Complete Mesocolic Excision With Central Vascular Ligation in Comparison With Conventional Surgery for the Right Colon Cancer: An Italian Randomized Trial
Phase: NA
Conditions: Colon Cancer
Sponsor: University of Turin, Italy

 
 
Complete Mesocolic Excision with central vascular ligation in Comparison 
With Conventional Surgery for the right colon cancer: An Italian randomized 
trial. 
 
 
Administrative and ID information. 
Acronym. 
CoME IN trial.  
Protocol version 
number and current 
status. 
23/01/2020 
Practice 
N.110/2019/U 
Funding 
The design, management, analysis and reporting of the study are non- 
financial supported. 
Ethics committee 
evaluation date 
29/01/2020 
Trial Sponsor 
Università degli studi di Torino- Facoltà di Medicina e Chirurgia, Campus 
San Luigi Gonzaga. 
Regione Gonzole, 10 -10043 Orbassano (To). Italy 
Contact name 
Prof. Maurizio Degiuli 
Telephone: + 39 011 90261      
E-mail: maurizio.degiuli@unito.it.  
https://www.oncology.unito.it/do/docenti.pl/Show?_id=mdegiuli 
Ethics committee 
Comitato Etico Interaziendale  
A.O.U. San Luigi Gonzaga 
Tel. 011.9026204 – 011.9026506 ore 10 – 12 da lunedì a venerdì 
Fax 0119026791 
E-mail: sperimentazioni@sanluigi.piemonte.it 
 
 
 
 
 

TABLE OF CONTEST 
1) ROLES. 
2) ORGANZATIONAL STRUCTURE AND RESPONSABILITYES. 
3) LIST OF ABBREVIATIONS/GLOSSARY. 
4) INTRODUCTION. 
5) BACKGROUND. 
6) PURPOUSE. 
7) GOOD CLINICAL PRACTICE. 
8) STUDY OBJECTIVES. 
9) STUDY DESIGN  
- Overview of study design 
- Number of patients 
- Duration of study 
- Study setting 
- Centers recruitment strategy 
- Study population 
10) ENROLLMENT, RANDOMIZATION AND ALLOCATION. 
11) TREATMENT. 
 -Preoperative preparation  
 - Generalities 
 - CME open approach 
 - CME laparoscopic approach 
12) SCHEDULE OF CLINICAL ASSESSMENT AFTER TREATMENT. 
13) EFFICACY AND SAFETY MEASURAMENTS 
14) STATISTICAL CONSIDERATIONS. 
15) VARIABLES. 
16) REPORT, DISSEMINATION AND PUBLICATION. 
 -Dissemination and publication. 
 -Protocol amendments 
 -Declaration of interests 
 -Access to data  
 -Confidentiality 
17) END OF TRIAL. 
18) COLLABORATORS. 
19) BIBLIOGRAPHY. 
 
 
 
 
 
 
 
 
 

1) ROLES 
 
Chief Investigator (CI):   
 
Maurizio Degiuli, MD 
 
Trial Coordinator (TC):  
 
Mario Solej, MD 
 
Trial statistician (TS):  
 
Monagheddu MD/ Ricceri MD. Ph.D. 
 
Trial Management Group (TMG).  Mario Solej MD,  
 
 
 
 
 
Prof. Maurizio Degiuli MD;   
Rossella Reddavid, MD.  
H. Aridai Resendiz MD.   
Giulia Marchiori MD. 
 
 
Clinical Monitor (CM):  
 
Patrizio Mao. MD. 
Nirvana Maroni. MD. 
Letizia Spidalieri.MD. 
 
Collaborators (Cols):  
 
Section 19 (page 23) 
 
Research Ethics Committee (REC): Comitato Etico Interaziendale A.O.U. San Luigi 
Gonzaga and Ethics committee of each collaborator centre  
 
Data coordinating centre (DOC): Università degli studi di Torino, Dipartimento di 
Oncologia, AOU San Luigi, Chirurgia Oncologica e Digestiva, Orbassano (TO) 
 
 
 
 
 
 
 

2. ORGANIZATIONAL STRUCTURE AND RESPONSABILITIES. 
Chief Investigator (CI) Responsibilities:  
CI is responsible for the intellectual conception and of the administrative and ethical aspects 
of the research project. CI ensures that all investigators, research associates/assistants and 
students on the project are fully informed of relevant University policy and administrative 
procedures associated with the project, including intellectual property and confidentiality 
provisions, ethical and other clearances that are required and  that the project is carried out 
in accordance with approved protocols and codes of good practice in research. CI is 
responsible for preparation of protocol and its revisions and progress and for final 
communication of any project outcomes.  
Trial Coordinator (TC) Responsibilities:  
Organization of steering committee meetings. 
Design and conduct of the study. 
Preparation of protocol and revisions. 
Preparation of investigators brochure and Case Report Forms. 
Trial Statistician (TS) Responsibilities: 
Design of the study and statistical analysis. 
Trial Management Group (TMG) Responsibilities: 
Establishment and monitoring of participating centers recruitment. 
Distribution and supply of data collection forms and other appropriate documentation for the 
trial. 
Preparation of protocol and revisions. 
Data collection and management. 
Data entry and cleaning. 
Data analysis. 
Organising and servicing the Independent Data and Safety Monitoring Committee ( IDSMC ) 
Clinical Monitor (CM) Responsibilities: 
Assurance of data security and quality, and  observance of data protection laws  Assurance 
that the trial is conducted by the good clinical practice in research. 
Revision and  and approval of  the Statistical Analysis Plan for the trial. 
Revision of  the trial progress and  analysis of  interim data. 
As the only body with access to the unblinded comparative data, the IDSMC is responsible 
for monitoring these data and making recommendations to the TMG on whether there are 
any ethical or safety reasons why the trial should not continue or protocol should be 
amended. To determine if additional interim analyses of trial data should be undertaken. 
Collaborators responsibilities: 
Design and execution of the protocol in ethic and safe terms. 
Data management and entry. 
Drafting, revision and approval of the final manuscript.  
Research Ethics Committee (REC) responsibilities:  
REC ensures that the project is carried out following approved protocols and codes of good 
practice in research. 
Data Coordinating Center (DOC) responsibilities: 
Contribution to the development of the protocol, and to all study documentation including 
datasheets. 
Design, production and regular update of all trial materials and arrangement of printing and 

supply of trial documentation.  
Monitoring of patient¶s recruitment and advice on remedial action if targets are not being 
met. 
DOC uses all reasonable efforts to ensure that data collected and reported are accurate, 
complete and identifiable at the source; and that record-keeping and data transfer 
procedures adhere to the Data Protection law. 
 
 
3. LIST OF ABBREVIATIONS/GLOSSARY 
ASA SCORE.  
The American Society of Anesthesiologists 
physical status classification system. 
BMI. 
Body Mass Index. 
CEA. 
Carcinoembryonic Antigen.  
CI. 
Chief Investigator. 
CM. 
Clinical Monitor. 
CME.  
Complete mesocolic excision. 
COLS. 
Collaborators. 
CRFS. 
The Case Report Forms. 
CT. 
Computed tomography. 
CVL.  
Central vascular ligation and apical 
lymphadenectomy. 
DFS. 
Disease-free survival  
DOC.  
Data coordinating center. 
EORTC 
European Organization for Research and 
Treatment of Cancer 
GIA 
Gastrointestinal anastomosis. 
IDSMC. 
Independent Data and Safety Monitoring 
Committee. 
QLQ. 
Quality of Life Questionnaire  
QOL. 
Quality of life. 
LLQ 
 Left-lower-quadrant. 
LN. 
Lymph nodes. 
LPS 
Laparoscopic 
LUQ 
 Left-upper-quadrant 
MCA. 
Middle Colic Artery. 
MCV. 
Middle Colic Vein. 
OS. 
Overall Survival  
REC. 
Research Ethics Committee. 
SLUH. 
San Luigi Universitari Hospital  
SMA. 
Superior mesenteric artery  
SMV. 
superior mesenteric vein. 
TC.  
Trial Coordinator. 
TME. 
Total mesorectal excision  
TMG.  
Trial Management Group. 
TNM 
The American Joint Committee on Cancer 
Staging 
TS.  
Trial statistician. 
WHO 
World health organization. 

4. INTRODUCTION  
Colorectal cancer is the third most common malignant disease worldwide and its incidence is 
significantly higher in men than in women. In men, colorectal cancer is the third most 
commonly occurring cancer after prostate and lung cancers while it is the second most 
commonly occurring cancer in women after breast cancer [1]. Over 1.8 million new cases 
were diagnosed in 2018 according to the world cancer research foundation [2].  
In Italy, it is the second most common tumor and leading cause of death [3] with 
approximately 53,000 new diagnoses of colorectal cancer estimated in 2017 [4]. 
Colorectal cancer is not a single type of tumor; its pathogenesis depends on the anatomical 
location of the tumor which differs between the right and the left side showing pathologic and 
molecular characteristics different between these tumor entities. Despite the location, 
surgical resection is the most effective procedure for its radical treatment at least in case of 
localized disease, and the long-term prognosis can be improved by improving surgical 
treatment without increasing perioperative mortality [5].   
In general, standard oncologic resection of the colon refers to a wide resection of the tumor-
bearing segment and the lymphatics draining along the named artery; recently, in  case of 
right colon cancer,  the application of the Complete mesocolic excision(CME) in addition  
with central vascular ligation (CVL) has been suggested to improve the oncological 
outcomes in analogy with total mesorectal excision(TME),  which  has been reported to   
enhance oncological results in patients with middle and low rectal cancer . 
The CME + CVL emphasizes the sharp dissection along the mesocolic plane between the 
visceral and parietal fascia layers with true central ligation of the main arteries and veins at 
their roots with the principle of en-bloc resection in a horizontal, vertical, and circumferential 
directions of the primary tumor with regional lymph nodes (LN) and all grossly suspected or 
involved lesions removed during operation. Therefore, the CME may remove a larger 
specimen with free margins, more mesocolon tissues and free tumor cells on peritoneal 
surface and may reduce potential sources of disease recurrence. 
 
 
5. BACKGROUND 
Many changes have occurred over the last three decades in the management of patients 
with colorectal cancer:  the advancements in imaging techniques, the setting of radiotherapy 
and the creation and development of multidisciplinary teams. But the most revolutionary 
contribution was the anatomic description of the mesorectum and the introduction of the total 
mesorectal excision (TME) supported by the concept of the "en-bloc clearance of the tumor¶s 
lymphatic drainage enveloped in the intact fascia of embryologic origin" by Heald et al. [6], in 
the 1980s. 
Later, in 2009 Hohenberger et al [7] applied the same concept of the TME as a curative 
treatment in patients with other colon cancer locations resulting in the complete mesocolic 
excision (CME). which, to date, remains a hot topic in the medical community.  
The pillars of the CME are sharp dissection of the anatomical leaves  and  dissection of the 
visceral plane from the parietal one, resulting in a higher quality of the specimen and in  a 
higher number of LN harvested  (Table 1), with no tears in the fascial leaf on each side of the 
mesocolon [7], with  central division of the feeding arteries at their origins from  the superior 

mesenteric artery (SMA) in case of  tumors of the right colon and from the inferior 
mesenteric artery (IMA) or the aorta in tumors of the left colon. 
Hohenberger analyzed 1329 patients undergoing R0 resection with application of the CME 
concepts and showed that local recurrence rate decreased from 6.5% to 3.6% and 5-year 
cancer-related survival rate increased from 82.1% to 89.1% [7].  Furthermore, the study of 
West et al [8] compared the CME specimens with specimens of standard surgery with non-
CME and observed that the CME surgery removed a greater area of the mesentery and 
achieved higher resection rates through the mesocolic plane when compared with standard 
non-CME surgeries. 
Six years after the introduction of this technique, Bertelsen CA et al [9] in a retrospective 
study of DFS after CME showed that CME surgery yielded better 4year DFS rates when 
compared to conventional non-CME surgery for patients with stage I colon cancer [9]. 
Data from supplemental trials confirmed the favorable outcomes reported after open CME 
also after minimally invasive approach [10, 11]. Additionally, in a recent study performed by 
Spinoglio, et Al [12] both laparoscopic and robotic right colectomy with CME were reported 
to be safe and feasible and resulted unsuccessful survival. 
At the moment, data from literature confirm that CME can guarantee: 
- a superior quality of the specimen in terms of integrity of anterior and posterior leaves, area 
of the resected mesentery distance from the tumor center to ligation of ICA and MC. Table 1, 
Kim NK [16].  
- A higher number of LN retrieved. Table 1, Table 2, Kim NK [16].  
- A better disease-free survival at 3 years (Table 2. Kim NK [16] with a medium survival gain 
close to 8-10 %.   
- A Lower local relapse.   
- A better disease-specific survival at 5-year.  
Table 3., Hohenberger [7], G. Galizia,[24]. 
On the opposite a longer operative time has been observed in the majority of reports; 
Overall, all systematic reviews and metanalyses of CME report morbidity and mortality rates 
comparable to those observed after non-CME. A higher rate of intraoperative injuries to the 
superior mesenteric vein and spleen was showed only in one study, although it seems 
directly correlated with the surgeon experience, Table 3. G. Galizia,[24].  
The importance of a higher number of  LN harvest using the CME + CVL is supported by the 
research published by Jhonson PM et al.[26] who examined the number of negative and 
positive nodes of 20,702 specimens obtained from patients  with stage IIIB and IIIC Colon 
Cancer and described the Disease-specific survival by substage according to the number of 
negative nodes identified and created a proportional hazards model to determine the effect 
of the number of negative nodes on survival ; In stage IIIB and IIIC patients, the Authors 
reported a significant decrease of disease-specific mortality  as the number of negative 
nodes increased (P< .0001).  
In patients with stage IIIC cancer with 13 or more negative nodes,  the reported 5-year 
mortality was 42%as compared to  65% of those with three or fewer resected negative LN  
(P <.0001); In stage  IIIA  patients, there was no association between the number of 
negative nodes identified and the disease-specific survival.  
Thereby, a higher number of negative nodes yielded is an important independent prognostic 
factor of DSS in patients with stage IIIB and IIIC colon cancer. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
One- to 5-year survival rate in node-positive right-sided colon cancers undergoing potentially curative 
surgery. CME group vs. classic group 2: HR=0.25 (95 % CI 0.11–1.02), p =0.05 
 
 
 

Table 4 
 
 2015  
Denmark 
Bertelsen CA, 
et al. [9] 
 
Retrospective study  
 
Left and right Colectomy 
CME, 364 pts, 4-year DFS  85·8% 
non-CME 1031 pts, 4-year DFS 75·9% 
Multivariable Cox regression showed that CME 
surgery was a significant, independent predictive 
factor for higher DSF for all patients. 
After propensity score matching, DFS was 
significantly higher after CME, irrespective of 
UICC stage, with 4-y DFS of 85·8% (95% CI 
81·4–90·1) after CME and 73·4% (66·2–80·6) 
after non-CME (log-rank p=0·0014). 
2014 
Italy  
G. Galizia, et 
al [24]  
Prospective study  
 
 Right Colectomy 
Number of harvested nodes and length of 
vascular ligation significantly better in CME 
(pௗ<ௗ0.01). 
A higher number of tumor deposits were 
harvested thus allowing chemotherapy in newly 
upstaged patients. 
Locoregional recurrences were never 
experienced in CME patients (pௗ=ௗ0.03). The risk 
of cancer-related death was reduced by over one 
half in all CME patients, and even by three 
quarters in node-positive tumors. 
The non-CME was significantly associated with 
poor outcome (pௗ<ௗ0.01). 
2011 
Denmark  
Bertelsen CA, 
et al. 
 
Prospective study  
 
Left and right Colectomy 
198 patients divided into two groups, those treated 
before (93) and those after (105) June 2008 when 
CME was introduced as a standard procedure.  
The overall mean high tie increased from 7.1 to 9.6 
cm (P 0.0001)   
the mean number of harvested LN from 24.5 to 
26.7 (P=0.0095).  
the risk of complications was not statistically 
different.  
The median length of hospitalization increased 
from 4 to 5 days (P= 0.04). 
2010 
Greece 
Pramateftakis 
MG.  
 
Prospective study  
 
 Right colectomy 
CME and high ligation in 115 patients undergoing 
a right hemicolectomy.  
postoperative morbidity was 13.9% (16/115)  
the overall 5-year survival: 72.4% (55/76). 

2010  
UK  
West NP et al.  
Prospective/retrospective 
 
Left and right Colectomy 
tissue morphometry and grading the plane of 
surgery in 49 CME + CVL specimens, and 40 
standard specimens  
tissue was removed with CME and CVL compared 
with µstandard¶ surgery in terms of distance 
between the tumor and the high vascular tie, the 
length of large bowel and ileum removed and the 
area of mesentery.  
A greater LN harvest (median, 30 vs 18; P< 
0.0001) and more accurate mesocolic plane 
resection (92% vs 40%; P < 0.0001) in CVL and 
CME.   
removal of an intact mesocolon in the mesocolic 
plane was oncologically superior implying a 15% 
overall survival advantage at 5 years  
2009 
Germany 
Hohenberger 
W, et al.  
 
Prospective study  
 
Left and right Colectomy 
data analysis from 1329 pts with R0 resection after 
colon cancer surgery from 1978 to 2002.  
The 5- year recurrence rate was reduced from 
6.5% to 3.6%  
the cancer-specific 5-year survival rate increased 
from 82.1% to 89.1%. 
 
 
 
 
 
 
6. PURPOSE. 
This study aims to compare the disease-free survival of the right hemicolectomy with 
CME+CVL with that of the standard non-CME right hemicolectomy in patients with stage II-
IV a right colon cancer  
 
 
 
7. GOOD CLINICAL PRACTICE 
The trial will be carried out following the Declaration of Helsinki [17], after approval of   the 
Ethics Committee of SLUH, Orbassano and afterwards by the Ethics Committees of each 
participating center. 
The protocol, the final version of the Patient Information Sheet, Consent Form, and all 
written information given to trial subjects must be approved or given a favorable opinion in 
writing by an Ethics Committee as appropriate. 
 
 

8.  STUDY OBJECTIVES. 
This is a National Multicenter Randomized Controlled Trial comparing two arms of treatment, 
the CME +CVL and the standard non-CME procedure in patients with right colon cancer.  
 
The primary endpoint is:  
- The 3-year DFS   
 
The secondary endpoints are:  
- Safety:  
- Operative time. 
  
 
- Intraoperative blood loss.  
  
 
- Intraoperative blood transfusion.  
  
 
- Intraoperative complications.  
  
 
- Early postoperative complications.  
  
 
- Late postoperative complication  
  
 
- Length of stay.  
  
 
- Postoperative mortality. 
- Oncologic outcomes:  
- The number of positive, negative and total LN harvested.   
- 3- and 5-year Overall Survival.  
- 5-year DFS 
 
- Quality of CME:  
- Area of the mesentery of the specimen  
- Integrity of the anterior and posterior leaves 
- Length from the tumor centre to the ligature of the ICA 
- Length from the tumour center to the ligature of the right 
branch or the main trunk of the MCA 
- Benz classification of the specimen quality 
 
- Quality of life (QoL).  
EORTC C-29/C-30 and SF36 
 
 
 
 
 
 
 
 
 

9.STUDY DESIGN  
OVERVIEW OF THE STUDY DESIGN 
This is a National multicenter randomized controlled trial in patients with a tumour of the right 
or proximal transverse colon as a primary diagnosis, requiring right hemicolectomy. 
All patients who meet the inclusion/exclusion criteria and agree to sign the informed consent 
will be randomized to receive the CME + CVL or the standard non-CME procedure. 
 
DURATION OF THE STUDY  
Estimated start date: 3/2020 
Estimated duration of the enrollment: according to the number of participants centres.  
(About 24 months) 
Estimated duration of participation: 36 months. 
Estimated duration of Follow-up: 60 months 
 
STUDY SETTING  
This is a Multicentre study conducted in Italian referral centres for colorectal cancer surgery 
and research coordinated by the Department of Oncology of SLUH, Turin, Italy. 
 
CENTERS RECRUITMENT STRATEGY. 
This protocol has been   presented, discussed and accepted in several colorectal cancer 
network meetings of the Italian Society of Surgical Oncology (SICO). Only national referral 
centres for colorectal cancer surgery and research with at least 30 procedures/year for right 
colon cancer   will be registered as enrolling centres in this trial. 
Each participating centre will be provided with a master video explaining the correct 
technique of CME and non-CME. A Scientific Committee will prepare these videos. The 
Scientific Committee includes the coordinating centre and two of all participating centres, 
chosen by the highest number of CME performed together with the highest H-index score of 
the participating centre PI.    
This Scientific Committee (also called Expert Panel) will evaluate the adequacy of all the 
steps of the technique performed in each participating centre through unedited movies 
prepared and sent by each centre. Additional pictures of the specimens at the end of the 
procedure will allow assessing each specimen according to the classification of S. BENZ et 
Al., which directly reflects the quality of the procedure [27]. 
Provisions for treating and/or compensating subjects who are harmed as a consequence of 
their participation in the study have been defined. The policy will be released to each ethic 
committee of the participant centers after the protocol approval. (Please find the quote policy 
by MEDICAL & COMMERCIAL INTERNATIONAL (ON BEHALF OF CERTAIN 
UNDERWRITERS AT LLOYD¶S) 4TH FLOOR 33 GRACECHURCH STREET LONDON 
EC3V 0BT UNITED KINGDOM in the annexes documents).  
 
 

STUDY POPULATION 
Patients are eligible to be included in the trial if they meet the following criteria: 
Inclusion criteria:  
Age > 18, 
ASA score I to III,  
Right colon cancer T2-T4a, any N. (*The right-sided location of the 
cancer is defined as the location from the caecum up to the proximal 
third of the transverse colon) 
N positive, any T 
*All patients will be staged by computed tomographic scan and will have an endoscopically 
and histologically proven malignant colon cancer. 
 
Exclusion criteria:  
Age > 85 years old.  
T1, N0 
T4b, any N 
BMI > 30.  
Metastatic disease (Abdominal and chest CT scan will be mandatory 
to exclude distant metastasis.) 
ASA IV. 
History of previous cancer,  
Need for Emergency surgery, 
Infectious disease requiring treatment. 
Pregnancy. 
Use of systemic steroids. 
No history of familial adenomatous polyposis, ulcerative colitis or 
Crohn's disease. 
 
 
 
10. ENROLLMENT, RANDOMIZATION AND ALLOCATION. 
The Investigator(s) must obtain the informed consent and the consensus for the treatment of 
sensitive data (according to the Regolamento Europeo sulla Protezione dei Dati (GDPR) n. 
679/2016a partire dal 19 settembre c.a., del D.Lgs n. 101 del 10 agosto 2018 pubblicato 
sulla Gazzetta Ufficiale del 04 settembre c.a.) of the patient or his/her designee before any 
procedures.   
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time and choosing not to participate will not affect the care or 
the treatment of their disease.   
Subjects will be told about alternative treatments available if they refuse to take part in the 
study and that such refusal will not prejudice future treatment.  
The subject or legally acceptable representative will be given enough time to read the 
informed consent form and the opportunity to ask questions. After this explanation and 
before entry into the study, consent should be appropriately recorded through either the 
subject's or his/her legally acceptable representative's dated signature.  
A copy of the signed informed consent form must be given to the subject.  
If the subject or legally acceptable representative is unable to read or write, an impartial 
in the past 5 years.

witness should be present for the entire informed consent process (which includes reading 
and explaining all written information) and personally date and sign the informed consent 
form after the oral consent of the subject or legally acceptable representative is obtained. 
The original consent form signed and dated by the patient and by the person consenting the 
patient before the patient's entry into the study must be maintained in the Investigator's study 
files and a copy given to the patient.  
Besides, if a protocol is amended and it impacts on the content of the informed consent, the 
informed consent must be revised. Patients participating in the study when the amended 
protocol is implemented must be re-consented with the revised version of the informed 
consent. 
 
RANDOMIZATION 
All included patients will be randomized with a 1:1 ratio between the two treatments CME + 
CVL vs. standard non-CME right colectomy. All surgical approaches (open, LPS or Robotic) 
are allowed.  
The randomization sequence will be generated centrally by a computed algorithm and kept 
concealed to investigators. 
The random assignment will be continuously available on a dedicated web-based platform. 
 
 
 
11. TREATMENT. 
PREOPERATIVE PREPARATION. 
Patients with colon cancer do not receive any mechanical bowel preparation and oral 
antibiotics and   fast only from midnight of the night before the surgery. 
The first-generation cephalosporin are used as a prophylactic antibiotic and administered 
just before the start of surgery and during the first postoperative day. 
If necessary, low molecular weight heparin is administered for thromboprophylaxis. 
 
GENERALITIES 
A video session will be prepared by the CI explaining the optimal technique of CME with 
CVL.  
 
CME 
A proper CME+CVL technique must include: 
1) Separation of the visceral fascia from the parietal fascia by sharp dissection leaving intact 
mesocolon coverage. Eventual defects of the anterior and posterior leaves will be annotated 
as percentage of the integrity (up to 100%) in the quality assessment measurements.  
 

2) Transecting the supplying vessels at their origin from the main vessels, in particular:  
- The Ileocolic Vein and Artery at their origin from the Superior Mesenteric Vessels. 
In particular, the SMV should be cleared from all adipose tissue all along its anterior 
surface until its intrapancreatic entrance.  
- The Right Colic Vein and Artery at their origin from SMV or Gastrocolic Trunk of 
Henle (GCTH) and from SMA,  
 - The superior right colic vein (when present) at its origin from the GCTH   
- The Right branches of the Middle Colic Vein (MCV) and of the Middle Colic Artery 
(MCA) at their origin from the main branches of the MCV and the MCA. 
- The MCV and MCA at their origin from the SVM (or the GCTH) and the SMA, in 
case of cancer of the hepatic flexure or of the very proximal third of the transverse 
colon, as well as The Right Gastroepiploic Vein and artery at their origin from the 
GCTH and the gastroduodenal artery 
 
NON-CME 
A standard non-CME procedure entail: 
- Transecting the Ileocolic Vein and Artery close to the Superior Mesenteric Vessels 
without clearing the SMV from the adipose tissue all along its anterior and medial 
surface  
- Transecting the Right Colic Vein and Artery peripherally, not at their origin from 
SMV or Gastro colic Trunk of Henle (GCTH) and from SMA,  
- Transecting the superior right colic vein (when present) peripherally, not at its   
origin from the GCTH   
- Transecting the Right branches of the Middle Colic Vein (MCV) and of the Middle 
Colic Artery (MCA) peripherally, not at their origin from the main trunk of the MCV 
and the MCA or anyway without clearing the main trunk of the MCV and of the MCA 
- The Right Gastroepiploic Vein and artery are never transacted. 
 
Both open and minimally invasive (laparoscopic and robotic) approaches can be used.  
Despite the surgical approach and the type of procedure adopted, the operation should be 
strictly conducted following the general rules for colorectal oncologic resection (See, for 
example, “Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 
for the treatment of colorectal cancer. Int J Clin Oncol. 2020 Jan); 25(1): 1-42. Doi: 
10.1007/s10147-019-01485-z. Epub 2019 Jun 15 “) particularly as concerns proximal and 
distal margins length and lymph node retrieval. 
A side-to-side anastomosis is usually performed, although an end-to-side anastomosis is 
also fashioned, particularly during the extracorporeal procedure. End-to-end anastomosis is 
rarely performed. 
The enterotomy is often hand-sutured, although its mechanical closure has been described 
and it's performed in few centers. 

Therefore, during minimally invasive procedures, both intracorporeal and extracorporeal 
anastomosis may be considered in this setting, with either side-to-side or end-to-side 
fashioning. Closure of the enterotomies may be performed either manually or mechanically 
(linear staplers), according to the surgeons' preference. 
Manual Reinforcement of a mechanical anastomosis is left to the surgeons' choice. 
In open surgery, totally hand-sewn anastomosis is still performed in some centres and 
therefore can be performed as an alternative to stapled anastomosis depending on each 
surgeon's custom.  
 
 
 
 
12. SCHEDULE OF CLINICAL ASSESSMENT AFTER TREATMENT. 
Postoperative months  
1 
3 
4 
6 
9 
12 
18 
24 
30 
36 
DFS 
 
 
 
 
 
X 
 
X 
 
X 
Postoperative mortality  
X 
 
 
 
 
 
 
 
 
 
EORTC C-29/C-30 and 
SF36  
 
 
X  
 
 
X  
 
 
 
 
Clinical assessment  
 
X  
 
X  
X  
X  
X  
X  
X 
X 
CT 
 
 
 
X 
 
X  
 
X  
 
X  
CEA  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Colonoscopy  
 
 
 
 
 
X  
 
 
 
 
Overall Survival  
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 

13.     EFFICACY AND SAFETY MEASUREMENTS 
The primary aim is to describe the DFS of the CME + CVL procedure in patients with a 
malignant tumor of the right or proximal transverse colon, and to compare it with that of the 
standard non-CME operation.  
DFS is defined as the length of time (months) after randomization (and surgical treatment, 
CME or non-CME) that the patient survives without any signs or symptoms of colon cancer. 
[Time frame: at 12 36 months after surgery]. 
*Patients who are lost to follow-up will be censored at their last assessment date. 
An absolute improvement of 0.10 of the 3-years DFS (from 0.70 to 0.80) is considered 
clinically promising the experimental treatment. 
The secondary aims are:  
1) To compare the safety of CME in terms of:  
- Operative time  
- Intraoperative blood loss  
- Intraoperative blood transfusion  
- Intraoperative Complications 
- Early postoperative complications 
- Late postoperative complication  
- Length of stay 
- Postoperative mortality 
 
OPERATIVE TIME. Total time from incision to skin closure expressed in minutes.  
[Time frame: after the intervention has ended] 
INTRAOPERATIVE BLOOD LOSS. Defined by the volume drained in cm2 into aspiration 
systems and weight of gauzes, calculated, subtracting the weight of the dry gauzes and 
volume of saline solution used for irrigation.  
[Time frame: after the intervention has ended] 
INTRAOPERATIVE BLOOD TRANSFUSION. Defined as the number of red blood cells 
units, platelets or plasma transfused during surgery and up to 24 h thereafter 
[Time frame: at 24 of the postoperative periods] 
INTRAOPERATIVE COMPLICATIONS. Defined as any deviation from the ideal 
intraoperative course occurring between skin incision and skin closure according to the 
Intraoperative Adverse Event Severity Classification [19]  
[Time frame: after the intervention has ended]. 
EARLY POSTOPERATIVE COMPLICATIONS. Defined as any event untoward correlated 
with the intervention within 30 days after surgery according to the Clavien-Dindo 
classification [20].  
[Time frame: at 30 days] 
LATE POSTOPERATIVE COMPLICATIONS. Defined as any event untoward correlated with 
the intervention 30 days before surgery according to the Clavien-Dindo classification [20]. 
[Time frame: at 3 months after intervention] 
LENGTH OF STAY.  A term defined as the length of an inpatient episode of care, calculated 
from the day of operation to the day of discharge and based on the number of nights spent in 

the hospital.  
[Time frame: ate the patient discharge] 
POSTOPERTIVE MORTALITY. Defined as any death, regardless of cause, occurring within 
30 days after surgery in or out of the hospital.  
[Time frame: at 30 posts surgical day] 
2) To compare the CME+CVL with standard non-CME treatment in terms of:  
- Positive, negative and total LN harvest 
- 5-year DFS 
- 3- and 5-year Overall Survival 
- Quality of life (QoL) 
 
OVERALL SURVIVAL (OS). Defined as the time from random assignment to the date of 
death due to any cause.  
[Time frame at 36 and 60 months] or to the date of censoring at the last time the subject was 
known to be alive in intention-to-treat populations.  
QUALITY OF LIFE (QoL). 
Defined as the overall satisfaction with life, or, a sense of personal psychological, physical 
and social well-being in being self-determining, independent and satisfied with control of 
disease processes using the punctuation of the EORTC C-29/C-30 and SF36  
[time frame: at 4 and 12 months after the treatment.] 
 
3) To describe the Quality of CME as performed in participating centers, by  
- Measuring the specimen µs area of the mesentery (cm2) 
- Defining the integrity of its anterior and posterior leaves (% with respect to a 100 pc of 
integrity)  
- Measuring the length from the tumor centre to the ligature of the ICA (cm) 
- Measuring the length from the tumor centre to the ligature of the right branch or the main 
trunk of the MCA (cm) 
- Assessing the Benz classification score to each specimen quality (0 to 3) [27].   
 
 
 
 
 
 
 
 
 
 

14. STATISTICAL CONSIDERATIONS 
STUDY DESIGN 
This is a national, multicenter, randomized, controlled, parallel-groupie trial in patients with 
malignant tumor of the right or proximal transverse colon as a primary diagnosis, requiring 
right hemicolectomy. 
 
SAMPLE SIZE CALCULATION 
Parameter specifications can be as follows: 
The study sample size has been calculated according to primary efficacy endpoint (DFS).  
An absolute improvement of 0.10 of the 3-years DFS (from 0.70 to 0.80) is considered 
clinically promising the experimental treatment.  
According to a single-stage (fixed sample size) design provided by Formula of Schoenfeld, 
Biometrika, Schoenfeld DA. Sample size formula for the proportional-hazards regression 
model. Biometrics 1983; 39:499-503, with 24 months of enrollment and 36 months of 
minimum follow-up, a total of 416 patients (208 each arm) are required to detect an increase 
in the 3-years DFS from 0.70 to 0.80 assessed with an alpha error of 5% (two tails) and a 
statistical power of 80% considering the 10% of follow up lost. 
Reference: Schoenfeld DA. Sample size formula for the proportional-hazards regression 
model. Biometrics 1983; 39:499-503.  
 
STATISTICS ANALYSIS 
Demographic and baseline characteristics will be presented for all patients. Discrete 
variables will be summarized by frequencies and percentages. Continuous variables will be 
summarized by use of standard measures of central tendency and dispersion (mean and 
standard deviation or median).  
Descriptive analyses will be performed using absolute frequencies and percentages for 
qualitative variables and means and standard deviations or medians and interquartile ranges 
for quantitative variables, depending on the normality of the distributions that will be tested 
using the Kolmogorov-Smirnov test. 
The univariate analysis will consider comparison between the two groups for all the relevant 
variables, using the appropriate tests (chi-square test for qualitative variables, t-test for 
quantitative normally distributed variables, and Wilcoxon sum rank test for quantitative not-
normally distributed variables). 
All outcomes (primary and secondary) will be compared between the two groups using the 
aforementioned tests. 
To control for confounders, multivariable semi-parametric Cox models will be performed, 
adjusting for all the relevant confounders (identified both biologically and from univariate 
analysis). Follow-up time will be defined as the time from recruitment to end of follow-up, 
death, loss-to-follow-up, or events occurrence (when the event is not death), whichever 
occurs first.  
To control for proportionality of hazards, Schoenfeld residuals will be considered. 

All analyses will be performed using STATA v15. 
After 12 months, the outcomes will be analyzed in order to evaluate 
advantages/disadvantages of the study, to perform pertinent amendments or end the study 
prematurely. 
 
 
15. VARIABLES  
Demographic variables. (See the Trial CRF for more details) 
- Age 
- Gender 
 
Clinical and preoperative variables. 
- ASA score 
- BMI 
- Comorbidities 
- Preoperative Carcinoembryonic Antigen (CEA) serum level 
- Tumor size 
- Tumor location 
- Grading  
 
Surgical characteristics. 
- Operative time 
- Intraoperative blood loss 
- Intraoperative transfusion 
- Intraoperative complications 
-Type of approach  
- Anastomosis type  
- Drain placement 
- Vascular ligature 
- Lymphadenectomy characteristics 
 
Postoperative characteristics 
- Postoperative blood loss (drain output within 72 hours) 
- Postoperative transfusion 
- Bowel movements 
- Return to oral feeding 
- Drain removal 
- Length of stay 
- Early complications type  
- Early complications by Clavien-Dindo Classification 
- Late complications type  

- Late complications by Clavien-Dindo Classification 
- Postoperative mortality. 
 
Pathological characteristics. 
- Resection margins 
- Length of the specimen 
- Distance of the tumor from thee vascular ties (ICA, MCA) 
- Area of the resected mesocolon 
- WHO histological classification.  
- TNM staging 
- Total number of LN retrieved 
- Number of positive LN retrieved 
- Number of positive LN specifically recruited in LN station during CME procedure (optional, 
but recommended) (at the proper origins of the ileocolic vessels, the right colic vessels, the 
gastroepiploic vein, the right branch of the middle colic vessels or the main trunk of middle 
colic vessels) 
- Status till the last follow-up. 
*For both groups the vessels ligated, and the level of these ligation will be recorded 
(ileocolic, right colic, gastroepiploic, the right branch of the middle colic, the origin of the 
middle colic vessels). 
*For the case-control group the same variables (with the exclusion of the number and the 
positivity of LN in nodal stations specifically recruited in the CME procedure) will be 
analyzed. 
 
 
 
16. REPORTS, DISSEMINATION, PUBLICATION AND CONFIDENTIALITY.  
DISSEMINATION  
The results of the trial will be reported first to trial collaborators during the meeting of the 
Colorectal Cancer Network of the Italian Society of Surgical Oncology.  
Individual unit data will be presented at local meetings. The main report will be drafted by the 
trial coordinating team, and the final version will be agreed by the Steering Committee before 
submission for publication, on behalf of the collaboration. 
The trial will be reported following the Consolidated Standards of Reporting Trials 
(CONSORT) guidelines (www.consort-statement.org). [2] 
Overall collective data will be published in peer-reviewed journals and presented at relevant 
surgical meetings. 
PROTOCOL AMENDMENTS  
Any modifications to the protocol which may impact on the conduct of the study, a potential 
benefit of the patient or may affect patient safety, including changes of study objectives, 
study design, patient population, sample sizes, study procedures, or significant 
administrative aspects will require a formal amendment to the protocol. Such amendment 

will be agreed and approved by the Ethics Committee before implementation and notified to 
the health authorities following local regulations. 
DECLARATION OF INTEREST  
The authors certify that they have NO affiliations with or involvement in any organization or 
entity with any financial interest (such as honoraria; educational grants; participation in 
speakers' bureaus; membership, employment, consultancies, stock ownership, or other 
equity interest; and expert testimony or patent-licensing arrangements), or non-financial 
interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in 
the subject matter or materials discussed in this manuscript.  
ACCESS TO DATA  
All Principal Investigators will be given access to the cleaned data sets. 
CONFIDENTIALITY.  
Participants' study information will not be released outside of the study without the written 
permission of the participant, except as necessary for monitoring by the country government 
and regulatory authorities. 
For protecting confidentiality and anonymity will be mandatory the employ of study codes on 
data documents (CRF) and keep a separate document that links the study code to subjects¶ 
identifying information locked in a separate location.  
All participant information will be stored in locked file cabinets in areas with limited access 
and all local databases will be secured with password-protected access systems.  
Forms, lists, logbooks, appointment books, and any other listings will be stored in a 
separate, locked file in an area with limited access (only allowing primary investigators 
access). 
All the Investigators must respect the treatment of sensitive data according to the 
Regolamento Europeo sulla Protezione dei Dati (GDPR) n. 679/2016 a partire dal 19 
settembre c.a., del D. Lgs n. 101 del 10 agosto 2018 pubblicato sulla Gazzetta Ufficiale del 
04 settembre c.a.) of the participants. 
 
 
 
 
17. END OF TRIAL  
The trial will be stopped prematurely if recommended by the Ethics Committee; by the 
IDSMC. 
The trial will be stopped prematurely after 12 months of enrolment in the absence of a clear 
advantage of the CME intervention at interim data analysis. 
The trial  Ethics Committee will be notified in writing if the trial has been concluded or 
prematurely terminated . 
 
 
 

CENTRE 
Surgeon 
Contact E- Mail
Address
Università 
Federico II di 
Napoli
Francesco 
Corcione. 
Umberto Bracale
francesco.corcione@unina.it 
umbertobracale@gmail.com
Corso Umberto I 40 - 80138 
Napoli
ASST Nord 
Milano - P.O.  
SSG
Gianandrea 
Baldazzi. 
Diletta CassiniI.
gbaldazzi@hotmail.com 
diletta_cassini@yahoo.it
P.O. “Citta” di Sesto San Giovanni 
Via Matteotti 83 – Sesto San 
Giovanni  
Ospedale E. 
Agnelli 
Pinerolo
Andrea Muratore.
amuratore@aslto3.piemonte.it
Via Brigata Cagliari, 39, 10064 
Pinerolo TO
Azienda Usl 
Toscana 
sud est
Paolo Pietro 
Bianchi.
bianchippt@gmail.com
Via Curtatone, 54, 52100 Arezzo 
AR
Struttura di 
chirurgia HPB 
e Colorettale 
di Candiolo 
Giuseppe 
Spinoglio. 
Dario Ribero.
gspinoglio@icloud.com 
dario.ribero@ircc.it
SP142, km 3,95, 10060 Candiolo 
TO
AUSL 
Bologna 
Elio Jovine. 
Raffaele Lombardi
elio.jovine@ausl.bologna.it
Via Castiglione, 29, 40124 
Bologna BO
Università 
degli Studi di 
Ferrara
Gabriele Anania.
g.anania@unife.it
Dipartimento di Scienze mediche 
Corso Giovecca 203 
44121 - Ferrara
Policlinico A. 
Gemelli Roma
Domenico D’Ugo 
Alberto Biondi
Biondi.alberto@gmail.com
Sede Operativa Largo Agostino 
Gemelli 8, 00168 Roma 
AOU G. 
Martino - 
Messina
Giuseppe Navarra
gnavarra@unime.it
Via Consolare Valeria 1 - 98124 
Messina (ME) 
IRCCS 
Policlinico 
San Martino 
Genova
Stefano Scabini
stefanoscabini@libero.it
Largo Rosanna Benzi, 10, 16132 
Genova GE
Tor Vergata 
Roma
Giuseppe Sica
sigisica@gmail.com
PTV, viale Oxford 81, 00133 
Roma 
piano I TORRE 9, studio 19
Ospedale S. 
Andrea La 
Spezia
Stefano Berti 
Andrea Gennai
stefano.berti@asl5.liguria.it 
andrea.gennai@asl5.liguria.it
Via Vittorio Veneto, 197, 19121 
La Spezia SP
Istituto 
Europeo di 
Oncologia
Fumagalli 
Romario Uberto  
Adamoli Laura
uberto.fumagalliromario@ieo.it 
laura.adamoli@ieo.it 
Via Ripamonti, 435 - 20141 
Milano
18. COLLABORATORS

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