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Cola

Total Mesorectal Excision (TME) is the gold standard surgical treatment of rectal cancer. According to the technique first described by Bill Heald, TME entails the resection of the rectum including the whole mesorectal fat and an intact mesorectal fascia. Open TME is accomplished through a midline xifo-umbilical laparotomy and requires a complete mobilization of the left colon and central ligature of inferior mesenteric artery and vein.

Laparoscopic TME mirrors the procedure performed through laparotomy with the same operative steps and performing rectal resection including the excision of the surrounding mesorectal fat and fascia.

Robotic TME mirrors the procedure described by Bill Heald for open surgery but the operation is performed by the master-slave DaVinci System under 3D laparoscopic guidance. The rectal resection is performed including mesorectal fat and fascia.

TaTME has first described by Antonio Lacy in 2012. This procedure has two steps: abdominal and perineal. The abdominal step is performed through a laparoscopic approach as described for laparoscopic TME but the caudal dissection is stopped right below the level of the peritoneal rectal reflection (Douglas pouch). The perineal step is accomplished transanally inserting a specially designed platform into the anal canal and performing the total mesorectal excision under endoscopic guidance.

Marco Maria Lirici, MD

TME is the gold standard surgical treatment of rectal cancer. Specimen quality, integrity of mesorectal fascia and lymph nodes harvest are expression of radicality and good surgery. The LOTARTME study is designed to assess which of the open, laparoscopic, robotic and endoscopic transanal approach is superior. Primary outcome is the evaluation of completeness of mesorectal fascia according to Quirke classification. Secondary outcomes are lymph nodes harvest, local recurrences, overall survivals, cancer related survivals. Inclusion criteria: any patient of any age and sex undergoing to intent-to-treat surgery operated by experienced surgeon. Exclusion criteria: patients with rectal cancer undergoing palliative surgery or multivisceral resection; all patients operated by less experienced surgeons. Study period January 1, 2017 - June 30 2021 and patients enrollment: January 1, 2017 - December 31, 2020. Data collection and analysis: data are collected in a prospective database and statical analysis is carried out using AnalystSoft StatPlus for Windows Software.

Developed in 1992 by Heald Total Mesorectal Excision improved the long-term results of rectal cancer treatment with overall survivals increasing up to 80% and local recurrences decreasing down to 4%. Notwithstanding the introduction of laparoscopy and robotic technology and their application in the field of rectal cancer surgery in the last decades, no further improvement of rectal cancer survivals have been reported. Actually, completeness of mesorectal fat and fascia excision seems not to be improved with these new approaches, compared to standard open surgery. It has been proved that local recurrences are strictly related to the quality of TME and are significantly higher when mesorectal fascia is incomplete according to Quirke classification. In 2012 A. Lacy first reported the transanal approach to TME, developed to overcome the high challenges represented by low rectal dissection when difficult anatomy is present (i.e. obese pts, narrow pelvis, bulging tumors) that may impair the quality of surgical specimen and, therefore, increase the incidence of local recurrences and, indirectly, overall cancer related survivals. There is an ongoing clinical trial (COLOR III) that has been designed to assess whether long term results after TaTME are similar, better or worse than those of open or laparoscopic TME. Until then scientists and researchers may evaluate the effectiveness of TaTME compared to other surgical approaches (open, laparoscopic, robotic) assessing the quality of surgical specimens (i.e. completeness of mesorectal excision and integrity of mesorectal fascia according to Quirke classification). Investigators have designed a prospective observational cohort study assessing the quality of specimen and mesorectal fascia in all patients undergoing TME through an open, laparoscopic, robotic and transanal (TaTME) approach between January 2017 and December 2020. All patients have been followed-up with a required minimum follow-up of 6 months. Therefore, the study was terminated on June 2021. Inclusion criteria were: any patient of any age and sex undergoing intent-to-treat surgery operated by experienced surgeon (with ≥ 100 TME performed). Exclusion criteria: patients with rectal cancer undergoing palliative surgery or multivisceral resection, all patients operated by less experienced surgeons (\< 100 TME performed).

Objective of the study:

Assessing the quality of the specimen after TME carried out through laparoscopic, open, robotic and endoscopic transanal approach; evaluating whether TaTME might be superior the other approaches in term of radicality of surgery and local recurrencies.

Primary outcome:

Quirke classification of mesorectal fat and fascia completeness. Three grade classification: complete, nearly complete, incomplete.

Secondary outcomes Lymph node harvest Local recurrences Overall survivals Cancer specific survivals Pathology assessment

A fresh specimen or in vacuum packing is sent for macroscopic assessment to the pathologist. The specimen is dealt as follows:

1) assessment of mesorectum quality; 2) ink painting of specimen non-peritonealized bare areas 3) the specimen is opened along the anterior aspect from the top and the bottom, leaving the bowel intact at a level just above and just below the tumour; 4) placement of formalin-soaked gauze wicks into the unopened ends of the bowel; 5) the specimen is fixed in 10% buffered formalin for at least 48 hours.

The fixed specimen is dealt as follows:

1) 3-5 mm intervals slices through the unopened rectum; 2) slices inspection to note: extent of tumour and the closest distance of tumour to the Circumferential Resection Margin (CRM); positive nodes and the distance of any positive node to the CRM; anterior, posterior or lateral closest distance of tumour to CRM; 3) lymph nodes detection within the fat away from the tumour

Block selection according to the followings:

1) tumor blocks showing closest CRM; 2) tumor blocks showing luminal aspect, 3) all lymph nodes; 4) any polyps; 5) proximal and distal resection margins (distal margin includes both mucosa and mesorectum).

The pathologist examined the specimen in a blinded fashion (unaware of the name of the operating surgeon and the technique performed).

Data are collected in a prospective database. Statistical analysis is carried out with AnalystSoft StatPlus for Windows Software. Chi-square test and chi-square test with Yates correction are used considering p-value significative at p\<.05.

Pathology Assessment of Mesorectal Fascia After TME by Laparoscopic, Open, TransAnal and Robotic Approaches (LOTARTME)

Pathology Assessment of Mesorectal Fascia and Specimen Quality After TME by Laparoscopic, Open, TransAnal and Robotic Approaches (LOTARTME)

Specimen quality i.e. integrity of mesorectal fascia and clearance of radial margins are an important factor with impact on local recurrency of rectal cancer. the 3-grade Quirke classification is used to assess completeness of mesorectal fascia: complete, nearly complete and incomplete

The number of lymph nodes harvested may influence patient's prognosis and survival. A minimum number of nodes is required to assess the cancer stage correctly: stage 2 rectal cancer with a less than 12 node harvest has a behaviour of a stage 3 rectal cancer in the medium and long term follow up.

Local recurrence rate is intended the incidence of pelvic tumor recurrence, especially localized in the presacral area, and anastomotic recurrence

short and medium term survivals (Kaplan-Meier estimate)

Cancer-specific survival (CSS) is defined as the duration from the date of diagnosis until death due to rectal cancer other than other causes

San Giovanni Addolorata Hospital

Professor of Surgery

Transanal approach of total mesorectal excision.

Type of surgical intervention as control group: Laparoscopic low anterior resection with total mesorectal excision for rectal cancer

The technique begins with the TEO equipment and a purse string 1 cm distal to the tumor. The dissection progresses in the posterior part until the laparoscopic TME field is reached. After the section of the rectum and TME transanal dissection, the anvil of the circular mechanical stapler is introduced through the TEO rectoscope. In the laparoscopic field, the mesosigma is sectioned at the point where the colon section is to be performed. The TEO rectoscope is withdrawn, and the bag containing the specimen is removed through the anus. The stapler is inserted. From the laparoscopic field, the strings of the purse are tightened and the purse is closed around the rectal stump with a clip. Then the stapler are joined to perform the anastomosis and a loop ileostomy is placed in the right flank.

TRANSANAL TOTAL MESORECTAL EXCISION

Standard laparoscopic low anterior resection of the rectum with total mesorectal excision and colorectal anastomosis

Laparoscopic-LAR

Serra-Aracil Xavier, MD, PhD

INTRODUCTION: Transanal TME (T-TME) combined with laparoscopy, called hybrid-NOTES, is a less invasive procedure that responds to some of the limitations of the rectal laparoscopic approach.

MAIN OBJECTIVE: To analyze that the T-TME gets a faster recovery due to a lower conversion rate to open surgery than laparoscopic low anterior resection (L-LAR) in rectal cancer with the same pathological, functional and oncologic results.

METHODOLOGY: A prospective multicenter randomized controlled study of patients with rectal cancer that, were randomized in the T-TME- and L-LAR group. The main variables are: general morbidity, anastomotic dehiscence, conversion rate to open surgery and hospital stay. The sample calculation is 58 patients per group.

INTRODUCTION: The laparoscopic total mesorectal excision (TME) has provided better patient recovery with less morbidity and shorter hospital stay compared with open surgery. However in laparoscopic low rectal surgery, overall conversion to open surgery is around 20%. Transanal TME (T-TME) combined with laparoscopy, called hybrid-NOTES, is a less invasive procedure that responds to some of the limitations of the rectal laparoscopic approach.

MAIN OBJECTIVE: To analyze that the T-TME gets a faster recovery due to a lower conversion rate to open surgery than laparoscopic low anterior resection (L-LAR) in rectal cancer with the same pathological, functional and oncologic results.

METHODOLOGY: A prospective multicenter randomized controlled study of patients diagnosed with adenocarcinoma of the rectum that after inclusion and exclusion criteria, were randomized in the T-TME- and L-LAR group. The main variables are: general morbidity, anastomotic dehiscence, conversion rate to open surgery and hospital stay. The other variables studied were: demographic, surgical, pathological, 30-day morbidity and mortality, quality of life and oncologic results. The sample calculation is 53 patients per group. With an estimated loss of 10%, the final number will be 116 patients.

Study of NOTES-TME Versus L-LAR in Rectal Cancer

Multicenter Prospective Randomized Controlled Study of the Transanal Total Mesorectal Excision Versus Laparoscopic Low Anterior Resection in Rectal Cancer

Evaluate surgical complications 30 days after surgery.

Evaluate functional results 6 months after ileostomy closure.

Corporacion Parc Tauli

Medical Doctor

Symptoms and General Pathology

Anastomotic Leak

Study procedure will consist in 2-team (combined) LAR with transanal TME using laparoscopic abdominal assistance.Transanal TME is performed either at the same time or following the above steps. Transanal endoscopic TME dissection will proceed circumferentially until the peritoneal cavity is entered anteriorly. Following complete mobilization of the rectosigmoid, the specimen is extracted transanally or using a Pfannenstiel incision followed by colorectal anastomosis, and a temporary diverting stoma will be created, which is standard of care following surgery for this type of cancer.

Procedure will consist in 1 team performing laparoscopic TME. Following stapled closure of the rectum below the tumor, and complete mobilization of the rectosigmoid, the specimen is extracted using a Pfannenstiel incision . A stapled (knight-Griffen) colorectal anastomosis or coloanal anastomosis will be created and a temporary diverting stoma will be fashioned which is standard of care following surgery for this type of cancer.

transanal approach to TME in rectal cancer

transanal TME

laparoscopic approach to TME in rectal cancer

laparoscopic TME

Francesca Aleotti

Andrea Vignali

This study is designed as a prospective, multi-center, randomized, open-labelled, parallel group, non-inferiority trial. The aim of this study is to evaluate the TaTME technique compared with conventional laparoscopic rectal surgery, focusing on, anastomotic dehiscence, conversion rate to open surgery, hospital stay and long-term functional outcomes.

This study is designed as a prospective, multi-center, randomized, open-labelled, parallel group, non-inferiority trial. The patients will be randomized and assigned to transanal mesorectal excision (TaTME) or laparoscopic mesorectal excision (LpTME) at a ratio 1:1, based on a centralized computer generated, blocked randomization list stratified by center. Six centers will be involved. Within each center a block size of four will be used, stratified by gender and age (±3 years). A central electronic data capture system will be generated by the promoting center for data collection. All the participating surgeons and centers will be required to document their previous experience with TaTME (a minimum of 10 documented procedures is required). Moreover, they will be invited to submit a video showing their surgical technique in performing a TaTME operation (said video must contain no reference to patient ID, and is used exclusively to demonstrate the participating surgeon's technique). The video will be reviewed by the promoting center in order to standardize the procedure, prior to the beginning of the recruitment process. In each center, before starting effective recruitment of patients to the trial, the surgical team will be required to perform a minimum of 4 TaTME operations based on the adopted standardized procedure to calibrate the participant surgeons.

All statistical analyses will be conducted on an "intention to treat" basis.

Statistical methodology The trial is designed as a non-inferiority trial. In statistical terms, the study will establish whether the anastomotic rate (%) for the experimental treatment is not worse than the anastomotic rate (%) for the standard treatment by more than a specific non-inferiority margin, δ, set to 0.05, with δ denoting the difference anastomotic rate rates (experimental vs. control). Formally, the study will test the one-sided null hypothesis H0: δ \> = 5% vs. the alternative H1: δ \< 5%, and will reject the null hypothesis with a 5% level of significance if the upper bound of a standard asymptotic 90% confidence interval for difference in proportions is below the 5% non-inferiority margin.

Sample size In recent studies (1-5) estimating the anastomotic leak ("failure") rate (%) in the standard LpTME (control technique) ranged from 6.4 to 18.8 % (median of studies, 13%), while in the two recent studies evaluating TaTME (experimental technique) it was 6.7% and 8.6 %, respectively, (resulting in a weighted rate of 7%). The investigators therefore hypothesised a failure rate of 13% (that equivalently means a "success" rate of 87%) in the control arm and a crude (relative) 6% (4.6%) reduction in the experimental arm (that equivalently means a "success" rate of 93%) over the standard arm. Based on the non-inferiority hypothesis and the above findings, and assuming a non-inferiority limit of 0.05, a total of 184 patients (92 for each arm) is required i.e., if there is a true difference in favour of the experimental treatment of 6%, then 184 patients are required to be 80% sure that the upper limit of a one-sided 95% confidence interval (or equivalently a 90% two-sided confidence interval) will exclude a difference in favour of the standard group of more than 5%. The inclusion period will be of 2 years. The results will be available within 3 years of starting recruitment. The investigators will consider still acceptable and not different clinically a failure rate of 18% (i.e., a non-inferiority limit of 5%) as this value is below the 18.8% maximum failure rate estimated in the standard LpTME. Additionally, the non-inferiority limit of 5% has been also recently indicated in a similar trial (ETAP-GRECCAR 11 TRIAL) (assuming conversion to open as "failure" event) registered at clinicalTrials.gov, NCT02584985.

Statistical analysis Both per-protocol and intention-to-treat analysis will be performed, as currently recommended in literature. Descriptive data for continuous variables will be reported as mean (standard deviation \[SD\]) or median (25th and 75th percentiles), as appropriate. Descriptive data for categorical variables will be reported as number of observations (percentage). For continuous variables, univariate comparison between LpTME and TaTME will be performed by the Student's t test for normally distributed data (based on the Kolmogorov-Smirnov test) or the Mann-Whitney U test for non-normally distributed data. The chi-square test, or the Fisher exact test, as well the Kruskal-Wallis test, as appropriate, will be used for comparing discrete variables. Logistic regression models will be additionally carried out and survival analysis of postoperative binary outcomes, as appropriate. All the statistical tests will be performed by using the SPSS statistical package, version 20.0 (SPSS Inc., Chicago, IL) for Windows (Microsoft, Redmond, WA).

Study procedure:

Study procedures will consist in 2-team (combined) low anterior resection with transanal TME using laparoscopic abdominal assistance. Laparoscopic abdominal access will be obtained followed by inferior mesenteric vessels transection, mobilization of the proximal colon and splenic flexure takedown will be performed in all cases. Transanal TME is performed either at the same time or following the above steps. Following pursestring closure of the rectum below the tumor, transanal endoscopic TME dissection will proceed circumferentially until the peritoneal cavity is entered anteriorly. Following complete mobilization of the rectosigmoid, the specimen will be extracted transanally or using a Pfannenstiel incision followed by colorectal anastomosis, and a temporary diverting stoma will be created, which is standard of care following surgery for this type of cancer. At the end of the surgical procedure a macroscopical examination of the specimen will be conducted by the surgeon in conjunction with the pathologist.

Postoperative care and follow-up:

All patients enrolled in the study will be managed according to same standard postoperative protocols. Postoperative visits and oncology follow-up visits will occur as per standard practice and oncologic outcomes. The duration of postoperative follow up for each patient will be 3 years.

DATA OWNERSHIP AND PUBLICATION

The single participating centers will gather the data which will then be analyzed centrally by the promoting center. The promoting center will aim to publish said data in an adequate scientific journal and share the results with the principal investigators (PIs) of all participating centers.

ADVERSE EVENTS

All adverse events will be notified to the promoting centre by Case Report File (CRF). The promoting center will then gather the data and promptly notify the PIs and Ethic Committees of all participating centers.

Transanal Versus Laparoscopic Total Mesorectal Excision for Rectal Cancer.

Transanal Versus Laparoscopic Total Mesorectal Excision For Mid And Low Rectal Cancer. A Multicentre Randomised Clinical Trial on Anastomotic Leak

Evaluate the effectiveness of the T-TME versus L-LAR in term of clinically evident anastomotic leak rate.

Evaluate the effectiveness of the T-TME versus L-LAR in term of conversion to open surgery

Complete pathology assessment of TME specimens according to Quirke classification

Evaluate the effectiveness of the T-TME versus L-LAR on quality of life assessed with Short-Form Health Survey (SF-36) score in patients with rectal cancer. The questionnaire consists of eight sections, each of which is evaluated 0 (most disability) to 100 (least disability).

Evaluating functional results after ileostomy closure. The evaluation will be done using the Fecal Incontinence Quality of Life Questionnaire (FIQL). Scales range from 1 to 4; with a 1 indicating a lower functional status of quality of life. Scales scores are the average (mean) response to all items in the scale.

Evaluating functional results after ileostomy closure.The evaluation will be done using Wexner scores (range 0-20 i.e. least-most incontinence) in patients with rectal cancer.

evaluating postoperative complications after surgery according to Clavien-Dindo Classification

evaluating long-term postoperative complications following hospital discharge

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pathology Assessment of Mesorectal Fascia After TME by Laparoscopic, Open, TransAnal and Robotic Approaches (LOTARTME)	NCT04949672	Rectal Cancer Surgery		-	San Giovanni Addolorata Hospital
Study of NOTES-TME Versus L-LAR in Rectal Cancer	NCT02550769	Rectal Cancer	TRANSANAL TOTAL... Laparoscopic-LA...	18 Years -	Corporacion Parc Tauli
Transanal Versus Laparoscopic Total Mesorectal Excision for Rectal Cancer.	NCT03413904	Rectal Cancer	transanal TME laparoscopic TM...	18 Years - 85 Years	IRCCS San Raffaele
Transanal Versus Laparoscopic Total Mesorectal Excision for Rectal Cancer.	NCT03413904	Rectal Cancer	transanal TME laparoscopic TM...	18 Years - 85 Years	IRCCS San Raffaele
Pathology Assessment of Mesorectal Fascia After TME by Laparoscopic, Open, TransAnal and Robotic Approaches (LOTARTME)	NCT04949672	Rectal Cancer Surgery		-	San Giovanni Addolorata Hospital

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