STUDY PROTOCOL

COLOR III: A MULTICENTRE RANDOMISED CLINICAL TRIAL COMPARING TRANSANAL TME VERSUS TRADITIONAL LAPAROSCOPIC TME FOR MID AND LOW RECTAL CANCER

Summary

To improve oncological and functional outcomes of patients with rectal cancer new surgical techniques are being developed. The adoption of the Total Mesorectal Excision (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 tumour involved circumferential resection margins (CRM) resulting in increased risk of recurrence.

The introduction of transanal single port surgery has led to the TaTME technique. 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 low and mid rectal cancer has shown to have potential benefits: less morbidity as result of avoiding extraction wounds in the majority of patients and more sphincter saving rectal resections without compromising oncological outcomes.

Currently, cohort series have demonstrated potential benefits of the TaTME for rectal cancer including a low morbidity rate and a high rate of sphincter saving procedures. We propose to evaluate the TaTME technique compared to conventional laparoscopic rectal resection for patients with mid and low rectal cancer in an international randomised trial: the COLOR III trial.

In attempt to improve the quality of the TME procedure in low rectal cancer and further improve oncological results the transanal total mesorectal excision (TaTME) has been developed, in which the rectum is dissected transanally according to TME principles. The objective of this study is to assess the role of TaTME in the treatment of rectal cancer.

 

 

The study will be a non-inferiority, international, randomized, multicenter trial comparing traditional laparoscopic and transanal TME for rectal cancer.

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.

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. Randomization will be in a 2:1 ratio in favor of the TaTME procedure. It will be stratified for participating center, preoperative (chemo)radiotherapy, T-stage, height of the tumor (mid or low) and gender. 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.

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.

Surgical Quality Assurance in COLOR III Trial

Pre-trial Phase

The main aim this study is to develop and validate a Quality Assurance Manual and a Competency Assessment Tool for technical and oncological quality in TaTME within the scope of COLOR III. These will be used for surgeon selection into the trial and to measure adherence to agreed standards during the trial. The specific research objectives are: 1) To perform Hierarchical Task Analysis (HTA) and to reach expert consensus on TaTME steps; 2) To develop an operation manual and quality assurance tool for the surgical performance in TaTME; and 3) To validate the quality assurance tool and video and photographic methodology. For the HTA a robust 4-round Delphi methodology will be applied with a peer-nominated international group of expert colorectal consultants in the TaTME technique (N ≈ 12). Round 1 of the Delphi methodology will include semi-structured interviews with experts. The results of Round 1 and semi-structured expert video observations (N ≈ 12 videos) will be used for the development of the HTA in order to identify the key stages and steps of TaTME. The HTA results will be included in the Delphi questionnaire (Rounds 2-4) in order to reach consensus on key procedural steps and quality. Agreement will be set at 70% for each step. The end product of the Delphi methodology will comprise a technical manual and operation logbook, and a competency assessment tool, which will be used for pre-trial entry and to monitor and measure adherence to agreed standards during the trial. A video and photographic methodology will be validated for use during the main COLOR III.

THE START DATE OF THE TRIAL

The study received first approval by the Medical Ethical Committee of the VU medical Center. The first patient was included on 02 january 2017.

SYNOPSIS

Trial Title COLOR III: A MULTICENTRE RANDOMISED CLINICAL TRIAL COMPARING TRANSANAL TME VERSUS TRADITIONAL LAPAROSCOPIC TME FOR MID AND LOW RECTAL CANCER
Internal ref. no. (or short title) COLOR III
Clinical Phase Phase 3
Trial design Multicentre, randomised clinical trial, non-inferiority design 2 (TaTME) : 1 (lap TME) randomisation
Trial Participants Patients with mid or distal rectal cancer
Main Inclusion criteria Histological biopsy showing adenocarcinomaCentral reviewed preoperative MRIDistance 0-10cm from dentate line (MRI defined)

Stage 1-3, curative and restorative intent

Main Exclusion criteria CRM positivity on MRI

T4 tumour

Ingrowth in m. levator requiring abdomino perineal resection

Previous rectal surgery (excluding local excision)

Intervention Rectal resection by transanal TME with laparoscopic surgery
Control arm Rectal resection by laparoscopic TME
Quality assurance procedure TaTME All surgeons will be trained and will have peer reviewed established procedure competence.All surgical procedures are recorded within patient record information database.
 Objectives  Outcome Measures
Primary Local recurrence at 3-years follow-up Imaging and pathology
Secondary • Quality of specimen
• Morbidity and mortality
• Involved CRM
• Disease-free and overall survival
• Sphincter saving procedure
• Functional outcomes
• Health related Quality of Life
• Costs
• “Quirke” assessment• Clavien Dindo, 30 day
• MRI, pathology
• Follow-up regimen
• Colostomy percentage1year
• Manometry, LARS score
• EORTC29, 30 questionnaire
• EQ5D, cost incremental analysis
Planned Sample Size 1104 patients in total; 669 in the TaTME arm and 335 in the laparoscopic TME arm to demonstrate a comparable local recurrence (LR) rate at 3-years follow-up. Expected LR rate is 5% in the control group, non-inferiority margin of 4% with a power 80% with a one-sided level of significance of 2.5%)
Follow up duration Five years
Planned Trial Period for inclusion Four years (20+ centres, multinational)
Total duration of trial Nine years