The Value of CE-LUS During Robot-assisted Surgery for Primary Colorectal Cancer
The Value of CE-LUS During Robot-assisted Surgery for Primary Colorectal Cancer
Laparoscopic ultrasound examination performed during surgery for primary cancer of the colon
 and rectum (CRC) has been shown to be able to detect liver metastasis that are not recognized
 by conventional computer tomography (CT scan) prior to surgery.

 Today most of the colorectal cancer resections are performed by laparoscopy, but robotic
 technology is gradually developed in an attempt to overcome some of the limitations
 characterized by laparoscopy. The use of contrast enhanced laparoscopic ultrasound
 examination (CE-LUS) of the liver during robot-assisted CRC surgery has not been studied, and
 this despite the fact that it seems technically possible to perform.

 With this project we will investigate whether CE-LUS associated with robotic surgery for CRC
 is technically feasible and whether it will be able to detect synchronous liver metastases
 that have not been detected on the preoperative imaging modalities.
Title:

 The value of contrast enhanced laparoscopic ultrasound examination during robot-assisted
 resection for primary colorectal cancer surgery.

 Project:

 The following project evaluates the value of contrast enhanced Laparoscopic Ultrasound
 examination (CE-LUS) in robot-assisted surgery for CRC.

 The project "The value of contrast enhanced laparoscopic ultrasound examination during
 robot-assisted resection for primary colorectal cancer surgery" is a part of a Ph.D study at
 the University of Southern Denmark.

 Purpose:

 1.1: The primary purpose is to investigate whether the use of contrast enhanced ultrasound
 examination in connection with LUS procedure increases the number of detected liver
 metastases.

 1.2: As a secondary objective; an evaluation of the technical feasibility of the CE-LUS
 procedure during robot-assisted resection for primary colorectal cancer surgery.

 Background:

 Laparoscopic surgery for cancer in the colon or rectum seems to be equal standing to open
 surgery with regards to the morbidity, mortality and the oncologic results (radicality and
 re-lapse frequency and long-term survival). Laparoscopic surgery for CRC is now a
 well-understood and well-established surgical method, but there are only few randomized
 trials dealing with the long-term results. The latest inventory work calls for better
 documentation of long-term results and calls for further randomized studies. Despite this,
 the number of laparoscopic operations for colorectal cancer (CRC) in Denmark is increasing,
 and laparoscopic surgery has become established as standard treatment for CRC. The
 development of minimally invasive surgery is not stopped by the laparoscopic approach, and
 robotic surgery is currently under evaluation in particular rectal surgery for CRC. Robot
 technology has been developed in an attempt to overcome some of the limitations that
 characterize the laparoscopic surgery. The establishment of a stable platform with
 instruments witch have increased rotating movements is an essential part of the robotic
 surgery. A motion-scaling and filtering makes sure that the image does not shake during the
 operation. The picture resolution is enhanced with 3D visualization and have visual
 magnification of the operating field. A combination of these features allows more precise
 dissection of tissue, suturing and improved bleeding-control compared to conventional
 laparoscopy.

 Liver metastases are frequent in patients with CRC and about 15-20% of patients already have
 metastases at the diagnosis (synchronous metastases). Ultrasound examination during open
 surgery (IOUS) has shown to be an important diagnostic tool with high sensitivity (98%) and
 positive predictive value (86%) for detection liver metastases that are undiagnosed on
 preoperative CT or positron emission tomography (PET-CT). IOUS is considered as the gold
 standard for hepatic metastases within open surgery for CRC. In laparoscopic surgery this
 option disappears, but it is likely that laparoscopic ultrasound examination (LUS), may
 provide the same information as found by IOUS.

 While laparoscopy and laparoscopic ultrasound examination (LUS) is well established in the
 staging and treatment of upper gastrointestinal cancers, this method is only sparsely
 evaluated in the treatment of CRC. There are only very few and older data dealing with the
 use of LUS in the TNM staging in patients with cancer in the colon and rectum. Several small
 studies have investigated the use of LUS to evaluate the M-stage in laparoscopic colorectal
 surgery and all studies show an increased detection of liver metastases. Overall, seems LUS
 to be better than the current pre-operative image modalities.

 In prospective and blinded studies a percutaneous contrast-enhanced ultrasound examination
 (CEUS) of the liver proved to be able to detect significantly more liver-metastases from CRC
 than conventional percutaneous ultrasound.

 With the new second-generation contrast agents CEUS seems to be equivalent to the
 contrast-enhanced CT and (magnetic resonance imaging) MRI for detection liver-metastases.

 Liver metastases are frequent in patients with CRC and the use of intraoperative ultrasound
 (IOUS) during open surgery for CRC, has previously been regarded as the gold standard.
 Contrast-enhanced IOUS (CE-IOUS) during open surgery for CRC is only sparsely evaluated, but
 has been shown to increase sensitivity for detection liver-metastases.

 Many patients with rectum cancer receive pre-treatment with chemotherapy and radiation
 therapy, and chemotherapy may make it difficult to identify existing metastases in the liver.
 Studies have shown an increased detection of metastases with contrast-enhanced ultrasound
 after pretreatment with chemotherapy.

 The sensitivity of ultrasound examination can be improved by use of contrast enhanced
 ultrasound.There is a single pilot study dealing with contrast-enhanced laparoscopic
 ultrasound (CE-LUS) during primary CRC resection and the study revealed an improved detection
 of metastases.

 In the same manner as in the laparoscopic resection of CRC, there is a need in the robot-
 assisted surgery to be able to compensate for the lack of intraoperative palpation and IOUS.
 The use of CE-LUS associated with robotic surgery in CRC patients has not been studied and
 this despite the fact that it appears technically possible to carry out the procedure for the
 robot procedure.

 With this project we want to elucidate whether the use of CE-LUS in robot-assisted surgery
 for CRC will increases detection rate for liver metastases and evaluate the technical
 feasibility of the CE-LUS procedure.

 Method:

 The project is a prospective, descriptive study with 50 consecutive patients scheduled for
 robot-assisted surgery for primary CRC.

 All patients had, prior to the scheduled surgery, completed a contrast enhanced CT of the
 chest and abdomen, as part of their Tumor, Lymph node and Metastases (TNM) evaluation. The CT
 scan was made according to current guidelines.

 At the beginning of the surgery the patient will get the LUS examination by a specialist with
 skills in contrast-enhanced ultrasound. All liver segments are systematically scanned and any
 findings will be recorded on a registration form. After the LUS examination of the liver the
 procedure will supplied with a contrast enhanced examination. CE-LUS is performed with a
 contrast agent SonoVue® containing Sulphurhexafluoride which is a according to the
 department's instructions for CE-LUS procedure. A bolus of 2.5 ml is injected into a
 peripheral vein followed by 10 ml of isotonic saline. The liver is then systematically
 scanned in 3 phases (arterial, venous and parenchymatous phase) searching for unrecognized
 liver metastases. The procedure is repeated after 5 minutes.

 The time it takes to do the LUS and CE-LUS is measured and any technical challenges are
 reported. Time, challenges and findings of liver metastases (number, segment and size) are
 entered on a registration form.

 If there at the CE-LUS examination is found undiagnosed liver metastases, then the patient
 get an intraoperative LUS-guided fine-needle aspirations- biopsy (FNA) or tru-cut biopsy
 performed by a liver surgeon specialist and the lesion will be marked with a little silver
 pin. The latter is used for follow-up after pretreatment and to locate potential rest tumor.
 The patient will then be sent to the Department of Surgery A, Odense University Hospital, for
 a multidisciplinary tumor conference (MDT).

 All other patients follow the Departments usual routines for adjuvant therapy. All patients
 included in the project will undergo a three-phase control CT scan 3 months after surgery.
 This is to evaluate whether there might be overlooked metastases during the CE-LUS
 evaluation.

 All the information about the patients are entered and recorded in a database.

 Ethics:

 The project was reviewed and approved by the Science Ethics Committee, Project No:

 S- 20140154. The project is reported to the Data Protection Agency. The studies will be
 registered in ClinicalTrials.com database. Participation in the project is voluntary, and
 patients may at any time withdraw their commitment to participation.

 To date no reports of serious or life-threatening complications of LUS examinations or its
 probe is reported.

 The LUS instrument/ probe is introduced into the abdominal cavity through the small holes
 ("gates") that the surgeon uses to do the operation with. Patients are not getting more scars
 / sores on the stomach than usual.

 It is a specialist with expertise in ultrasound scanning, which handles the actual scan.

 If there during the ultrasound scan is found spread of the cancer, which was not known before
 surgery, it may be necessary to take tissue samples from the suspicious area and perhaps mark
 this with a small silver pin. This is in order to regain these areas later, and to determine
 whether it is about the spread of cancer. In this case the patient will be further diagnosed
 and treated by the department's usual guidelines in this area.

 The contrast agent used in this context is not associated with any serious risks and is a
 well-known and approved contrast agent. The ultrasound scan itself is not dangerous, and the
 contrast agent can give temporarily problems in form of headaches and nausea (prevalence
 1-10%), and, rarely, transient weakness, vasodilation, hyperglycemia, sensory disturbances,
 rash and visual disturbances (frequency 0.1-1%). The contrast medium circulates only briefly
 in the body and the patient is monitored and are in general anesthetic, when administered.
 [26].

 There is a minimal risk of bleeding in connection with a tissue sampling, but otherwise there
 are no side effects associated with the operation or construction of a small silver pin.

 In the follow-up there is included an extra CT scan in relation to the department's usual
 procedure. There is a theoretical, but very modest risk- 0.01% in order to develop a new
 cancer disease.

 Time and place The project is carried out at The RAK-Center at the department of Surgery A,
 Odense University Hospital, and the management at Department of Surgery A, Odense University
 Hospital, approves the project.

 Schedule:

 January 2015 - March 2016 : Inclusion of patients. March 2016 - September 2016: Data
 Processing and publications.

 Project Manager:

 MD PhD-student Signe Bremholm Ellebaek, Surgical Department A, Odense University Hospital

 Other project participants:

 Odense University Hospital, Surgical Department A. Professor, MD, PhD Michael Bau Mortensen
 MD PhD Claus W. Fristrup MD. Peiman Poornoroozy MD. Torsten Pless MD Bassam Mahdi, Radiology
 Department MD. Per V. Andersen

 Economic Conditions:

 There are sought financial support from various foundations, including the Cancer Society and
 the Region of Southern research funding, to conduct the study.

 There are no commercial support givers, and the involved staff members get no financial gain.
Inclusion Criteria:

 -  patients scheduled to robot-assisted CRC resection

 -  patients with histologically verified cancer i colon or rectum

 -  informed consent

 -  patients with minimum age of 18

 -  patients without liver metastases

 Exclusion Criteria:

 -  patients who have not given informed consent

 -  patients with severe heart disease, lung hypertension, or had had a heart attack < 7
 days

 -  patients with alcohol or drug abuse.

 -  patients with liver metastases