Outcome measures
Primary outcomes
The primary endpoints are safety, efficacy, and being oncologically clear. Perioperative morbidity will be divided into intraoperative morbidity observed during the operation and postoperative morbidity observed during the hospital stay and within 30 days at the outpatient clinic. Postoperative morbidity will be assessed according to the Clavien-Dindo classification. Real-time polymerase chain reaction (RT-PCR) will be used to test whether the novel total “no-touch” isolation technique could potentially reduce tumor cells shedding into the portal circulation, peripheral circulation and peritoneal cavity. Other primary outcomes include 3-year disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and recurrence pattern (local recurrence, metastasis).
Secondary outcomes
Secondary endpoints will be measured and recorded prospectively on a case report form (CRF). Intraoperative outcomes include operation time, blood loss, intraoperative complications, and incision length. Pathologic evaluation includes tumor size, grading the plane of surgery (mesocolic plane, intramesocolic plane, muscularis propria plane), length of proximal and distal resection margins, distance between the tumor and the central arterial high tie, distance between the nearest bowel wall and the same high tie, area of mesentery resected, width of the chain of lymph-adipose tissue (the width of the central lymph node region through the high tie), length of the central lymph-adipose chain (the length of the central lymph node region through the high tie), and number of harvested lymph nodes. Postoperative inflammation and immune response (procalcitonin (PCT), C-reactive protein (CRP), interleukin (IL)-6) will be measured at 24 h, 72 h, and 120 h postoperatively. A horizontal visual analogue scale with a 0 to 10 cm scale will be used to measure pain intensity on postoperative days 1, 3, and 5. Postoperative recovery including time to first flatus, liquid diet, and duration of hospital stay will be recorded daily in hospital.
Follow-up
The follow-up is consistent with the National Comprehensive Cancer Network (NCCN) guidelines. Within 1 month after surgery, all the consecutive patients in this prospective study will meet the chief surgeon in the outpatient clinic for checking of wounds, recording any complications arising after discharge, and determining the optimal schedule of adjuvant chemotherapy according to the pathohistology. Then 3 months after surgery, and every 3 months for the first 2 years, participants will be followed-up. After 2 years, the surveillance interval will be every 6 months until 3 years or dropout. Data are collected prospectively, including physical examination, blood tests (blood cell count and blood chemistry), tumor markers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9)) every 3 months and CT scans of the chest and abdomen every 6 months. Colonoscopy will be performed 1 year after surgery and will be repeated at 3 years if no lesions are found.
Sample size and statistical analysis
As the primary aim of the prospective trial is exploratory, no sample size calculation is performed. The statistical tests will be performed in the SPSS software program (version 13.0, SPSS, Chicago, IL, USA). A two-sided P value less than 0.05 will be considered statistically significant. Descriptive statistics will be used for baseline demographic and clinical characteristics of participants (i.e., mean and standard deviation for continuous variables, proportions for categorical variables). A χ2 test or Fisher’s exact test will be applied for categorical variables. Student’s t test or the Mann-Whitney U test will be used for continuous variables. Kaplan-Meier curves and log-rank analysis will be used to compare the differences in DFS and OS among the three parallel groups.
Discussion
Since total mesorectal excision (TME) has been accepted worldwide, the survival from rectal cancer has significantly improved, and is even better than for colon cancer in some countries [
14‐
17]. In 2007, CME with CVL for colon cancer was suggested in Western countries which follows similar oncological principles as TME does for rectal cancer [
6]. The principles of CME require resection of the affected colon with its associated lymphovascular supply through complete removal of the mesocolon as an envelope to minimize the risk of spillage of tumor cells into the peritoneal cavity and central ligation of the vascular supply at its origins to increase lymph node harvest. In a series of studies, CME has shown an improved survival and reduced local recurrence when compared with standard surgery [
7,
8,
18,
19].
Realizing that removing draining lymph nodes potentially eliminates the probability of leaving behind residual disease, which has implications for local control and survival, more emphasis is placed on lymphadenectomy in Eastern countries. Moreover, a D3 extended lymphadenectomy is considered the standard of care for clinical stage II and III colon disease in Asian countries, especially in Japan [
20]. Actually, both CME and D3 lymphadenectomy follow the same oncological principles, mainly including excision of the mesocolon within an intact fascial envelope and central vascular ligation. Furthermore, both techniques have shown impressive outcomes as compared with standard excision.
For left-sided colon cancer, exposure and ligation the origin of the inferior mesenteric artery is not difficult, as the TME principles are commonly followed. However, in order to identify the origins of the vessels supplying the right-side colon and perform true D3 lymphadenectomy, the head of the pancreas, the anterior surface of the SMV, and the superior mesenteric artery (SMA) should be fully exposed, which are all technical challenges and more traumatic, leading to longer operation times than the standard operation [
21,
22]. The original CME initially described by Hohenberger was performed via a laparotomy. Due to laparoscopic surgery with short- and long-term benefits, there are a series of studies looking at the feasibility of laparoscopic-CME especially for right colon cancer. Finally, although these studies have shown the feasibility and safety of this procedure with acceptable morbidity and oncological outcomes, laparoscopic right hemicolectomy with CME and true center vascular ligation for right colon cancer remains technically challenging especially for obese patients [
9,
22,
23].
Since HALS returns the sense of touch to the surgeon, this procedure may represent a valid alternative approach to standard laparoscopy. Furthermore, HALS has been shown to eliminate a substantial part of the technical challenges of standard laparoscopy along with having an acceptable learning curve and reducing operative time, but patient morbidity rates and recovery are comparable with standard laparoscopy [
12,
13]. However, this HALS technique allows for hand assistance during laparoscopic surgery and tactile sensation of the lesion, and people argue that this approach is against the “no-touch” isolation technique.
The virtue of the “no-touch” isolation technique is another controversial issue in the field of colorectal disease. In 1952, Barnes first described and adopted a special technique for resection of right colon cancer: ligation of the vascular pedicles and division of the bowel before handling the cancer-bearing segment [
24]. This special technique was first named a “no-touch” isolation technique by Turnbull in 1953, based on previous clinical and basic research [
25]. The aim of this technique is to reduce cancer cells flowing from the primary tumor site to the liver and other organs by ligation of the vascular pedicles first. However, since then, the value of the “no-touch” technique in colon surgery has always been debated. In a retrospective analysis, although Turnbull et al. had demonstrated that “no-touch” isolation resection could greatly improve survival rates compared with conventional manipulative resection, these results might be due to more extended resections in the no-touch group [
25]. The only prospective randomized controlled trial did suggest a limited benefit of the “no-touch” isolation technique with regard to the overall survival, and a tendency for reduction in occurrences of liver metastases [
26]. Another randomized controlled trial is currently underway in Japan to demonstrate the superiority of the special technique (JCOG1006) [
27]. Whether surgical manipulation of the cancer-bear segment would increase the detachment and circulation of tumor cells into the peripheral circulation is also still debated. Hayashi et al. [
28] demonstrated that the “no-touch” isolation technique may prevent cancer cells from being shed into the portal circulation by using mutant-allele-specific amplification, while Garcia-Olmo et al. [
29] found CEA products only in one of eighteen patients who underwent conventional surgery by using RT-PCR.
In this trial, the novel HALS-CME procedure, which takes full advantages of the HALS technique and potential “no-touch” isolation technique, has several technical merits:
1)
After transecting the distal ileum and its mesentery, the distal end of the superior mesenteric vessels are easily exposed, especially for obese patients.
2)
Transecting the transverse colon and returning the two ends back into peritoneal cavity, the neck of the pancreas can be easily observed and be a landmark during lymph node dissection along the left and surface of the SMV, which is true D3 lymphadenectomy.
3)
It is well known that there are fewer venous branch drains into the left of the SMV; dissection along the left axis of the SMV in a repeated unidirectonal/longitudinal manner facilitates location and ligation of the root of the ileocolic vessels, right colic vessels, and Henle’s trunk, avoiding injuring these branches.
4)
After vascular pedicles, the transverse colon, and the distal ileum are ligated, the cancer-bearing segment is manipulated from medial to lateral, which is more consistent with the “no-touch” isolation technique described by Barnes [
24]. The total “no-touch” isolation technique appears to have potential benefits for decreasing tumor cells spreading into the portal vein and circulatory system during the operative manipulation.
5)
After transecting the bowel and ligating feeding vessels, the medial to lateral approach is adopted to avoid direct contact with the tumor. The surgeon’s hand provides better retraction for mobilization of the involved colon and dissection along the Toldt’s fascia, which shortens the operation time.
There are potential limitations in this trial. 1) The trial will be carried out in only one center, which may impact participant recruitment and limit the applicability of the outcomes to other centers. 2) The open-label nature of the trial may cause biased estimates of the treatment effect. However, it is not possible to blind the surgeon for the special nature of nonpharmacologic trials. Although the surgeons, researchers, and participants are not blinded, the pathologists, statisticians, and follow-up staff will be blinded to the group assignment, which contributes to reducing the treatment effect estimation bias. 3) The relatively short follow-up time has an impact on comparing long-term outcomes. In summary, if the feasibility, short-term safety, long-term oncological safety, and potential total “no-touch” isolation technique benefits of HALS-CME are verified, this technique could be recommended as a new approach to overcome the technical challenges in right hemicolectomy for right colon cancer.