Introduction
Endoscopic full-thickness resection (EFTR) is emerging as an effective and safe technique
for difficult colorectal lesions [1]
[2]. It may offer a valid alternative to surgery for “nonlifting” lesions that are not
amenable to standard resection with endoscopic mucosal resection (EMR) or endoscopic
submucosal dissection (ESD) because of fibrosis or invasion beyond the submucosal
layer.
EFTR procedures are traditionally divided into exposed and nonexposed techniques.
The exposed approach involves performing full-thickness resection first, with subsequent
closure of the temporary peritoneal exposure. Exposed EFTRs are classified as tunneled
or non-tunneled techniques and originate from ESD. In nonexposed EFTR, a secure serosa-to-serosa
apposition is obtained before full-thickness resection of an isolated lesion [3]; this is commonly achieved using over-the-scope (OTS) clip deployment with the Ovesco
full-thickness resection device (FTRD; Ovesco Endoscopy, Tübingen, Germany). The colonic
FTRD obtained a CE mark for EFTR in the lower gastrointestinal tract in 2014. A later
version of the device is also registered for the gastroduodenal tract, improving its
safety profile even in particularly critical areas.
With increasing adoption of this system, there has been growing evidence supporting
its effectiveness and safety [4]
[5]
[6]
[7]
[8]. The largest recently published meta-analysis reported a technical success rate
of 87 % using the Ovesco FTRD only, and an R0 resection rate ranging from 78.8 % to
81.6 % [9]
[10]. Despite these satisfying results, EFTR remains a technically demanding procedure
with some limitations and potential risks [11]
[12]. The use of the FTRD for colorectal lesions has been linked in previous studies
to the risk of clip misdeployment or snare dysfunction, leading to procedure failure
or unpredictable adverse events (AEs). Technical failures have been reported differently
among the published studies, with a lack of standardization and of a detailed cause–effect
relationship with AEs.
The aim of the present study was to quantify and classify the technical failures occurring
during colorectal EFTR with the FTRD system.
Methods
This was a retrospective study, involving 17 Italian centers, that included all consecutive
technical failures during colorectal EFTR using the FTRD from 2018 to 2022. All of
the centers had experience in advanced resection techniques and ≥ 5 years of expertise
in Ovesco devices. All cases in which it was impossible to reach the lesion with the
device (e. g. because of severe diverticular diseases, stenosis, or curvature) were
excluded.
The Ethics Committee of the center that proposed the research approved the data collection,
which was subsequently shared with the other participating centers. The study conformed
to the current EU regulation on the protection of personal data, Regulation (EU) 2016/679
of the European Parliament, and to the Declaration of Helsinki's ethical guidelines.
Device and endoscopic technique
Each participant confirmed the correct use of the FTRD according to the manufacturer’s
settings and guidelines [3]. The colonic FTRD consists of an applicator cap with a ready-to-use mounted FTRD
clip, integrated snare, and thread. The cap carries a modified 14-mm OTS clip that
can be mounted over a standard colonoscope, similarly to the OTS clip system. Compared
with the conventional OTS clip system, the cap has greater depth (23 mm vs. 6 mm)
to accommodate more tissue, and the clip design is slightly modified. The outer diameter
of the device is 20 mm. A 13-mm monofilament snare is preloaded in the tip of the
cap. The snare catheter runs along the outer surface of the colonoscope, constrained
by a transparent plastic sheath to prevent entrapment of tissue between the scope
and the snare. The complete positioning of the device on the colonoscope allows control
of the system through a handwheel. The target lesion is pulled into the cap with a
grasping or anchoring device before clip deployment. Turning the handwheel tensions
the thread and the clip is released. The target tissue is cut above the clip using
the integrated snare. Immediately after clip deployment, the tissue above the clip
is resected with the snare.
All of the participants confirmed that a previous endoscopic evaluation of technical
feasibility had been performed in terms of reaching the lesion and evaluating the
polyp’s size and location [13].
Definitions
All of the investigators participated in several online meetings to share video cases,
discuss definitions, and obtain agreement on failure classification.
“Technical failure” was considered in terms of device dysfunction and defined as the
inability to achieve en bloc resection after successful application of the OTS clip
system. The inability to achieve complete enclosure of the lesion inside the cap or
insufficient traction/suction into EFTR cap was classified as “cap misplacement”;
the inability to release the clip was classified as “clip misdeployment”; the inability
to achieve resection of the lesion after snare placement and electrical current application
was defined as “snare noncutting.” Classification into types I, II, or III was subsequently
assigned according to the reported frequency of each. A graphical representation is
reported in the [Fig. 1].
Fig. 1 Schematic showing the proposed classification of technical failure, assigned according
to the reported frequency of each, as: a type I, snare noncutting; b type II, clip misdeployment; c type III, cap misplacement. Source: Michelle Lorusso.
In addition, investigators were invited to state whether the dysfunction related to
the device itself or was patient related, considering unexpected factors like angulation
of the lesion site or heavily fibrotic tissue to resect. Clinical success was considered
in terms of the rates of EFTR (histologically confirmed full-thickness resection)
and R0 resection (complete removal of the tissue with tumor-free lateral and deep
margins on histologic examination).
AEs were classified according to the AGREE classification [14] as follows. Grade I includes any deviation from the standard post-procedural course,
without the need for pharmacologic treatment or endoscopic, radiologic, or surgical
intervention. It also includes hospital admission of < 24 hours, without any intervention
or the prescription of drugs such as antiemetics, antipyretics, analgesics, and electrolytes
or diagnostic tests (radiology and laboratory tests). Grade II refers to AEs requiring
pharmacologic treatment with drugs other than those allowed for grade I AEs (i. e.
antibiotics, antithrombotics, etc.), or blood or blood product transfusion, or hospital
admission for > 24 hours. Grade III AEs include events requiring endoscopic, radiologic,
or surgical intervention (grade IIIa, endoscopic or radiologic intervention; grade
IIIb, surgical intervention). Grade IV AEs include those requiring intensive care
unit/critical care unit admission (grade IVa, single-organ dysfunction [including
dialysis]; grade IVb, multiorgan dysfunction). Grade V refers to the death of the
patient.
AEs were also divided into intraprocedural and post-procedural AEs depending on whether
they occurred during the procedure or after the procedure had been completed, in subsequent
hours of observation and in the following days, with all patients followed up for
at least 3 months.
Each center was invited to report the training performed for full-thickness resection,
experience in exposed FTRDs, colorectal ESD, and suturing devices, with participation
in national EFTR registries or screening programs also evaluated. According to the
median number of overall EFTRs performed in the study period, centers were divided
into high volume (> 30 procedures/study period) or low volume (< 30 procedures).
Outcomes and patient population
The primary outcome was to assess the device dysfunction rate, overall and according
to the proposed classification. Secondary outcomes included the management of dysfunction,
clinical success, the rate and grading of AEs, and the correlation between a center’s
experience in EFTR and the occurrence of the aforementioned outcomes.
The study included consecutive colorectal nonexposed EFTR procedures using the Ovesco
FTRD with failure due to device dysfunction. Exclusion criteria were: EFTR performed
by an exposed technique, procedures with devices other than the Ovesco FTRD, cases
confirmed as failure due to inability to reach the lesion, and inability of the patient
to give informed consent for data collection.
Statistical analysis
Data were reported as mean (SD) for quantitative variables, and absolute and relative
frequencies for categorical variables, when necessary 95 %CIs were properly calculated.
An a priori sample size determination was not feasible owing to the explorative nature
of the present data collection.
Heterogeneity between subgroups (high vs. low volume centers) was also estimated.
This measure indicates whether data from all centers can be pooled into one measure,
or have a variance that prevents them being pooled overall (P < 0.05 in the latter case), indirectly indicating whether differences exist between
the subgroups.
Two-sided P values < 0.05 were considered to be significant. Analyses were conducted using STATA
17 (StataCorp. 2017, release 15; StataCorp LLC, College Station, Texas, USA) with
the “metaprop” function.
Results
During the study period, a total of 750 patients underwent colorectal full-thickness
resection. Dysfunction occurred in 77 patients (10.3 %). The most frequent type of
failure was snare noncutting (type I) in 41 patients (53.2 %). Clip misdeployment
(type II) occurred in 24 patients (31.2 %), with cap misplacement (type III) reported
in 12 patients (15.6 %). Endoscopic images of included population are shown in [Fig. 2]. The dysfunction events were judged by endoscopists to be strictly device related
in 44 patients (57.1 %) and to be patient related in the remaining cases. Among the
former group, there were 22 events reported as type I, 19 as type II, and three as
type III. Baseline data for patient and lesion characteristics, and procedure details
are reported in [Table 1].
Fig. 2 Endoscopic images of: a–c type I failure showing snare noncutting; d–f type II failure with clip misdeployment leading to: d,e perforation and; f clip release at the end of the procedure; g–i type III failure with lesions not completely pulled into the cap, corresponding to
cap misplacement.
Table 1
Baseline characteristics of the 77 included patients, their lesions, and the procedures
they underwent.
|
Patients with eFTR
|
|
Patient characteristics, n (%)
|
|
Sex, male
|
42 (54.5 %)
|
|
Age, mean (SD), years
|
69.4 (8.9)
|
|
Lesion characteristics, n (%)
|
|
Colorectal site
|
|
|
9 (11.7 %)
|
|
|
5 (6.5 %)
|
|
|
22 (28.6 %)
|
|
|
9 (11.7 %)
|
|
|
16 (20.8 %)
|
|
|
16 (20.8 %)
|
|
Size, mean (SD), mm
|
18.4 (7.5)
|
|
Morphology according to Paris Classification [13]
|
|
|
9 (11.7 %)
|
|
|
68 (88.3 %)
|
|
Recurrent lesion
|
40 (51.9 %)
|
|
|
38 (49.4 %)
|
|
|
2 (2.6 %)
|
|
Histology
|
|
|
17 (22.1 %)
|
|
|
53 (68.8 %)
|
|
|
2 (2.6 %)
|
|
|
5 (6.5 %)
|
|
Procedure characteristics, n (%)
|
|
Use of the PrOVE cap
|
27 (35.1 %)
|
|
Trimming performed
|
5 (6.5 %)
|
|
Rescue endoscopic resection
|
61 (79.2 %)
|
|
|
57 (74.0 %)
|
|
|
4 (5.2 %)
|
|
Surgical treatment
|
6 (7.8 %)
|
|
|
4 (5.1 %)
|
|
|
2 (2.6 %)
|
|
Positioning of another OTS clip
|
8 (10.4 %)
|
|
Treatment with suturing device
|
1 (1.3 %)
|
|
En bloc resection
|
55 (71.4 %)
|
|
Injury to extraluminal structures
|
|
|
5 (6.5 %)
|
EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; OTS, over
the scope.
R0 resection was obtained in 49 cases (63.6 %). Other post-procedural outcomes are
reported in [Table 2]. There were 61 lesions (79.2 %) where endoscopic resection was completed by conservative
rescue endoscopic resection. The remaining 10 cases did not require further intervention
despite the intraprocedural failure, mostly represented by clip misdeployment. Four
patients (5.1 %) underwent elective surgical treatment because of failure of the endoscopic
resection.
Table 2
Summary of post-procedure outcomes.
|
Outcome
|
n (%)
|
|
Histologically confirmed full-thickness resection
|
47 (61.0 %)
|
|
R0 resection
|
49 (63.6 %)
|
|
Over-the-scope clip retained for > 12 weeks
|
12 (15.6 %)
|
|
RemOVE system used
|
1 (1.3 %)
|
A total of 21 AEs were reported after technical failure and were mainly classified
as grade I (n = 13; 16.9 %); four cases (5.2 %) of intraprocedural perforation were
managed during the procedure and were classified as grade II. The remaining AEs included:
one intraprocedural perforation observed at a different site to the location of the
EFTR probably due to snare cutting damage that required endoscopic reintervention
(full-thickness suture with a dedicated device), and a late post-procedure pericolic
hematoma after intraprocedural OTS clip placement that required radiologic drainage
(both grade IIIa; 2.6 %); two perforations were treated by urgent surgical intervention
(grade IIIb; 2.6 %).
Of the 21 AEs, 18 were intraprocedural (23.4 %), including bleeding and perforation
(both 10.4 %), along with two cases of substenosis of the lumen secondary to OTS clip
closure. The post-procedural complication rate was 3.9 % and included two perforations
and one pericolic hematoma occurring 1 week after the procedure. The AEs are summarized
in [Table 3].
Table 3
Summary of adverse events.
|
Adverse events
|
n (%)
|
|
Overall
|
21 (27.3 %)
|
|
Grade according to the AGREE classification
|
|
|
13 (16.9 %)
|
|
|
4 (5.2 %)
|
|
|
2 (2.6 %)
|
|
|
2 (2.6 %)
|
|
|
0
|
|
|
0
|
|
Intraprocedural events
|
18 (23.4 %)
|
|
|
8 (10.4 %)
|
|
|
8 (10.4 %)
|
|
|
2 (2.6 %)
|
|
Post-procedural events
|
3 (3.9 %)
|
|
|
2 (2.6 %)
|
|
|
1 (1.3 %)
|
The training and experience of the centers are summarized in Table 1 s, see online-only Supplementary material. As can be seen in [Fig. 3], heterogeneity between the low and high volume centers was not significant (P = 0.08) and similar results were obtained for the overall AEs rate, being 1.8 % (95 %CI
0.2 %–4.5 %) in high volume centers and 1.2 % (95 %CI 0.1 %–5.3 %) in low volume centers
(P = 0.70), and for the rescue resection rate, being 7.9 % (95 %CI 3.6 %–13.5 %) in
high volume centers and 6.3 % (95 %CI 1.8 %–12.4 %) in low volume centers (P = 0.71).
Fig. 3 Heterogeneity between failure rate according to centers’ experience (high versus
low volume centers, defined as > 30 or < 30 procedures/study period).
Discussion
Performing colorectal EFTR is now recognized as a safe and effective technique for
advanced resection of complex lesions; large international registries support this
evidence and its use is increasing. The use of nonexposed resection devices is further
encouraged by their ease of handling and simple procedural steps. The present study
confirmed that colorectal EFTR is a challenging procedure, with unpredictable technical
failures occurring because of device dysfunction and a wide spectrum of consequences.
We observed a failure rate of 10.3 % among eligible patients, with type I (snare dysfunction)
the most frequently observed; however, when considering all of the failures reported,
they were related to the device itself in only half of cases, so this could require
more attention be given to patient selection and lesion characteristics (recurrent
fibrotic lesions [51.9 %] or advanced histology such as adenocarcinoma [21.9 %]).
In an Italian multicenter experience with EFTR published in 2019 [15], including 114 patients, with a technical success rate of 94.4 %, full-thickness
resection was achieved in 91 % of patients, with lateral and deep R0 resection in
90 % and 92 %, respectively. AEs were reported in 11 % of the study population, while
technical issues with snare malfunction were described in 12 cases (11 %) and incomplete
clip deployment in five (4.5 %). Similar results were reported from a larger German
registry that collected data from 1178 colorectal procedures from 2015 to 2019 [16]. Furthermore, reporting the Dutch experience, EFTR was shown to be an effective
and relatively safe procedure for oncologic purposes, with an overall technical success
rate of 87.0 %, R0 resection rate of 85.6 %, and severe AE rate of 2.2 % [17].
Technical issues can however arise, although it is still unclear the frequency of
these and the consequences they may have for patients. Zwager et al. recently published
the largest study describing AEs occurring during colorectal EFTR, based on the experience
of the German and Dutch registries [18]. Among 1892 procedures, the overall AE rate was 11.3 %, with female sex and technical
issues being the main factors related to complications; however, no clear definition
of technical issues was provided. Our study was the first to classify dysfunction
based on the different procedural steps and to analyze the eventual link with complications.
The classification was formulated on the assumption that the procedural steps were
correctly observed. It should be noted though that the observed rate of AEs in our
study was higher than that previously reported, but it was considered only in the
subgroup of cases of technical failures and not in the entire population undergoing
EFTR during the study period. We believe that this result is in line with the Dutch
and German registries, which show that technical dysfunction increases the risk of
AEs (mainly mild or moderate in severity) for patients, although two-thirds of dysfunctions
were not followed by AEs.
Clinical success (i. e. the achievement of R0) was achieved in more than half of the
study population. Despite the failures, most lesions (79.2 %) were managed with rescue
endoscopic resection, mainly EMR of complex lesions. This leads us to consider that
the first-line treatment of relapsed or nonlifting colorectal lesions is debatable.
A number of recent studies have compared resection with ESD and EFTR, with varying
results according to the experiences in different countries.
A recent French multicenter retrospective study reported data extracted from the prospectively
collected national databases of ESD cases and the FTRD register, including a total
of 275 patients [19]. The en bloc and R0 rates were significantly higher for ESD on multivariate analysis
after adjustment for lesion size; AEs were also higher in the ESD group. The authors
suggested that ESD should be proposed as the best option for residual colorectal neoplasia
whatever the size and location of the lesion, while considering use of the FTRD for
lesions < 20 mm or when ESD was unavailable. It must though be noted that ESD had
an enormous spread within French endoscopy circles thanks to the uptake of traction
techniques and intensive standardized training, which is currently not similarly widespread
in Italy and the rest of Europe. Indeed, the randomized trial conducted in Italy in
four referral centers over the same time period showed comparable R0 resection rates
for ESD versus EFTR [20].
Some additional insights should be given to the costs of these devices. In Italy,
there is currently no uniformly recognized reimbursement for EFTR procedures and,
in all cases, we are dealing with the high cost of this device. Surely the future
will involve a thorough economic and ecologic evaluation.
EMR also maintains a role in the treatment of recurrent and residual lesions, especially
when combined with low cost ancillary techniques. Tate et al. first proposed a standardized
approach with cold-forceps avulsion and adjuvant snare-tip soft coagulation (CAST)
for nonlifting large laterally spreading colonic lesions [21]
[22], with AEs and recurrences comparable to standard EMR, without the need for additional
expensive devices. More recently, the use of cold EMR snares combined with ablation
using hybrid argon plasma coagulation has been suggested to overcome the intrinsic
limits of submucosal fibrosis in an approach known as the “COld Snare with Ablation”
(COSA) technique [23]
[24].
Interestingly, we showed that the occurrence of AEs, including intraprocedural and
late complications, was quite low despite failures due to device dysfunction, which
is in line with previous publications and demonstrates the safety of the device. The
rate of surgical intervention, either immediately or post-procedurally, is low, which
means that management has predominantly been conservative and performed by the endoscopist.
AEs were mainly grade 1 according to the AGREE classification and no severe or fatal
AEs (grade IV or V) were reported.
Any endoscopic technique has a learning curve: this consideration led us to assess
whether high and low volume centers showed differences in the main outcomes, such
as the failure rate, their ability to adopt an endoscopic salvage technique, and the
complication rate. Although low volume centers showed a homogeneous trend toward higher
dysfunction rates for all three outcomes, there were no significant differences. It
may be argued that the cutoff chosen to define high vs. low volume centers may have
been too low; however, this was in line with data published from the Dutch registry
[17]. Furthermore, the learning curve in EFTR with a dedicated device is quite rapid.
In our experience, according to self-reported training, 7.6 % of participants had
no specific prior training and 35.3 % had no hands-on training in models; we think
this is an important point to emphasize in the context of national scientific societies
that should verify and promote standardized training meetings throughout their national
territory. An annual cutoff of procedures should be established, given that the low
rate of AEs in our study population probably reflects centers with great experience
in other resection methods [25]. Furthermore, performing colorectal EFTR could be the first training step, followed
by upper digestive tract procedures, such as for submucosal gastric lesions or alternatively
for complex duodenal lesions [26]
[27]
[28].
We acknowledge that the 17 centers that participated in our study were extremely heterogeneous
in terms of experience, training, and joining the national register. Additionally,
the sample size may not have been large enough to detect such a difference with a
nominal P value of < 0.05.
Our study has many other limitations. First, it involved retrospective cohort data
collection and not a prospectively collected complete registry, so it was not possible
to exclude some reporting bias. In addition, the sample was limited to cases where
device dysfunction occurred and therefore we could not explore predictive or protective
factors for device dysfunction.
In conclusion, we conducted the first multicenter study showing that unpredictable
technical issues can complicate EFTR procedures and must be considered in all cases,
despite the recognized safety profile [29]. Our proposal for a classification is to invite all endoscopists who perform this
procedure to share a single language and merge data from national registries. In this
way, it will be possible to obtain precise indications and recommendations for this
procedure, limiting its risks and adverse consequences. We reported a failure rate
of 10.3 % among eligible patients, with type I (snare noncutting) being most frequently
observed, which could bring more attention to patient selection. Technical failure
was observed more often in low volume centers, but this may be considered part of
the learning curve. Surgery was needed in < 10 % of patients and no severe AEs or
deaths were reported. Experience in rescue resection techniques and multidisciplinary
management are mandatory in this setting. These factors should be considered for future
guidelines and recommendations on EFTR.
