Mini-laparotomy versus transrectal natural orifice specimen extraction for minimally invasive colorectal cancer surgery: study protocol for a randomized controlled trial (MINITR-NOSE trial, TCAR2514 protocol)

Abstract

Background

Minimally invasive surgery (MIS) has improved colorectal cancer (CRC) treatment by reducing recovery time, pain, and infection risk compared to traditional open surgery, though a mini laparotomy is still needed for specimen removal. Natural orifice specimen extraction (NOSE) offers a promising alternative by using natural body openings for extraction, potentially minimizing complications further, yet requires more evidence to confirm its safety and effectiveness over conventional methods.

Methods

This single-center randomized controlled trial at Linkou Chang-Gung Memorial Hospital includes CRC patients meeting specific eligibility criteria, randomly assigned to undergo either NOSE or conventional MIS. Primary outcomes focus on postoperative C-reactive protein (CRP) levels as a marker of inflammation, with secondary outcomes evaluating short-term complications, recovery, readmission, and long-term survival. Both groups will receive routine perioperative care following modified Enhanced Recovery After Surgery (ERAS) protocols, with postoperative pain and complications systematically recorded and graded.

Discussion

This study seeks to determine whether the NOSE approach offers advantages over conventional MIS by reducing inflammation and complications, potentially improving patient recovery and outcomes. If effective, NOSE may present a less invasive alternative for CRC resection, contributing to advancements in colorectal surgical oncology.

Trial registration

ClinicalTrials.gov NCT05740267. Registered on March 1, 2023.

Administrative information

Title {1}	Mini-laparotomy versus transrectal natural orifice specimen extraction for minimally invasive colorectal cancer surgery: study protocol for a randomized controlled trial (MINITR-NOSE trial)
Trial registration {2a and 2b}	ClinicalTrials.gov (NCT05740267). Registered on March 1, 2023
Protocol version {3}	2022–3-16 Version 3
Funding {4}	This research was funded by the Chang Gung Medical Research Fund (CPRPG3N0031). The funder had no role in the study’s design, data collection, analysis, or interpretation of results, ensuring the research’s independence and integrity
Author details {5a}	1 Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University, College of Medicine, Taoyuan
Name and contact information for the trial sponsor {5b}	Ai-Lun Lo1, Yu-Jen Hsu1, Yih-Jong Chern1, Ching-Chung Cheng1, Bor-kang Jong1, Zhen-Hao Yu1, Li-Yang Chan1, Jeng-Fu You1 Email: alan66625@gmail.com; jenodyssey@gmail.com Address: No. 5, Fu-Hsing Rd., Kueishan, Taoyuan, Taiwan 333, Tel.: + 886–3-228–1200 (ext. 2101); Fax: + 886–3-328–5818
Role of sponsor {5c}	This Investigator-Initiated Trial is led by Professor Jeng-Fu You, the principal investigator responsible for designing the study, developing the project, implementing it, and overseeing data collection, management, analysis, and interpretation. Although the study is funded by the Chang Gung Medical Research Fund, the funding body is not involved in the study’s design and will not participate in its conduct, data analysis, or reporting of results, thereby ensuring the research’s independence and integrity

Introduction

Background and rationale {6a}

Minimally invasive surgery (MIS) has revolutionized the management of colorectal cancer (CRC) by providing alternatives to traditional open surgical techniques. These alternatives are associated with reduced postoperative pain, shorter recovery times, and lower infection risks [1]. However, conventional minimally invasive techniques still necessitate a mini-laparotomy incision for specimen extraction, which can lead to complications such as infections, bleeding, hernias, and increased postoperative pain [2]. To address these issues, natural orifice specimen extraction (NOSE) has emerged as a promising technique that utilizes natural body orifices, such as the rectum, for specimen removal, thereby eliminating the need for abdominal incisions [3, 4].

The NOSE technique aligns well with the principles of Enhanced Recovery After Surgery (ERAS), which emphasizes minimizing surgical trauma and optimizing recovery [3]. Early studies indicate that NOSE may lead to reduced postoperative pain and improved recovery outcomes compared to traditional MIS [5, 6]. For instance, a systematic review and meta-analysis demonstrated that NOSE is associated with lower complication rates, including reduced postoperative pain and wound infections, compared to conventional laparoscopic surgery [7]. Furthermore, the technique has shown promising oncological outcomes, with adequate lymph node dissection and no gross or microscopic positive resection margins reported in studies [8].

Despite the advantages of NOSE, the current body of research remains limited, primarily comprising retrospective studies focused on rectosigmoid tumors [9]. Few randomized controlled trials (RCTs) have comprehensively compared NOSE with conventional approaches across a broader spectrum of CRC cases, particularly for tumors located beyond the rectosigmoid region [10, 11]. While NOSE represents a promising advancement in surgical techniques, it is essential to acknowledge the associated risks, including anastomotic leakage, fecal incontinence, and intra-abdominal contamination [12]. To minimize risks, patient selection is crucial, considering factors like tumor size and invasion depth [2, 12]. Studies have shown that NOSE techniques, such as transrectal specimen extraction, can be safely performed for early-stage low sigmoid and rectal cancers [13]. While NOSE procedures may have longer operation times, they demonstrate similar oncological outcomes to conventional laparoscopic surgeries [14]. As NOSE gains popularity, standardization through international consensus is essential for its long-term progress in colorectal surgery [2].

While NOSE offers a promising advancement in minimally invasive colorectal cancer surgery by potentially reducing postoperative pain and improving recovery, there is a critical need for additional high-quality studies to validate its benefits across diverse clinical settings. Careful patient selection, considering factors like tumor size and invasion depth, is essential to minimize associated risks such as anastomotic leakage and intra-abdominal contamination. As NOSE techniques gain popularity, ongoing research and international standardization are imperative to enhance our understanding of their safety and efficacy, ultimately contributing to the refinement of surgical strategies in colorectal cancer management.

Objectives {7}

The primary objective of this trial is to evaluate whether NOSE can reduce the systemic inflammatory response, as measured by C-reactive protein (CRP) levels on the third postoperative day, compared to conventional MIS using a mini-laparotomy for specimen removal in CRC patients.

Secondary objectives include assessing the differences between the NOSE and conventional surgery groups in terms of 30-day postoperative complications, pain levels, time to first flatus, time to soft diet, length of hospital stay, unplanned 30-day readmissions, number of lymph nodes retrieved, recurrence rates, and long-term survival outcomes such as overall, disease-free, and cancer-specific survival.

Trial design {8}

The MINITR-NOSE study is designed as a two-arm, single-center, parallel-group RCT with an equivalent framework. Participants will be randomly assigned to either the NOSE intervention group or the conventional MIS group at a 1:1 allocation ratio. This design aims to compare the efficacy and safety of NOSE against traditional mini laparotomy in patients undergoing surgery for CRC. The trial will utilize stratified random sampling, dividing the population into three subgroups based on the type of bowel resection performed (right hemicolectomy, left hemicolectomy, and anterior resection) to ensure balanced representation within each treatment group. The equivalence framework will facilitate a thorough assessment of whether NOSE provides comparable or enhanced outcomes relative to conventional techniques, specifically regarding postoperative inflammatory response and associated complications.

Methods: participants, interventions, and outcomes

Study setting {9}

The MINITR-NOSE trial will take place at the Colorectal Division of Linkou Chang-Gung Memorial Hospital, a single medical center with a substantial population of CRC patients, treating approximately 1,000 new cases annually. Both mini laparotomy and NOSE procedures are recognized as standard of care. Ethics approval for the study has been granted by the Institutional Review Board (IRB) (No. 202102468A3).

Eligibility criteria {10}

Inclusion criteria

Patients must meet all the following eligibility requirements to participate in the study:

1. Histological or cytological confirmation of colorectal adenocarcinoma

2. Age ≥ 18

3. Performance status of 0–2 on the ECOG (Eastern Cooperative Oncology Group) scale

4. American Society of Anesthesiology (ASA) score is 1–3

5. Tumor location: the lower margin of the tumor greater than 10 cm from the anal verge

6. Preoperative clinical T staging: T0–T4a at preoperative evaluation according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 8th Edition

7. Preoperative clinical M staging: M0 according to AJCC Cancer Staging Manual 8th Edition

8. Tumor size: 4 cm or less in diameter by clinical computed tomography image

9. Written informed consent for participation

Exclusion criteria

Patients who fulfill any of the following exclusion criteria will be excluded from this study:

1. Not suitable for MIS

2. Body mass index (BMI) > 30 kg/m.²

3. Malnutrition: albumin level less than 3.5 g/dl

4. Previous pelvic surgery with pelvic adhesion

5. Emergency surgery

Who will take informed consent? {26a}

Patients diagnosed with CRC and seeking treatment at Chang-Gung Memorial Hospital will have the opportunity to participate in this study. Their colorectal surgeon will screen them in the outpatient clinic to assess eligibility. If they meet the inclusion criteria and express interest in participating, they will receive detailed information about the study and will have time to consider their decision prior to admission for surgery.

Upon admission, patients will undergo a comprehensive assessment to determine their eligibility based on the study’s inclusion and exclusion criteria. Those who qualify and wish to proceed will be referred to the research team for further screening and briefing. Well-trained research staff will provide an in-depth explanation of the study, allowing patients to ask questions and clarify any concerns.

All participating patients will be required to sign an informed consent form, which will be written in clear, patient-friendly language and comply with local laws and regulations. The informed consent document will be signed by a member of the research team, the colorectal surgeon, a physician assistant, and the patient.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Patients will also be encouraged to voluntarily participate in a biobank, with participation entirely optional. Samples will only be collected with the patient’s written consent, and opting out will not affect their treatment. Upon receiving consent, the physician may collect and store tumor tissue, adjacent normal tissue, and blood for research purposes. Identifiable information will be removed and replaced with a unique code to protect patient confidentiality. The hospital prioritizes patient privacy, ensuring that all information is securely safeguarded. Patients retain the right to revoke their consent at any time without facing any repercussions.

Interventions

Explanation for the choice of comparators {6b}

Both comparators, NOSE and traditional MIS, are well-executed for CRC patients at Chang-Gung Memorial Hospital. While both methods are established and effective, they differ in how they remove the tumor-containing bowel segment. Conventional MIS involves removing the affected bowel segment through a small abdominal incision known as a mini-laparotomy. In contrast, the NOSE technique removes the specimen transrectally in this trial. This advanced approach eliminates the need for a mini-laparotomy incision, potentially reducing postoperative pain and accelerating recovery.

Numerous studies have described the transrectal NOSE procedure, primarily focusing on rectosigmoid colon tumors, with limited information available on tumors located proximal to the sigmoid colon [15, 16]. In fact, malignancies above the sigmoid colon have been primarily approached via the transvaginal route [17, 18]. Therefore, there is a clear need for a RCT to compare the efficacy of the transrectal NOSE procedure with traditional MIS for tumors throughout the entire colon, not just those confined to the rectosigmoid region.

This study aims to evaluate whether the transrectal NOSE approach achieves clinically significant outcomes, particularly concerning complications such as intra-abdominal contamination and anastomotic leaks. Conventional MIS with a mini-laparotomy incision has been chosen as the standard comparator for this trial, as it is the most performed technique for resecting the bowel segment containing the tumor.

Intervention description {11a}

Common procedures for both groups

Preoperative preparation

All patients will undergo standard preoperative assessments, including physical examinations and laboratory tests, to ensure surgical eligibility. Bowel preparation will be administered to minimize fecal contamination during the procedure.

Anesthesia and induction

After confirming eligibility and obtaining informed consent, general anesthesia will be administered in the operating room.

Surgical procedure

Multi-port laparoscopic access will be established, and the targeted bowel segment will be identified and mobilized. Bowel anastomosis will be performed according to the designated approach for each group.

Intraoperative evaluation

Following anastomosis, peritoneal lavage with 50 ml of normal saline will be performed to assess contamination and ensure no residual fluid remains. Peritoneal washing cytology (PWC) will be analyzed postoperatively to evaluate potential peritoneal dissemination.

Duration

The total surgical time for both procedures is expected to range from 2 to 4 hours, depending on case complexity and the surgeon’s experience.

Timing of administration

Both interventions will be performed in the operating room after preoperative evaluations and patient consent. The duration of each procedure will be closely monitored to ensure adherence to study protocols and optimize patient safety.

Surgeon expertise

All procedures will be conducted by experienced colorectal surgeons proficient in the respective surgical techniques to ensure consistency and reliability in study outcomes.

Distinct procedures for each group

NOSE surgery group (natural orifice specimen extraction):

• Transrectal extraction: The rectosigmoid colon will be accessed transrectally. A bowel clamp will be used to block the colonic lumen, and transrectal endoscopic microsurgery (TEM) or an Alexis wound protector will be inserted into the rectum. After an enterotomy is performed, the specimen will be extracted using the TEM scope following anastomosis completion.

• Closure of rectal opening: The rectal opening will be closed with a barbed suture, followed by an air leak test to evaluate anastomotic integrity.

Conventional laparoscopic surgery group:

• Extracorporeal technique: If an extracorporeal anastomosis is performed, a mini-laparotomy wound will be created to exteriorize the bowel for anastomosis.

• Specimen removal: The specimen will be extracted through the mini-laparotomy incision after anastomosis is completed.

Criteria for discontinuing or modifying allocated interventions {11b}

Patients are free to withdraw from the study at any time and for any reason, with no repercussions. Researchers retain the right to remove participants from the study for ethical or health-related reasons. Additionally, if the operating rectoscope is unable to access the upper rectum due to rectal angulation or narrowing of the lumen, or if advanced malignancy or peritoneal seeding is identified during surgery, the colorectal surgeon may choose to discontinue the intervention. This decision prioritizes the patient’s safety and well-being, preventing any potential adverse consequences associated with the procedure. The surgeon’s experience and judgment are crucial in these circumstances, as they determine whether to continue the intervention and ultimately influence the patient’s potential outcome.

Strategies to improve adherence to interventions {11c}

To enhance adherence to the interventions outlined in this study, only trained and proficient colorectal surgeons experienced in transrectal NOSE procedures will be involved. Given the complex and delicate nature of this surgery, it is essential that the surgeon possesses a high level of competence and experience. The surgeon’s expertise and clinical judgment are critical to the success of the procedure, as they directly influence its feasibility, safety, and the optimal outcome for the patient.

Relevant concomitant care permitted or prohibited during the trial {11d}

Patients in both the intervention and control groups will receive standard perioperative care, which is essential to the concept of ERAS. This comprehensive care encompasses the period before, during, and after surgery, aiming to improve patient outcomes and reduce hospital stays. Throughout the trial, there are no restrictions on concomitant care, allowing participants to receive appropriate and safe treatments for their conditions. This approach ensures that patients benefit from integrated care that addresses all aspects of their health during and after surgery, including pain management, nutrition, physiotherapy, and other therapies to optimize recovery.

Provisions for post-trial care {30}

Patients participating in this study who experience adverse events (AEs) related to their involvement in the clinical trial will not receive compensation. The role of treating physicians is critical in ensuring that patients receive appropriate post-trial care. The study prioritizes participant safety and rehabilitation by adhering to standard clinical protocols for managing research-related complications. While the study team cannot guarantee financial compensation for participants, healthcare practitioners will provide ongoing treatment as needed.

Outcomes {12}

Primary outcome

The primary outcome of this study is the difference in CRP levels measured on the third postoperative day. CRP, an acute-phase protein produced by the liver, can be quickly and quantitatively assessed in blood samples to monitor postoperative inflammation and infection [19]. Inflammation and infection are common complications following colorectal surgery and can significantly affect patient recovery and prognosis. Given that the rectum must be accessed and opened during the transrectal NOSE technique, monitoring for infection is particularly critical. Several studies have shown that CRP serves as a reliable marker for identifying postoperative complications such as surgical site infections, pneumonia, and, notably, anastomotic leaks, which can be life-threatening after gastrointestinal surgery [20, 21]. Additionally, the CRP test is readily accessible, cost-effective, and quick to perform, making it a valuable tool for monitoring postoperative inflammation and infection [22, 23]. CRP testing provides a more objective and quantitative measure compared to clinical signs, symptoms, or imaging studies, which may be subject to observer bias [24, 25].

Secondary outcomes

The secondary outcomes to be assessed include the following:

1. Short-term complications: morbidity and mortality within 30 days

2. Postoperative pain levels

3. Postoperative recovery course: time to first flatus passage and time to a soft diet

4. Length of hospital stay

5. Unplanned readmissions within 30 days of discharge

6. Number of lymph nodes retrieved

7. Incidence and pattern of recurrence

8. Long-term survival: overall survival, disease-free survival, and cancer-specific survival

9. Postoperative care will follow the principles of the ERAS program, with specific modifications tailored to the needs of our institution. The modified ERAS protocol aims to optimize patient outcomes, enhance recovery, and minimize complications.

Postoperative complications are defined as AEs occurring within 30 days following the surgical procedure. These complications can include various categories, such as wound-related issues (e.g., infection, wound dehiscence), pulmonary complications (e.g., atelectasis, pneumonia), cardiovascular complications (e.g., myocardial infarction, stroke, embolism), urinary complications (e.g., urinary tract infection, neurogenic bladder), gastrointestinal complications (e.g., obstruction, ileus, bleeding), and abdominal issues (e.g., abscess, internal bleeding). Anastomosis-related complications, including leakage or stenosis, as well as other rare complications, will also be recorded. Postoperative mortality is defined as death occurring within 30 days of the surgical procedure. The severity of postoperative complications will be graded using the Clavien-Dindo classification system, providing a standardized approach to assess and categorize complications based on their impact and management needs.

Pain intensity will be recorded daily for three consecutive days following surgery to evaluate the level of pain experienced by patients. This assessment will utilize a numeric rating scale (NRS) ranging from 0 to 10, where a score of 0 indicates no pain and a score of 10 represents the worst imaginable pain [26]. This scale allows healthcare professionals to quantify and monitor postoperative pain intensity, aiding in the management and adjustment of pain relief strategies as necessary.

Participant timeline {13}

	Study period
	Pre-screen	Treatment	Post-allocation
Timepoint (day)	− 7 ~ 0	0	1	2	3	10 ± 3	30 ± 3
Enrolment	Screening/baseline	Operation day	POD1 ward run	POD2 ward run	POD3 ward run	OPD visit	Final study visit
Clinical visit/inform consent	X
Inclusion/exclusion criteria	X
Medical and surgical history and demographics	X
Physical exam	X
High and body weight	X
Laboratory data	X
Interventions
Randomization/administration	X
Surgery		X
Peritoneal fluid analysis		X
Assessments
Vital signs		X	X	X	X
Morbidity/mortality		X	X	X	X	X	X
Postoperative recovery		X	X	X	X
The length of hospital stays		X	X	X	X
Inflammatory and immune markers			X		X
Pathology report						X

Sample size {14}

The null hypothesis (H0) posits that there is no clinically significant difference in CRP levels between the two surgical approaches. Based on our prior clinical experience, we assume a mean CRP level of 60 for conventional laparoscopic surgery with a standard deviation of approximately 30, compared to a mean of 70 for NOSE surgery.

For sample size calculation, we aim to achieve 80% power (1 − β = 0.8) at a 5% significance level (α = 0.05) with an equal allocation ratio between the NOSE and conventional groups. The analysis yields an initial sample size of 143 participants per group. Accounting for an anticipated dropout rate of 10%, we have adjusted the sample size to 318 participants in total, with 159 allocated to each group.

Recruitment {15}

Patients diagnosed with colorectal adenocarcinoma and meeting the eligibility criteria will be recruited from the Colorectal Division at Linkou Chang-Gung Memorial Hospital. Given the high volume of cases (approximately 1000 new CRC cases annually), the hospital’s electronic health record (EHR) system will be utilized to identify eligible patients who meet the inclusion criteria.

To enhance recruitment, colorectal surgeons will introduce the study during outpatient consultations, providing patients with an overview and answering initial questions. Patients who express interest will receive detailed information about the study protocol and potential benefits. Additionally, study information will be made available via the hospital’s website and patient information centers, facilitating patient awareness and self-referral opportunities.

Based on current patient flow, we anticipate enrolling the target of 318 participants within an 18–24-month recruitment period, accounting for a 10% dropout rate. Regular progress reviews will allow adjustments to ensure enrollment goals are met efficiently.

Assignment of interventions: allocation

Sequence generation {16a}

The randomization sequence will be generated by an independent statistician at the clinical trial center, following the Standard Operating Procedure and ensuring adherence to Good Clinical Practice standards. The sequence will be created using computer-generated random codes to allocate participants in a 1:1 ratio between the NOSE surgery group and the conventional laparoscopic mini-laparotomy resection group. No stratification factors will be applied to the sequence.

Concealment mechanism {16b}

To ensure allocation concealment, the generated randomization codes will be securely sealed within sequentially numbered, opaque, and tamper-proof envelopes. These envelopes will remain inaccessible to all study personnel involved in participant care until an intervention assignment occurs in the operating room. Additionally, the envelopes will be stored and distributed only by the independent research assistant responsible for randomization, minimizing potential biases and maintaining allocation concealment.

Implementation {16c}

After confirming patient eligibility and completing all necessary preoperative assessments, the research team will enroll participants. During the surgery, an independent research assistant, who has no involvement in other aspects of the trial, will assign the participants to their intervention group by opening the appropriate sealed envelope. This assignment occurs only after surgical induction, thus upholding the integrity of the randomization process. The clinical trial center’s statisticians are responsible solely for generating the randomization codes, and the surgical team will not have access to allocation details until the assignment is confirmed by the research assistant.

Assignment of interventions: blinding

Who will be blinded {17a}

Due to the inherent characteristics of surgical procedures, double blinding of participants and surgical teams is not feasible. Nevertheless, the study maintains rigorous blinding protocols for outcome assessors and data analysts throughout the trial duration. All postoperative evaluations, including measurements of inflammatory markers, analysis of peritoneal fluid samples, and monitoring of complications, are conducted by personnel who have no knowledge of treatment allocation, thereby minimizing detection bias. Access to allocation codes is strictly limited to the independent data management team, with comprehensive data access restricted to the designated project data manager and administrator. The primary statistical analyst maintains complete blinding during the initial outcome analyses, with unmasking permitted only for subsequent secondary and post hoc analyses.

Procedure for unblinding if needed {17b}

Not relevant in the present study.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Comprehensive outcome assessments will be conducted at multiple time points, encompassing intra-operative peritoneal lavage fluid analysis, 30-day post-operative evaluations of complications, bowel function recovery, and length of stay, as well as long-term monitoring of recurrence rates, disease-free survival, and overall survival. The study employs various validated instruments, including PWC for cancer dissemination detection, standardized microbiological protocols for bacterial culture analysis of peritoneal fluid samples, and validated questionnaires to assess bowel function recovery and quality of life at predetermined post-surgical intervals. To ensure data quality and reliability, all outcome assessors will participate in standardized training sessions to maintain consistency in evaluation methods, while critical measurements such as inflammatory markers will be performed in duplicate for enhanced accuracy verification.

Plans to promote participant retention and complete follow-up {18b}

To achieve optimal retention rates, the study implements a comprehensive communication strategy encompassing regular phone calls, emails, and text messages to maintain participant engagement and provide timely reminders for follow-up appointments and assessments. In cases where participants discontinue or deviate from intervention protocols, the research team maintains a rigorous approach to data collection, documenting withdrawal reasons, AEs, and follow-up outcomes where feasible, thereby preserving data integrity and minimizing potential bias in the study results.

Data management {19}

All data is entered into a secure electronic database system, with strictly controlled access limited to authorized personnel only. Regular range checks are performed to identify and rectify potential outliers or implausible entries. For optimal data protection and preservation, all collected information is stored on encrypted servers with systematic backup procedures in place to prevent data loss. These rigorous data management protocols are thoroughly documented and readily accessible within the trial.

Confidentiality {27}

Personal information is collected via encrypted online forms, with identifiers systematically separated from trial data. To maintain privacy, only de-identified data is utilized for analyses and publication of results. Any data sharing activities strictly adhere to ethical guidelines, ensuring no identifiable information is disclosed to third parties without explicit participant consent. The commitment to confidentiality extends beyond the trial period, with all data securely stored for a defined duration before systematic destruction.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Specimens include intra-operative peritoneal lavage fluid collected after bowel anastomosis but before wound closure, and day-3 post-operative blood samples for assessing inflammatory markers such as complete blood cell count, CRP, procalcitonin, and interleukin-6. Laboratory evaluation comprises PWC for cancer dissemination assessment, microbiological cultures for contamination analysis, and inflammatory marker measurements, all conducted using validated techniques. Specimens are stored in a temperature-controlled biobank facility with unique identifiers and comprehensive documentation. Unused specimens are preserved for potential future studies, with all procedures adhering to ethical guidelines and participant consent requirements.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The primary outcome will focus on the relationship between surgical approaches of NOSE versus conventional laparoscopic surgery, and postoperative CRP levels, measured three days post-surgery. To analyze this outcome, a two-sample t-test will be used to compare mean CRP levels between the two groups, assuming normal distribution. If normality assumptions are not met, the Mann–Whitney U test will serve as a non-parametric alternative. Statistical significance will be established with a p-value of less than 0.05, ensuring the validity of the findings.

Secondary outcomes will encompass a range of postoperative factors, including complications, bowel function recovery, hospital stay duration, and rates of reoperation and readmission. These will be analyzed through various methods: postoperative complications will be classified using the Clavien-Dindo system and compared via chi-square tests; bowel function recovery will be assessed using Kaplan–Meier survival analysis and the log-rank test; length of stay will be summarized and compared using independent-sample t-tests; and reoperation and readmission rates will also be analyzed with chi-square tests.

All analyses will be conducted with appropriate statistical software, and strategies such as multiple imputations will address missing data. Long-term outcomes, including disease-free and overall survival, will utilize Cox proportional hazards models to adjust for covariates, with a detailed statistical analysis plan documented in the trial’s supplementary materials.

Interim analyses {21b}

Not applicable. Interim analysis will not be performed in the present study.

Methods for additional analyses (e.g., subgroup analyses) {20b}

Subgroup analyses will be conducted based on key demographic factors, such as age, sex, body mass index (BMI), and baseline clinical conditions. These subgroup analyses will help identify any variations in treatment efficacy between different populations, allowing for a nuanced interpretation of the results.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

The primary analysis will follow the intention-to-treat (ITT) principle, including all randomized participants in their assigned groups regardless of adherence to the protocol. A per-protocol (PP) analysis will also be conducted as a sensitivity analysis to assess the robustness of the primary findings. Due to the constraints of our data collection process, which are limited to a single assessment on the third postoperative day, we will implement deletion methods to address any missing data. Specifically, we will consider complete case analysis or partial case analysis as appropriate. Sensitivity analyses will be conducted to evaluate the potential impact of missing data handling strategies.

Plans to give access to the full protocol, participant-level data and statistical code {31c}

To ensure transparency and reproducibility in the MINITR-NOSE trial, we will provide access to the full study protocol, participant-level data, and statistical code, adhering to Taiwan’s Personal Data Protection Act (PDPA). The study protocol will be publicly available, while access to participant-level data will be tightly controlled and granted only with explicit project group approval, ensuring participant privacy through anonymization. Statistical code will be available upon request with documentation for reproducibility, managed by the research unit head. We aim to balance transparency with the protection of participant confidentiality in compliance with legal standards.

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}

The IRB of Chang Gung Medical Foundation is responsible for overseeing and coordinating the overall project. Challenges and reflections of the process will be shared with the core research group to ensure sustainability of recruitment. Furthermore, the core research group will continuously review the progress of the study and any necessary changes to the protocol to facilitate the smooth running of the study.

Composition of the data monitoring committee, its role and reporting structure {21a}

The Independent Data and Safety Monitoring Board (DSMB) is responsible for monitoring and evaluating human research projects. If necessary, this board will assist in establishing a Data and Safety Monitoring Committee. The DSMB will regularly review execution records, safety data, and key efficacy indicators for each trial to minimize deviations, ensure the integrity of the study, and protect participants’ rights. Furthermore, the trial must adhere to the regulations set forth by the IRB. Neither the DSMB nor the IRB will be included in the present study, as the sponsors are not involved in the study design, data collection, or analysis. The research group will be responsible for promptly reporting any adverse incidents to the IRB.

Adverse event reporting and harms {22}

Participants will be encouraged to report any AEs immediately, which will be documented using standardized forms. Clinical research coordinators will assess the severity and relationship of AEs to the intervention, categorizing them as mild, moderate, severe, or life-threatening. All serious AEs will be reported directly to the IRB of Chang Gung Medical Foundation, following the Serious Adverse Event Reporting Procedures and Guidelines available on the IRB’s Clinical Trials Resource section. This systematic reporting process ensures that all solicited or spontaneously reported AEs and unintended effects are collected, assessed, and managed throughout the trial. This approach enhances participant safety and regulatory compliance, enabling prompt identification and response to trial-related risks.

Frequency and plans for auditing trial conduct {23}

The IRB of Chang Gung Medical Foundation is free to conduct an audit at any time during the trial. Access to the source data and study-related files will be granted on such occasions. All documents and data analyses will be available for auditing for at least 5 years after the conclusion of the study.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

The research team will ensure that all significant amendments are reported to the IRB of Chang Gung Medical Foundation and documented according to their procedures. Additionally, updates will be provided to trial participants to keep them informed about changes that may affect their involvement in the study. The modifications will also be reported to clinical trial registries, including ClinicalTrials.gov (Identifier: NCT05740267), and any relevant journals or regulatory bodies as necessary. This structured communication plan aims to maintain transparency and uphold the integrity of the trial throughout its duration.

Dissemination plans {31a}

The results of the MINITR-NOSE trial will be disseminated through multiple channels to effectively communicate with participants, healthcare professionals, and the public. Key methods include publishing findings in international peer-reviewed journals, covering both positive and negative results to enhance understanding of treatment efficacy. Additionally, results will be presented at national and international conferences for knowledge sharing. There will be no publication restrictions, ensuring transparent reporting in line with ethical guidelines and scientific integrity.

Discussion

The advent of MIS has transformed the management of colorectal diseases by offering significant advantages over open surgery, including smaller incisions, reduced postoperative pain, and quicker recovery periods. Despite these benefits, conventional MIS techniques often require a mini-laparotomy incision for specimen extraction, which can still lead to wound-related complications such as infections, hernias, and increased discomfort.

To further minimize surgical trauma and enhance cosmetic outcomes, the NOSE technique was developed. This approach involves retrieving the surgical specimen through natural orifices like the rectum, thereby eliminating the need for an additional abdominal incision. Prior studies have demonstrated the feasibility of NOSE in procedures like laparoscopic right hemicolectomy with transvaginal extraction and transrectal removal of sigmoid colon and rectal specimens, showing favorable short-term surgical outcomes and acceptable long-term results [1, 5, 27].

However, the NOSE procedure is not without its challenges. One of the primary concerns is the potential for bacterial contamination during intracorporeal anastomosis and specimen extraction through natural orifices. One research has indicated higher rates of peritoneal fluid contamination in NOSE procedures compared to conventional laparoscopic surgeries [28]. The clinical significance of this contamination is still under investigation, as it does not consistently correlate with increased postoperative infection rates. Protective strategies, such as using sterile specimen bags during extraction, have been suggested to mitigate these risks [12, 29, 30].

Another area of concern is the risk of anastomotic leakage and intra-abdominal infections. While some studies report comparable complication rates between NOSE and traditional methods [7], others have noted higher incidences of specific complications in NOSE procedures such as higher rates of incontinency, impotency, and stenosis and the risk of anastomotic leakage [31, 32]. These discrepancies highlight the need for meticulous surgical technique, proper patient selection, and strict adherence to surgical protocols to minimize adverse outcomes.

Our RCT aims to provide potent evidence regarding the efficacy and safety of the NOSE technique compared to conventional MIS. By focusing on postoperative inflammatory responses, specifically measuring CRP levels on the third postoperative day, we seek to objectively assess whether NOSE can reduce systemic inflammation. A lower inflammatory response may translate to decreased postoperative pain, fewer complications, and expedited recovery, ultimately enhancing patient outcomes.

Additionally, this study endeavors to expand the applicability of the NOSE technique to a broader spectrum of colorectal cancer cases beyond rectosigmoid tumors. By evaluating its effectiveness in various types of colorectal resections, we aim to determine whether NOSE can be generalized as a standard practice in colorectal surgery.

In conclusion, while the NOSE procedure offers promising advantages in reducing surgical trauma and improving recovery, it is essential to thoroughly assess its potential risks and benefits. This trial is designed to address existing concerns by providing high-quality evidence on the NOSE technique’s safety and efficacy. The outcomes of this research could significantly influence future surgical practices, potentially leading to the adoption of NOSE as a preferred method for minimally invasive colorectal cancer surgery and improving overall patient care.

Abbreviations

CRC

Colorectal cancer

NOSE

Natural orifice specimen extraction

CRP

C-reactive protein

ERAS

Enhanced recovery after surgery

IRB

Institutional Review Board

ASA

American Society of Anesthesiology

AJCC

American Joint Committee on Cancer

BMI

Body mass index

TEM

Transrectal endoscopic microsurgery

EHR

Electronic health record

PWC

Peritoneal washing cytology

RCT

Randomized controlled trial

PDPA

Personal Data Protection Act

DSMB

Data and Safety Monitoring Board

AEs

Adverse events

MIS

Minimally invasive surgery

Authors’ contributions {31b}

Professor Jeng-Fu You led the study design and research. All other authors participated in conducting the study and discussing the research plan. The manuscript draft was prepared by Ai-Lun Lo and Jeng-Fu You. All authors reviewed the manuscript, provided revisions, and approved the final version.

Funding {4}

This project is funded by the Chang Gung Medical Research Fund (grant number CPRPG3N0031). Financial support covers costs related to personnel, materials, data collection, and analysis necessary for conducting the study. The funders have not been involved in the design of the study; collection, analysis, or interpretation of data; or the writing of the manuscript. This ensures the independence and integrity of the research throughout its development and execution.

Data availability {29}

The principal investigator and the project data manager will have exclusive access to the final trial dataset. Access to the data will be strictly controlled to protect participant confidentiality and comply with relevant data protection regulations. Any requests for access to the trial data will be considered on an individual basis after the publication of the final trial results. Such requests must be submitted in writing and will be reviewed and approved by the project group, ensuring that any data sharing aligns with ethical standards and legal requirements. Due to the sensitive nature of the personal data collected in this study, the final dataset will not be publicly available. This is in accordance with Taiwan’s PDPA and other applicable laws.

Declarations

Ethics approval and consent to participate {24}

Approval has been obtained from the IRB of Chang Gung Medical Foundation (No. 202102468A3). Before obtaining written informed consent, participants will be provided with information about the study in both written and verbal forms. Additionally, participants will be informed that they may withdraw from the project at any time without any obligation.

Consent for publication {32}

All authors have granted permission for the material to be published.

Competing interests {28}

The authors declare that they have no competing interests.