Introduction
Endoscopic full-thickness resection (eFTR) is a recently introduced minimally invasive
endoscopic technique for resecting non-lifting or difficult-to-reach colorectal lesions
in which other advanced techniques, such as endoscopic mucosal resection (EMR) or
endoscopic submucosal dissection (ESD), are unsuccessful [1]
[2]
[3]. eFTR may be an alternative to surgery in selected cases of both benign and malignant
colorectal lesions. It has evolved significantly since its introduction and several
specific techniques coexist [3]. The single-step eFTR device from Ovesco Endoscopy AG (FTRD) uses a modified over-the-scope-clip
(OTSC) which is placed below the lesion prior to removing a circular transmural specimen.
This technique is also referred to as “clip first, cut later” and allows en-bloc resection,
determination of both depth-of-invasion and radicality of resection, while minimizing
the risk of fecal spill [1]
[2]
[3]. The procedure is performed in the endoscopy suite, under procedural sedation, with
a short hospital stay. The available data concerning eFTR suggest a good safety and
efficacy profile [2]
[4]
[5]
[6]. We aim to present our experiences with FTRD and evaluate eFTR indication, efficacy
and safety.
Patients and methods
Study design
Data from all eFTR procedures performed for colorectal lesions in adult patients (≥ 18
years) in our hospital from July 2015 through October 2017 were prospectively collected
using Castor EDC and retrospectively analyzed [7]. Primary outcome parameter was technical success defined as both en-bloc and macroscopically
radical resection of the lesion. Secondary outcome parameters were: R0 rate defined
as free resection margins or no detectable residual lesion in the pathology report,
resection specimen size, transmural resection (muscularis propria fully present, including
serosal layer), margins free of scar tissue (if applicable), length of hospital stay,
adverse events within 30 days as described previously [8] and recurrent lesion and/or clip presence at surveillance endoscopy. Patients were
included according to intention-to-treat principles and the acquired data concerning
patient characteristics, outcomes, and adverse events (AEs) were analyzed accordingly.
The procedure was excluded from the histopathological analysis if no specimen was
obtained.
Case selection
Informed consent was obtained. All patients agreed to undergo eFTR, accepted peri-procedural
risks and allowed coded data to be collected for research purposes. Patients undergoing
eFTR for a suspected T1 colorectal carcinoma (T1 CRC) or resection of scar tissue
from a low-risk T1 CRC were extensively informed about the possibility of existing
and remaining lymph node metastases (± 5 %) and this was balanced against the risk
of undergoing an oncologic resection.
To reach consensus on eFTR indication, all patients with benign or T1 CRC lesions
were discussed within our gastroenterology department or multidisciplinary oncology
meeting respectively. Tumors were classified as T1 according to the TNM-staging system
(tumor invades submucosa, but not muscularis propria). All cases with suspected or
confirmed T1 CRC underwent standard dissemination work-up for colorectal cancer, in
compliance with current national guidelines. In all patients other available endoscopic
resection techniques were deemed insufficient. Cases in which eFTR did not seem feasible
(e. g. because of a large lesion or suspected T-stage > T1) were not included in the
database. T1 CRC was treated with eFTR either because of suspected low-risk T1 based
on endoscopic features as described by Vleugels et al [9] (treatment-naïve) or because of a low-risk T1 based on earlier pathologic findings
after initial polypectomy (no lymphovascular invasion, good/moderate differentiation
grade, invasion restricted to submucosa) in which only the criterion of a > 1 mm tumor-free
resection margin was not met (T1 scar). Depth of submucosal invasion was not evaluated
in most T1 CRC cases and therefore not analyzed. The category of non-lifting adenomas
was subdivided in incomplete resected lesions after use of techniques other than eFTR
(primary non-lifting), treatment-naïve lesions not suitable for techniques other than
eFTR (primary non-lifting) and recurrent lesions identified upon surveillance endoscopy
not suitable for techniques other than eFTR (secondary non-lifting). Small neuroendocrine
tumors were resected by eFTR if low-grade and small in accordance with national guidelines.
Eligibility for eFTR in selected patients was based on direct inspection during previous
endoscopy or after careful examination of third-party endoscopy reports (including
photographs) and discussed by two advanced endoscopists (BS and GH).
eFTR technique and procedure
All procedures were performed by BS and GH, both skilled in EMR/ESD and trained previously
in eFTR on an ex-vivo pig model. In all eFTR procedures the FTR-device from Ovesco
Endoscopy AG, Tübingen, Germany was used. This non-reusable device is mounted onto
the colonoscope and consists of a transparent cap, on which a modified OTSC is preloaded.
Through the endoscope’s working channel a grasping forceps can be inserted. By manually
turning a handwheel (secured to the endoscope’s biopsy valve) the release thread (which
runs through the endoscopes working channel) allows clip deployment. Inside the distal
end of the cap, just beneath the tip, there is a built-in snare, with its sheath running
alongside the scope. The FTR-device is shown in [Fig. 1].
Fig. 1 FTRD (full-thickness resection device) System, Ovesco Endocopy AG. Left: the system
consists of a single use transparent cap (1), a modified over-the-scope clip (2),
polypectomy-snare (3) and a grasping forceps (4) which is advanced through the colonoscopes
working channel. Right: endoscopic view after mounting the FTRD® onto a colonoscope.
The eFTR procedure itself involves several consecutive steps, which are illustrated
in [Fig. 2]. First the lesion is identified and marked properly by applying circumferential
markings using coagulation current with the provided marking probe. Then, after reintroduction
with a mounted device onto the colonoscope, the lesion is grasped and fully brought
into the cap. The modified OTSC is then placed below the lesion, capturing all colonic
wall layers in its grasp. In the final step, which follows only seconds after the
previous, the specimen is snared above the clip, after which it is secured for histopathological
examination. After securing the specimen and dismounting the device, the colonoscope
is reintroduced to inspect the resection site for radicality, full closure of the
defect and possible bleeding. This single-step “clip first, cut later” full-thickness
resection technique prevents extraluminal fluid leakage and the built-in snare avoids
the need to reposition the endoscope before snaring, increasing chances of complete
resection.
Fig. 2 eFTR illustration a Scar tissue was identified, previously marked with ink. b The site was marked with marking probe. c After mounting the cap onto the colonoscope (FTRD System) the lesion was identified
once more. d Tissue is pulled into the cap with a grasping forceps. e The modified over-the-scope clip is released and tissue is snared. Inside the clip
the muscle layer and peri-colic fat are clearly visible. f Preparation of the lesion outside the patient.
A single shot of an intravenous broad-spectrum antibiotic was administered to all
patients. Procedural sedation consisted of either midazolam or propofol in combination
with alfentanil. Planned procedure time in right- and left-sided interventions was
90 and 60 minutes, respectively. Patients with left-sided eFTR were prescribed polyethylene
glycol once daily for 14 days to prevent clip displacement.
Follow-up
All patients were contacted after eFTR to discuss histopathological results and to
inquire about any complications. Endoscopic surveillance was planned 3 months after
eFTR to detect recurrence and evaluate clip presence. For further follow-up national
guidelines for polyp surveillance were followed, including endoscopic surveillance
after 9 months for T1 CRC. Patients referred for additional surgery (step-up approach)
were excluded from regular surveillance endoscopy and were treated according to national
guidelines concerning follow-up.
Data analysis
Data were analyzed using SPSS (IBM Corp. Released 2012. IBM SPSS Statistics for Windows,
Version 21.0. Armonk, NY: IBM Corp.). Baseline characteristics are displayed descriptively.
Categorical variables are displayed both as absolute and relative frequencies (in
percentages). For differences in mean specimen size between two groups we used an
independent samples t-test. P values < 0.05 were considered significant.
Results
From July 2015 through October 2017, a total of 51 eFTR procedures were performed
in 48 patients (63 % men, median age 69). Three patients underwent two separate eFTR
procedures for different lesions/locations: two patients with unclear margins of T1
CRC after polypectomy had two scars in close proximity, warranting eFTR of both scars.
In a third patient, eFTR was performed on both a non-lifting adenoma and a scar from
T1 CRC in one session. eFTR was performed for various indications as described in
the Methods section and shown in [Table 1]. [Table 2] shows the technical success and R0-resection rates. Five resections were macroscopically
incomplete and in one case no specimen could be obtained due to inability to mobilize
the lesion into the cap. Mean estimated lesion size was 12.2 mm (range 2 – 30). Mean
maximum resection specimen diameter was 23 mm (range 11 – 45). No significant difference
was found in mean specimen diameter in the rectum vs. proximal colon and sigmoid (21.0
vs 24.0 mm P = 0.147) or between scar lesions of T1 CRC vs. other indications (23.1 vs 22.8 mm,
P = 0.889).
Table 1
Patient characteristics.
|
Patients, total (%)
|
48
|
(100)
|
|
Mean patient age, years (range)
|
67
|
(49 – 76)
|
|
Male sex, number (% of total)
|
30
|
(63)
|
|
Procedures, total (%)
|
51
|
(100)
|
|
Indication for eFTR, number (% of total)
|
|
|
|
|
19
|
(37)
|
|
|
12
|
(24)
|
|
|
4
|
(8)
|
|
|
3
|
(6)
|
|
|
28
|
(55)
|
|
|
26
|
(51)
|
|
|
2
|
(4)
|
|
|
2
|
(4)
|
|
|
2
|
(4)
|
|
Location of lesion, number (% of total)
|
51
|
(100)
|
|
|
1
|
(2)
|
|
|
8
|
(16)
|
|
|
2
|
(4)
|
|
|
6
|
(12)
|
|
|
16
|
(31)
|
|
|
18
|
(35)
|
|
Estimated lesion size, mean in millimeters (range)
|
12.2
|
(2 – 30)
|
A total of 51 eFTR procedures were performed in 48 patients.
eFTR; endoscopic full-thickness resection; T1, primary tumor site with deepest invasion
into the submucosa according to the international TNM classification; CRC, colorectal
cancer
Table 2
Procedure and specimen characteristics.
|
Technical success (macroscopically complete & en-bloc), number (% of total)
|
45
|
(88)
|
|
|
5
|
(10)
|
|
|
1
|
(2)
|
|
Histology, number (% of total)
|
50
|
(100)
|
|
|
43
|
(86)
|
|
|
40
|
(80)
|
|
Histology of T1-CRC after incomplete resection, number (% of total)
|
26
|
(100)
|
|
|
25
|
(96)
|
|
|
7
|
(27)
|
|
Specimen diameter, mean in millimeters (range)
|
|
|
|
|
21
|
(11 – 45)
|
|
|
23
|
(11 – 9)[2]
|
|
|
23
|
(13 – 42)[3]
|
CRC, colorectal cancer; OTSC, over-the-scope clip
1 Case 1: diminutive residual lesion visible within OTSC, no residual lesion at follow-up
endoscopy; case 2: marking visible outside OTSC after resection, without visible residual
lesion, no residual lesion at follow-up endoscopy; case 3: residual lesion after incomplete
eFTR, referral for surgery; case 4: residual lesion after incomplete eFTR, referral
for surgery; case 5: diminutive residual lesion visible within OTSC, no residual lesion
at follow-up endoscopy
2 Rectum vs. colon P = 0.147
3 T1 CRC scar vs other indications P = 0.889
Histopathology confirmed full-thickness resection in 43 of 50 specimens (86 %) and
radical resection (R0) in 40 procedures (80 %). Two large lesions (30 mm) were treated
by combining EMR and eFTR in a single session, in both cases radicality could not
be confirmed due to the piecemeal resection technique. eFTR specimens obtained from
scars of previous indeterminate T1 CRC resection were free of residual carcinoma in
25 of 26 cases (96 %). In one case eFTR of macroscopic unsuspicious scar tissue showed
residual adenocarcinoma, with invasion of the muscularis propria (T2). This patient
was referred for additional oncologic surgery. Radicality of scar tissue, defined
as no fibrous tissue in the lateral and basal resection margins, was confirmed only
in 7 of 26 cases (27 %).
In six patients a total of eight AEs occurred ([Table 3]). Four of these patients had minor bleeding not necessitating blood transfusion.
No emergency surgery was necessary. Six patients needed additional surgery because
of either high risk for lymph node metastases (n = 4; three patients with T2-T3 CRC
and one patient with lymphatic invasion in T1 CRC), technical failure of eFTR (n = 1)
or endoscopically untreatable adenoma recurrence at surveillance (n = 1). None of
the oncologic surgical resections showed residual tumor or lymph node metastases,
nor did the surgeon report technical difficulties related to OTSC presence.
Forty-two of 48 patients underwent surveillance endoscopy after a mean period of 130
days (± 11.9). In five patients no inspection of eFTR-scar was performed because of
surgical resection and one patient wanted no surveillance ([Table 3]). Five patients had a residual/recurrent lesion, either treated conservatively (n = 2),
with additional EMR (n = 2) or surgery (n = 1).
Table 3
Adverse events, outcome and surveillance endoscopy.
|
Adverse events within 30 days, number of patients (% of total n = 48)[1]
|
6
|
(13)
|
|
|
4
|
(8)
|
|
|
1
|
(2)
|
|
|
1
|
(2)
|
|
|
1
|
(2)
|
|
|
1
|
(2)
|
|
Need for surgery, number of patients (% of total n = 48)
|
6
|
(13)
|
|
|
4
|
(8)
|
|
|
1
|
(2)
|
|
|
1
|
(2)
|
|
|
0
|
(0)
|
|
Mean duration of hospital stay, nights (range)
|
1.3
|
(0 – 8)
|
|
Surveillance endoscopy, number of patients (% of total n = 42)[2]
|
42
|
(100)
|
|
|
6
|
(14)
|
|
|
5
|
(12)
|
|
|
130
|
(± 11.9)
|
|
2nd surveillance for T1-CRC, number of patients (% of total n = 26)[3]
|
17
|
(65)
|
|
|
17
|
(100)
|
|
|
317
|
(± 24.5)
|
CRC, colorectal cancer; eFTR, endoscopic full-thickness resection; OSTC, over-the-scope
clip
1 Eight complications occurred in 6 patients. In one patient a per-procedural perforation
due to inadequate clip release was closed immediately by OTSC placement with good
clinical recovery. On Day 4 an acute coronary artery syndrome was treated with platelet
inhibitors, followed by a colonic bleed requiring transfusion.
2 Lost: after surgical resection n = 5, patient wish n = 1.
3 Lost: after surgical resection n = 4, comorbidity n = 1, high-grade dysplasia n = 1,
planned n = 3.
Second surveillance is available in 17 of 26 patients following eFTR for T1 CRC after
a mean period of 317 (± 24.5) days. No local recurrence was detected.
Discussion
Results from this retrospective case-series describing 51 procedures suggest that
eFTR is a feasible and safe option for resecting colorectal lesions, where other advanced
endoscopic techniques do not suffice. Technical success (88 %) and R0-resection (80 %)
were reasonable and comparable with eFTR-data reported elsewhere [2]
[4]
[5]
[6].
Minor AEs occurred in five patients (10 %) and major AEs in one patient (2 %). We
experienced one immediate perforation, caused by a non-releasing OTSC, with the clip-releasing
system obscured from view by the lesion itself, illustrating the importance of a clear
view on OTSC deployment at all times during the procedure. Fortunately, in this case,
the perforation could be corrected endoscopically by OTSC. However, following eFTR,
this patient developed acute coronary artery syndrome and subsequently a colonic bleed
after introduction of platelet inhibitors. Endoscopic inspection showed no bleeding
site and adequate closure of the perforation. Schmidt et al published five cases of
immediate and one case of late perforation (3.3 %) confirming the relevance of this
complication in eFTR [2]. Complications reported elsewhere, including entrapment of extracolonic organs within
the OTSC, such as the small bowel, and acute appendicitis after eFTR of the appendix
base did not occur in our series. It is important to state that, although reported
in 34 cases by Schmidt and colleagues, in our series no eFTR of lesions at the appendix
base was performed [2]. Overall, most complications concerned patient who reported minor bleeding (8 %)
that did not necessitate blood transfusion. This is comparable to wide-field EMR and
seems acceptable, especially when compared to mortality and morbidity numbers in colorectal
surgery, which is considered the alternative procedure in these cases.
Although colonic lumen diameter may appear to be diminished directly after eFTR, no
clinically relevant stenosis occurred, nor has this been described elsewhere. The
OTSC tended to spontaneously dislocate unnoticed (OTSC in situ in only 14 % after
a mean follow-up of 130 days). Although rarely indicated, a clip cutter device exists
allowing endoscopic clip removal [10].
We performed additional eFTR of scar tissue after endoscopic resection of low-risk
T1 CRC in cases in which radical resection could not be confirmed microscopically
(i. e. after piecemeal resection or ≤ 1 mm tumor-free resection margin). In 25 of
26 cases, local radical resection was plausible after eFTR (lateral and basal margins
free of carcinoma) and surgery could be avoided. In T1 CRC, several histologic features
are associated with either low or high risk for lymph node metastases and local recurrence
is rare after R0-endoscopic resection [11]. In the Dutch guideline, radical resection, good/moderate differentiation and absence
of lymphovascular invasion classify T1 CRC as low-risk. Endoscopic R0-resection is
regarded as an adequate treatment strategy for low-risk T1 CRC as oncologic surgical
resection has a high number-needed-to-treat and significant morbidity/mortality [12]
[13].
Overall 30-day mortality and postoperative complicated course rates for oncologic
surgery in the Netherlands in 2015 were 2.3 %/15 % (colon) and 1.2 %/20 % (rectum)
respectively [14]. After endoscopic R0-resection of low-risk T1-CRC by conventional polypectomy the
patient and his or her consulting physician have to decide upon the need for additional
oncologic surgery. This implies weighing the risk of residual lymph node metastases
against morbidity and mortality of colorectal surgery. However, R1 resection after
EMR/ESD/polypectomy for otherwise low-risk T1 CRC occurs frequently, warranting additional
treatment, often resulting in oncologic surgery. Therefore, safe and reliable minimally
invasive endoscopic treatment approaches are needed to lower the burden of treatment
for T1 CRC. This is of increasing importance as colorectal cancer screening programs
cause a shift towards earlier tumor stages at diagnosis [15]
[16]. eFTR has been reported by others as an option for confirming radical local excision
in T1 CRC [2]
[4]
[5]
[6]
[17]. In our center, colorectal surgery is performed only for low-risk T1 CRC when eFTR
fails to achieve radical local excision. We refer to this two-stage strategy as the
“eFTR step-up approach.” Although most guidelines require a resection margin > 1 mm
to confirm radicality of resection and to allow endoscopic surveillance for low-risk
T1 CRC, no residual tumor was found in 25 /26 cases (96 %) with inconclusive radicality
in our series. This casts doubts on the relevance of the > 1 mm margin requirement
and the necessity for eFTR, introducing additional complication risks, in all of these
cases. Furthermore, histopathological confirmation of complete scar tissue resection
was confirmed in only 27 %, raising questions about the ability of eFTR to completely
resect scar tissue and truly confirm radicality of resection. Therefore, scar size
as estimated by the endoscopist, being no smaller than the initial lesion’s base diameter,
may limit FTRD use in these cases. Nevertheless, we found no recurrence of CRC so
far in these patients during follow-up endoscopies.
Adequate case selection is challenging and requires experience and careful pre-procedural
evaluation. Mean specimen diameter (23 mm) limits FTRD use to relatively small lesions.
Therefore, we propose a clinical algorithm for eFTR case selection ([Fig. 3]).
Fig. 3 Proposed clinical algorithm for eFTR in malignant (left) and benign (right) colorectal
lesions. It incorporates lesion size, morphology and location. It involves a stepwise
approach and may assist the clinician in decision-making on eFTR indication and applicability.
In T1 CRC a multidisciplinary consideration, weighing the risk of residual lymph node
metastases after eFTR against morbidity and mortality of colorectal surgery, and the
informed consent of the patient are mandatory.
Left frame: (suspected) T1-colorectal carcinoma = suspected low-risk T1 CRC based
on endoscopic features as described by Vleugels et al [9] or confirmed (low-risk) T1 CRC based on histopathologic findings after initial polypectomy
or biopsy; histologically favorable factors = no lymphovascular invasion, good/moderate
differentiation grade and invasion restricted to submucosa; irradical resection = the
criterium of > 1 mm tumor-free resection margin was not met; scar size = scar size
as estimated by the endoscopist, being no smaller than the initial lesion’s base diameter;
flat, sessile lesion = lesion morphology according to the Paris endoscopic classification
of superficial neoplastic lesions, types 0-IIa, 0-IIb, 0-IIc (flat) and 0-Is (sessile)
respectively.
Right frame: (suspected) benign lesion = suspected benign colorectal lesion based
on endoscopic features as described by Vleugels et al [9] or confirmed benign lesion based on histopathologic findings after initial incomplete
polypectomy or biopsy;
The eFTR learning curve is unknown. We have experienced that mastering the eFTR-technique
has a significantly shorter learning curve than EMR or ESD, but requires proper training,
for example on an ex vivo pig model.
This study is limited by its retrospective, single-center nature, introducing possible
selection bias and questioning reproducibility of the results. Prospective studies
need to clarify the role of eFTR in the treatment of low-risk T1 colorectal cancer,
the necessity of antibiotic prophylaxis, the need for post-eFTR hospitalization and
need to produce universally accepted treatment algorithms.
Conclusion
Based on these data, eFTR using this single-step FTR-device seems successful and safe
in the colon and rectum. Technical success, R0-resection and major AEs rate were reasonable
and comparable with eFTR data reported elsewhere. Mean specimen diameter (23 mm) limits
its use to relatively small lesions. With eFTR gastroenterologists may avoid the need
for surgery in selected cases of low-risk T1 colorectal carcinoma, non-lifting adenoma,
submucosal tumors and lesions in difficult-to-reach locations. Prospective studies
are necessary to clarify the role of eFTR in the treatment of low-risk T1 colorectal
carcinoma, comparing oncological outcome, weighing risk of residual lymph node metastases
after eFTR against morbidity and mortality of colorectal surgery. Furthermore, the
necessity for antibiotic prophylaxis in a procedure without fecal spill and the need
for post-eFTR hospitalization have yet to be determined.
van der Spek B, Haasnoot K, Meischl, C et al. Endoscopic full-thickness resection
in the colorectum: a single-center case series evaluating indication, efficacy and
safety Endoscopy International Open 2018; 06: E1227-E1234. DOI: 10.1055/a-0672-1138
In the above mentioned article an author name was corrected. Correct is: Dimitri Heine.
