Study design
This is a multicenter, prospective, superiority, double-arm, open-label, parallel, randomized controlled trial. We followed the standardized program intervention: Standard Protocol Item Recommendations for Interventional Trials (SPIRIT)(9).
Population
The target population of this study is patients with middle and low rectal cancer.
The inclusion criteria are as follows: 1) patients aged 18–90 years, diagnosed with rectal cancer by pathological biopsy; 2) no distal metastasis, as confirmed by abdominal contrast-enhanced and chest computed tomography (CT) (or positron emission tomography [PET]-CT); 3) preoperative rectal nuclear magnetic resonance (MR) results confirming that the distal margin of the tumor is below the peritoneal reflux and at least 1 cm above the intersphincteric groove; 4) tumors located above the hiatus of the levator ani muscle were evaluated by MR as cT1-3, cN0-1, M0, and MRF (-), and tumors located below the hiatus of the levator ani muscle must be evaluated by MR as cT1-2, cN0-1, M0, and MRF (-); after neoadjuvant treatment, the tumor above the hiatus of the levator ani muscle was staged ycT3NxM0 or below, and the tumor below the hiatus of the levator ani muscle was staged ycT2NxM0; and lastly, 5) the patient underwent LATME surgery or RATME surgery.
The exclusion criteria are as follows: 1) multiple primary cancers; 2) history of open surgery; 3) no preoperative MR evaluation, and/or incomplete evaluation of tumor clinical staging; 4) patients with rectal cancer who received endoscopic resection and required subsequent transabdominal resection; 5) pregnancy; 6) concomitant inflammatory bowel disease; 7) patients with preoperative complete intestinal obstruction or requiring emergency surgery; 8) preoperative evaluation indicating that the patient may require combined organ resection; 9) recently received treatment for other malignant tumors; 10) Bordeaux type IV low rectal cancer (10); and 11) preoperative pathological results indicating pathological types as signet ring cell carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, or poorly differentiated carcinoma.
The exit criteria include: 1) refusal to undergo surgical treatment after randomization; 2) open surgery was performed for treatment after randomization; and 3) patient request to withdraw from the study at any time during the entire study process after randomization.
It may take 4 years to complete the enrollment of patients. The follow-up duration will be 3 years. The duration of the entire study (including the establishment of the study, recruitment, follow-up, and data analysis) may be 7 years. The primary outcome will be analyzed after the last enrolled patient has completed a 1-month follow-up. Survival data will be analyzed after the last patient has completed the 3-year follow-up. The research will commence in the First Hospital of Jilin University in January 2024, and will soon be extended to other hospitals.
Blinding and randomization:
After enrollment, the patients will be randomized into the LATME and RATME groups (Figure 1). Stratified randomization will be performed using a computer according to the following factors: research center, sex, tumor size (>5 cm or <5 cm), BMI (>28 kg/m2 or <28 kg/m2), and treatment with neoadjuvant radiochemotherapy. The randomization ratio of RATME to LATME is 1:1. In this trial, allocation cannot be blinded to the researcher because the researcher completes the procedure. Similarly, patients cannot be blinded because they know the allocation when browsing medical records. In addition, patients are not necessarily blinded because blinding patients will not affect the primary outcomes. However, the senior pathologists of each participating center and data analysts are blinded to the allocation.
Surgical procedure
In this study, the enrolled patients will undergo RATME or LATME. There is no limitation on the ligation site of the inferior mesenteric artery (high or low tie), D3 or D2 dissection, splenic flexure mobilization, preventive stoma, use of transabdominal or transanal drainage tubes, and lateral lymph node dissection. All the above procedures are permissible and can be performed in accordance with the surgeon’s decision.
ISR will be determined by the surgeon during the operation. The location of distal resection margin needs to be recorded if it is below the hiatus of the levator ani muscle (above the dentate line, at the dentate line, between the dentate line and intersphincteric groove, or at the intersphincteric groove). Further, the subtypes of ISR will also be recorded according to the location of the distal resection margin (partial ISR at the dentate line, subtotal ISR between the dentate line and intersphincteric groove, and total ISR at the intersphincteric groove).
All mesorectal excision procedures should be completed via the transabdominal approach in both groups. If it cannot be completed according to the allocated plan, conversion to the open or transanal TME (TaTME) will be required. TaTME is performed in the presence of an imaging system and endoscopic instruments in the transanal approach. Conversion during surgery is determined according to technical reasons, adverse events, and surgical quality and safety considerations.
The above information will be recorded in CRF.
Endpoints and data collection
The primary endpoint of this study is the ISR rate. The ISR was defined according to the definition provided by a Japanese study group (11). ISR at the intersphincteric groove is defined as total ISR; subtotal-ISR is between the dentate line and intersphincteric groove; and partial-ISR is at the dentate line.
Secondary outcomes included coloanal anastomosis (CAA), conversion to open surgery, conversion to TaTME, incidence of APR, postoperative morbidity and mortality within 30 days after surgery, pathological outcomes, 3-year overall survival (OS), 3-year disease-free survival (DFS), 3-year locoregional recurrence (LR), functional outcomes, and quality of life (3-year urinary function, sexual function, defecation function, and comprehensive quality of life).
Data will be collected within 2 weeks before the operation. Information on sex, age, medical history, preoperative radiotherapy or chemotherapy, laboratory test results, American Society of Anesthesiologists (ASA) status, body mass index (BMI), rectal MR results, and the pelvic meridian index will all be recorded. Operative data including operating time, lateral lymph node dissection, method of specimen extraction (via the abdomen or anus), anastomosis method (no anastomosis, circular stapler or handsewn, end-to-end or end-to-side, intracorporeal or extracorporeal), preventive stoma, and stoma site (ileum or colon) will also be recorded. Finally, postoperative data, including readmission rate within 30 days after discharge, length of postoperative hospital stay, and hospitalization cost will be recorded as well. This trial will also grade the difficulty of surgery according to the grading scale in Table 1. A grade below 6 indicates a low risk of surgical difficulty, whereas a grade of ≥6 indicates a high risk of difficulty (12). In addition, surgeons are instructed to complete the Surgery Task Load Index. This index comprises six subscales addressing mental, physical, and temporal demands, task complexity, situation, and distractions. All questions are rated on a 20-point scale (0 = low, 20 = high) (13).
Definitions and grades
CAA was defined as an anastomosis of the distal colon and surgical anal canal; in CAA, the distal resection margin is located below the hiatus of the levator ani muscle. Conversion to open surgery is defined as an abdominal incision larger than necessary for specimen retrieval extraction. Conversion to TaTME is defined as a TME that could not be completed via the transabdominal approach and had to instead be completed by a transanal approach with the help of an imaging system and endoscopic instruments. It should be noted that if the TME is completely performed via the transabdominal approach, simply dissecting the internal sphincter and intersphincteric space or finishing the coloanal anastomosis via the transanal approach will not be classified as TaTME.
The pathological outcomes included macroscopic completeness of resection, CRM positivity rate, distal resection margin (DRM) positivity rate, tumor volume, number of lymph nodes, and pathological TNM stage. The macroscopic completeness of resection is classified into complete, nearly complete, and incomplete, following the standard of Nagtegaal et al.’s (14). CRM will also be evaluated according to previously reported methods (15). CRM positivity is defined as tumor cells within 1 mm from the CRM by microscopy. The distance to the CRM is defined as the shortest distance between the tumor and CRM. The distance to the DRM is defined as the shortest length between the tumor and the DRM. DRM positivity is defined as a distal margin within 1 mm of the tumor. Tumor volume was evaluated according to the pathological report, and calculated by multiplying the length, width, and thickness of the tumor following formalin fixation. The pathological TNM classification was determined according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition.
The operating time is defined as the time from cutting to suturing the skin, or finishing the enterostomy. The definition for 30-day morbidity is intraoperative adverse events and postoperative complications within 30 days. Possible intraoperative adverse events include intraoperative bleeding (>200 ml), pelvic vascular and nerve injury, vascular injury in other parts, digestive tract injury, ureteral injury, and anastomotic defects. Pelvic vascular nerve injury is defined as bleeding during dissection of the vascular nerve bundle that requires energy instruments to halt the bleeding. Vascular injury in other parts is defined as rupture and active bleeding of the branches of the inferior mesenteric artery, inferior mesenteric vein, genitourinary vessels, or iliac vessels. Digestive tract injury is defined as damage to at least the serous layer of the intestine. In addition, ureteral injury is defined as damage to the ureteral smooth muscle layer that requires suturing or implantation of a ureteral stent. Anastomotic defects are defined as incomplete anastomosis rings. Furthermore, the 30-day postoperative complications will be evaluated according to the Clavien–Dindo classification (16). DFS is defined as the time from randomization to the discovery of locoregional recurrence, distant metastasis, or death. LR is defined as tumor recurrence (assessed by PET-CT, enhanced CT, or MRI) at the surgical site, and confirmed by pathological biopsy or surgery. Distant metastasis refers to metastasis in the lung, liver, bone, or other regions outside the surgical site, confirmed using enhanced CT, MRI, or PET-CT. OS is defined as the time from randomization to death for any reason.
Postoperative treatment
Postoperative treatment will be performed according to the treatment plans in different medical centers. Postoperative adjuvant chemotherapy will be determined by pathological results and follows the National Comprehensive Cancer Network guidelines for rectal cancer.
Follow-up
The total follow-up duration has been set at 3 years, and the follow-up time must comply with the guidelines in Table 2. The measures to assess at follow-up include CA19-9, CEA, CT, magnetic resonance imaging (MRI), colonoscopy, or radionuclide scanning. For patients with LR or distant metastasis, follow-up should last at least 3 years after recurrence or until death.
The 30-day postoperative complications will be evaluated by daily ward rounds, outpatient services, telephone calls, or questionnaires. Mortality and complications of Clavien–Dindo grade III or higher will be included in the analysis. Postoperative complications to be included for analysis in the statistics are intra-abdominal hemorrhage, gastrointestinal bleeding, anastomotic leakage, chylous fistula, surgical site infection, intra-abdominal infections, wound infection, intestinal obstruction, postoperative diarrhea, pulmonary infection, urinary tract infection, cardiovascular accident, cerebral vascular accident, and thrombotic disease.
Questionnaires will be administered to the patients at 1, 3, 6, 12, 24, and 36 months postoperatively. All urinary (International Consultation on Incontinence Questionnaire - Short Form and one prostate function), sexual (International Index of Erectile Function-5), and defecation functions (Low Anterior Resection Syndrome score) will be evaluated.
Quality assurance
Qualifications of the research center: all medical centers should complete at least 30 LATME and 30 RATME procedures for rectal cancer yearly. A research quality control group, composed of senior surgeons in the field of colorectal surgery, will review the unedited videos of six consecutive cases (three LATME and three RATME) before each medical center joins the trial. Only centers who meet these surgical quality indices will be eligible for this trial. The Delphi method will be used for evaluation.
Photos of the surgical site and specimen: the photo of distal resection line in ISR will be needed. After completing anterior rectal resection and lymph node dissection, the surgeons will also need to take photos of the surgical site, including the pelvis and root of the inferior mesenteric artery. Surgeons should also obtain photographs of the specimens (anterior and posterior sides of the mesorectum, proximal and distal margins before formalin fixation). The quality of mesenteric excision will be evaluated by senior pathologists in each center as complete, nearly complete, or incomplete. Pathologists will be blinded to the allocation. In addition, the medical center must record the reasons for not retaining the above photos. Participating centers also need to retain surgical videos for each operation. Videos and photos will be reviewed by the data and safety monitoring board (DSMB) to judge whether surgical quality or conversion is acceptable.
Participating centers
Five tertiary medical centers will participate in this study. These medical centers are: the First Hospital of Jilin University, Jilin Provincial Tumor Hospital, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University, the Second Affiliated Hospital of Dalian Medical University, and the Tumor Hospital of Harbin Medical University. Other medical centers will join the study in the future.
Data and safety monitoring
DSMB will be established before the trial begins. This includes senior colorectal surgeons, ethicists, and statisticians. The DSMB will meet before the study and every 6 months during the trial. In addition, the DSMB will evaluate the safety and quality of the study, including adverse events, primary and secondary outcomes, and dropouts. LATME and RATME are well-established techniques for the surgical treatment of rectal cancer. Hence, there are no termination parameters for the entire project. However, if intermediate evaluations show that different medical centers show huge heterogeneity in primary and secondary outcomes, the DSMB will analyze the reason and can stop the enrollment of corresponding medical centers for patient safety.
Sample size calculation
This study is a superiority trial. The sample size calculation is based on the ISR rate. According to previous reports and data from our center (17,18), the ISR rates of the control (LATME) and intervention groups (RATME) are estimated as 5% and 10%, respectively. The superiority margin ratio between the intervention and control groups is set to 1.02. The patients will be randomly assigned to the LATME and RATME groups in a 1:1 ratio. Thus, with a significance level of 2.5%, a one-sided test, and 80% power calculated using the PASS 15 software, 461 people in the control group and 461 in the intervention group will be required. Assuming a dropout rate of 10%, an estimated 513 people are needed in each group.
Statistical analysis
Continuous variables will be described as the mean ± SD or median (Q1, Q3). The classification data will be presented as N (%). The analysis of primary outcomes will be conducted based on the mITT. In mITT analysis, patients will be analyzed according to their allocation plan after randomization, even if they undergo the other treatment. However, patients who meet the exit criteria after randomization will be excluded from the mITT analysis. In addition, this study will conduct the as-treated analysis (ATA). In ATA, the analysis is carried out according to the treatment received by the patients. All hypothesis tests are bilateral, with a significance level of 5%.
In analyzing primary and secondary outcomes, we will compare the risk differences between the two groups before and after adjustment. Logistic regression will be used to adjust for factors affecting the ISR rate (medical center, sex, T stage, BMI, tumor height, and preoperative concurrent chemoradiotherapy). The locoregional recurrence rate, DFS, and OS within 3 years will be compared using the log-rank test and Kaplan‒Meier curve. Exploratory analysis of the prognostic effects of various baseline factors on DFS and OS will be performed using multivariate Cox regression. We will further consider using sensitivity analysis to explain the impact of missing data on the overall results. We will also conduct a subgroup analysis to explore surgical results in different situations. Subgroups will be set according to medical center, sex, age, ASA, T stage, BMI, tumor height, and preoperative concurrent chemoradiotherapy.
Data management and missing data
Data storage and backup will be managed in the secure online database, which will track all changes to the data and retain a history for each variable. Data will be encoded to protect patient privacy. All data will be entered by trained research assistants. Double data entry will be adopted to ensure accuracy. Discrepancies and missing data will be reported back to participating centers to be clarified by the local investigator.
Ethics and dissemination
This trial has been approved by the Ethics Review Committee of the First Hospital of Jilin University (23K163-001). Protocol modifications will be reviewed by the Ethics Review Committee and communicated to all participating centers. Further, the trial has been registered on ClinicalTrials.gov website, NCT06105203. This trial follows the principles of the Declaration of Helsinki. All eligible patients will be informed of the study’s purpose, procedures, potential benefits, and risks. Informed consent will be obtained by the principal investigator or their sub-investigators.
We will analyze the primary outcomes and write an initial paper after a 1-month follow-up of the last enrolled patients. Subsequent studies will be completed after the 3-year follow-up period. The findings will be presented internally at scientific conferences. The feasibility results are intended for publication in journals. People who have made significant contributions to this trial will be listed as co-authors.
Confidentiality
Participants will be assigned a unique code to ensure that the participants’ anonymity is maintained. Documents containing personal information will be stored separately from assessment data in locked cabinets. Nobody except for the Principal Investigator (PI) and authorized research assistants will have access to the dataset, unless there is an institutional or regulatory requirement. The fully anonymized experimental data will be stored on secure servers of the Jilin University First Hospital and will be preserved for at least 5 years after study close-out.