SECOND UNIVERSITY OF NAPLES – SCHOOL OF MEDICINE
" "F. Magrassi and A. Lanzara" Department of Clinical and Experimental Surgery
Chair of General Surgery
Surgical Oncology
Naples, 18 December 2007
Evaluation of safety and oncological adequacy of complete mesocolic excision with central
vascular ligation in histologically proven adenocarcinoma of the right colon undergoing
potentially curative right hemicolectomy
Protocol of the study
Complete mesocolic excision (CME) with central vascular ligation (CVL) has been proposed for
treatment of colon cancer based on the same principles as total mesorectal excision. Impressive outcomes
have been reported, however direct comparisons with the classic procedure are lacking.
From January 2008, all consecutive patients with histologically proven adenocarcinoma of the right
colon, referred to the Division of Surgical Oncology - School of Medicine -Second University of Naples,
eligible for potentially curative right hemicolectomy will be enrolled, provided written informed consent
is obtained, in order to be operated on with a surgical procedure including:
1) Median laparotomy;
2) Lateral access to mobilize the right colon;
3) Sharp dissection of the visceral fascia layer from the parietal one up to the mesenteric root, at the
origin of the superior mesenteric vessels (complete mesocolic excision);
4) Ligation of the ileocolic, right colic (if present), and right branch (cancer of hepatic flexure) or mean
trunk of the middle colic vessels (cancers of the right transverse colon), at their origin from the
superior mesenteric vessels (central vascular ligation);
5) Ileal and bowel resection, followed by ileocolic anastomosis, as usual;
6) At the end of the operation, evaluation by a surgeon and a pathologist, on the fresh specimen, of the
length of resected bowel and the high tie value, defined as the shortest distance between the tumor and
the ligation point of vessels supplying the tumor.
These patients will represent the CME group, and they will be compared with patients with
histologically proven adenocarcinoma of the right colon who had undergone conventional right
hemicolectomy in the preceding years. Since oxaliplatin became available on July 2004, all patients
treated from July 2004 to December 2007 will be considered as classic group, in order to avoid disparities
between the two groups (namely, different regimens of adjuvant chemotherapy).
For both groups patients meeting the Amsterdam II criteria for hereditary non-polyposis colorectal
cancer syndrome or with carcinoma associated to inflammatory bowel disease will be considered
ineligible since recurrence and survival rates are known to differ from those of sporadic large bowel
carcinomas.
Palliative operations, namely noncurative resections or ileocolic by-pass, will be excluded by further
analyses since such procedures might cause misinterpretation of the results related to survival rate.
Sample size estimation
The actuarial recurrence and disease-free survival rates in the right-sided colon cancer patients,
undergoing conventional right hemicolectomy have been 24% and 75%, respectively.
The study has been designed assuming that the new surgical procedure might significantly reduce the
local recurrence rate resulting in a 20% increase in the 5-year survival rate.
A sample size of at least 51 patients will therefore be required to give a 80% power (type II error) for
a two-sided significant difference reaching a p value of 0.05 (type I error < 5%).
Interim Analysis
In July 2008, external evaluators (Prof. Carlo Pignatelli as team leader) will perform the first interim
analysis to assess the intra and postoperative complication rates. The next interim analysis will be
performed in January 2009. If intra and postoperative complication rates will be judged unacceptable,
the study will be stopped.
End-points
At the end of the study the historical group and the group undergoing CME with CVL will be
compared. Safety of the procedure will be assessed by evaluating operation time, total intraoperative
blood loss, and postoperative complication rate.
Primary end-points for oncological adequacy will be survival rate and total and loco-regional tumor
recurrence rates (defined as histologically proven recurrent carcinoma into the region of lymphatic
drainage of primary resection or peritoneal relapse).
Secondary end-points will be length of the resected bowel and high tie value, number of harvested
nodes, and tumor deposits (defined as presence of extranodal cancer cells in the mesentery or
nonperitonealized pericolic tissue).
Statistical analysis
Statistical analysis will be carried out using the SPSS statistical package (SPSS Inc., Chicago, Illinois)
integrated by the Medcalc® software version 9.4.2.0 (Mariakerke, Belgium). In all analyses, the
significance level will be specified as p < 0.05. The equality of group means and comparisons between
proportions will be analyzed by using unpaired Student's t test and chi-square test, respectively. Patients
deceased for causes other than colon cancer without evidence of disease will be regarded as censored
events for cancer-related mortality rate or disease-specific survival (DSS). Univariate statistical analysis
will be determined by log-rank test (Mantel-Cox); curves will be plotted using the Kaplan-Meier method,
and p values and hazard ratios (HR) with 95% confidence interval (CI) will be generated. The
independent significance of each factor will be determined by Cox’s proportional hazards model,
following inclusion of prognostic variables showing a p value < 0.1 at univariate analysis. A stepwise
multivariate analysis will be performed in order to generate a model of the best linear combination of
variables predicting DSS.
Professor Gennaro Galizia will be the sole responsible for the whole procedure.
The study, in its original version, is approved today by the Ethical Committee of the Department of
Clinical and Experimental Medicine and Surgery of the Second University of Naples with ref. n°
00134/2007, 18 December 2007.
Dr. Gennaro Galizia,MD,PhD
Associate Professor of Surgery
Second University of Naples School of Medicine
"F. Magrassi - A. Lanzara" Dept of Clin & Exp Med & Surgery
c/o II Policlinico, Edificio 17
Via Pansini, 5
80131 Naples, Italy
Tel. +39-081-566-6613 Fax +39-081-566-6637
e-mail gennaro.galizia@unina2.it