Comparison of Laparoscopic Versus Open Right Colectomy for Right Colon Cancer, According to the Complete Mesocolic Excision (CME) Principles: a Prospective Randomized Controlled Trial
Phase: NA
Conditions: Colon Cancer
Sponsor: Larissa University Hospital

COVER PAGE
Study Protocol
OFFICIAL TITLE: Comparison of laparoscopic versus open right 
colectomy for right colon cancer, according to the complete mesocolic 
excision (CME) principles: a prospective randomized controlled trial
BRIEF TITLE: Laparoscopic versus open right colectomy for right colon cancer
UNIQUE PROTOCOL ID: LORC 
DOCUMENT DATE: February 2023
CLINICALTRIALS.GOV ID: NCT05713903
Principal Investigator:
Konstantinos Perivoliotis, MD
Telephone: 00302413501000
Email: kperi19@gmail.com
Sub-Investigators:
Ioannis Baloyiannis, MD, PhD Assistant Professor of Surgery
Study Director
George Tzovaras, Professor of General Surgery
Telephone: 00302413502804
Email: gtzovaras@hotmail.com
Department of Surgery
University Hospital of Larissa
Mezourlo 41110 Larissa
Greece
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1. INTRODUCTION
1.1 Literature Review
Colorectal cancer is the third and second most common malignancy in male and female 
patients, respectively, with up to 1.8 million new cases and 860,000 deaths per year [1].
Anterior resection with total mesorectal excision (TME) was first proposed by Heald in 1982 
[2] and is currently the gold standard surgical technique for middle and lower rectal cancer. Heald 
considered that the metastatic spread of the tumor occurs through micro-implantations in the 
lymph node network of the mesorectum, and much less through horizontal intramural infiltration, 
and thus defined rectal resection margins at 5cm or even 2cm for well-differentiated neoplasms. 
Therefore, he suggested that mesorectum displays a greater risk for micro-metastatic disease and 
should be removed en-bloc with intact resection margins.
Similarly in 2009, Hohenberger proposed the complete mesocolon excision (CME) concept for 
the treatment of colon cancer, based on the respective embryological development anatomical 
planes. After analyzing a large cohort of patients, he concluded that this operation type leads to a 
significant reduction in the local recurrence and an increase in the overall survival rates [3].
Hohenberger proposed open CME as the optimal surgical technique for colon cancer, under the 
premise that the following principles are met [3]:
• Dissection of Toldt's fascia and mesocolon preservation 
• Central vascular ligation 
• Extensive locoregional lymph node dissection
CME technique, as described by Hohenberger in 2008, is an extension of Heald's TME and it is 
based on the sharp dissection and separation of the visceral fascia that surrounds the colon from 
the parietal fascia. The aim is to fully mobilize the colon and the corresponding mesocolon, which 
is surrounded bilaterally by sheets of visceral fascia. This ensures the complete resection of the 
tumor and the corresponding lymph nodes. At the same time, central vascular ligation allows the 
dissection of the apical lymph nodes [3].
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There are three resection planes: the mesocolic, intramesocolic and muscularis propria plane. 
The ideal resection plane is the mesocolic, in which the colon is removed, along with the entire 
mesocolon and all the venous and lymphatic tissue, without violating the visceral fascia [4]. 
Surgical specimens categorized into either of the other two resection planes are associated with 
reduced R0 resection rates [6] and with reduced overall survival. Characteristically, the muscularis 
propria resection plane has been associated with up to 15% reduced survival rate compared to the 
mesocolic plane [7 , 8].
There are specific morphometric characteristics of surgical specimens that are used to assess 
their quality. These include tumor and proximal colon high vascular ligation distance, number of 
lymph nodes, length of resected small bowel and colon, and total area of the mesocolon [7, 8]. 
These characteristics are directly related to the number of harvested lymph nodes and, therefore, to 
overall survival [7, 8].
According to initial results, CME specimens were larger in size, contained a longer length of 
colon, a larger mesenteric surface and a greater number of lymph nodes compared to the standard 
colectomy specimens [3]. In addition, a greater distance of the tumor from the resection margins 
was highlighted [3]. Specifically for right colon cancers, recent publications [6–8, 11–14] have 
shown that CME can achieve better morphometric specimen characteristics and a greater number 
of lymph nodes. In a recent randomized study, Di Buono et al. [15] compared the completion of 
CME or not, during laparoscopic right colectomy. A significant difference was found in favor of 
CME, regarding the specimen length and the lymph node harvest.
Despite  these,  the  literature  evidence  regarding  the  morphological  and  qualitative 
characteristics of laparoscopic and open CME specimens are still inconclusive. Specifically for 
right colectomies, in the comparative study by Gouvas et al. [6], it was observed that the 
percentage of the mesocolic resection level was 100% in open colectomy, in contrast to 85.7% in 
the  laparoscopic  approach.  However,  this  difference  was  not  statistically  significant.  In  a 
retrospective study by Ali Koc et al. [17], no difference was found between open and laparoscopic 
CME in terms of specimen length, R0 resection rate and number of resected lymph nodes. A recent 
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publication by Ali Zedan et al. [18], argued that open CME is associated with longer specimens, 
larger mesenteric area, and increased resection margins. Another interesting finding was that the 
number of lymph nodes and the distance of the ligation site were greater in the laparoscopic CME 
group. However, the meta-analysis by Anania et al. [19] failed to validate any difference between 
the two methods in the total number of lymph nodes. Finally, a comparative analysis of our own 
series of patients did not show superiority of one technique over the other in terms of resection 
level, specimen length and number of lymph nodes [20].
Additional qualitative characteristics of a colon cancer operation include operative time, 
intraoperative blood loss, time of bowel function recovery, length of postoperative hospital stay, 
postoperative complications, as well as overall survival and local recurrence rate [2, 6, 8–10]. In a 
recent meta-analysis by Anania et al. [16] applying the principles of CME to right colectomies did 
not affect the rates of postoperative leaks, bleeding, overall complications, and reoperations. 
However, CME right colectomy was associated with optimal results in terms of 3-year overall 
survival and 5-year disease-free survival [16].
Regarding the application of laparoscopy principles to CME colectomies, previous studies [6–
8, 11–14] have confirmed that it is a technique with optimal results, such as faster postoperative 
recovery, shorter hospital stay, and lower morbidity. There is agreement between studies regarding 
the  perioperative  benefits  of  laparoscopic  CME  right  colectomy  versus  the  open  method. 
According to Huang et al. [21], the length of operative time between the two techniques was 
comparable. Laparoscopic right colectomy was associated with significantly lower intraoperative 
blood loss and faster initiation of feeding. In addition, these patients were discharged earlier 
compared to their counterparts in the open colectomy group. Moreover, no differences were 
observed in complication and local recurrence rates [21]. These findings were also confirmed by 
the comparative study of Sheng et al. [22], where the application of the minimally invasive 
technique resulted in lower levels of postoperative pain, and faster recovery. Accordingly, Shin et 
al. [23], applying propensity score analysis, to remove possible confounding factors, in a sample of 
2249 right colectomies and found that the technique is an independent predictor for 5-year disease-
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free survival. Pooled data from Anania et al. [19], confirmed the superiority of laparoscopic CME 
in the rates of postoperative complications, intraoperative bleeding, and length of hospital stay. 
These  are  also  in accordance with our  own  experience,  where  a significant benefit  of  the 
laparoscopic approach was shown in the duration of hospitalization and septic complications, at 
the cost of prolonged surgical time [20].
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2. OBJECTIVE 
2.1 Description of the proposed project
The purpose of this research protocol is to compare open versus laparoscopic right colectomy 
(according to the CME technique of complete mesocolic excision) for right colon cancer. This 
study will be designed as a prospective randomized controlled trial. The comparison of the two 
techniques will include endpoints regarding the quality characteristics of the specimens and the 
oncological results. In addition, the effectiveness of the two methods will be evaluated in terms 
of the early and late postoperative period.
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3. MATERIAL AND METHODS
3.1 Population
The sample will consist of males and females aged 18 to 90 years.
3.2 Diseases
The study will include patients with right colon cancer that will be submitted to right 
colectomy based on the CME principles.
3.3 Inclusion / Exclusion Criteria
Inclusion criteria are the following:
• Histologically confirmed right colon cancer (cecum, ascending colon, hepatic flexure)
• Surgical resection based on the CME principles
• Patient 18 to 90 years old
• ASA score ≤III
• Τ≤3
• Elective operation
• Signed informed consent of the patient
Exclusion criteria are the following:
• Non elective operation (hemorrhage, perforation, obstruction) 
• Locally advanced disease (T4)
• Distant metastases (Stage IV)
• ASA≥IV
• Previous laparotomy
• BMI >35 kg/m2
• Active sepsis or systemic infection
• Untreated physical and mental disability
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• Pregnancy or breast-feeding
• Lack of compliance with the protocol process
• Non-granting of signed informed consent
3.4 Study Arms
There will be two study groups in this trial. Patients randomized to the control arm will be 
submitted to open right colectomy. Accordingly, the experimental study group will undergo 
laparoscopic right colectomy. Both techniques will adhere to operative principles of complete 
mesocolic excision (CME).
In the open right colectomy group, the operation will start with a midline incision and dissection 
based on the lateral to medial approach [6]. The lateral peritoneal fold along Toldt's line will be 
incised and the ascending colon will be mobilized from the retroperitoneum according to the 
embryological dissection planes. Dissection will continue until the anterior surface of the 
superior mesenteric vessels at the third duodenal part. Ileocolic and right colic vessels will be 
ligated at their origins. For hepatic flexure tumors, the middle colic vessels will be also ligated 
at their origin [6]. The ileocolic anastomosis will be performed using an automatic stapler. The 
anastomosis will be completed either with staples or sutures.
In laparoscopic right colectomy subgroup, the patient will be placed in a lithotomy position [21]. 
Entrance in the peritoneal cavity will be completed via the open Hasson method. With the 
installation of the pneumoperitoneum (12 mmHg) an exploratory laparoscopy with a 30° optical 
camera will be performed. Overall, 4 ports will be used: 10mm at the umbilicus for optical 
entry, 12mm in the left midclavicular line below the umbilicus as the main working port, 5mm 
at the McBurney point, and 5mm between the umbilicus and the xiphoid process [21]. An 
incision will be made in the mesenteric peritoneum under the ileocolic vessels [6]. Dissection of 
the peritoneal fold, under the terminal ileum, will be performed based on the medial to lateral 
approach. The dissection will continue laterally, below the right paracolic peritoneal fold, and 
above the pancreas and duodenum, to the conjoined fascias of the lesser epiploic sac. Similar to 
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the open approach, the ileocolic vessels, as well as the right branches of the middle colic will be 
ligated at their origin for cecal and proximal ascending tumors. For hepatic flexure cancers, the 
medial colic vessels will be ligated. Dissection will be completed with the transection of the 
right gastrocolic ligament, the peritoneum of the right paracolic groove and the peritoneal recess 
of the terminal ileum. An automatic stapler will be used for the transection of the terminal ileum 
and the transverse colon. The ileocolic anastomosis will be completed either intracorporeally or 
extracorporeally, using staples or sutures [6].
3.5 Anesthesia
Patients will receive general anesthesia.
3.7 Primary endpoint
Mesocolic Resection Plane. Occurence of Mesocolic Resection Plane. If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined 
as=0 'NO'. [Time Frame: 1 month postoperatively]
3.8 Secondary endpoints
Secondary endpoints of the present study are:
Open Conversion. Occurrence of Open Conversion. If such an episode occurs, then it will be 
defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. [Time 
Frame: Intraoperative period]
    Operative Time. The total operative time will be recorded. Measurement unit: minutes 
[Time Frame: Intraoperative period]
    Type of Anastomosis. Occurrence of Stapled or Handsewn Anastomosis. If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined 
as=0 'NO' [Time Frame: Intraoperative period]
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    Intraoperative Transfusion. Occurrence of Intraoperative Transfusion. If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined 
as=0 'NO' [Time Frame: Intraoperative period]
    Postoperative Complication. Occurrence of Postoperative Complication. If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined 
as=0 'NO'. [Time Frame: 1 month postoperatively]
    Bowel Function Recovery. Postoperative time until the recovery of bowel function is 
achieved. Measurement unit: days. [Time Frame: 7 days postoperatively]
    Length of Hospital Stay. Postoperative time that the patient can be safely discharged. 
Measurement unit: days. The patient will be discharged when it is ensured that is medically safe 
to be released. In particular, as the exit time of the patient, will be regarded the time that the 
patient will fulfil the Clinical Discharge Criteria. [Time Frame: Maximum time frame 39 days 
postoperatively]]
    Negative Resection Margin. Occurrence of Negative Resection Margin. If such an episode 
occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined 
as=0 'NO'. [Time Frame: 1 month postoperatively]
    Local Recurrence Occurrence of Local Recurrence. If such an episode occurs, then it will 
be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. [Time 
Frame: 5 years postoperatively]
    Disease Free Survival. Occurrence of Disease Free Survival. If such an episode occurs, then 
it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. 
[Time Frame: 5 years postoperatively]
    Overall Survival. Occurrence of Overall Survival. If such an episode occurs, then it will be 
defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO'. [Time 
Frame: 5 years postoperatively]
3.9 Calculation of the sample size
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Sample size calculation was based on the primary outcome. According to the literature [6] the 
percentage of mesocolic plane preservation in open and laparoscopic colectomy is 100% and 85.7%, 
respectively. Therefore, for a=5%, power=80%, 10% dropout rate, and 1:1 allocation ratio, the 
calculated sample in each group is 57 patients. Therefore, the total sample of the study is 114 
patients.
3.10 Randomization
The randomization of the patients will be performed using a dedicated software with a 1:1 
allocation ratio. The allocation group will be concealed with opaque envelopes that will be opened 
upon entrance of the patient in the operation theatre. 
3.11 Blindness
There will be no blindness at the level of the patient, the treating physicians (surgeon, 
anesthesiologist) and the researcher who will record the data.
3.12 Exit criteria
The patient will be discharged when it is ensured that is medically safe to be released. The exit 
time will be regarded as the time that the patient will fulfill the Clinical Discharge Criteria. More 
specifically, the patient should display the following: steady vital signs, fully oriented, without 
nausea or vomiting, mobilized with a steady gait and without a notable bleeding [22].
3.13 Monitoring
Following hospital discharge, the patient will be called for reassessment one month after the 
operation to evaluate any postoperative complications. At the same time, the pathology report of the 
specimen and the adjuvant treatment will be recorded. In addition, at 5 years postoperatively, 
overall, disease-free survival and recurrence rates will be recorded.
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3.14 Medication
Both preoperative and postoperative patient treatment will be standardized. The principles of the 
ERAS protocols will be applied to patients [23]. More specifically, antimicrobial prophylaxis will 
include the administration of intravenous antibiotics within 60 minutes prior to the onset of 
operation.  Patients  will  receive  preoperative,  mechanical  bowel  preparation  and  per-os 
antimicrobial prophylaxis. Prior to surgery, patients will abstain from solid and liquid foods for 6 
and 2 hours, respectively. The nasogastric tube will be removed postoperatively and repositioned 
only in case of ileus. Postoperative analgesia will include a multidisciplinary approach using 
analgesics (paracetamol, lornoxicam) in combination with dorsal or epidural analgesia. Opioid 
administration  will  be  avoided.  Postoperative  nausea  and  vomiting  prophylaxis  will  include 
granisetron 3mg / 3ml IV. Mechanical and pharmaceutical thromboprophylaxis will be used. A 
zero-balance approach to fluid losses will be applied. Mobilization will be initiated from the first 
postoperative day.  Feeding will be initiated on the basis of the intestinal function recovery.
3.15 Study Group
All participating members have years of experience in their field and have, therefore, completed 
the learning curve for the required techniques. Data collection and recording will be carried out by 
an independent, third party, researcher.
3.16 Conducting a Study
The study will be conducted in the Department of Surgery of University Hospital of Larissa. 
Patient data will be recorded both in the patient charts and in an electronic database. The required 
laboratory examinations will be defrayed by the patient insurance funds.
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4. LITERATURE
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