Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04606992 |
| Other study ID # |
REG-006-2020 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 10, 2020 |
| Est. completion date |
August 8, 2022 |
Study information
| Verified date |
February 2022 |
| Source |
Zealand University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is a pilot feasibility study on high risk patients due to frailty and comorbidity who
have early stage colon cancer (UICC 1). We will use a novel resection technique with expected
less risk of complications called the Combined Endoscopic and Laparoscopic Surgery (CELS).
After the histopathologic evaluation. Patients will be placed in either low risk or high risk
group. Depending on this, they will be followed for 3 years or referred to standard resection
Description:
Combined Endoscopic and Laparoscopic Surgery (CELS) for early colon cancer in high risk
patients
Investigator Morten Frederik Schlaikjær Hartwig
Local research group Ismael Gögenur Lasse Bremholm Hansen Mustafa Bulut Rasmus Dahlin Bojesen
Jens Ravn Eriksen Susanne Eiholm Mads Klein Morten Rasmussen Bo Rud
International research group Phil Quirke Scarlet Brockmoeller
Background Colorectal cancer is the second most common cancer in Europe and the third most
common cancer worldwide. The introduction of screening programs for colorectal cancer has
resulted in an increased detection and incidence of early cancers (T1-T2). Early cancers are
seen in 54% of the patients in the screening programs compared with 25 % of symptomatic
patients.
Mortality rates following elective colorectal surgery range between 2.5-6% and increase for
the elderly and frail patient regardless of T-stage. Nationwide morbidity rates are 16%, with
approximately half of these patients requiring re-operation. The elderly patients have
decreased 1-year survival leading to decreased cancer specific survival. Postoperative
morbidity leads to decreased 3 year disease free survival and overall 5-year survival
regardless of recurrence. Further, postoperative altered bowel function, chronic pain, and
reduced quality of life affect many patients.
Numerous different scoring systems exist to assess patient frailty. Studies have shown that
regardless which definition of frailty is used, the patients have a higher risk of developing
adverse outcomes. Performance Status (PS) is a simple and easy to use scoring system to
assess frailty. Data from DCCG has shown that performance status is independently associated
with postoperative complications and death following surgery for colorectal cancer and that
there is a "dose-response" relationship with increased performance score leading to higher
1-year mortality.
The risk for lymph node metastases is 8.6 % and 22 % for T1 and T2 colon cancer respectively
and is dependent on several histopathological characteristics of the tumor. These
histopathologic high-risk features include low tumor differentiation, lymphovascular invasion
and high grade tumor budding. The presence of these features is independently related to
increased risk of lymph node metastasis. If a T1 or T2 tumor has no high risk features, the
risk of lymph node metastasis has been reported to be 1,2% and 3,8%respectively.
According to the Danish Colorectal Cancer Group (DCCG) annual report in 2017, there was 253
T1 and 325 T2 colon cancers. Out of these there were 84,3% and 82,9% N0 respectively. This
indicates that the majority of patients with early colon cancer (ie. T1 and T2) have no
benefit of additional oncological resection besides tumor excision.
Due to the low risk of lymph node metastases in early colon cancer, and the substantial risk
of morbidity and mortality, local excision of the tumor could be an option in selected high
risk patients (with subsequent bowel resection if final pathological evaluation shows
presence of high-risk histopathological characteristics).
The Combined Endoscopic and Laparoscopic Surgery (CELS) is a novel hybrid procedure that
enables large local excisions of the colon without segmental resection. It is used in some
centers for local resections of large benign polyps not resectable by advanced endoscopic
techniques alone such as Endoscopic Mucosal Resection (EMR).
CELS procedure Combined Endoscopic and Laparoscopic Surgery covers a variety of endoscopic
procedures with simultaneous laparoscopic view and laparoscopic procedures with simultaneous
endoscopic view. In our study we focus exclusively on laparoscopic resection guided by
endoscopic view - an excision biopsy.
The main surgical advantage in this procedure is the ability to view the colon intra- and
extraluminally simultaneously. The laparoscopic approach enables manipulation and
mobilization of the colon, while the endoscopic view secures that the resection is complete
and not overlapping the ileac valve or creating stenosis.
Compared to the traditional segmental oncological colon resection, the CELS resection is a
minimally invasive procedure and assumed leading to a reduced surgical stress response. A RCT
has compared CELS with right sided hemicolectomy and shown, shorter operating time, less
intravenous fluid treatment, faster time to pass stool and shorter length of stay.
The CELS procedure has been evaluated both in retrospective and prospective randomized trials
in patients with benign lesions not suitable for endoscopic resection, and is shown to be a
safe procedure with comparable complication rates, but shorter convalescence and lower cost.
The question is if the CELS procedure is a safe resection in the malignant tumor, as in the
benign tumor.
The present study is designed to show if the CELS can be used for patients diagnosed with an
early colon cancer and in high risk of operative morbidity and mortality after conventional
resection due to comorbidity and frailty.
Aim The primary aim of this study is to assess feasibility and safety in high risk patients
treated with CELS resection with early colon cancer.
Methods This is a non-randomized prospective feasibility study conducted at the Department of
Surgery, Zealand University Hospital, Herlev University Hospital, Hvidovre University
Hospital and Bispebjerg University Hospital.
The data will be collected and stored online at easytrial.net and physically at the
Department of Surgery, Zealand University Hospital.
Statistical power analysis We plan to include 25 high risk patients with early colon cancer
in the study. Based on data from DCCG concerning clinical tumor stage and comorbidity
assessments, we expect 150 eligible patients a year in the described region of Denmark. The
feasibility in the study requires that we include patients with different tumor locations
throughout the colon. We believe that this will be obtained with 25 patients.
The study has started 1/3 2020 and is expected to end on the 28/2 2022.
Patient selection
Setting:
The patient has been referred to the surgical department after a colonoscopy has revealed a
lesion in the colon not suitable for local endoscopic treatment and is either with endoscopic
suspicion of being a cancer or there is a histological diagnosis. Usual staging will be
performed with contrast enhanced CT scan of the thorax and abdomen. The patient will
discussed at a MDT (Multidisciplinary Team) conference, prior to the first outpatient visit.
The MDT will finally decide if the patient is a candidate for CELS resection. The patients
that are included at Herlev, Hvidovre and Bispebjerg University Hospitals are reassessed at
the MDT conference at Køge. Here it will finally be decided if the patient is suited for CELS
resection.
If the patient meets the inclusion criteria, the patient is informed of the clinical trial
orally and with written information by a medical assistant or consultant. The patient is
booked and prepared for the procedure decided at the ambulatory visit.
The patient will afterwards be contacted by one of the principal investigators and given more
detailed information. The informed consent is signed by the patient as described under
"guidelines for obtaining well informed consent".
If the patient does not wish to participate, the patient is booked for the standard procedure
at the regional hospital.
CELS procedure After introduction of general anesthesia, an orogastric tube and a foley
catheter is placed. After introduction of the colonic endoscope, the abdomen is draped in
sterile fashion. Then an umbilical camera port is inserted and additional ports are placed
according to the location of the tumor. Standard antibiotic prophylaxis is administered
intravenously.
The tumor is identified by the endoscopist. A 60mm. endo-GIA is inserted and the tumor is
resected and placed in a bag intraabdominally and removed trough the umbilical port. The
resection is evaluated intra- and extraluminally to ensure sufficiency and hemostasis.
The colonoscope is retracted with simultaneous desufflation. The additional laparoscopic
ports are removed and the incisions closed while hemostasis is observed.
After the operation, the patient is referred to the surgical ward in an enhanced recovery
setting. The patient is discharged following assessment by colorectal surgeon typically the
same or next day.
The patient is referred to the surgical outpatient unit to receive the pathological
assessment of the tumor and to inform of and schedule the further treatment or follow up.
After 30 and 90 days, the patient will be contacted by telephone by the principal
investigator for a follow up interview.
Pathological assessment After the CELS resection, the tumor is sent as a malignant tumor
specimen without conservation and as a whole resection to the Department of Pathology,
Zealand University Hospital Roskilde. Here it is cast as a whole specimen and cut into
relevant slides and these are evaluated. The procedure for the pathological preparation and
assessment is already implemented in the clinics standard operating procedure. After the
assessment of the tumor, the tumor is defined as "high-risk" or "low risk". This defines the
further follow up and treatment of the patient. (For details see "Patient flow chart").
When we have included all 25 patients, the slides of the tumors are scanned and sent as
pseudo-anonymized photos to the Department of Pathology, Leeds University for reassessment by
Professor Philip Quirke and Dr. Scarlet Brockmoeller.
The pathological assessment is hereby evaluated as "consensus". The department of Pathology,
Zealand University Hospital Roskilde will have the final decision in case there is not
consensus.
The CELS patients with low risk histopathology will follow a watchful waiting (WW) program
consisting of colonoscopy after 3 and 12 months, CT scans at 6, 12 and 36 months and blood
sampling for circulating tumor cell DNA (CT-DNA) after 3, 6, 12 and 36 months. This is more
intense than the follow up program for locally resected malignant polyps. After 1 year, the
colonoscopy will be after every 5 years until the patient reaches 75 years.
The CELS patients with high risk histopathology will be referred to standard resection and
subsequently placed in the regular control group for colonic cancer defined by DCCG.
Technical and practical experiences The surgical department at Zealand University Hospital
Køge, performs CELS procedures on a regularly monthly basis on benign lesions. At the moment
more than 70 CELS procedures have been performed at the department.
The department has over 2 years of experience with assessment of CELS operability in
multidisciplinary team conferences.
Risks and side effects The literature concerning CELS for benign lesions show a general
complications risk of approximately 5%. This covers both medical and surgical complications.
The most frequent complication is pneumonia and urinary tract infections. Of the surgical
complications, wound/port site infection is the most frequent. Bleeding from intestinal
resection or skin incisions and stapling insufficiency leading to intraabdominal abscess
formation has been reported.
The CELS procedure is regarded as a safe and low risk procedure.
Safety issues With regard to the benign lesions, the literature has reported 0-13% risk of
local recurrence. No study has reported the recurrence for malignant resection with CELS
technique. The safety of the oncological resection is of great importance in this study.
Prior to the study an independent safety committee is formed by 2 external surgeons and 1
external pathologist. Every patient with a R1/R2 section or a severe complication
(Clavian-Dindo≥3b) is evaluated in the committee with regard to discussion of terminating the
study. The pathologist will review the specimen as a second opinion. The surgeons will
evaluate the basis for decision of CELS resection, surgical procedure and postoperative
treatment to ensure proper treatment. The evaluations are coordinated by the primary
investigator.
If more than 4 patients have a R1/R2 resection, the study will automatically be terminated or
if we experience more than 3 local recurrences with adenocarcinoma the study will be
terminated.
Perspectives If this study proves that CELS is a safe and feasible treatment, the next study
will be a randomized controlled trial to prove its efficacy in high risk patients. It could
be the future treatment of patients with high risk morbidity and early colon cancer following
the principles of personalized surgery.
Dissemination of the results Results will be presented at major endoscopy and surgery
meetings and at national and international relevant congresses. The study results will be
submitted for publication in international peer reviewed scientific journals with Morten
Hartwig as the first author. All co-authors will adhere to the Vancouver rules.
Ethical aspects The study is approved by the National Committee on Health Research Ethics
(Den Nationale Videnskabsetiske Komité) (SJ-795) and reported to the Data Protection Agency
(Datatilsynet). The study is registered at www.clinicaltrials.gov. Research subjects will
have to give informed consent, based on written and oral information before inclusion in the
study. Participants will be informed about any side-effects, risks or unplanned events that
might occur during the implementation of the study. The minimal risks will be outweighed by
the potential implications for future patient care. The study will be carried out with
respect to the mental and physical integrity of the participants.
Guidelines in obtaining informed consent from participants Well informed signed consent from
the research subjects is an essential criterion for inclusion in the trial. Both written and
oral information will be provided to each candidate to the study by either the chief
investigator or other health care persons that are qualified in explaining the project in
detail. The patient will be made aware of the possibility of a second person (e.g. caregiver,
relative) to be present at the interview. The interview will take place in a private room in
order to provide an uninterrupted communication. The detailed information on the project will
be covered, in oral and written form, at the interview, including an easy-to-read
presentation of the project with its predictable risks and side-effects, expected outcomes
and benefits for the research.
The subjects will be entitled to some reflection time before giving consent (24-48 hours),
taking care that the time limit stipulated will not interfere with the routine clinical
investigations and treatments of the patient.
Sponsors The research project is initiated by, Ismail Gögenur, MD, DMSc. The study will be
funded through local and national funds.
