therefore, STSC is considered the most cost-effective modality and, consequently,
suggested as primary thermal ablative treatment modality in most cases. Furthermore,
a recent study in porcine models showed possible superiority of STSC over APC, demonstrated
by less incomplete ablation with islands of preserved mucosa after STSC compared to
APC [26].
Conclusions
Thermal ablation of mucosal defect margins significantly reduces the risk of recurrence
after resection of large non-pedunculated colorectal polyps and should be used universally
for piecemeal-resected large non-pedunculated colon polyps. Although evidence for
superiority is lacking, STSC is preferred over APC because this is the most evidence-based
and probably most cost-effective modality. Further (randomized) studies are needed
to investigate the difference between APC and STSC efficacy in reducing recurrence
after endoscopic resection of large non-pedunculated colorectal polyps.
