The goal of this type of study: a prospective, randomized controlled clinical trial is to assess the safety and feasibility of NOSE surgery to compare the NOSE and conventional laparoscopy groups in Colorectal cancer patients. The main questions it aims to answer are measuring the postoperative inflammatory response and monitoring the early morbidity and mortality rate after surgery. Participants will be assigned patients to undergo either NOSE surgery or conventional laparoscopic mini-laparotomy resection. If there is a comparison group: Researchers will compare the control group to see if postoperative inflammatory response.

Endpoints (Outcome measure)：

Primary endpoint:

The primary outcome measure was the postoperative inflammatory response, which was evaluated by monitoring the C-reactive protein (CRP) level during hospitalization on the 3rd day following surgery. Early morbidity and mortality rate (postoperative 30 days): The early morbidity and mortality rate is defined as the event observed during the operation and within 30 days after surgery. Postoperative 30-day hospital readmission data will be also collected.

1. Secondary endpoints:

   A. Duration of Operation time: The length of the surgery will be recorded. B.Peritoneal Cytologyduring surgery: The investigators assess the tumor cells identified by peritoneal cytologic specimens. Given the relationship of positive cytology with metachronous peritoneal seeding, it is essential to evaluate datasets from patients who undergo the NOSE group.

   C. Peritoneal Contamination during surgery: Peritoneal fluid samples were collected under sterile circumstances at the end of the surgery and sent for aerobic and anaerobic cultures. The investigators evaluate the contamination rate of peritoneal fluid in the two groups.

   D.Postoperative Pain Score:

   Pain intensity is assessed using a Numeric Rating Scale (NRS) with scores from 0 to 10 (10 = the worst pain). The highest pain scores of patients on each day for three consecutive days postoperatively will be recorded for further evaluation.

   E.Postoperative Recovery course:

   Time to first flatus passage Time to the first liquid diet Time to the first soft diet The length of hospital stays F.Number of retrieved lymph nodes G.Recurrence incidence and pattern

2. Exploratory endpoints (if any):

Long-term outcome:

Overall survival Disease-free survival Cancer-specific survival Inclusion/Exclusion Criteria： Patient Enrollment Histological or cytological confirmation of colorectal adenocarcinoma. Inclusion criteria

1. Age ≥ 18
2. Performance status of 0 - 2 on the ECOG (Eastern Cooperative Oncology Group) scale
3. American Society of Anesthesiology (ASA) score is Ⅰ-Ⅲ
4. Tumor location: CRC with the lower margin of the tumor greater than 10 cm from the anal verge
5. Pre-operative T staging: T0-T4a at preoperative evaluation according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 8th Edition
6. Preoperative M staging: M0 according to AJCC 8th
7. Tumor size: 4 cm or less
8. Written informed consent for participation Exclusion criteria

(1) Not suitable for minimally invasive surgery (2) Body mass index (BMI) >30 kg/m2 (3) Malnutrition: albumin level less than 3.5 (4) Previous pelvic surgery (5) Emergency surgery Study Procedures： Randomization Randomization will be performed in the operating room at the Colorectal division, Linkou Chang Gung Memorial Hospital. Following the induction of minimally invasive surgery, an independent research assistant randomly assigned patients to undergo either NOSE surgery or conventional laparoscopic mini-laparotomy resection by sealed-envelope randomization. To ensure every group is similar in terms of covariates, especially the operation method (including right hemicolectomy, left hemicolectomy, and anterior resection). Randomization assignment is performed by the statisticians of the clinical trial center to generate random codes.

Minimally invasive surgery Minimally invasive surgery will be performed in all operations, including multi-port laparoscopic surgery and robotic surgery. After the segment of bowel resection, the strategy for surgical specimen removal is according to the result of randomization.

# Conventional laparoscopy group: The investigators can select either the intracorporeal or extracorporeal method to create bowel anastomoses. For the extracorporeal way, a mini-laparotomy wound is created and exteriorizes the bowel to do the anastomosis. The specimen is removed via the mini-laparotomy wound after the anastomosis is accomplished for the intracorporeal approach.

# NOSE group: After bowel resection, all bowel anastomoses are created via side-to-side intracorporeal anastomosis, either isoperistaltic or antiperistaltic. The surgical steps of NOSE with the transrectal method are illustrated in Figure 1. First, the rectosigmoid colonic lumen is blocked with a bowel clamp. After rectal irrigation with povidone-iodine water, a transanal endoscopic microsurgery (TEM) scope or Alexis wound protector is inserted through the anus, reaching the upper rectum. Enterotomy is performed at the upper rectum, and a suction device is used to clean any fecal spillage. The TEM scope is pushed forward beyond the rectal opening, and the specimen is extracted with the TEM scope. The rectal opening is closed with a barbed suture, and an air leak test is performed to identify anastomotic leakage.

Intra-operative evaluation

Peritoneal lavage with 50 ml of normal saline on the Douglas pouch and the sub-phrenic area will be performed after the bowel anastomosis and before the abdominal wound closure. The estimated time would be 5 to 10 minutes. No additional risk will occur during the procedure. The investigators will do the peritoneal lavage fluid analysis in the following two phases:

• Peritoneal washing cytology (PWC) Peritoneal washing cytology (PWC) is a helpful indicator of peritoneal surface involvement and peritoneal dissemination of colorectal cancer. It may identify subclinical peritoneal spread and thus provide prognostic information. PWC is a useful prognostic tool in patients undergoing curative surgery for colorectal cancer since positive PWC was shown to be a potential risk factor for recurrence. The investigators will compare the positive rate of peritoneal cytology in the two groups.
• Peritoneal fluid bacterial culture:

Although minimally invasive surgery is performed with standard procedure, contamination is inconceivable to avoid. In the NOSE group, the rectum is opened and exposed to the peritoneal cavity, and bacterial contamination is inevitable. After finishing the anastomosis in each group, a microbiological sample is obtained from the peritoneal fluid specimens. The investigators will collect the data and analyze the correlation between NOSE and wound infection and intra-abdominal infection rates.

Post-operative assessment

The postoperative outcome will be analyzed as below:

1. Postoperative complications The complication within 30 days will be recorded and categorized according to the Clavien-Dindo classification.
2. Bowel function recovery The investigators will record and analyze the time to the first flatus passage, the first liquid diet, and the time to a soft diet.
3. The length of hospital stays The length of hospital stays is calculated from the date of operation to the discharge date.
4. Second operation and Readmission Reoperation and unplanned readmission will be recorded.

Inclusion Criteria:

Patient Enrollment Histological or cytological confirmation of colorectal adenocarcinoma. Inclusion criteria

1. Age ≥ 18
2. Performance status of 0 - 2 on the ECOG (Eastern Cooperative Oncology Group) scale
3. American Society of Anesthesiology (ASA) score is Ⅰ-Ⅲ
4. Tumor location: CRC with the lower margin of the tumor greater than 10 cm from the anal verge
5. Pre-operative T staging: T0-T4a at preoperative evaluation according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 8th Edition
6. Preoperative M staging: M0 according to AJCC 8th
7. Tumor size: 4 cm or less
8. Written informed consent for participation

Exclusion Criteria:

1. Not suitable for minimally invasive surgery
2. Body mass index (BMI) >30 kg/m2
3. Malnutrition: albumin level less than 3.5
4. Previous pelvic surgery
5. Emergency surgery

Randomization assignment is performed by the statisticians of the clinical trial center to generate random codes.