Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT01023984 |
| Other study ID # |
EAES-2 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
January 2012 |
| Est. completion date |
December 2019 |
Study information
| Verified date |
September 2023 |
| Source |
European Association for Endoscopic Surgery |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Objective: Recent non-randomized studies suggest that extended endoscopic submucosal
dissection (ESD) is equally effective in removing large rectal adenomas as transanal
endoscopic microsurgery (TEM). If equally effective, ESD might be a more cost-effective
approach as this strategy does not require expensive equipment, general anesthesia and
hospital admission. Furthermore, ESD appears to be associated with fewer complications. In a
randomized trial we will compare the cost-effectiveness and cost-utility of TEM and ESD for
the resection of large rectal adenomas.
Study design: 15 centers will participate in this multicenter randomized trial comparing TEM
versus ESD.
Study population: Patients with a large rectal adenoma (≥2cm), located between 2 and 15 cm
from the anal verge. Invasive cancer is excluded by histopathology and endoscopic
ultrasonography. Patients must be in a health condition that permits general anesthesia.
Interventions: Patients will be randomized between
a. TEM: under general anesthesia b. ESD under sedation
1. a TEM tube will be inserted in the rectum. With specialized instruments the adenoma will
be dissected en bloc by a full thickness excision, after which the patient will be
admitted to the hospital.
2. an endoscope will be inserted into the rectum and the submucosa underneath the lesion
will be injected with saline to lift the adenoma. With an endoscopic knife (Insulated
Tip Knife, Olympus or Water Jet, Erbe) the lesion will be resected through the
submucosal plane in an eb-bloc fashion, after which the patient will be observed for at
least 24h in-hospital.
Primary Endpoint: incidence of recurrence at 12 months
Secondary Endpoints:
morbidity, subdivided into major (requiring surgery) and minor (requiring endoscopic or
medical intervention) anorectal function. disease specific and general quality of life;
number of days not spent in hospital from initial treatment until 2 years afterwards; adenoma
Sample size: Assuming a comparable baseline recurrence rate for TEM and ESD of 6% and
considering an upper limit of 10% for ESD to be non-inferior (beta-error 0.2 and one-sided
alpha-error 0.05), 60 patients are needed per group. These numbers provide sufficient power
to reveal relevant differences in expected morbidity and in number of days not spent in
hospital.
Economic evaluation: A cost-effectiveness and cost-utility analysis of ESD against TEM for
large rectal adenomas from a societal perspective with respectively the costs per recurrence
free patient and the cost per quality adjusted life year as primary outcome measures.
Description:
PROBLEM DEFINITION Rectal cancer is a common disease in Western countries, increased with
high age, male sex and obesity (1,2). As for other districts, premalignant intraepithelial
neoplasia inside a rectal adenoma precedes the occurrence of invasive rectal cancer (3,4).
Early endoscopic detection and removal of rectal adenomas prevents the development of rectal
cancer and is therefore the most reliable contributor to the 'cure' of this disease (5,6).
When rectal adenomas become large, however, standard endoscopic therapies like loop
polypectomy or one-step endoscopic resection result inadequate. Therefore, large rectal
adenomas must be removed en-bloc either surgically or by extended endoscopic submucosal
dissection (ESD).
In 1983 a novel surgical approach for the resection of large rectal adenomas has been
introduced in the clinical practice in Germany: Transanal Endoscopic Microsurgery (TEM).(7)
This procedure encompasses general anesthesia and the use of expensive specialized equipment.
On the other hand, it generally allows a full-thickness rectal wall excision. Since its
introduction, many surgical practices have adopted TEM as the new standard therapy for large
rectal adenomas (8). In more recent years advanced endoscopic therapies like extended ESD
have rapidly evolved.(9).
For extended ESD an en-bloc specimen, including mucosa and consistent portion of the
submucosal layer, are resected instead of the full-thickness rectal wall, combining the
advantages of an en-bloc resection with potential benefit of fewer complications.
Supporters of the TEM technique praise the excellent exposure of the rectum and the minimal
invasiveness, as opposed to conventional surgical techniques.(10-12) Besides, recurrence
rates after TEM appear to be lower when compared to conventional surgical transanal
excision.(13) The TEM technique has shown to be highly efficacious in several retrospective
and prospective case series with reported recurrence rates of 0-19% and complication rates of
2-21%.(14-23) On the other hand, extended ESD has gained more and more support in the last
few years, mainly due to good clinical results after ESD of neoplasia in the esophagus and
stomach as reported in Japanese centers (24,25) ESD has also been described for the treatment
of large colorectal adenomas, revealing recurrence rates of 0-9% and complication rates of
only 0-9% (9,27). If adenomas could not be removed completely during one ESD attempt, repeat
ESD for residual disease generally led to an overall success rate of 96-100%. In general, all
recurrences were detected during the first control endoscopy after 3 months; repeat
endoscopic resection of residual disease led to an overall success rate of almost 100%.
Since the efficacy of extended ESD for large rectal adenomas appears to be comparable to TEM,
we decided to design this randomized trial. In fact, until now, TEM and ESD have never been
formally compared, and no such comparative studies have been registered at this moment.
Although selection bias inevitably exists in prospective and retrospective case series, the
results of these studies suggest that both TEM and ESD have comparable recurrence rates. Even
when recurrences occur after TEM or ESD, most of these can successfully be re-treated without
the need for radical surgery. The literature furthermore suggests that ESD is associated with
fewer complications, reduced hospital admission, and no general anesthesia is required for
ESD, all of which are favorable in both patients' and societal perspective. These contrasts
of the two procedures might well lead to differences in costs and quality of life. Therefore,
we designed a multicentre randomized trial to compare TEM and ESD for the resection of large
rectal adenomas.
RELEVANCE Colorectal cancer (CRC) is the second most common cancer in Western countries.
Rectal cancer accounts for approximately 40% of CRC cases. The treatment of rectal cancer
encompasses a multidisciplinary collaboration including gastroenterologists, surgeons,
oncologists, radiotherapists and specialized nurse practitioners. Standard therapy consists
of radical surgery in combination with radiotherapy (and possibly chemotherapy), which have
major morbidity and mortality (28). Therefore, this disease has a major impact on health care
services (29).
Since early detection and removal of rectal adenomas prevents the occurrence of rectal
cancer, CRC screening has been adopted in many western countries (30). When CRC screening was
introduced, this inevitably lead to an increased detection of early rectal neoplasia (31). It
is therefore expected that more rectal adenomas will need endoscopic or surgical treatment in
the forthcoming years. Consequently, the most appropriate therapy concerning efficacy,
safety, quality of life and costs must be selected to deal with the expected increase in
rectal adenomas.
Traditionally, adenomatous colorectal lesions that could not be resected endoscopically were
referred for surgery. Conventional surgical approaches like radical surgery and
trans-sphincteric or trans-sacral operations have nowadays been replaced by TEM, since this
procedure has higher efficacy and lower morbidity. In recent years endoscopic therapies have
further evolved, as a result of which large rectal adenomas more often are treated by
flexible endoscopy. In case series, endoscopic resection of large colorectal adenomas has led
to recurrence rates that were slightly higher than to TEM (18.0% versus 6%), but all
retreated endoscopically, and to complication rates that appeared to be low and equivalent if
not slightly lower (4% versus 8%) (32). Furthermore, ESD can safely be performed under
conscious sedation, and short hospital admission is required as opposed to TEM. The reduced
morbidity, reduced hospital admission and redundancy of anesthesia associated with ESD are
beneficial from both patients' and societal perspective.
OBJECTIVE Hypothesis Transanal endoscopic microsurgery (TEM) and extended endoscopic
submucosal dissection (ESD) are both effective treatments for large rectal adenomas with
comparable recurrence rates. However, ESD does not require general/spinal anesthesia and may
be associated with lower morbidity. Therefore, ESD may improve quality of life and reduce
health care costs.
Objective The main objective of the proposed randomized study is to compare the effectiveness
of TEM and ESD for the removal of large rectal adenomas.
Primary Endpoint: incidence of recurrence at 3 months
Secondary Endpoints:
morbidity, subdivided into major (requiring surgery) and minor (requiring endoscopic or
medical intervention) anorectal function. disease specific and general quality of life;
number of days not spent in hospital from initial treatment until 12 months
STRATEGY Design This will be a multicentre randomized trial comparing TEM and ESD in patients
with large rectal adenomas with respect to cost-effectiveness and safety.
Randomization Patient data are entered into a computerized database and by means of an
unchangeable computer generated number patients will be randomized to undergo TEM or ESD.
Blinding Blinding of patients and physicians during treatment is unfeasible, since the two
treatment strategies are highly different in nature and in associated care.
Study population
Patients are eligible for this trial when they meet the following inclusion criteria:
Diagnosed with a large non-pedunculated rectal adenoma (sessile or flat) with a largest
diameter of ≥2 cm (estimated by an opened resection snare of 20 or 30 mm).
The lower and upper borders of the adenoma are located at ≥2 cm and ≤15 cm from the anal
verge, respectively.
Biopsies of the lesion did not show malignant neoplastic tissue on histopathological
evaluation; only lesions with low or high grade dysplasia are suitable for inclusion.
During flexible video endoscopy there are no signs of endoscopic suspicion for submucosal
invasive cancer (Kudo pit pattern type V; excavated/depressed type morphology; fold
convergence; or large smooth nodule >1 cm in a flat lesion) (33). In case of doubt, patients
will undergo EUS as described at (2).
In case doubt remains after flexible video endoscopy, endoscopic ultrasonography (EUS) of the
rectal adenoma should exclude invasion into the submucosal layer and exclude pathological
lymphadenopathy (lymph nodes >1 cm). When pathological lymph nodes are present, fine needle
aspiration will be performed to exclude lymph node metastasis (N+ disease).
If not performed already, total colonoscopy will be done to detect and remove all synchronous
colonic adenomas or cancers first. Cecal intubation must be confirmed by identification of
the appendiceal orifice and ileocecal valve.
The general health condition of the patient permits general anesthesia (ASA- classification
I-III).
Absence of non-correctable coagulopathy (international normalized ratio >1,5, or platelet
count <90 × 109/l).
Patient age of 18 years or older.
Intervention strategies Transanal endoscopic microsurgery: TEM will be performed as described
by Buess.(7) Under general anesthesia a specialized TEM rectoscope of 12 or 20 cm in length
(Wolf GmbH Knittlingen) or 15 cm in length (Storz GmbH Tuttlingen, Germany) is inserted
within the rectum to assure proper visualization of the lesion. The rectoscope is fixed to
the operating table by a supporting device, providing the opportunity to reposition the
rectoscope during ongoing surgery. The rectal cavity is insufflated with CO2 by a combined
endosurgical unit to achieve constant distension for appropriate visualization of the rectal
adenoma. The combined endosurgical unit further regulates irrigation and suction, thereby
maintaining a constant intra rectal pressure. With the use of a binocular stereoscopic
eyepiece for three-dimensional view (Wolf GmbH only) or a forward oblique telescope (Storz
GmbH) a magnified view is being created for visualization of the lesion. With various HF
monopolar and bipolar instruments, Ultracision harmonic scalpel (Ethicon Endo-Surgery,
Cincinnati, USA), needle diathermy, tissue handling forceps, needle holder, suction probe,
injection needle, clip applicator) the adenoma will be dissected by means of an en-bloc
full-thickness rectal wall excision until the perirectal fat. Postoperatively, patients will
preserve a urinary catheter that will be removed at the first postoperative day. Patients are
admitted to the hospital in accordance with current practice.
After 3 months a control flexible endoscopy will be performed by the surgeon who performed
the TEM procedure. If presumed residual disease is seen, biopsies will be taken to confirm
the presence of neoplasia by histology. Hereafter, the residual adenomatous tissue will be
resected endoscopically by either ESD (if >20 mm) or endoscopic mucosal resection (EMR) (if
<20mm). Any intervention by ESD/EMR at 3 months is part of the TEM treatment strategy.
Endoscopic submucosal dissection: Endoscopic submucosal dissection is performed as described
by Fujiro (9) At the discretion of the endoscopist, conscious sedation is used with 2.5-10 mg
midazolam and/or 25-100 µg of fentanyl. An endoscope is inserted into the rectum and air
insufflation via the endoscope will provide proper distension of the rectum. The submucosa
underneath the lesion will be injected through an endoscopic injection catheter with a
solution of saline 0.9%, 1 ml methylene blue, and 1:10,000 units adrenaline in order to lift
the adenoma (no upper volume limit). The lesion will be marked around with a 5 mm disease
free margin by APC dots. An endoscopic knife (Insulated Tip Knife, Olympus or Water Jet,
Erbe) will be used to resect the lesion through the submucosal plane in an en-bloc fashion.
Visible submucosal vessels will be treated by endoscopic clips or electro-coagulation to
prevent delayed bleeding. Hereafter, the edges of the mucosal defect and potential remnants
within the resection crater will always be treated with APC to increase adenoma clearance. If
bleeding during the procedure precludes >90% clearance of the adenoma, the ESD procedure will
be considered as failure. All patients are admitted to the hospital for at least 24-hours
observation; in accordance with current practice.
After 3 months the treating endoscopist will perform a control endoscopy. If presumed
residual disease is seen, biopsies will be taken to confirm the presence of neoplasia by
histology. Hereafter, the residual adenomatous tissue will be resected endoscopically by
either ESD (if >20 mm) or endoscopic mucosal resection (EMR) (if <20mm). Any intervention by
ESD/EMR at 3 months is part of the TEM treatment strategy.
Intervention failure When for technical reasons ESD procedures turn out not to be performable
after randomization or when ESD fails to remove >90% of the adenoma, the patient will
automatically undergo the TEM treatment strategy.
Histopathological evaluation Resection specimens after TEM and ESD will be stretched and
pinned on a cork plate before immersion into formalin. After standard processing the
resection specimen will be transected each cm for evaluation by a gastrointestinal
pathologist. The lateral and basal resection margins will be evaluated for absence of
neoplasia, when possible.
The risk of lymph node metastases is increased in case of malignant neoplasia extending into
the submucosal layer, poor tumor differentiation, mucinous cancer, vascular invasion and
tumor budding, all of which warrant further radical surgery (34-37). By strict adherence to
the inclusion criteria, the risk of invasive cancer is reduced to 1.6-3% (33,38). In case of
an unexpected invasive cancer despite adherence to the inclusion criteria, the patient will
be excluded after the histopathological evaluation (late exclusion). In case of intramucosal
cancer (i.e. not invading through the muscularis mucosae), both TEM and ESD will be regarded
as sufficient treatment when the lesion is radically removed.
Outcome parameters
Primary outcome measure (for non-inferiority):
Recurrence of neoplasia, defined as the presence of histologically proven neoplastic tissue
in either visible recurrent lesions or in random biopsies, taken at surveillance endoscopies
after the intervention strategy has been completed.
Any remnant adenoma identified and treated by ESD/EMR/APC at 3 months is considered part of
the initial intervention strategy in both arms. Hereafter, patients will undergo surveillance
endoscopies at 6 and 12 months by an independent endoscopist who is blinded for the primary
treatment. During each surveillance endoscopy recurrence will objectively be defined by the
Higaki criteria for recurrence: tumor appearing within a clear resection scar; tumors with
convergent folds; and tumors nearby a clear resection scar (within 5 mm).(39) Targeted
biopsies will be taken for histological confirmation; in case of an apparently healed normal
scar without evidence of recurrence, biopsies will be taken from the basis and 3 from the
edges of the scar to detect occult recurrent neoplasia.
The following standardized discharge criteria will be applied in all participating hospitals:
normal intake of nutrition; normal mobility; absence of fever (<38°C); and stable hemoglobin
level during 1 day (<1 mmol/L) in case of rectal blood loss.
Additional outcome measures:
1. Complications: subdivided into procedural (during treatment) and delayed complications
(after ending the procedure); and further subdivided into major (requiring additional
surgery) and minor (requiring endoscopic or medical intervention) complications.
During admission patients will be monitored for complications. In case of same day
discharge from the hospital patients will be called by telephone 1 day after the
procedure whether adverse events have happened. Two weeks after the intervention, a
research nurse will contact the patient by telephone again and ask for occurred
complications.
2. Generic and disease-specific health related quality of life will be measured at
baseline, 2 weeks, 3 months, 6 months, 1 and year follow-up by the SF-36 and Wexner
score (for incontinence) questionnaires.
3. Measurement of anorectal functional outcome by anal manometry and rectal volumetry
(barostat) before and 3 months after treatment.
4. Costs of TEM and ESD from a societal perspective, based on primary data (see economic
evaluation section).
5. Patient preferences regarding TEM or ESD will be measured at the end of follow-up by a
structured questionnaire to enable a discrete choice experiment addressing the burden of
care, burden of complications, prognostic uncertainties, and recurrence rates of both
treatments.
Sample size calculation Assuming a baseline recurrence rate of 6% for both TEM and ESD
(average recurrence based on a systematic review) and considering an upper limit of 10% for
ESD to be non-inferior, with a β-error of 0.2 and α-error of 0.05, 60 patients are needed per
randomization group.
Since ESD is known to be effective in even more than 2 attempts, an upper limit of 10% seems
reasonable, whereas higher recurrence rates would lead to many additional procedures which
renders this strategy impracticable and probably not cost-effective.
Patient recruitment Consecutive eligible patients will be recruited at the outpatient clinic
in the participating centers by the involved physician (surgeon/gastroenterologist). All
patients fulfilling the above-mentioned criteria will be informed about the study by the
physician. After consent is given, central randomization will take place web-based and
patients will be treated according to the study protocol. Patients unable or refusing to
provide informed consent will be treated according to current clinical guidelines.
Data-analysis Since the main outcome of this study is the neoplasia recurrence rate, i.e.
proportion of patients with recurrent disease, the Chi-square test will be used to compare
the intervention groups (TEM versus ESD). Since the event of recurrence, and not time to
recurrence, is the most important indicator for treatment failure, Kaplan Meier methods will
not be used. The complication and mortality rates will be compared in the same manner. The
number of days not spent in hospital as additional primary outcome measure will be compared
by the Wilcoxon rank sum test.
Differences between the intervention groups in continuous outcome measures (e.g. Wexner
incontinence scale, quality of life questionnaires, and manometry/volumetry) will be tested
by the student's t-test or Wilcoxon rank sum test, where appropriate. All analyses will be
carried out primarily on an intention-to-treat basis.
Time schedule Patients will be recruited for this study from October 2009 until December 2010
in all participating centers. All randomized patients will be followed up for 12 months
(until December 2011). The last 3 months (until March 2012) will be used for statistical
analysis and reporting of data.
