Symptoms and General Pathology

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Digestive System Diseases

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Syndrome

Low Anterior Resection Syndrome

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Patients undergoing open low anterior resection

Patients undergoing laparoscopic low anterior resection

Patients undergoing robotic low anterior resection

Patients undergoing transanal Total Mesorectal Excision (taTME)

Open approach for Total Mesorectal Excision

Open Total Mesorectal Excision

Laparoscopic approach for Total Mesorectal Excision

Laparoscopic Total Mesorectal Excision

Robotic approach for Total Mesorectal Excision

Robotic Total Mesorectal Excision

Transanal approach for Total Mesorectal Excision

Transanal Total Mesorectal Excision

Patricia Tejedor

Carlos Pastor

The surgical management of rectal cancer includes a Total Mesorectal Excison (TME); depending on the height of the tumor, the problem of preservation of the anal sphincter arises, being able to perform a low anterior resection, an ultra-low anterior resection (RAUB) or an intersphincteric dissection. In some cases invading the sphincters or the puborectalis muscle, an abdominoperineal resection needs to be performed, being the gold standard in this particular situation so far.

TME can be performed by open, laparoscopic, robotic or transanal approaches, as long as the oncological principles for the resection are achieved. Unfortunately, up to 90% of these patients will present a change in bowel habit, ranging from an increased frequency of bowel movements to the degree of fecal incontinence or evacuation dysfunction. Of these patients, 25-50% will have a severe alteration in the quality of life. This wide spectrum of symptoms has been called "low anterior resection syndrome" (LARS). Other collateral damage is the change in sexual and urinary function, due to hypogastric plexus injury. There is a significant lack of multicenter prospective studies that provide evidence, and that reveal the functional results and quality of life of these techniques available to date for the management of rectal cancer.

The study is set up as a prospective multicentre observational study. Inclusion criteria are: 1) patients over 18 years old, 2) diagnosed with rectal cancer located below the peritoneal reflection, defined by preoperative MRI, 3) undergoing Open, laparoscopic, robotic or Transanal Total Mesorectal Excision (taTME) approaches, 4) with/without derivative stoma and 5) with/without neoadjuvant treatment. Exclusion criteria are: 1) Upper rectal cancer, located above the peritoneal reflection, 2) previous radical prostatectomy, 3) previous pelvic radiotherapy, 4) rectal resection without primary anastomosis, 5) intraoperative findings of peritoneal carcinomatosis, 6) stage IV disease, 7) multivisceral or en-bloc resection, which includes uterus, prostate, vagina or bladder, 8) rectal resection due to a benign condition, 9) rectal resection due to a recurrence of rectal cancer (previous anterior resection or another primary neoplasm), 10) rectal resection following a 'watch \& wait' program, 11) emergency surgery, 12) previous derivative colostomy 13) inflammatory bowel disease.

Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 45 subjects are necessary in first group and 45 in the second to recognize as statistically significant a difference greater than or equal to 2 units. The common standard deviation is assumed to be 3. It has been anticipated a drop-out rate of 20% Primary outcomes are LARS and Vaizey score. Secondary outcomes included are QLQ C30 and CR29, sexual function questionnaire (female/male), urinary function questionnaire and postoperative complications (Clavien-Dindo classification) Data will be collected in an online secure and protected repository (Castor edc). The planned study period is 2 years (September 2021 - September 2023).

It is essential to have a validated instrument that allows us to assess sphincter function and the different aspects of quality of life in operated patients, since increased survival in this pathology has led to greater importance in the evaluation functional outcome and quality of life; Furthermore, there are recent studies that speak of the direct relationship between these factors.

Patient Reported Outcomes Following Cancer of the Rectum

LARS score from 0-42 where 0 means better outcomes

Incontinence score from 0-28 where 0 means better outcomes

Quality of life questionnaire, colorectal cancer related

University of Navarrra Hospital (Clinica Universitaria)

Hospital de Leon

Hospital del Río Hortega

University Hospital Gregorio Marañón

Principal Investigator

Carcinoma

Laparoscopic TME

TaTME

Hendrik J. Bonjer, MD, PhD

Antonio M. Lacy, MD, PhD

George B. Hanna, MD, PhD

Jurriaan B. Tuynman, MD, PhD

Colin Sietses, MD, PhD

Background Surgery for mid and low rectal cancer is associated with relative high rates of incomplete mesorectal excisions and high rates of circumferential resection margin (CRM) involvement resulting in significant number of local recurrences. Moreover, patients with mid and low rectal cancer suffer from high rates of morbidity, permanent colostomies and impairment of quality of life. The transanal TME (TaTME) has been developed to improve the quality of TME surgery in mid and low rectal cancer.

Study design The COLOR III trial is an international multicentre randomised study comparing short- and long-term outcomes of TaTME and laparoscopic TME for rectal cancer. The study will include a quality assessment phase before randomisation to ensure required competency level and uniformity of the new TaTME technique and the laparoscopic TME. During the trial clinical data will be reviewed centrally to ensure uniform quality.

Endpoints The primary endpoint of the study is the local recurrence rate at 3-years follow-up. Secondary endpoints include sphincter saving procedures, short-term morbidity and mortality, involved circumferential resection margin (CRM), disease-free and overall survival at 3 and 5 years, completeness of mesorectum and quality of life.

Statistics In laparoscopic TME the percentage of local recurrence at 3-years follow-up is estimated 5%. With the non-inferiority margin set at 4%, with a one-sided level of significance of 2.5% and a power of 80%, a total of 1104 patients is needed, 669 patients in the TaTME arm and 335 patients in the laparoscopic TME arm. All analyses will be performed on intention-to-treat basis.

Main selection criteria Patients with histologically proven single mid or distal rectum carcinoma (0 to 10 cm from anal verge) at MRI, eligible for restorative surgery with a curative intent, are included. Patients with a T1 tumor suitable for local excision, T3 tumors with a suspected involved circumferential resection margin and T4 tumors are excluded.

Hypothesis The hypothesis is that TaTME will result in a comparable local recurrence rate at 3-years follow-up with benefit of lower morbidity and conversions. Furthermore, because of direct endoscopic visualization, even in very low tumors a coloanal anastomosis can be created, resulting in a lower colostomy rate compared with laparoscopic and open resection. Because long-term outcomes are unknown, within a trial setting the technique can be standardized and quality control can be performed.

To improve oncological and functional outcomes of patients with rectal cancer new surgical techniques are being developed. The adoption of the TME technique has resulted in better oncological outcome in the last decades. The addition of neoadjuvant therapy has further improved oncological outcome. The minimal invasive laparoscopic resection of rectal cancer has shown to be safe and to result in improved short-term outcomes and reduced morbidity.

Nevertheless, the laparoscopic resection of mid and low rectal cancer remains challenging due to the anatomy of the narrow pelvis and is associated with a relative high risk of resections with an involved CRM resulting in increased risk of a local recurrence.

In attempt to improve the quality of the TME procedure in low rectal cancer and further improve oncological results the TaTME has been developed, in which the rectum is dissected transanally according to TME principles. First series have been described since 2010 and although randomised evidence is still lacking this new technique has shown to be feasible and safe. The rectum including the total mesorectum is mobilised transanally in a reversed way with minimally invasive surgery including high quality imaging techniques.

The TaTME technique for mid and low rectal cancer has shown to have potential benefits: better specimen quality with less R1 resections, less morbidity, less conversion to laparotomy and more sphincter saving rectal resections without compromising oncological outcomes.

The investigators propose to evaluate the TaTME technique compared with conventional laparoscopic rectal resection for patients with mid and low rectal cancer in an international randomised trial: the COLOR III trial.

COLOR III Trial: Transanal vs Laparoscopic TME

COLOR III: A Multicentre Randomised Clinical Trial Comparing Transanal TME Versus Laparoscopic TME for Mid and Low Rectal Cancer

We are not sharing confidential individual patient data.

Local recurrence rate, determined by MRI at 3 year follow-up

Pathological microscopic examination of specimen

Amsterdam UMC, location VUmc

Professor of Surgery, MD, PhD, FRCSC

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
Patient Reported Outcomes Following Cancer of the Rectum	NCT04936581	Sphincter Ani I... Rectal Cancer	Open Total Meso... Laparoscopic To... Robotic Total M... Transanal Total...	18 Years - 100 Years	University Hospital Gregorio Marañón
Patient Reported Outcomes Following Cancer of the Rectum	NCT04936581	Sphincter Ani I... Rectal Cancer	Open Total Meso... Laparoscopic To... Robotic Total M... Transanal Total...	18 Years - 100 Years	University Hospital Gregorio Marañón
Patient Reported Outcomes Following Cancer of the Rectum	NCT04936581	Sphincter Ani I... Rectal Cancer	Open Total Meso... Laparoscopic To... Robotic Total M... Transanal Total...	18 Years - 100 Years	University Hospital Gregorio Marañón
COLOR III Trial: Transanal vs Laparoscopic TME	NCT02736942	Rectal Carcinom... Surgery	Laparoscopic TM... TaTME	18 Years -	Amsterdam UMC, location VUmc
Transanal Versus Laparoscopic Total Mesorectal Excision for Rectal Cancer.	NCT03413904	Rectal Cancer	transanal TME laparoscopic TM...	18 Years - 85 Years	IRCCS San Raffaele
Patient Reported Outcomes Following Cancer of the Rectum	NCT04936581	Sphincter Ani I... Rectal Cancer	Open Total Meso... Laparoscopic To... Robotic Total M... Transanal Total...	18 Years - 100 Years	University Hospital Gregorio Marañón
Transanal Versus Laparoscopic Total Mesorectal Excision for Rectal Cancer.	NCT03413904	Rectal Cancer	transanal TME laparoscopic TM...	18 Years - 85 Years	IRCCS San Raffaele
COLOR III Trial: Transanal vs Laparoscopic TME	NCT02736942	Rectal Carcinom... Surgery	Laparoscopic TM... TaTME	18 Years -	Amsterdam UMC, location VUmc

Spots Global Cancer Trial Database for laparoscopic tme