Trial Information

The 'SILVERMAN1' Trial Single Incision Laparoscopic Versus Existing Resection (Minimal Access) for Neoplasia

The 'SILVERMAN' 1 Trial Single Incision Laparoscopic Versus Existing Resection (Minimal
Access) for Neoplasia- A Multi-institutional Randomised Controlled Trial

Applicant:

Professor Desmond C Winter, Institute for Clinical Outcomes Research and Education (iCORE),
St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.

winterd@indigo.ie

Background Colonic cancer is the third commonest cause of cancer mortality in women and men
in the developed world[1]. Old age, adenomatous colorectal polyps, inflammatory bowel
disease, low intake of dietary fibre and family history of colorectal cancer all predispose
to the development of colonic cancer[2-4]. Certain genetic syndromes such as Hereditary
Non-Polyposis Colon Cancer (HNPCC), Familial Adenomatous Polyposis (FAP), Peutz-Jeghers
Syndrome (PJS) and Juvenile Polyposis have a significant lifetime risk of developing colonic
cancer[5-8]. Historically, open surgery has been the mainstay of treatment for localised,
potentially curable colonic cancer. Laterally, minimally invasive or laparoscopic surgery
has largely supplanted open surgery in the management of colonic cancer[9,10,11]. Published
data have shown that laparoscopic assisted resection has equivalent oncological outcomes in
terms of long term survival when compared to conventional open surgery. Similarly, Level 1
evidence from the major randomised controlled trials in this field suggests that
laparoscopic colonic resection confers advantages over the open approach during the
perioperative period in terms of reduced requirement for parenteral narcotics and oral
analgesics, earlier restoration of intestinal function, earlier ambulation, and shorter
hospital stay. To date there remains no consensus or accepted guidelines on the surgical
management of potentially curable right colonic cancer. The NHS published guidelines on
management of colorectal cancer simply state that surgeons offering their patients
potentially curative laparoscopic resections should be appropriately trained in such
specialist techniques12. Currently, surgeons competent in minimal access surgery favour
laparoscopic right hemicolectomy as the technique of choice for right colonic resection.
Intestinal continuity can be restored intracorporeally, or extracorporeally by exteriorising
the mobilised segment of ileum/right and transverse colon.

The advent of "single incision laparoscopic surgery" (SILS) has further advanced the
minimally invasive approach to the management of complex surgical diseases. SILS, currently
in the embryonic stages of development, utilises a single incision to insert a single access
device into the abdominal cavity under direct vision. Typically, the device is inserted in
the midline and utilises a 2-3cm incision around the umbilicus, itself an embryonic natural
orifice.

The optical and operating trocars are inserted through the access device and the procedure
is carried out as a conventional laparoscopic procedure. Many short case series and reports
have been published describing the feasibility of SILS in performing complex surgical
procedures for both benign and malignant disease[13,14,15]. Specialised, complex colorectal
procedures such as proctocolectomy with ileal pouch-anal anastomosis (IPAA), ileocolic
resection for terminal ileal Crohn's mass and colonic resection for cancer have been
successfully performed using single incision laparoscopic surgery[16,17,18,19]. To date,
several short series of SILS right hemicolectomy have been published in the
literature[20,21].Thus, rather than a new or novel technique, SILS is a derivation of
laparoscopic surgery, performed through a single incision. There is no evidence in the
literature that SILS colectomy confers any disadvantages over conventional laparoscopic
surgery and to dtae, there are no reports of SILS putting patients at increased risk of
complication. Postulated benefits of SILS colectomy over conventional laparoscopic colectomy
include reduced number of incisions, improved cosmesis, less pain, faster return to normal
activities/work and shorter hospital stay. Heretofore, there has been no randomised
controlled clinical trial comparing SILS and standard laparoscopic right hemicolectomy for
cancer. Having previously demonstrated the benefits of laparoscopic resection over open
resection in the treatment of colon cancer we feel the time is ripe to further extrapolate
these data by comparing laparoscopic right hemicolectomy with a proposed new treatment
modality, single incision laparoscopic right hemicolectomy, in the format of a multicentre,
international randomised controlled clinical trial.

Knowledge transfer/implementation Current evidence regarding the optimal surgical approach
to potentially curable right colonic cancer is based on numerous, well designed randomised
controlled clinical trials. Currently, eminence based opinion suggests that an alternative
surgical technique, SILS, may improve short and long term outcomes after minimally invasive
right colonic resection. A true, prospective analysis comparing standard of care
(laparoscopic right hemicolectomy) and this "new" therapy(SILS) has yet to be published.
Having established the optimum treatment modality the minimally invasive approach to right
colonic tumors the results will be communicated at national and international meetings.
Findings will be submitted to an international surgical journal to ensure maximal
communication of results and will be made available to national and international academic
societies to enable the establishment of guidelines of best practice for surgical management
of right colonic cancer.

Objective

To compare patient outcome following standard of care (laparoscopic right hemicolectomy) and
an alternative, established, recognized therapy (SILS right hemicolectomy) for the treatment
of right colonic tumors. Specific research questions include:

1. Which treatment modality confers least perioperative morbidity and mortality in the
surgical management of right colonic tumors?

2. Does treatment influence length of time to discharge home and return to activities of
daily living?

3. Are treatment modalities equivalent in terms of extent of resection (lymph node yield,
resection margins etc)?

Strategy An Irish based, multi-centre, international trial will be performed with the aim of
comparing two treatment modalities for patients presenting with right colonic cancer.
Pre-operative details, intraoperative findings and post-operative course will be
prospectively accrued by the operating surgeon. Each surgeon has previous experience in
performing this procedure and currently offer SILS colectomy to their patients outside of a
clinical trial setting. All patients will be followed up and primary and secondary
end-points will be recorded.

Primary End-points

1. Qualitative - Lymph node yield

- Histopathological grade of specimen

- Conversion rate

- 30 day mortality

- Cancer free survival

Secondary Endpoints

2. Quantitative- operative time

- pain scores (visual analog scale)

- cosmesis satisfaction

- earlymorbiditywound/respiratory /urosepsis, thromboembolic,cardiorespiratory,
anastomotic leak, intra- abdominal abscess and reoperation

- Intravenous narcotic/ oral analgesic requirements

- Resumption of intestinal function/ diet

- Duration to discharge home

- Return to normal activity

Study Design The study will be an international multi-centred ,randomized controlled trial.
Ethical approval will be sought prior to study implementation.

Inclusion criteria

1. Age 18-85 years

2. Histologic confirmation of right colonic cancer

3. Informed consent

Exclusion criteria

1. Inability to give informed consent (e.g. dementia)

2. Previous midline laparotomy incision

3. T4 tumour diagnosed on pre-operative imaging or intra-operatively

4. Previous pelvic irradiation

5. FAP/ HNPCC

6. Colonic carcinoma against a background of ulcerative colitis.

7. Emergent surgery for perforated/obstructing right colonic cancer

Study outline All patients with histologically confirmed right colonic tumours will be
eligible for the study. Individual patient consent will be sought. Each patient will be
randomized at the pre-operative visit the day prior to surgery; thus, each patient will
know, in advance, which procedure they are undergoing.

Patients should be staged pre-operatively with Computed Tomography of abdomen and pelvis to
facilitate therapeutic and operative strategy. All patients will be given prophylaxis
against deep vein thrombosis (sequential intermittent pneumatic compression
devices/compression stockings and low molecular weight heparin).

A single, prophylactic dose of antibiotics will be given perioperatively; the choice of
antibiotic will be determined according to institutional guidelines. Operative procedure
will be according to standard practice.

At laparoscopic right hemicolectomy, pneumoperitoneum will be established following
insertion of a 12mm umbilical port. Two or 3 further operating trocars (5mm) will be
inserted; the number and position will be at the operating surgeons discretion. When it is
necessary to use more than two 5mm trocars to complete the procedure this will be recorded.
Ligation of the vascular pedicle must be performed intracorporeally using an endovascular
stapling device, endoclips or an electrothermal coagulation device. If the major vessels are
ligated extracorporeally when the mobilised colon has been exteriorised for resection the
procedure will be classified as "laparoscopic assisted"- i.e. converted to an open
procedure- for the purposes of this trial. Intestinal continuity will be restored
extracorporeally using end to end, end-to side or side-to side anastomosis. The type of
anastomosis will be at the surgeons' discretion (stapled vs. handsewn) and will be recorded.

Patients having SILS right hemicolectomy will receive the same perioperative care as those
undergoing conventional laparoscopic resection. The SILS access device is inserted through a
4-5cm incision (max 6cm incision), 2cm above and 1 cm below the umbilicus. The access device
utilises three 5mm trocars facilitating entry to the peritoneal cavity. The choice of
access device will be at individual surgeons' discretion. In the event of additional ports
being required to complete a SILS minimally invasive procedure the number of additional
trocars used will be recorded. Oral fluids will be commenced on the evening of surgery and
diet will be introduced the following morning, depending on clinical status. Urinary
catheters will be removed on post-operative day 1 and ambulation encouraged.

Data Collection Data collection will be performed by the operating surgeon, a designated
member of the surgical team (present at time of operation) or Dr. Martin, Co-PI on the
study, and recorded on an electronic pro-forma and submitted to an on-line database (the
iCore website- Institute for Clinical Outcomes in Research and Education). Each patient
enrolled in the study will be given a study number and all data will be registered under
this number. Patients will thus be deidentified. Any data that could potentially identify
patients such as D.O.B/ date of surgery, date of discharge will be excluded . It will
include patient demographics (age, sex), American Society of Anaesthesiologists (ASA) grade
and specific co-morbidities, intervention performed, operation performed, number of ports
used, technique for ligation of vascular pedicle, type of anastomosis, re-intervention
during index admission (radiological or operative) in-hospital morbidity (myocardial
infarction, deep vein thrombosis, pulmonary embolism, wound infection, abscess requiring
drainage, urosepsis, renal failure or respiratory insufficiency), mortality, analgesic
requirements, time to return to diet, time to discharge to home. Further details will be
recorded at post-operative visits including the number of days alive following discharge,
reinterventions within 12 months and patient satisfaction. Each patient will be seen at 3
and 12 months post-operatively. For those patients from out of state who prefer to be
followed up locally we will perform a telephone interview at the timelines outlined. Patient
satisfaction will be determined using the Short Form (SF-36) questionnaire at 3 and 12
months.

Sample Size The main short-term endpoints of the study are both qualitative (lymph node
yield, grade of specimen) and quantitative (operative time, cosmesis satisfaction,
resumption of normal diet/intestinal function, length of hospital stay). Cancer-related
survival is the main long-term primary end-point. The working hypothesis is that there will
be no significant differences in this variable between SILS and conventional laparoscopic
right hemicolectomy, but that differences in variables related to the short-term outcome
(i.e. morbidity and duration of hospital stay) would favour SILS. We assume that a
difference in cancer-related survival of less than 15% between treatments indicates an
equivalent efficacy. Assuming a 70% 5-year cancer-related survival in the laparoscopic
colectomy group, a minimum of 100 patients per group is required to show that both surgical
techniques are equivalent with an α level of 0•20 and a β error of 0•05. Recruitment of
patients is not expected to be difficult because evidence to date is convincing of at least
equivalent outcome and we believe that most patients would hope to be assigned to the SILS
group, with potentially shorter hospital stay, less pain and improved cosmesis. From a
surgeon's perspective, SILS is technically feasible and represents only a slight
modification of the conventional laparoscopic procedure.

Hospital Inclusion and Patient Accrual All eligible patients (see exclusion criteria)
presenting to participating hospitals with right colonic tumors will be recruited for the
trial. . Each patient will be randomized at the pre-operative visit the day prior to
surgery; thus, each patient will know, in advance, which procedure they are undergoing.

Patients will be furnished with a patient information leaflet and will have the implications
of inclusion in the trial explained to them by the operating surgeon. It will be explained
that non-willingness to participate in the trial will not have any negative impact on their
treatment. If the patient is willing to participate in the trial, verbal and written consent
will be obtained prior to transfer to the operating theatre.

Randomisation schedules will be in blocks, with the proposed treatment delivered in writing
in sequentially numbered, opaque, sealed envelopes. If inferiority of efficacy is
demonstrable on preliminary statistical analysis, the trial will be stopped prematurely to
prevent harm to patients. We aim to perform a preliminary analysis of the pooled data at
6/12/18/24 months or when 100/150/200 patients have been entered into the trial; whichever
comes first will prompt preliminary analysis. Each adverse event will be included in the
electronic file of each patient in the study. The data will then be communicated with the PI
at each site participating in the study. In the event of one technique being of greater risk
to patients, the lead center in Dublin, Ireland will terminate the study prematurely.
Similarly, in the event of a PI in the study being unhappy with the outcomes of the study,
they are free to withdraw from the trial at any time. This withdrawal will be reported in
publishing the data.

Statistical Analysis Data will be assessed according to the intention-to-treat principle.
Because the scope of the study is non-metastatic colon cancer, patients in whom metastases
are detected intra-operatively will not be included in the analyses of long-term outcome.
Survival is calculated from surgical resection of primary tumour to the last visit or death.
For cancer-related survival, patients who die from other causes will be censored from the
study at time of death. Probability curves will be constructed with the Kaplan-Meier method
and compared with the log-rank test.

We will use proportional-hazards modeling with forward selection to determine the influence
of patients' baseline characteristics on cancer-related survival and other variables. The
surgical procedure and any variable reaching a p value of less than 0•10 in the univariate
analysis will then undergo multivariate analysis to identify independent predictors.

Categorical variables will be compared by χ2 test, with the Yates correction when necessary.
Continuous variables will be compared by the Student's t test or the Mann-Whitney U test,
depending on their distribution.

All p values will be two-sided with a p value of less than 0•05 indicating a significant
difference. All calculations will be performed with SPSS (version 18.0 for Windows).