A Multicenter Randomized Clinical Trial Comparing Surgical Site Infection After Intracorporeal Anastomosis and Extracorporeal Anastomosis for Left Colon Cancer (STARS)
Phase: NA
Conditions: Colon Cancer
Sponsor: Jilin University

Supplemental Digital Content 
 
Surgical Site Infection After Intracorporeal Anastomosis for Left-Sided Colon 
Cancer: A Multicenter Randomized Controlled Trial (STARS Trial) 
Protocol and Statistical Analysis Plan Amendment History 
 
 
 
CONTENTS 
1. CLINICAL STUDY PROTOCOL (CSP) .............................................................. 2 
1.1 CSP ORIGINAL VERSION 1.0 (DEC 20, 2019) .......................................................... 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 CSP FINAL VERSION 2.1 (JUL 16, 2023) ……………………………………… 41
1.3 CSP AMENDMENTS SUMMARY............................................................................. 82
2. STATISTICAL ANALYSIS PLAN (SAP) ............................................................ 83
SAP VERSION 1.0 (DEC 05, 2023) ............................................................................. 83

 
 
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Protocol 
 
 
A Multicenter Randomized Clinical Trial Comparing Surgical Site Infection after Total 
Laparoscopic and Laparoscopic-assisted Radical Surgery for Left Colon Cancer 
(STARS) 
 
Principal investigator: 
Wang Quan 
D e p a r t m e n t: 
Department of Gastrocolorectal Surgery 
Version: 
1.0 
Release date: 
December 20, 2019 
Telephone： 
+86 15843073207
 
 
Email: 
wquan@jlu.edu.cn 

 
 
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Abstract 
Title 
A Multicenter Randomized Clinical Trial Comparing Surgical Site 
Infection after Total Laparoscopic and Laparoscopic-assisted Radical 
Surgery for Left Colon Cancer 
Study Center 
First Hospital of Jilin University 
Peking Union Medical College Hospital 
Cancer Hospital Affiliated to Fudan University 
Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of 
Medicine 
Beijing Friendship Hospital , Capital Medical University 
PLA General Hospital 
Daping Hospital Affiliated to Army Military Medical University 
Shengjing Hospital Affiliated to China Medical University 
Chinese Academy of Medical Sciences Cancer Hospital 
China - Japan Union Hospital of Jilin University 
The First Affiliated Hospital of China Medical University 
Nanfang Hospital of Southern Medical University 
Study Purpose 
The purpose of this study is to investigate the effects of intracorporeal 
anastomosis and extracorporeal anastomosis in laparoscopic-assisted 
radical left hemicolectomy on surgical site infection. Also consider 
perioperative recovery, safety, and oncology outcomes. 
Study Type 
 
 
 
 
Patients 
Selection 
Inclusion Criteria: 
(1) age between 18 and 80 years;  
(2) histologically or cytologically confirmed left-sided colon cancer 
(distal transverse colon, left colic flexure, descending colon, or 
proximal sigmoid colon);  
(3) clinical stage T1–4a, N0–2, and M0;  
A prospective, multicenter, non-inferiority, two-arms, single-blind, 
randomized controlled study

 
 
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(4) Eastern Cooperative Oncology Group (ECOG) performance status 
≤ 2; 
(5) suitable for laparoscopic colectomy;  
(6) no previous systemic chemotherapy or radiotherapy;  
(7) willing to provide written informed consent and comply with the 
research procedures. 
Exclusion criteria 
(1) cardiopulmonary dysfunction (NYHA cardiac function 
classification II-IV), liver dysfunction (MELD score greater than 12), 
or kidney dysfunction (serum creatinine above the upper limit of 
normal); 
(2) metastatic or multiple carcinoma; 
(3) patients with bowel obstruction, bowel perforation, or bowel 
bleeding requiring emergency surgery; 
(4) be accompanied with severe psychiatric illness; 
(5) be pregnant or during lactation; 
(6) fail to control diabetes mellitus (6.1–8.3 mmol/L); 
(7) patients with a history of taking hormone drugs; 
(8) planned synchronous abdominal organ resections; 
(9) end-to-end anastomosis. 
Exit criteria 
(1) After enrollment, patients who need emergency surgical resection 
due to intestinal obstruction, intestinal perforation, or intestinal 
bleeding. 
(2) Patients with distant metastases confirmed by intraoperative 
exploration or postoperative pathology. 
(3) Combined organ resection is required after intraoperative 
exploration. 
(4) Serious adverse events occurred preoperatively (according to the 

 
 
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Common Terminology Criteria for Adverse Events, CTCAE version 
5.0). 
Intervention 
Methods 
Intracorporeal anastomosis group: Total laparoscopic technology is 
used. The tumor is resected according to surgical specifications for 
radical colon cancer surgery. Mesentery resection is performed under 
laparoscopy, and anastomosis is completed under laparoscopy. A small 
incision is made to extract the specimen. 
Extracorporeal anastomosis group: Traditional laparoscopy-assisted 
technology is used. The tumor is resected according to surgical 
specifications for radical colon cancer surgery. A small incision is made 
in the middle of the abdomen to trim the mesentery, remove the 
specimen, and complete the anastomosis operation. 
Primary 
Outcome 
Measures 
The primary endpoint of this study was the surgical site infection 
within 30 days after surgery. 
Follow-up Plan The follow-up period for the primary endpoint was within 30 days after 
surgery. Follow-up is done through in-patient observation, outpatient 
consultations, and telephone inquiries. On the 30th day after surgery, 
patients are required to return to the hospital for blood routine, liver 
function, kidney function, urinary routine, lung CT, and abdominal CT 
examinations. It also documents the patient's surgery-related 
complications and grades over this period, as well as solutions. 
The total follow-up time for patients after surgery is 5 years. For patients 
with recurrent tumors, follow-up should continue for at least 3 years 
after recurrence or metastasis is discovered or until death. 
Sample Size 
354 cases 

 
 
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Statistical 
Methods 
1 Full analysis set 
A comparative analysis of the primary outcomes will be conducted 
based on “modified intention-to-treat (mITT)”. In the mITT analysis, 
patients will be analyzed according to their randomization allocations.  
2 Per-protocol analysis 
In per-protocol analysis, only cases treated strictly in accordance with 
random groups and assigned treatment plans will be included. Patients 
who haven't been treated with a randomly assigned protocol will be 
excluded from the analysis. 
 
 
 
 

 
 
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TABLE OF CONTENTS 
1. 
Title ...................................................................................................................................... 8 
2. 
Introduction ......................................................................................................................... 8 
3. Study Purpose and Endpoint ................................................................................................. 8 
3.1 Study purpose ................................................................................................................ 8 
3.1.1 Main study purpose: ............................................................................................. 9 
3.1.2 Secondary study purpose ...................................................................................... 9 
3.2 Study endpoint .............................................................................................................. 9 
3.2.1 Primary endpoint and its definitions ..................................................................... 9 
3.2.2 Secondary endpoint and its definitions ................................................................. 9 
4. Study design .......................................................................................................................... 11 
4.1 Overall study design .................................................................................................... 11 
4.2 Study time frame ......................................................................................................... 11 
5. Study population ................................................................................................................... 11 
5.1 Inclusion criteria ......................................................................................................... 11 
5.2 Exclusion criteria ........................................................................................................ 12 
5.3 Exit criteria .................................................................................................................. 12 
6. Study treatment grouping .................................................................................................... 12 
6.1 Randomization and allocation concealment .............................................................. 13 
6.2 Blinding and unblinding ............................................................................................. 13 
7. Intervention and study flow ................................................................................................. 13 
7.1 Preparation procedures .............................................................................................. 13 
7.2 Surgical Techniques: ................................................................................................... 14 
7.2.1 Experimental Group Procedure .......................................................................... 14 
7.2.2 Control Group Procedures: ................................................................................. 17 
7.3 Concurrent treatment and follow-up. ........................................................................ 17 
7.4 Patients compliance and exit ...................................................................................... 18 
7.5 Deviation from the plan .............................................................................................. 19 
8 Evaluation .............................................................................................................................. 19 
8.1 Efficacy Evaluation ..................................................................................................... 19 
8.2 Safety Assessment ........................................................................................................ 19 
8.2.1 Baseline Signs and Symptoms ............................................................................ 19 
8.2.2 Laboratory Safety Assessment ............................................................................ 19 
8.2.3 Physical Examination and Vital Signs ................................................................ 20 
9. Adverse event report ............................................................................................................. 20 
9.1 Definition of adverse events ........................................................................................ 20 
9.2 Severe adverse event ................................................................................................... 20 
9.3 Severity assessment ..................................................................................................... 21 
9.4 Relevance judgement .................................................................................................. 21 
10. Data processing and storage ............................................................................................... 21 
11. Quality management ........................................................................................................... 21 
12. Statistical analysis ............................................................................................................... 22 
12.1 Method for determining sample size ........................................................................ 22 

 
 
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12.2 Analytical population ................................................................................................ 22 
12.2.1 Full analysis set ................................................................................................ 23 
12.2.2 Per-protocol analysis ........................................................................................ 23 
12.3 Effect analysis and statistical method ...................................................................... 23 
12.3.1 primary endpoint analysis ................................................................................. 23 
12.3.2 Secondary endpoint analysis ............................................................................ 23 
12.4 Interim analysis ......................................................................................................... 24 
12.5 Terminal analysis ....................................................................................................... 24 
12.6 Data Monitoring Committee .................................................................................... 24 
13. Data collection and management ....................................................................................... 25 
13.1 Electronic Case Report Form ................................................................................... 25 
13.2 Data management ...................................................................................................... 25 
14. Ethics ................................................................................................................................... 25 
14.1 Ethics Committee ...................................................................................................... 25 
14.2 Patients information and informed consent ............................................................ 26 
15. Definition of Study Completion ......................................................................................... 26 
16. Study organizational structure .......................................................................................... 26 
17. Confidentiality and Data Security ..................................................................................... 27 
18. Insurance and Compensation ............................................................................................. 27 
19. Publication notes ................................................................................................................. 28 
20. References ............................................................................................................................ 28 
21. Attachments ......................................................................................................................... 30 
Attachment 1: Definition and classification of SSI according to CDC ................................ 30 
Attachment 2: ASA Classification Criteria .......................................................................... 33 
Attachment 3: ECOG Physical Fitness Assessment Criteria ............................................... 34 
Attachment 4: Postoperative Complications Clavien-Dindo System Grading ..................... 35 
Attachment 5: TNM Stages of Colon Cancer (AJCC, 8th Edition, 2018) ........................... 36 
Attachment 6: The VAS pain score ..................................................................................... 38 
Attachment 7 Completeness of Specimens .......................................................................... 39 
 
 
 
 
 
 
 
 
 
 

 
 
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1. Title 
A Multicenter Randomized Clinical Trial Comparing Surgical Site Infection after Total 
Laparoscopic and Laparoscopic-assisted Radical Surgery for Left Colon Cancer (STARS) 
2. Introduction 
It is estimated that there were more than 1.09 million new cases of colon cancer and more 
than 500,000 deaths from colon cancer in 2018. In developed countries, the incidence of colon 
cancer is higher than in developing countries. Usually, cancers proximal to the splenic flexure 
are defined as right-sided and cancers at or distal to the splenic flexure are defined as left-
sided (1). It is reported that left-sided colon cancer has different clinical and biological 
characteristics from right-sided colon cancer (2) and has a more favorable prognosis than the 
latter (3). Although neoadjuvant therapy and postoperative chemotherapy had been 
demonstrated to reduce the risk of tumor recurrence and death (4,5), surgery remains the main 
treatment for patients with potentially curable colon cancer(6). Currently, main surgical 
methods include traditional open surgery, minimally invasive surgery using laparoscopic 
techniques, and emerging robotic surgery. Compared with open surgery, laparoscopic surgery 
has achieved similar oncological outcomes in colon cancer or left-sided colon cancer (7,8). 
As for overall survival, laparoscopic surgery has been demonstrated oncologically safe, and 
was non-inferior to open surgery for patients with stage II or III colon cancer (9,10). However, 
surgical site infection (SSI) is one of the most common nosocomial infection in colonic 
surgery, with an incidence that varies between 5 and 30%(11,12). SSI is usually split into 
superficial incisional SSI, deep incisional SSI, and organ/space SSI(13,14). Data from the 
American College of Surgeons National Surgical Quality Improvement Program showed the 
overall SSI rate was 12.3%, and left resections had increased odds of superfici al SSI 
compared with right resections (15). There is an urgent need to determine the incidence of 
SSI, as well as strategies to reduce SSI rate(16). The aim of STARS trial is to evaluate the 
incidence of SSI and safety of the intracorporeal anastomosis after left-sided colon surgery.  
3. Study Purpose and Endpoint 
3.1 Study purpose 

 
 
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3.1.1 Main study purpose:  
To investigate the effects of intracorporeal anastomosis and extracorporeal anastomosis 
in laparoscopic-assisted radical left hemicolectomy on surgical site infection. 
3.1.2 Secondary study purpose 
To investigate the difference in postoperative recovery, safety, and oncology outcomes 
between intracorporeal anastomosis and extracorporeal anastomosis in laparoscopic-assisted 
radical left hemicolectomy. 
3.2 Study endpoint 
3.2.1 Primary endpoint and its definitions 
The primary endpoint is SSI within 30 postoperative days. SSI was defined according to 
the U.S. Centers for Disease Control and Prevention (Attachment 1). The overall SSI included 
any superficial and deep incisional SSIs or organ/space SSI. Any patient suspected of having 
organ/space SSI underwent abdominal computed tomography (CT) or digestive contrast 
radiography to further confirm anastomotic leakage. In our study, anastomotic leakage was 
categorized as organ/space infection. 
3.2.2 Secondary endpoint and its definitions 
The secondary outcomes included:  
(1) Operating time: It is defined as the period from cutting the skin to suturing the skin 
or doing enterostomy. It is measured in minutes. 
(2) Total blood loss during operation: It is defined as the blood loss during operation and 
is measured in milliliters. 
(3) Conversion to open surgery: It is defined as an abdominal incision larger than that 
necessary for specimen extraction. 
(4) Postoperative complications: Postoperative complications are investigated within 30 
days after an operation. It includes fever of unknown origin, bowel obstruction, anastomotic 
leakage, SSI, other incisional complications, respiratory complications, urinary complications, 
cardiovascular and cerebrovascular complications, diarrhea, chylous fistula, intraperitoneal 

 
 
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hemorrhage, digestive hemorrhage, gastroparesis, and others (including bacteremia, 
cholecystitis, ion discharge, pancreatitis, and mental and behavioral abnormalities). 
Complications are graded according to the Clavien–Dindo classification (17). The diagnosis 
of anastomotic leakage is based on the patient’s postoperative clinical symptoms, signs of 
abdominal infection, or drainage properties and is confirmed by imaging (angiography or 
computed tomography) or secondary surgery. Postoperative intraperitoneal/digestive 
hemorrhage is defined as bloody drainage/bloody stool > 100 mL in 1 h or evidence of 
hemorrhage on CT, endoscopy, or angiography. The respiratory complications include 
pulmonary complications or pleural effusion. Urinary complications include infections, 
retention, and leakage. 
(5) Completeness of specimens: It is evaluated according to the West classification.(18) 
The resected specimens will be classified into three groups according to the plane of dissection: 
mesocolic plane, intramesocolic plane, and muscularis propria plane 
(6) Number of lymph nodes dissected: The number of lymph nodes in the mesentery will 
be calculated. Additionally, the metastatic lymph nodes will be counted. The pathological 
TNM staging was performed according to the American Joint Committee on Cancer (AJCC) 
Cancer Staging Manual, 8th edition.  
(7) Postoperative recovery: Postoperative recovery information includes time to first 
flatus, time to first defecation, time to start food intake, and postoperative hospital stay. These 
are measured in days. 
(8) Length of incision: The incision length is measured with an aseptic ruler at the end 
of the surgery, after the incision is sutured. It is measured in millimeters. 
(9) Visual analog score (VAS) of pain: Pain severity was assessed 48 hours after the 
operation using a ruler about 10 cm long. The ruler is numbered from 0 to 10. 0–3 points 
indicate no to mild pain. 4–6 points represent moderate pain. 7–10 points stand for severe 
pain.  
(10) 3-year disease-free survival (DFS) and 5-year overall survival (OS): DFS was 
defined as the time from randomization until the discovery of local recurrence, distant 
metastasis, or death from the tumor. OS was defined as the time from randomization to death 

 
 
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due to any cause. 
4. Study design 
4.1 Overall study design 
   
 
 
 
 
   
4.2 Study time frame 
The subject recruitment period is 3 years, and the follow-up period lasts 5 years. The 
entire study, which includes study establishment, patient recruitment, patient follow-up, and 
data analysis, is expected to take 8 years. We'll conduct a primary endpoint analysis of the 
study after all patients finish their first month of post-operative follow-up. Additionally, a 
second analysis of results involving survival data will be done after all patients complete 5 
years of follow-up. 
Figure 1 the study design flowchart 
 
5. Study population 
5.1 Inclusion criteria 
(1) age between 18 and 80 years;  
(2) histologically or cytologically confirmed left-sided colon cancer (distal transverse 
colon, left colic flexure, descending colon, or proximal sigmoid colon);  
(3) clinical stage T1–4a, N0–2, and M0;  
(4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
(5) suitable for laparoscopic colectomy;  
(6) no previous systemic chemotherapy or radiotherapy;  
(7) willing to provide written informed consent and comply with the research procedures. 
 
This is a prospective, multicenter, non-inferiority, two-arms, single-blind, randomized 
controlled study.

 
 
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5.2 Exclusion criteria 
(1) cardiopulmonary dysfunction (NYHA cardiac function classification II-IV), liver 
dysfunction (MELD score greater than 12), or kidney dysfunction (serum creatinine above 
the upper limit of normal); 
(2) metastatic or multiple carcinoma; 
(3) patients with bowel obstruction, bowel perforation, or bowel bleeding requiring 
emergency surgery; 
(4) be accompanied with severe psychiatric illness; 
(5) be pregnant or during lactation; 
(6) fail to control diabetes mellitus (6.1–8.3 mmol/L); 
(7) patients with a history of taking hormone drugs; 
(8) planned synchronous abdominal organ resections; 
(9) end-to-end anastomosis. 
5.3 Exit criteria 
(1) After enrollment, patients who need emergency surgical resection due to intestinal 
obstruction, intestinal perforation, or intestinal bleeding. 
(2) Patients with distant metastases confirmed by intraoperative exploration or 
postoperative pathology. 
(3) Combined organ resection is required after intraoperative exploration. 
(4) Serious adverse events occurred preoperatively (according to the Common 
Terminology Criteria for Adverse Events, CTCAE version 5.0).  
The data of patients who withdrew from the study were not used, and these patients were 
not allowed to re-enter the study. 
6. Study treatment grouping 
Experiment group: Total laparoscopic intracorporeal anastomosis group (IA group) 
The tumor is resected according to surgical specifications for radical colon cancer surgery. 
Mesentery resection is performed under laparoscopy, and anastomosis is completed under 
laparoscopy. A small incision is made to extract the specimen after the anastomosis is 
completed. 

 
 
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Control group: Laparoscopy assisted extracorporeal anastomosis group (EA group) 
The tumor is resected according to surgical specifications for radical colon cancer 
surgery. A small incision is made in the middle of the abdomen to trim the mesentery, remove 
the specimen, and complete the anastomosis. After completing the anastomosis, the incision 
will be sutured. 
6.1 Randomization and allocation concealment 
Randomization will be conducted immediately after recruitment. To guarantee 
randomization concealment adequately, and not be influenced either by the surgeon or the 
participants, randomization will be performed by a researcher who is not participating in this 
study from the Research Centre of Clinical Epidemiology (RCCE), Jilin University First 
Hospital. The random codes will be designed in a 1:1 ratio (experimental group or control 
group) using the R (version 3.3.3, University of Auckland, Oakland, New Zealand). The 
random codes will be sealed in an opaque envelope and handed to the researcher responsible 
for grouping in RCCE. The site investigators can submitted the participants’ details to the 
RCCE and apply for randomization through text messages, e-mail, or telephone application. 
The researcher responsible for grouping in RCCE will review patient eligibility. When 
grouping, the envelope with the unique identification number for the participant will be 
opened, and the group assignment will immediately be delivered to the researcher of the study 
site by RCCE through text messages, e-mail, or telephone.  
6.2 Blinding and unblinding 
The clinical surgeons, outcome assessors, data recorders, and statisticians will all operate 
independently. Due to the nature of the surgical interventions, the surgeons will not be blinded 
to treatment allocation. However, the outcomes assessor who assess or analyze the end point 
will be blinded. The patients will also be blinded to group allocation to reduce the risk of bias. 
Unblinding will not be performed unless the finalization of the main data analysis or required 
for patient’s safety. After the data analysis, we will have a blinded interpretation of the study 
results to minimize misleading data interpretation. 
7. Intervention and study flow 
7.1 Preparation procedures 

 
 
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Prior to the surgical intervention, patients are required to undergo a series of preparation 
steps to ensure optimal conditions for surgery and to minimize the risk of complications. On 
the evening before the operation, patients will consume a solution containing polyethylene 
glycol electrolytes to cleanse the bowel. This bowel preparation is crucial for visualization 
during surgery and to reduce the risk of infection. The day before surgery, patients will also 
be administered oral antibiotics, specifically metronidazole at a dosage of 800 mg and 
gentamycin sulfate at 160 mg, to target a broad spectrum of potential infectious agents. 
Furthermore, as a prophylactic measure against infection, mezlocillin sodium will be given 
20 minutes prior to the induction of anesthesia. 
7.2 Surgical Techniques: 
General Surgical Procedures: On the day of surgery, patients are positioned supine on the 
operating table with their legs spread to allow ample space for the surgical team. The surgeon 
and assistant will be positioned on the right side of the operating bed, facilitating access to 
the surgical site. The initial incision, approximately 10mm in size, will be made above the 
umbilicus using an open technique, which allows for the introduction of the primary port for 
laparoscopic instruments. Subsequently, four additional ports will be strategically placed 
under laparoscopic guidance. Throughout the procedure, the principles of complete mesocolic 
excision (CME) and central vascular ligation will be adhered to. This involves a medial-to-
lateral approach, where mesenteric vessels, including the inferior mesenteric vein, left colic 
artery, and one to two sigmoid arteries, are carefully exposed and divided at their origins using 
either absorbable or non-absorbable clips. The greater omentum is then separated from the 
transverse colon using a harmonic scalpel, and the splenic flexure and descending colon are 
mobilized. 
7.2.1 Experimental Group Procedure 
In the experimental group, the surgeon will use a 10-cm medical suture and methylene 
blue solution to mark the resection margin. The marginal vessels and mesentery will be 
divided inside the body. The proximal and distal colons are resected using a 60mm linear 
laparoscopic stapler. Side-to-side intracorporeal anastomotic techniques like anti-peristaltic, 
iso-peristaltic, or overlap methods will be applied (Figure 2-4). Once the anastomosis is 

 
 
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completed, the specimen is retrieved. The surgeon can place the specimen in a sterile plastic 
bag for retrieval. Alternatively, the surgeon can use a disposable incision retraction fixator to 
protect the wound. An abdominal drainage tube is inserted. Three different intracorporeal 
anastomotic methods are shown in Figures 2, 3, and 4.  
7.2.1.1 Isoperistaltic Side-to-Side Anastomosis: This method involves making two small 
enterotomies on the antimesenteric borders, approximately 8 cm from the ends of the colon. 
The colonic ends are then positioned in the upper left abdomen. Each end of a 60mm linear 
laparoscopic stapler is inserted through the enterotomies, closed along the antimesenteric 
borders, and fired to create the anastomosis (Figure 2A). Subsequently, the common 
enterotomy is continuously sutured using a 3-0 knotless absorbable suture (Figure 2B). 
 
Fig. 2 A Two ends of a 60-mm linear laparoscopic stapler are inserted into the colons 
through enterotomies separately, then close along the antimesenteric borders and fire. B The 
common enterotomy is sutured continuously. 
7.2.1.2 Antiperistaltic Side-to-Side Anastomosis: Similar to the isoperistaltic method, 
two small enterotomies are made on the antimesenteric borders of the colon ends. These ends 
are placed near the midline of the abdomen. The 60mm linear laparoscopic stapler is used in 
the same manner to close the antimesenteric borders and create the anastomosis (Figure 3A). 
The common enterotomy can then be closed using either a reloaded 60mm linear laparoscopic 
stapler positioned perpendicular to the colon ends (Figure 3B) or by continuous suturing with 
a 3-0 knotless absorbable suture. 

 
 
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Fig. 3 A Two ends of 60-mm linear laparoscopic stapler are inserted into the colons through 
enterotomies separately, then close along the antimesenteric borders and fire. B The 
common enterotomy is closed by a reload 60-mm linear laparoscopic stapler perpendicular 
to colon ends 
7.2.1.3 Overlap Side-to-Side Anastomosis: The choice between a cephalic or caudal 
approach for inserting the linear laparoscopic stapler depends on the tumor location and the 
ease of anastomosis. When the transverse colon end has limited mobility, the caudal approach 
offers greater convenience (Figure 4A). In this approach, one small enterotomy is made at the 
antimesenteric border of the transverse colon end, and another enterotomy is made 
approximately 8 cm from the descending or sigmoid colon end. The 60 mm linear 
laparoscopic stapler is inserted through the caudal trocars, with both ends being introduced 
into the colons via the enterotomies, closed along the antimesenteric borders, and fired to 
complete the anastomosis (Figure 4B). The common enterotomy is then continuously sutured 
using a 3-0 knotless absorbable suture. In the cephalic approach, the positions of the two 
enterotomies on the colons are made in opposition to those in the caudal cases. 
 
Fig. 4 A Two ends of 60-mm linear laparoscopic stapler are inserted into the colons through 

 
 
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the enterotomies separately, then close along the antimesenteric borders and fire. B The 
common enterotomy is sutured continuously 
7.2.2 Control Group Procedures: 
For patients in the control group, the surgeon uses wound edge protectors to exteriorize 
the colon through a small incision in the midline of the abdomen. A ruler and methylene blue 
solution are employed to mark the area for colon resection. This guarantees a 10-cm margin 
from the tumor. Guided by these markers, the marginal vessels and mesentery are divided 
outside the body. The method of anastomosis is at the surgeon's discretion. A side-to-side 
anastomosis (including antiperistaltic, isoperistaltic, or overlapping anastomosis) is 
performed. After completing the anastomosis, the incision is sutured. An abdominal drainage 
tube is inserted at the end of the operation. 
 
 
 
7.3 Concurrent treatment and follow-up. 
Postoperative chemotherapy is recommended according to the NCCN guidelines for 
colon cancer treatment. The post-operative follow-up period must be in accordance with the 
time specified in this study (Table 1). Each participant will be followed until recurrence or 
death over a period of 5 years after the scheduled surgery. 
The follow-up period for the primary endpoint is within 30 days after surgery. Follow-
up will be conducted through in-patient observation, outpatient consultations, and telephone 

 
 
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inquiries. SSI presence will be assessed daily during hospitalization and weekly after 
discharge. At least two surgeons perform SSI surveillance. The outcome assessors are trained 
on the Centers for Disease Control and Prevention (CDC) definitions of SSI to produce good 
inter-rater reliability for the assessment of SSI. If SSI is suspected during follow-up, CT or 
abdominal ultrasonography will be done. All patients will have an abdominal or pelvic CT on 
the 30th day after surgery. If the CT shows evidence of SSI, the radiologist and surgeon will 
assess whether there is an SSI. 
The patient's surgery-related complications and Clavien–Dindo grade within 30 
postoperative days will be recorded. The overall follow-up period for patients after surgery is 
5 years, which includes 5-year overall survival (OS) and 3-year disease-free survival (DFS). 
For patients with recurrent tumors, follow-up should continue for at least 3 years after 
recurrence or metastasis is discovered or until death. 
Appropriate strategies will be used to improve patient adherence and ensure data integrity. 
When signing the informed consent form, all participants will be informed of the study 
procedures, potential benefits, and risks to make them fully understand the inconvenience and 
significance of data collection. 
In addition, patients who have had abdominal surgery need to return to our hospital for 
other treatment of combined injuries, including suture removal. Our medical team will provide 
standard post-operative care for enrolled participants to promote their adherence. 
Investigators will contact patients 1 week before the follow-up session to increase the 
attendance rate. Patients who miss a scheduled appointment will be contacted to reschedule 
another appointment within 1 week. Telephone follow-up calls, WeChat group discussions, 
and personal interviews will be used to maximize retention and complete follow-up. 
7.4 Patients compliance and exit 
To improve patient compliance, before randomization, physicians will communicate with 
patients in detail about surgical procedures, possible random groupings, relevant and evolving 
treatment, and patient safety and security conditions. They will obtain informed consent to 
ensure patients clearly understand the treatment and research procedures. The randomization 
time should be as close as possible to the time before surgery (the day before surgery) to 

 
 
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prevent accidental exclusion of patients after randomization. After randomization, patients 
can withdraw from the trial at any time. If a patient requests withdrawal from the study, the 
main researcher at their research center will communicate with them to avoid disrupting the 
balance of random groups due to exclusion. If the patient still insists on withdrawing, they 
will be removed from the trial. Clinical information relating to this patient will not be included 
in any data analysis related to this trial. 
7.5 Deviation from the plan 
Researchers involved in the trial will conduct corresponding surgical operations and data 
recording in line with the experimental requirements. Any event that strays from the original 
test plan must record the time and specific reason for occurrence to explain the deviation from 
the test plan. 
8 Evaluation 
8.1 Efficacy Evaluation 
The methodologies for evaluating the efficacy of diverse anastomosis techniques 
encompass, but are not restricted to: intraoperative assessment and meticulous records of 
postoperative examinations, evaluation of postoperative symptoms and signs, and 
postoperative abdominal CT evaluation. 
8.2 Safety Assessment 
8.2.1 Baseline Signs and Symptoms 
The baseline signs and symptoms include temperature, pulse, respiratory rate, and blood 
pressure. Surgeons also need to pay attention to specific symptoms such as dizziness, nausea, 
and vomiting. Additionally, hematological tests and imaging tests before surgery will be 
performed to ensure the patient group has no surgical contraindications and fully meets the 
inclusion criteria. These baseline data will serve as reference indicators for the evaluation. 
8.2.2 Laboratory Safety Assessment 
Continuous indicators show the postoperative measurements of each study subject and 

 
 
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the changes in values compared to the preoperative baseline. Laboratory indicators are 
classified as low, normal, and high based on the normal value range. They describe transitions 
from a normal or high baseline to a low value after the baseline, and from a normal or low 
baseline to a high value after the baseline. The lower or higher value after the baseline is 
calculated using the minimum or maximum observed value. The physician evaluates these 
abnormal indicators to determine their clinical significance. The proportion of subjects with 
“abnormal and clinically significant” changes is described.  
8.2.3 Physical Examination and Vital Signs 
Physical examination includes general examination, head examination, neck 
examination, chest and lung examination, heart and blood vessels examination, abdominal 
examination, spine and limbs examination, and nervous system examination. Vital signs 
consist of blood pressure, heart rate, and body temperature. Situations where vital signs 
deviate from the normal range or are abnormal are described and recorded. 
9. Adverse event report 
9.1 Definition of adverse events 
Adverse events studied include intraoperative secondary injuries in patients and serious 
complications and deaths within 30 days after surgery. All adverse events reported 
spontaneously by test subjects or observed by staff will be recorded in a database and promptly 
reported to the test steering committee. 
An adverse event is defined as any adverse experience that occurs in the subject during 
the study, regardless of whether it's considered associated with total laparoscopic 
anastomosis. All adverse events reported spontaneously by test subjects or observed by 
investigators are recorded. These include: 1) Accidental secondary damage during surgery. 
2) Serious complications after surgery (grade III and above). 
9.2 Severe adverse event 
A serious adverse event includes any of the following adverse medical events: 1) events 
leading to death; 2) life-threatening events; 3) requiring hospitalization or prolonged 
hospitalization of patients; 4) Causing persistent or significant disability, or incapacity for 

 
 
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conduct. 
9.3 Severity assessment 
The severity of adverse events will be assessed using the Clavien—Dindo grading 
criteria for complications. 
9.4 Relevance judgement 
Determining the correlation between adverse events and surgical interventions will be 
made by researchers subjectively. 
10. Data processing and storage 
 
All relevant clinical data including demographic and medical information will be 
collected from the electronic medical record. The collected data will be encoded to protect the 
privacy of all participants and then be entered into an electronic case report forms (eCRFs) 
by trained research assistants in each sub-center. Double data entry will be performed to 
ensure that the data collected are accurate and verifiable from source documents. Input rules 
including field and range checks will also be set to minimize data entry errors. The research 
coordinator will periodically check the data distribution, verify outliers, and track missing 
data to improve data integrity and data validation. Data storage and backup will be managed 
by the edocdata platform (https://jlcrc.edocdata.com/), which will track all changes to the data 
and retains a history for each variable. Unauthorized persons or institutions will not be able 
to access any data stored on this server. When the trial is completed, the data will be locked 
and stored on edocdata platform, after which the researchers can no longer modify the data. 
Both paper and electronic documents will be preserved for at least 5 years after publication. 
11. Quality management 
Research center participation criteria: Surgeons involved in this study must complete at 
least 100 cases of laparoscopy-assisted left colectomy and have a minimum of 20 cases of 
intraoperative anastomosis in laparoscopy-assisted left colectomy. This study establishes a 
trial steering committee (TSC). The TSC is composed of surgeons with at least 10 years of 
experience in colorectal cancer surgery. Before enrolling in the research center, participating 
centers should provide surgical videos of two consecutive IA cases and two EA cases by the 

 
 
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same operator recently to determine if the surgery quality meets expectations and if they can 
qualify as enrolment units. The evaluation method is the Delphi method. 
Evaluation of surgical quality during research: Surgery quality is assessed using videos 
and photographs. Surgical teams are required to take photographs of the laparoscopic 
investigation of the tumor site, surgical area after lymph node removal, and the anastomosis. 
The TSC evaluates the videos and photographs to assess surgical quality and ensure 
compliance with the allocated intervention. Any surgical procedures deviating from the 
randomized allocation plan are documented. If participating centers cannot obtain imaging 
data, they must document the reason for not being able to leave a video or photo. 
Surgeons participating in the trial are required to record the surgical procedure and explain 
any surgical procedures that deviate from standardized procedures. The trial steering 
committee will evaluate the enrollment situation and quality of enrolled cases at each center 
every half a year and supervise and control the quality of enrolled cases at each center. 
12. Statistical analysis 
12.1 Method for determining sample size 
This study is a multicenter, randomized, controlled, noninferiority trial specifically 
designed for patients within the age range of 18 to 80 years old who are diagnosed with left-
sided colon cancer. In light of the previous data from our single center, it has been observed 
that the incidence of overall surgical site infection following extracorporeal anastomosis left 
colon cancer surgery stands at 23.3%, while the incidence of SSI after intracorporeal 
anastomosis is 16.7%. When there is a difference in the SSI rate of more than 5% within 30 
days after surgery, intracorporeal anastomosis is regarded as inferior to extracorporeal 
anastomosis. Consequently, the sample size for this study is calculated based on non-
inferiority, taking into account a difference of 5%, a one-sided level of significance of 0.025, 
a ratio of 1:1, a power of 0.80, and a 20% drop-out rate. In total, 354 patients are required 
for this study, with 177 patients in the experimental group and an equal number of 177 
patients in the control group. 
12.2 Analytical population 

 
 
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12.2.1 Full analysis set 
The primary outcome will be comparatively analyzed based on “modified intention-to-
treat (mITT)”. In the mITT analysis, patients will be analyzed according to their 
randomization allocations. If patients randomly assigned to the IA group actually receive EA 
during surgery, they will be analyzed according to the IA group in mITT analysis. If patients 
randomly assigned to group EA actually receive IA during surgery, they will be analyzed 
according to group EA. Patients who meet the exit criteria after randomization will not be 
included in the mITT population. 
12.2.2 Per-protocol analysis 
In per-protocol (PP) analysis, only cases treated strictly in accordance with random 
groups and assigned treatment plans will be included. Patients who haven't been treated with 
a randomly assigned protocol will be excluded from the per-protocol analysis. 
12.3 Effect analysis and statistical method 
12.3.1 primary endpoint analysis 
In analyzing the primary outcomes, the rate of overall SSI will be reported as frequencies 
and percentages. We will calculate the absolute risk differences and the corresponding 95% 
confidence interval (CI) between two groups. If the absolute risk differences and the 
corresponding 95% CI are within the non-inferiority margin (<5%), non-inferiority is 
established. If not, IA is not non-inferior to EA. The analysis of the primary endpoint will be 
carried out in the mITT population, the PP population. 
12.3.2 Secondary endpoint analysis 
The analysis of the secondary endpoints will be carried out in the mITT population. In 
the analysis of secondary endpoints, categorical variables will be reported as frequencies and 
percentages. Groups will be compared using the χ2 test or Fisher’s exact test. Absolute risk 
differences and the corresponding 95% CI will be calculated. Continuous variables will be 
described as mean ± standard deviation or median (quartile). Groups will be compared using 
the t-test or Mann-Whitney U test, as appropriate. Hodges-Lehmann method will be used to 
calculate the difference in median and the corresponding 95% CI. 
The comparison of 3-year DFS and 3-year OS between the two groups will utilize the 

 
 
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Kaplan–Meier curve and the Cox proportional risk model. Relevant risk factors will be 
adjusted in Cox proportional risk model.  
The missing data in this trial is expected to be minimal. If it occurs, it will be treated as 
censored data and not imputed. All statistical tests were 2-sided, and statistical significance 
was set at P <0.05. All statistical analyses were performed using R or SPSS. 
12.4 Interim analysis  
There will be no interim analysis for this study 
12.5 Terminal analysis 
We will conduct an analysis of the main endpoints of the study and publish the relevant 
findings after all patients have completed the first month of follow-up after surgery. After all 
patients have completed 5 years of follow-up, we will analyze results involving survival 
data, and publish relevant research results. 
12.6 Data Monitoring Committee 
The data and safety monitoring board (DSMB) was composed of senior surgeons, 
ethicists, and statistical analysts. Each member of the DSMB is independent of this trial and 
is not likely to affect the competitive interests of the trial. The DSMB will receive and review 
the safety data for this trial. If the DSMB believes the number of adverse events in the trial is 
biased between groups, they will notify the chair of the trial steering committee. 
There will be no interim analysis for this project. However, once the study begins, the 
DSMB will evaluate the results of the study every year. The assessment included primary and 
secondary endpoint records, adverse events, and loss of study samples. It also assesses 
differences with expectations, and potential conflicts with new findings and/or developments 
in the field of colon cancer. DSMB members are not allowed to share confidential information 
with anyone outside of the DSMB, with the exception of the trial steering committee. 
The techniques used in this research institute are all techniques currently used in surgical 
treatment of colon cancer, and patients are not at higher risk. Therefore, this study did not set 
suspension parameters for the entire project. However, if in the DSMB's regular assessments, 
a center shows a huge difference in safety indicators compared to other centers and is 
significantly worse than the current international level, then the DSMB will submit its 

 
 
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recommendations in writing to the trial steering committee, requesting that the trial plan be 
revised, or the quality of cases in the corresponding center be re-evaluated, or even suspended 
or terminated the clinical trial enrollment of the corresponding center. 
At the discretion of the DSMB during the trial process, the DSMB may decide to meet 
early to discuss testing procedures together about adverse events and promptly clarify any 
issues with key investigators. 
13. Data collection and management 
13.1 Electronic Case Report Form 
An electronic case report form (eCRF) is developed by the lead investigator. The CRF 
table includes the primary endpoint and Secondary endpoints. Additionally, general baseline 
data on patients will be included. 
All relevant clinical data including demographic and medical information will be 
collected from the electronic medical record. The collected data will be encoded to protect the 
privacy of all participants and then be entered into an eCRF by trained research assistants in 
each sub-center. Double data entry will be performed to ensure that the data collected are 
accurate and verifiable from source documents. Input rules including field and range checks 
will also be set to minimize data entry errors. The research coordinator will periodically check 
the data distribution, verify outliers, and track missing data to improve data integrity and data 
validation.  
13.2 Data management 
Data 
storage 
and 
backup 
will 
be 
managed 
by 
the 
edocdata 
platform 
(https://jlcrc.edocdata.com/), which will track all changes to the data and retains a history for 
each variable. Unauthorized persons or institutions will not be able to access any data stored 
on this server. When the trial is completed, the data will be locked and stored on edocdata 
platform, after which the researchers can no longer modify the data. Both paper and electronic 
documents will be preserved for at least 5 years after publication. 
14. Ethics 
14.1 Ethics Committee 
This trial has been approved by the Ethics Review Committee of the First Hospital of 

 
 
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Jilin University (Approval number: 19K135-001). Each sub-center must conduct an ethical 
application before participating in this trial. 
14.2 Patients information and informed consent 
Eligible patients should receive in-person notification from the treating surgeon and 
written information about the trial. Each patient should provide informed consent in 
accordance with local ethics committee guidelines before entering the random allocation of 
studies. 
 
The informed consent procedure should be carried out by the doctors of each centre. 
Information provided to patients with informed consent includes: 1) a statement about the 
study involved in the trial; 2) a full and fair explanation of the procedures to be followed; 3) 
a full explanation of the nature, anticipated length, and purpose of the study; 4) a description 
of any risk or discomfort that the patient can reasonably anticipate; 5) a description of any 
benefits that can be reasonably anticipated; 6) a statement that patient data will be treated with 
care and confidentiality and that the data will be kept for 15 years; 7) a statement about the 
patient's physical material will be kept for 15 years; 8) a statement about voluntary 
participation, where the statement will state the refusal Participation in the trial does not 
involve any punishment or loss of benefits the patient is entitled to, and patients can stop 
participating at any time without being penalized or losing benefits, in which case the patient 
will receive standard treatment with the same level of care. 
15. Definition of Study Completion 
The completion of the study was defined as all enrolled patients completed 5 years of 
follow-up. Follow-up outcomes include disease-free survival, recurrence survival, death, or 
loss of visits. 
16. Study organizational structure 
This study includes several medical centers. The research initiation center is First 
Hospital of Jilin University. Participating centers in clinical research include: Peking Union 
Medical College Hospital, Fudan University Cancer Hospital, Ruijin Hospital Affiliated to 
Shanghai Jiao Tong University School of Medicine, Beijing Friendship Hospital Affiliated to 

 
 
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Capital Medical University, Chinese People's Liberation Army General Hospital, Daping 
Hospital Affiliated to Army Military Medical University, Shengjing Hospital Affiliated to 
Chinese Medical University, Chinese Academy of Medical Sciences Cancer Hospital, China 
- Japan Union Hospital of Jilin University, First Affiliated Hospital of China Medical 
University, Southern Medical University Southern College. The members of the TSC are 
heads of the corresponding departments of the above centers: Wang Quan, Lin Guole, Li 
Xinxiang, Feng Bo, Zang lu, Yao Hongwei, Du Xiaohui, Tong Weidong, Zhang Hong, Liu 
Qian, Xie Zhongshi, Wu Aiwen, and Deng Haijun. The members of the trial guidance team 
are attending physicians and above in the corresponding medical teams of each center. The 
DSMB is comprised of senior surgeons, ethicists, and statistical analysts. Each member of the 
DSMB is independent of this trial and is not likely to affect the competitive interests of the 
trial. 
17. Confidentiality and Data Security 
Participants are given a unique code to maintain their anonymity. Personal information 
documents are stored separately from assessment data in locked cabinets. Only the authorized 
research assistants and DSMB can access to the dataset. Unless there is an institutional or 
regulatory requirement, nobody else can access it. DSMB members can know the patient 
allocation and be aware of accumulated data. The DSMB will discuss the relevant data results 
with the TSC. DSMB members are not allowed to share confidential information with anyone 
outside the DSMB. The fully anonymized experimental data is stored on secure servers of 
Jilin University First Hospital. 
18. Insurance and Compensation 
Enrolled patients have all purchased medical commercial insurance jointly offered by our 
hospital and insurance companies before surgery. This insurance covers surgery-related 
complications and deaths. This study was funded by the Development Center for Medical 
Science & Technology, National Health Commission of the People’s Republic of China 
(W2017ZWS01 and WA2021RW19). The funder had no role in the study's design and will 
not have any role in data collection, analysis, interpretation, or manuscript writing. 

 
 
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19. Publication notes 
No relevant data for this study will be published until the collection of primary 
outcomes is completed. We will conduct an analysis of the primary endpoints of the study 
and publish the relevant findings after all patients have completed the first month of follow-
up after surgery. After all patients complete 5 years of follow-up, the results involving 
survival data will be analyzed again, and the relevant research results will be published. 
20. References 
1. 
Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002 Oct 
10;101(5):403–8.  
2. 
Lee MS, Menter DG, Kopetz S. Right Versus Left Colon Cancer Biology: Integrating the 
Consensus Molecular Subtypes. J Natl Compr Canc Netw. 2017 Mar;15(3):411–9.  
3. 
Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N. Is there a difference in survival 
between right- versus left-sided colon cancers? Ann Surg Oncol. 2008 Sep;15(9):2388–94.  
4. 
Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: 
selecting optimal treatments for individual patients. J Clin Oncol. 2015 Jun 1;33(16):1787–
96.  
5. 
Hawkins AT, Ford MM, Geiger TM, Hopkins MB, Kachnic LA, Muldoon RL, et al. 
Neoadjuvant radiation for clinical T4 colon cancer: A potential improvement to overall 
survival. Surgery. 2019 Feb;165(2):469–75.  
6. 
Mohamed F. Colon cancer surgery: is it what you do, or the way you do it that matters? 
Lancet Gastroenterol Hepatol. 2017 Apr;2(4):237–8.  
7. 
Liu ZH, Wang N, Wang FQ, Dong Q, Ding J. Oncological outcomes of laparoscopic versus 
open surgery in pT4 colon cancers: A systematic review and meta-analysis. Int J Surg. 2018 
Aug;56:221–33.  
8. 
Park JH, Park HC, Park SC, Sohn DK, Oh JH, Kang SB, et al. Laparoscopic approach for left-
sided T4 colon cancer is a safe and feasible procedure, compared to open surgery. Surg 
Endosc. 2019 Sep;33(9):2843–9.  
9. 
Kitano S, Inomata M, Mizusawa J, Katayama H, Watanabe M, Yamamoto S, et al. Survival 
outcomes following laparoscopic versus open D3 dissection for stage II or III colon cancer 
(JCOG0404): a phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2017 
Apr;2(4):261–8.  
10. 
Yamaguchi S, Tashiro J, Araki R, Okuda J, Hanai T, Otsuka K, et al. Laparoscopic versus open 
resection for transverse and descending colon cancer: Short-term and long-term 
outcomes of a multicenter retrospective study of 1830 patients. Asian J Endosc Surg. 2017 
Aug;10(3):268–75.  
11. 
Zywot A, Lau CSM, Stephen Fletcher H, Paul S. Bundles Prevent Surgical Site Infections 
After Colorectal Surgery: Meta-analysis and Systematic Review. J Gastrointest Surg. 2017 
Nov;21(11):1915–30.  
12. 
Olguín Joseau S, Bollati NP, Reimondez S, Signorini F, Rossini AM, Maldonado PS, et al. 
Risk factors for surgical site infection in colon surgery in our population. Rev Fac Cien Med 

 
 
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Univ Nac Cordoba. 2018 Nov 14;75(4):229–33.  
13. 
Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of 
Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital 
Infection Control Practices Advisory Committee. Am J Infect Control. 1999 Apr;27(2):97–
132; quiz 133–4; discussion 96.  
14. 
Ban KA, Minei JP, Laronga C, Harbrecht BG, Jensen EH, Fry DE, et al. American College of 
Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update. J 
Am Coll Surg. 2017 Jan;224(1):59–74.  
15. 
Murray ACA, Pasam R, Estrada D, Kiran RP. Risk of Surgical Site Infection Varies Based on 
Location of Disease and Segment of Colorectal Resection for Cancer. Dis Colon Rectum. 
2016 Jun;59(6):493–500.  
16. 
Caroff DA, Chan C, Kleinman K, Calderwood MS, Wolf R, Wick EC, et al. Association of 
Open Approach vs Laparoscopic Approach With Risk of Surgical Site Infection After Colon 
Surgery. JAMA Netw Open. 2019 Oct 2;2(10):e1913570.  
17. 
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new 
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 
2004 Aug;240(2):205–13.  
18. 
West NP, Morris EJ, Rotimi O, Cairns A, Finan PJ, Quirke P. Pathology grading of colon cancer 
surgical resection and its association with survival: a retrospective observational study. 
Lancet Oncol. 2008 Sep;9(9):857–65.  
 
 

 
 
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21. Attachments 
Attachment 1: Definition and classification of SSI according to CDC 
Surgical site infection (SSI) can be subdivided into infections of the subcutaneous tissue 
(superficial SSI), deep soft tissues such as fascial and muscle layers (deep SSI) and infections 
of organs or spaces (organ/space SSI) that occur within 30 days after surgery. 
Superficial 
Incisional SSI 
Infection occurs within 30 days after the operation and infection 
involves only skin or subcutaneous tissue of the incision and at least 
one of the following: 
1. Purulent drainage, with or without laboratory confirmation, from 
the superficial incision. 
  2. Organisms isolated from an aseptically obtained culture of 
fluid or tissue from the superficial incision. 
  3. At least one of the following signs or symptoms of infection: 
pain or tenderness, localized swelling, redness, or heat and 
superficial incision is deliberately opened by surgeon, unless 
incision is culture-negative. 
  4. Diagnosis of superficial incisional SSI by the surgeon or 
attending physician. 
  **Notes**: Do not report the following conditions as SSI: 
  1. Stitch abscess (minimal inflammation and discharge confined 
to the points of suture penetration). 
Deep Incisional SSI 
Infection occurs within 30 days after the operation and the infection 
appears to be related to the operation and infection involves deep 
soft tissues (e.g., fascial and muscle layers) of the incision and at 
least one of the following: 

 
 
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  1. Purulent drainage from the deep incision but not from the 
organ/space component of the surgical site. 
  2. A deep incision spontaneously dehisces or is deliberately 
opened by a surgeon when the patient has at least one of the 
following signs or symptoms: fever (>38°C), localized pain, or 
tenderness, unless site is culture-negative. 
  3. An abscess or other evidence of infection involving the deep 
incision is found on direct examination, during reoperation, or by 
histopathologic or radiologic examination. 
  4. Diagnosis of a deep incisional SSI by a surgeon or attending 
physician. 
  **Notes**: 
  1. Report infection that involves both superficial and deep 
incision sites as deep incisional SSI. 
  2. Report an organ/space SSI that drains through the incision as a 
deep incisional SSI. 
Organ/Space SSI 
Infection occurs within 30 days after the operation and the infection 
appears to be related to the operation and infection involves any part 
of the anatomy (e.g., organs or spaces), other than the incision, 
which was opened or manipulated during an operation and at least 
one of the following: 
  1. Purulent drainage from a drain that is placed through a stab 
wound into the organ/space. 
  2. Organisms isolated from an aseptically obtained culture of 
fluid or tissue in the organ/space. 

 
 
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  3. An abscess or other evidence of infection involving the 
organ/space that is found on direct examination, during reoperation, 
or by histopathologic or radiologic examination. 
  4. Diagnosis of an organ/space SSI by a surgeon or attending 
physician. 
 
 
 
 

 
 
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Attachment 2: ASA Classification Criteria 
It refers to the six levels into which patients are classified by the American Society of 
Anesthesiologists (ASA) prior to anesthesia based on their physical condition and risk to 
surgery. 
classification condition 
Level I 
Physical health, good development and nutrition, and 
normal functioning of organs. 
Level II 
In addition to surgical disease, there is mild 
coexisting 
disease 
with 
sound 
functional 
compensation. 
Level III 
Coexisting conditions are severe and physical 
activity is limited, but can still manage daily 
activities. 
Level IV 
Severe coexisting conditions, loss of ability to 
perform daily activities, and frequent life-threatening 
situations. 
Level V 
Dying patients who have difficulty sustaining life for 
24 hours, with or without surgery. 
Level VI 
Confirmed brain death and his organs are intended 
for organ transplantation. 
 
 
 

 
 
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Attachment 3: ECOG Physical Fitness Assessment Criteria 
Physical condition 
Grading 
Normal activity 
0 
Mild symptoms, comfortable living, able to do light physical activities 
1 
Can withstand the symptoms of the tumor and take care of one's own life, 
but not spend more than 50% of the time in bed during the day 
2 
The symptoms are severe. You spend more than 50% of your time in bed 
during the day, but you can still get up and stand, so you can take care of 
yourself for part of your life 
3 
Sick and unable to stay bedridden 
4 
Death 
5 
 
 
 
 

 
 
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Attachment 4: Postoperative Complications Clavien-Dindo System Grading 
Grading 
Definition 
I 
There are complications of unnecessary medication, surgery, 
laparoscopic, and reflex intervention after surgery, but they include 
medications for antiemetics, fever-reducing drugs, pain relievers, 
diuretics, dielectrics, and physiotherapy, as well as incision infections 
opening at the bedside; 
II 
Patients requiring medication not including phase 1 medication, 
incisional infections require antibiotic treatment, blood transfusions, 
and parenteral nutrition included 
III. 
Surgical, laparoscopic, and interventional radiological treatment is 
required 
 
IIIa 
Does not require general anesthesia 
IIIb 
General anesthesia required 
IV 
Life-threatening complications (including central nervous system 
complications) that require IC (intermittent monitoring) or ICU 
treatment 
 
iVa 
Insufficiency of one organ (including dialysis) 
ivB 
multiple organ dysfunction 
V 
Death 
 
 
 

 
 
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Attachment 5: TNM Stages of Colon Cancer (AJCC, 8th Edition, 2018) 
Primary tumors: 
Tx: the primary tumor cannot be evaluated; 
T0: no evidence of primary tumor; 
Tis: Carcinoma in situ, intramucosal cancer (the tumor invades the lamina propria of the 
mucosa but does not break through the myofascial layer); 
T1: The tumor invades the submucosal layer (the tumor invades the submucosal layer but 
does not involve the intrinsic muscle layer); 
T2: the tumor invades the intrinsic muscle layer; 
T3: the tumor penetrates the intrinsic muscle layer to the peri-colorectal tissue; 
T4: the tumor invades the sublayer of the peritoneum or invades or adheres to nearby organs 
or structures; 
T4a: Tumor penetrates the mesenteric peritoneum (including intestinal perforation at the 
tumor site visible to the naked eye, and continuous infiltration of the tumor through the 
inflamed area to the surface of the peritoneum layer); 
T4b: Tumor directly invades or attaches to neighboring organs or structures. 
regional lymph nodes (N) 
Nx: regional lymph nodes cannot be evaluated; 
N0: no regional lymph node metastasis; 
N1: There are 1-3 regional lymph node metastases (tumor diameter in the lymph nodes is 
greater than 0.2 mm), or no regional lymph node metastasis, but there are any number of 
tumor nodules; 
N1a: there is 1 regional lymph node metastasis; 
N1b: There are 2-3 regional lymph node metastases; 
N1c: no regional lymph node metastasis, but tumor nodules in subserous, mesenteric, or 
peri-peritoneal tissues; 
N2: There are 4 or more regional lymph node metastases; 
N2a: There are 4-6 regional lymph node metastases; 
N2b: There are more than 7 regional lymph node metastases. 

 
 
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Distant Metastasis (M) 
Mx: distant transfers cannot be evaluated; 
M0: no distant metastasis on imaging, that is, there is no evidence of metastatic tumors in 
distant sites and organs (this classification should not be determined by pathologists); 
M1: the presence of metastases in one or more distal parts, organs, or peritoneum; 
M1a: distant metastases are limited to a single distant site or organ, but there is no peritoneal 
metastasis; 
M1b: Distal metastases distributed to two or more distant sites or organs, no peritoneal 
metastases; 
M1c: Peritoneal metastases, with or without other site or organ metastases. 
 
 
 

 
 
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Attachment 6: The VAS pain score 
It is a straight line about 10 centimeters long. One end of the line is marked as "0", 
representing no pain, and the other end is marked as "10", representing the most severe pain 
imaginable. There are no other scale marks on the line, maintaining a simple visual 
presentation. 
Self - assessment by the Patient: The patient marks a point on the line according to his or 
her current pain experience to represent the degree of pain. This process is completely 
completed by the patient independently to fully reflect his or her subjective pain experience. 
For example, if the patient feels mild pain, he or she may mark a point closer to the "0" end; if 
the pain is very severe, the mark will be closer to the "10" end. 
Degree of Pain 
VAS Score Range 
Description 
No Pain - Mild 
Pain 
0 - 3 points 
A score of 0 represents no pain at all; a score of 1 - 3 
indicates mild pain, which has a relatively minor 
impact on daily life and generally does not require 
strong painkillers. 
Moderate Pain 
4 - 6 points 
The pain begins to have a certain impact on daily life, 
intensifies during daily activities, and may require 
relief measures such as rest and the use of over-the-
counter painkillers. 
Severe Pain 
7 - 10 points 
Unbearable pain that has a severe impact on the 
quality of life, greatly interfering with daily 
activities, sleep, and emotions, and requires strong 
painkillers. 
 
 
 

 
 
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Attachment 7 Completeness of Specimens 
Grading 
Descriptions  
Mesocolic plane 
Smooth intact mesocolic excision. 
Intramesocolic plane 
The excision disrupts the mesocolon but do not reach down to the 
muscularis propria. 
Muscularis propria plane 
The excision disrupts the mesocolon and exposed the muscularis propria. 
 

 
 
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Protocol 
 
 
A Multicenter Randomized Clinical Trial Comparing Surgical Site Infection after 
Intracorporeal Anastomosis and Extracorporeal Anastomosis for Left Colon Cancer 
(STARS) 
 
Principal investigator: 
Wang Quan 
Department : 
Department of Gastrocolorectal Surgery 
Version: 
2.1 
Release date: 
July 16, 2023 
Telephone： 
+86 15843073207
 
 
Email: 
wquan@jlu.edu.cn 

 
 
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Abstract 
Title 
A Multicenter Randomized Clinical Trial Comparing Surgical Site 
Infection after Total Laparoscopic and Laparoscopic-assisted Radical 
Surgery for Left Colon Cancer 
Study Center 
First Hospital of Jilin University 
Peking Union Medical College Hospital 
Cancer Hospital Affiliated to Fudan University 
Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of 
Medicine 
Beijing Friendship Hospital , Capital Medical University 
PLA General Hospital 
Daping Hospital Affiliated to Army Military Medical University 
Shengjing Hospital Affiliated to China Medical University 
Chinese Academy of Medical Sciences Cancer Hospital 
China-Japan Union Hospital of Jilin University 
The First Affiliated Hospital of China Medical University 
Nanfang Hospital of Southern Medical University 
Study Purpose 
The purpose of this study is to investigate the effects of intracorporeal 
anastomosis and extracorporeal anastomosis in laparoscopic-assisted 
radical left hemicolectomy on surgical site infection. Also consider 
perioperative recovery, safety, and oncology outcomes. 
Study Type 
A prospective, multicenter, non-inferiority, two-arms, single-blind, 
randomized controlled study 
Patients 
Selection 
Inclusion Criteria: 
(1) age between 18 and 80 years;  
(2) histologically or cytologically confirmed left-sided colon cancer 
(distal transverse colon, left colic flexure, descending colon, or 
proximal sigmoid colon);  

 
 
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(3) clinical stage T1–4a, N0–2, and M0;  
(4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 
2; 
(5) suitable for laparoscopic colectomy;  
(6) no previous systemic chemotherapy or radiotherapy;  
(7) willing to provide written informed consent and comply with the 
research procedures. 
Exclusion criteria 
(1) Have a history of malignant colorectal tumor or have been recently 
diagnosed with other malignant tumors. 
(2) Patients with intestinal obstruction, intestinal perforation, intestinal 
bleeding, etc. who need emergency surgery. 
(3) Patients who need to undergo combined organ resection or robot-
assisted colectomy. 
(4) Patients who are receiving preoperative neoadjuvant therapy. 
(5) ASA grade≥IV and/or ECOG performance status score > 2. 
(6) Patients with severe impairment of liver and kidney function, 
cardiopulmonary function, coagulation disorders or accompanied by 
severe underlying diseases and unable to tolerate surgery. 
(7) Patients with a history of severe mental illness. 
(8) Pregnant or lactating women. 
(9) Patients who have a history of taking hormonal drugs. 
(10) Diabetic patients whose blood sugar cannot be controlled to be 
within 6.1 - 8.3 mmol/L. 
(11) Patients with other clinical and laboratory conditions that are 
considered by researchers as inappropriate for participating in this trial. 
Exit criteria 
(1) Patients with other non-tumor diseases that prevent them from 

 
 
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continuing to receive this treatment regimen. 
(2) Patients who need emergency surgical resection due to intestinal 
obstruction, intestinal perforation, intestinal bleeding, etc. after being 
enrolled in the study. 
(3) Patients with distant metastasis confirmed by intraoperative 
exploration or postoperative pathology, including liver, pelvic cavity, 
ovary, peritoneum, distant lymph node metastasis, etc. 
(4) Patients who need combined organ resection as determined by 
intraoperative exploration. 
(5) Patients who request to withdraw from this study cohort for various 
reasons after being enrolled in the study, or who cannot complete the 
study plan and follow-up for various reasons. 
Intervention 
Methods 
Intracorporeal anastomosis group: Total laparoscopic technology is used. 
The tumor is resected according to surgical specifications for radical 
colon cancer surgery. Mesentery resection is performed under 
laparoscopy, and anastomosis is completed under laparoscopy. A small 
incision is made to extract the specimen. 
Extracorporeal anastomosis group: Traditional laparoscopy-assisted 
technology is used. The tumor is resected according to surgical 
specifications for radical colon cancer surgery. A small incision is made 
in the middle of the abdomen to trim the mesentery, remove the specimen, 
and complete the anastomosis operation. 
Primary 
Outcome 
Measures 
The primary endpoint of this study was the surgical site infection within 
30 days after surgery. 
Follow-up Plan 
The follow-up period for the primary endpoint was within 30 days after 
surgery. Follow-up is done through in-patient observation, outpatient 
consultations, and telephone inquiries. On the 30th day after surgery, 

 
 
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patients are required to return to the hospital for blood routine, liver 
function, kidney function, urinary routine, lung CT, and abdominal CT 
examinations. 
It 
also 
documents 
the 
patient's 
surgery-related 
complications and grades over this period, as well as solutions. 
The total follow-up time for patients after surgery is 5 years. For patients 
with recurrent tumors, follow-up should continue for at least 3 years after 
recurrence or metastasis is discovered or until death. 
Sample Size 
350 cases 
Statistical 
Methods 
1 Full analysis set 
A comparative analysis of the primary outcomes will be conducted 
based on “modified intention-to-treat (mITT)”. In the mITT analysis, 
patients will be analyzed according to their randomization allocations.  
2 Per-protocol analysis 
In per-protocol analysis, only cases treated strictly in accordance with 
random groups and assigned treatment plans will be included. Patients 
who haven't been treated with a randomly assigned protocol will be 
excluded from the analysis. 
3 As-treated analysis set 
In the as-treated analysis set, we'll analyze patients according to the 
actual treatment plan they received instead of the allocated plan for 
random groups. 
 
 
 

 
 
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TABLE OF CONTENTS 
1. 
Title .......................................................................................................................................... 8 
2. 
Introduction ............................................................................................................................ 8 
3. Study Purpose and Endpoint ..................................................................................................... 8 
3.1 Study purpose ................................................................................................................... 9 
3.1.1 Main study purpose: ................................................................................................ 9 
3.1.2 Secondary study purpose ......................................................................................... 9 
3.2 Study endpoint .................................................................................................................. 9 
3.2.1 Primary endpoint and its definitions ........................................................................ 9 
3.2.2 Secondary endpoint and its definitions .................................................................... 9 
4. Study design .............................................................................................................................. 11 
4.1 Overall study design ....................................................................................................... 11 
4.2 Study time frame ............................................................................................................ 11 
5. Study population ...................................................................................................................... 11 
5.1 Inclusion criteria ............................................................................................................. 11 
5.2 Exclusion criteria ............................................................................................................ 12 
5.3 Exit criteria ..................................................................................................................... 12 
6. Study treatment grouping ........................................................................................................ 13 
6.1 Randomization and allocation concealment ................................................................. 13 
6.2 Blinding and unblinding ................................................................................................ 14 
7. Intervention and study flow ..................................................................................................... 14 
7.1 Preparation procedures .................................................................................................. 14 
7.2 Surgical Techniques: ...................................................................................................... 14 
7.2.1 Experimental Group Procedure ............................................................................. 15 
7.2.2 Control Group Procedures: .................................................................................... 17 
7.3 Concurrent treatment and follow-up. ........................................................................... 18 
7.4 Patients compliance and exit ......................................................................................... 19 
7.5 Deviation from the plan ................................................................................................. 20 
8 Evaluation .................................................................................................................................. 20 
8.1 Efficacy Evaluation ........................................................................................................ 20 
8.2 Safety Assessment ........................................................................................................... 20 
8.2.1 Baseline Signs and Symptoms ............................................................................... 20 
8.2.2 Laboratory Safety Assessment ............................................................................... 21 
8.2.3 Physical Examination and Vital Signs ................................................................... 21 
9. Adverse event report ................................................................................................................ 21 
9.1 Definition of adverse events ........................................................................................... 21 
9.2 Severe adverse event ....................................................................................................... 22 
9.3 Severity assessment ........................................................................................................ 22 
9.4 Relevance judgement ..................................................................................................... 22 
10. Data processing and storage .................................................................................................. 22 
11. Quality management .............................................................................................................. 22 
12. Statistical analysis .................................................................................................................. 23 

 
 
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12.1 Method for determining sample size ........................................................................... 23 
12.2 Analytical population ................................................................................................... 24 
12.2.1 Full analysis set ................................................................................................... 24 
12.2.2 Per-protocol analysis ........................................................................................... 24 
12.2.3 As-treated analysis set ......................................................................................... 24 
12.3 Effect analysis and statistical method ......................................................................... 24 
12.3.1 primary endpoint analysis .................................................................................... 24 
12.3.2 Secondary endpoint analysis ............................................................................... 25 
12.4 Interim analysis ............................................................................................................ 25 
12.5 Terminal analysis .......................................................................................................... 25 
12.6 Data Monitoring Committee ........................................................................................ 25 
13. Data collection and management .......................................................................................... 26 
13.1 Electronic Case Report Form ...................................................................................... 26 
13.2 Data management ......................................................................................................... 27 
14. Ethics ....................................................................................................................................... 27 
14.1 Ethics Committee ......................................................................................................... 27 
14.2 Patients information and informed consent ............................................................... 27 
15. Definition of Study Completion ............................................................................................. 28 
16. Study organizational structure .............................................................................................. 28 
17. Confidentiality and Data Security ........................................................................................ 28 
18. Insurance and Compensation ................................................................................................ 29 
19. Publication notes .................................................................................................................... 29 
20. References ............................................................................................................................... 29 
21. Attachments ............................................................................................................................ 32 
Attachment 1: Definition and classification of SSI according to CDC .................................. 32 
Attachment 2: ASA Classification Criteria ............................................................................. 35 
Attachment 3: ECOG Physical Fitness Assessment Criteria .................................................. 36 
Attachment 4: Postoperative Complications Clavien-Dindo System Grading ....................... 37 
Attachment 5: TNM Stages of Colon Cancer (AJCC, 8th Edition, 2018) .............................. 38 
Attachment 6: The VAS pain score ......................................................................................... 40 
Attachment 7 Completeness of Specimens ............................................................................. 41 
 
 
 

 
 
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1. Title 
A Multicenter Randomized Clinical Trial Comparing Surgical Site Infection after 
Intracorporeal Anastomosis and Extracorporeal Anastomosis for Left Colon Cancer 
2. Introduction 
It is estimated that there were more than 1.09 million new cases of colon cancer and more 
than 500,000 deaths from colon cancer in 2018. In developed countries, the incidence of colon 
cancer is higher than in developing countries. Usually, cancers proximal to the splenic flexure 
are defined as right-sided and cancers at or distal to the splenic flexure are defined as left-sided 
(1). It is reported that left-sided colon cancer has different clinical and biological characteristics 
from right-sided colon cancer (2) and has a more favorable prognosis than the latter (3). 
Although neoadjuvant therapy and postoperative chemotherapy had been demonstrated to 
reduce the risk of tumor recurrence and death (4,5), surgery remains the main treatment for 
patients with potentially curable colon cancer(6). Currently, main surgical methods include 
traditional open surgery, minimally invasive surgery using laparoscopic techniques, and 
emerging robotic surgery. Compared with open surgery, laparoscopic surgery has achieved 
similar oncological outcomes in colon cancer or left-sided colon cancer (7,8). As for overall 
survival, laparoscopic surgery has been demonstrated oncologically safe, and was non-inferior 
to open surgery for patients with stage II or III colon cancer (9,10). However, surgical site 
infection (SSI) is one of the most common nosocomial infection in colonic surgery, with an 
incidence that varies between 5 and 30%(11,12). SSI is usually split into superficial incisional 
SSI, deep incisional SSI, and organ/space SSI(13,14). Data from the American College of 
Surgeons National Surgical Quality Improvement Program showed the overall SSI rate was 
12.3%, and left resections had increased odds of superfici al SSI compared with right resections 
(15). There is an urgent need to determine the incidence of SSI, as well as strategies to reduce 
SSI rate(16). The aim of STARS trial is to evaluate the incidence of SSI and safety of the 
intracorporeal anastomosis after left-sided colon surgery.  
3. Study Purpose and Endpoint 

 
 
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3.1 Study purpose 
3.1.1 Main study purpose:  
To investigate the effects of intracorporeal anastomosis and extracorporeal anastomosis in 
laparoscopic-assisted radical left hemicolectomy on surgical site infection. 
3.1.2 Secondary study purpose 
To investigate the difference in postoperative recovery, safety, and oncology outcomes 
between intracorporeal anastomosis and extracorporeal anastomosis in laparoscopic-assisted 
radical left hemicolectomy. 
3.2 Study endpoint 
3.2.1 Primary endpoint and its definitions 
The primary endpoint is SSI within 30 postoperative days. SSI was defined according to 
the U.S. Centers for Disease Control and Prevention (Attachment 1). The overall SSI included 
any superficial and deep incisional SSIs or organ/space SSI. Any patient suspected of having 
organ/space SSI underwent abdominal computed tomography (CT) or digestive contrast 
radiography to further confirm anastomotic leakage. In our study, anastomotic leakage was 
categorized as organ/space infection. 
3.2.2 Secondary endpoint and its definitions 
The secondary outcomes included:  
(1) Operating time: It is defined as the period from cutting the skin to suturing the skin or 
doing enterostomy. It is measured in minutes. 
(2) Total blood loss during operation: It is defined as the blood loss during operation and 
is measured in milliliters. 
(3) Conversion to open surgery: It is defined as an abdominal incision larger than that 
necessary for specimen extraction. 
(4) Postoperative complications: Postoperative complications are investigated within 30 
days after an operation. It includes fever of unknown origin, bowel obstruction, anastomotic 

 
 
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leakage, SSI, other incisional complications, respiratory complications, urinary complications, 
cardiovascular and cerebrovascular complications, diarrhea, chylous fistula, intraperitoneal 
hemorrhage, digestive hemorrhage, gastroparesis, and others (including bacteremia, 
cholecystitis, ion discharge, pancreatitis, and mental and behavioral abnormalities). 
Complications are graded according to the Clavien–Dindo classification (17). The diagnosis of 
anastomotic leakage is based on the patient’s postoperative clinical symptoms, signs of 
abdominal infection, or drainage properties and is confirmed by imaging (angiography or 
computed tomography) or secondary surgery. Postoperative intraperitoneal/digestive 
hemorrhage is defined as bloody drainage/bloody stool > 100 mL in 1 h or evidence of 
hemorrhage on CT, endoscopy, or angiography. The respiratory complications include 
pulmonary complications or pleural effusion. Urinary complications include infections, 
retention, and leakage. 
(5) Completeness of specimens: It is evaluated according to the West classification.(18) 
The resected specimens will be classified into three groups according to the plane of dissection: 
mesocolic plane, intramesocolic plane, and muscularis propria plane 
(6) Number of lymph nodes dissected: The number of lymph nodes in the mesentery will 
be calculated. Additionally, the metastatic lymph nodes will be counted. The pathological TNM 
staging was performed according to the American Joint Committee on Cancer (AJCC) Cancer 
Staging Manual, 8th edition.  
(7) Postoperative recovery: Postoperative recovery information includes time to first flatus, 
time to first defecation, time to start food intake, and postoperative hospital stay. These are 
measured in days. 
(8) Length of incision: The incision length is measured with an aseptic ruler at the end of 
the surgery, after the incision is sutured. It is measured in millimeters. 
(9) Visual analog score (VAS) of pain: Pain severity was assessed 48 hours after the 
operation using a ruler about 10 cm long. The ruler is numbered from 0 to 10. 0–3 points 
indicate no to mild pain. 4–6 points represent moderate pain. 7–10 points stand for severe pain.  
(10) 3-year disease-free survival (DFS) and 5-year overall survival (OS): DFS was defined 
as the time from randomization until the discovery of local recurrence, distant metastasis, or 

 
 
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death from the tumor. OS was defined as the time from randomization to death due to any cause. 
4. Study design 
4.1 Overall study design 
This is a prospective, multicenter, non-inferiority, two-arms, single-blind, randomized 
controlled study.  
4.2 Study time frame 
The subject recruitment period is 3 years, and the follow-up period lasts 5 years. The entire 
study, which includes study establishment, patient recruitment, patient follow-up, and data 
analysis, is expected to take 8 years. We'll conduct a primary endpoint analysis of the study 
after all patients finish their first month of post-operative follow-up. Additionally, a second 
analysis of results involving survival data will be done after all patients complete 5 years of 
follow-up. 
Figure 1 the study design flowchart 
 
5. Study population 
5.1 Inclusion criteria 
(1) age between 18 and 80 years;  
(2) histologically or cytologically confirmed left-sided colon cancer (distal transverse 
colon, left colic flexure, descending colon, or proximal sigmoid colon);  
(3) clinical stage T1–4a, N0–2, and M0;  
(4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 
(5) suitable for laparoscopic colectomy;  
(6) no previous systemic chemotherapy or radiotherapy;  

 
 
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(7) willing to provide written informed consent and comply with the research procedures. 
5.2 Exclusion criteria 
(1) Have a history of malignant colorectal tumor or have metastatic or multiple 
carcinoma. 
(2) Patients with intestinal obstruction, intestinal perforation, intestinal bleeding, etc. who 
need emergency surgery. 
(3) Patients who need to undergo combined organ resection or robot-assisted colectomy. 
(4) Patients who are receiving preoperative neoadjuvant therapy. 
(5) ASA grade ≥ IV and/or ECOG performance status score > 2. 
(6) Cardiopulmonary dysfunction (NYHA cardiac function classification II-IV), liver 
dysfunction (MELD score greater than 12), or kidney dysfunction (serum creatinine above the 
upper limit of normal); 
(7) Patients with severe psychiatric illness. 
(8) Pregnant or lactating women. 
(9) Patients who have a history of taking hormonal drugs. 
(10) Diabetic patients whose blood sugar cannot be controlled to be within 6.1 - 8.3 
mmol/L. 
(11) Patients with other clinical and laboratory conditions that are considered by researchers 
as inappropriate for participating in this trial. 
5.3 Exit criteria 
(1) Patients with other non-tumor diseases that prevent them from continuing to receive 
this treatment regimen. 
(2) Patients who need emergency surgical resection due to intestinal obstruction, intestinal 
perforation, intestinal bleeding, etc. after being enrolled in the study. 
(3) Patients with distant metastasis confirmed by intraoperative exploration or 
postoperative pathology, including liver, pelvic cavity, ovary, peritoneum, distant lymph node 
metastasis, etc. 
(4) Patients who need combined organ resection as determined by intraoperative 
exploration. 

 
 
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(5) Patients who request to withdraw from this study cohort for various reasons after being 
enrolled in the study, or who cannot complete the study plan and follow-up for various reasons. 
The data of patients who withdrew from the study were not used, and these patients were 
not allowed to re-enter the study. 
6. Study treatment grouping 
Experiment group: Total laparoscopic intracorporeal anastomosis group (IA group) 
The tumor is resected according to surgical specifications for radical colon cancer surgery. 
Mesentery resection is performed under laparoscopy, and anastomosis is completed under 
laparoscopy. A small incision is made to extract the specimen after the anastomosis is completed. 
Control group: Laparoscopy assisted extracorporeal anastomosis group (EA group) 
The tumor is resected according to surgical specifications for radical colon cancer surgery. 
A small incision is made in the middle of the abdomen to trim the mesentery, remove the 
specimen, and complete the anastomosis. After completing the anastomosis, the incision will 
be sutured. 
6.1 Randomization and allocation concealment 
Randomization will be conducted immediately after recruitment. To guarantee 
randomization concealment adequately, and not be influenced either by the surgeon or the 
participants, randomization will be performed by a researcher who is not participating in this 
study from the Research Centre of Clinical Epidemiology (RCCE), Jilin University First 
Hospital. The random codes will be designed in a 1:1 ratio (experimental group or control group) 
using the R (version 3.3.3, University of Auckland, Oakland, New Zealand). The random codes 
will be sealed in an opaque envelope and handed to the researcher responsible for grouping in 
RCCE. The site investigators can submitted the participants’ details to the RCCE and apply for 
randomization through text messages, e-mail, or telephone application. The researcher 
responsible for grouping in RCCE will review patient eligibility. When grouping, the envelope 
with the unique identification number for the participant will be opened, and the group 
assignment will immediately be delivered to the researcher of the study site by RCCE through 
text messages, e-mail, or telephone.  

 
 
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6.2 Blinding and unblinding 
The clinical surgeons, outcome assessors, data recorders, and statisticians will all operate 
independently. Due to the nature of the surgical interventions, the surgeons will not be blinded 
to treatment allocation. However, the outcomes assessor who assess or analyze the end point 
will be blinded. The patients will also be blinded to group allocation to reduce the risk of bias. 
Unblinding will not be performed unless the finalization of the main data analysis or required 
for patient’s safety. After the data analysis, we will have a blinded interpretation of the study 
results to minimize misleading data interpretation. 
7. Intervention and study flow 
7.1 Preparation procedures 
Prior to the surgical intervention, patients are required to undergo a series of preparation 
steps to ensure optimal conditions for surgery and to minimize the risk of complications. On 
the evening before the operation, patients will consume a solution containing polyethylene 
glycol electrolytes to cleanse the bowel. This bowel preparation is crucial for visualization 
during surgery and to reduce the risk of infection. The day before surgery, patients will also be 
administered oral antibiotics, specifically metronidazole at a dosage of 800 mg and gentamycin 
sulfate at 160 mg, to target a broad spectrum of potential infectious agents. Furthermore, as a 
prophylactic measure against infection, mezlocillin sodium will be given 20 minutes prior to 
the induction of anesthesia. 
7.2 Surgical Techniques: 
General Surgical Procedures: On the day of surgery, patients are positioned supine on the 
operating table with their legs spread to allow ample space for the surgical team. The surgeon 
and assistant will be positioned on the right side of the operating bed, facilitating access to the 
surgical site. The initial incision, approximately 10mm in size, will be made above the 
umbilicus using an open technique, which allows for the introduction of the primary port for 
laparoscopic instruments. Subsequently, four additional ports will be strategically placed under 
laparoscopic guidance. Throughout the procedure, the principles of complete mesocolic 
excision (CME) and central vascular ligation will be adhered to. This involves a medial-to-

 
 
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lateral approach, where mesenteric vessels, including the inferior mesenteric vein, left colic 
artery, and one to two sigmoid arteries, are carefully exposed and divided at their origins using 
either absorbable or non-absorbable clips. The greater omentum is then separated from the 
transverse colon using a harmonic scalpel, and the splenic flexure and descending colon are 
mobilized. 
7.2.1 Experimental Group Procedure 
In the experimental group, the surgeon will use a 10-cm medical suture and methylene 
blue solution to mark the resection margin. The marginal vessels and mesentery will be divided 
inside the body. The proximal and distal colons are resected using a 60mm linear laparoscopic 
stapler. Side-to-side intracorporeal anastomotic techniques like anti-peristaltic, iso-peristaltic, 
or overlap methods will be applied (Figure 2-4). Once the anastomosis is completed, the 
specimen is retrieved. The surgeon can place the specimen in a sterile plastic bag for retrieval. 
Alternatively, the surgeon can use a disposable incision retraction fixator to protect the wound. 
An abdominal drainage tube is inserted. Three different intracorporeal anastomotic methods are 
shown in Figures 2, 3, and 4.  
Note that only these three anastomotic methods are allowed in intracorporeal anastomosis. 
If the anastomosis was completed by inserting the circular stapler through the anus after patients 
were assigned to the IA group, it is considered a conversion to EA. This is because the surgeons 
had to make an incision and insert the circular stapler anvil into the proximal colon with the 
abdomen open. In these cases, the anastomosis was not completed under laparoscopy. 
7.2.1.1 Isoperistaltic Side-to-Side Anastomosis: This method involves making two small 
enterotomies on the antimesenteric borders, approximately 8 cm from the ends of the colon. 
The colonic ends are then positioned in the upper left abdomen. Each end of a 60mm linear 
laparoscopic stapler is inserted through the enterotomies, closed along the antimesenteric 
borders, and fired to create the anastomosis (Figure 2A). Subsequently, the common enterotomy 
is continuously sutured using a 3-0 knotless absorbable suture (Figure 2B). 

 
 
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Fig. 2 A Two ends of a 60-mm linear laparoscopic stapler are inserted into the colons through 
enterotomies separately, then close along the antimesenteric borders and fire. B The common 
enterotomy is sutured continuously. 
7.2.1.2 Antiperistaltic Side-to-Side Anastomosis: Similar to the isoperistaltic method, two 
small enterotomies are made on the antimesenteric borders of the colon ends. These ends are 
placed near the midline of the abdomen. The 60mm linear laparoscopic stapler is used in the 
same manner to close the antimesenteric borders and create the anastomosis (Figure 3A). The 
common enterotomy can then be closed using either a reloaded 60mm linear laparoscopic 
stapler positioned perpendicular to the colon ends (Figure 3B) or by continuous suturing with 
a 3-0 knotless absorbable suture. 
 
Fig. 3 A Two ends of 60-mm linear laparoscopic stapler are inserted into the colons through 
enterotomies separately, then close along the antimesenteric borders and fire. B The common 
enterotomy is closed by a reload 60-mm linear laparoscopic stapler perpendicular to colon 
ends 
7.2.1.3 Overlap Side-to-Side Anastomosis: The choice between a cephalic or caudal 

 
 
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approach for inserting the linear laparoscopic stapler depends on the tumor location and the 
ease of anastomosis. When the transverse colon end has limited mobility, the caudal approach 
offers greater convenience (Figure 4A). In this approach, one small enterotomy is made at the 
antimesenteric border of the transverse colon end, and another enterotomy is made 
approximately 8 cm from the descending or sigmoid colon end. The 60 mm linear laparoscopic 
stapler is inserted through the caudal trocars, with both ends being introduced into the colons 
via the enterotomies, closed along the antimesenteric borders, and fired to complete the 
anastomosis (Figure 4B). The common enterotomy is then continuously sutured using a 3-0 
knotless absorbable suture. In the cephalic approach, the positions of the two enterotomies on 
the colons are made in opposition to those in the caudal cases. 
 
Fig. 4 A Two ends of 60-mm linear laparoscopic stapler are inserted into the colons through 
the enterotomies separately, then close along the antimesenteric borders and fire. B The 
common enterotomy is sutured continuously 
7.2.2 Control Group Procedures: 
For patients in the control group, the surgeon uses wound edge protectors to exteriorize 
the colon through a small incision in the midline of the abdomen. A ruler and methylene blue 
solution are employed to mark the area for colon resection. This guarantees a 10-cm margin 
from the tumor. Guided by these markers, the marginal vessels and mesentery are divided 
outside the body. The method of anastomosis is at the surgeon's discretion. A side-to-side 
anastomosis (including antiperistaltic, isoperistaltic, or overlapping anastomosis) is 
recommended. Side-to-end or end-to-end anastomosis (sewn by hand or by inserting a circular 
stapler through the anus or proximal colon) is also allowed (Figure 5). After completing the 

 
 
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anastomosis, the incision is sutured. An abdominal drainage tube is inserted at the end of the 
operation. 
 
 
A 
B 
 
Fig. 5 A Side-to-end anastomosis. It can be completed by inserting a circular stapler 
through the anus. Alternatively, it can be done by inserting the circular stapler through the end 
of the proximal colon and then using another linear stapler to close the end of the proximal 
colon after anastomosis. Hand sewing is also permitted. B end-to-end anastomosis. It can be 
completed by inserting a circular stapler through the anus. Alternatively, it can be done by 
sewing it by hand. 
 
7.3 Concurrent treatment and follow-up. 
Postoperative chemotherapy is recommended according to the NCCN guidelines for colon 

 
 
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cancer treatment. The post-operative follow-up period must be in accordance with the time 
specified in this study (Table 1). Each participant will be followed until recurrence or death 
over a period of 5 years after the scheduled surgery. 
The follow-up period for the primary endpoint is within 30 days after surgery. Follow-up 
will be conducted through in-patient observation, outpatient consultations, and telephone 
inquiries. SSI presence will be assessed daily during hospitalization and weekly after discharge. 
At least two surgeons perform SSI surveillance. The outcome assessors are trained on the 
Centers for Disease Control and Prevention (CDC) definitions of SSI to produce good inter-
rater reliability for the assessment of SSI. If SSI is suspected during follow-up, CT or abdominal 
ultrasonography will be done. All patients will have an abdominal or pelvic CT on the 30th day 
after surgery. If the CT shows evidence of SSI, the radiologist and surgeon will assess whether 
there is an SSI. 
The patient's surgery-related complications and Clavien–Dindo grade within 30 
postoperative days will be recorded. The overall follow-up period for patients after surgery is 
5 years, which includes 5-year overall survival (OS) and 3-year disease-free survival (DFS). 
For patients with recurrent tumors, follow-up should continue for at least 3 years after 
recurrence or metastasis is discovered or until death. 
Appropriate strategies will be used to improve patient adherence and ensure data integrity. 
When signing the informed consent form, all participants will be informed of the study 
procedures, potential benefits, and risks to make them fully understand the inconvenience and 
significance of data collection. 
In addition, patients who have had abdominal surgery need to return to our hospital for 
other treatment of combined injuries, including suture removal. Our medical team will provide 
standard post-operative care for enrolled participants to promote their adherence. 
Investigators will contact patients 1 week before the follow-up session to increase the 
attendance rate. Patients who miss a scheduled appointment will be contacted to reschedule 
another appointment within 1 week. Telephone follow-up calls, WeChat group discussions, and 
personal interviews will be used to maximize retention and complete follow-up. 
7.4 Patients compliance and exit 

 
 
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To improve patient compliance, before randomization, physicians will communicate with 
patients in detail about surgical procedures, possible random groupings, relevant and evolving 
treatment, and patient safety and security conditions. They will obtain informed consent to 
ensure patients clearly understand the treatment and research procedures. The randomization 
time should be as close as possible to the time before surgery (the day before surgery) to prevent 
accidental exclusion of patients after randomization. After randomization, patients can 
withdraw from the trial at any time. If a patient requests withdrawal from the study, the main 
researcher at their research center will communicate with them to avoid disrupting the balance 
of random groups due to exclusion. If the patient still insists on withdrawing, they will be 
removed from the trial. Clinical information relating to this patient will not be included in any 
data analysis related to this trial. 
7.5 Deviation from the plan 
Researchers involved in the trial will conduct corresponding surgical operations and data 
recording in line with the experimental requirements. Any event that strays from the original 
test plan must record the time and specific reason for occurrence to explain the deviation from 
the test plan. 
8 Evaluation 
8.1 Efficacy Evaluation 
The methodologies for evaluating the efficacy of diverse anastomosis techniques 
encompass, but are not restricted to: intraoperative assessment and meticulous records of 
postoperative examinations, evaluation of postoperative symptoms and signs, and postoperative 
abdominal CT evaluation. 
8.2 Safety Assessment 
8.2.1 Baseline Signs and Symptoms 
The baseline signs and symptoms include temperature, pulse, respiratory rate, and blood 
pressure. Surgeons also need to pay attention to specific symptoms such as dizziness, nausea, 

 
 
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and vomiting. Additionally, hematological tests and imaging tests before surgery will be 
performed to ensure the patient group has no surgical contraindications and fully meets the 
inclusion criteria. These baseline data will serve as reference indicators for the evaluation. 
8.2.2 Laboratory Safety Assessment 
Continuous indicators show the postoperative measurements of each study subject and the 
changes in values compared to the preoperative baseline. Laboratory indicators are classified 
as low, normal, and high based on the normal value range. They describe transitions from a 
normal or high baseline to a low value after the baseline, and from a normal or low baseline to 
a high value after the baseline. The lower or higher value after the baseline is calculated using 
the minimum or maximum observed value. The physician evaluates these abnormal indicators 
to determine their clinical significance. The proportion of subjects with “abnormal and 
clinically significant” changes is described.  
8.2.3 Physical Examination and Vital Signs 
Physical examination includes general examination, head examination, neck examination, 
chest and lung examination, heart and blood vessels examination, abdominal examination, 
spine and limbs examination, and nervous system examination. Vital signs consist of blood 
pressure, heart rate, and body temperature. Situations where vital signs deviate from the normal 
range or are abnormal are described and recorded. 
9. Adverse event report 
9.1 Definition of adverse events 
Adverse events studied include intraoperative secondary injuries in patients and serious 
complications and deaths within 30 days after surgery. All adverse events reported 
spontaneously by test subjects or observed by staff will be recorded in a database and promptly 
reported to the test steering committee. 
An adverse event is defined as any adverse experience that occurs in the subject during 
the study, regardless of whether it's considered associated with total laparoscopic anastomosis. 
All adverse events reported spontaneously by test subjects or observed by investigators are 

 
 
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recorded. These include: 1) Accidental secondary damage during surgery. 2) Serious 
complications after surgery (grade III and above). 
9.2 Severe adverse event 
A serious adverse event includes any of the following adverse medical events: 1) events 
leading to death; 2) life-threatening events; 3) requiring hospitalization or prolonged 
hospitalization of patients; 4) Causing persistent or significant disability, or incapacity for 
conduct. 
9.3 Severity assessment 
The severity of adverse events will be assessed using the Clavien—Dindo grading criteria 
for complications. 
9.4 Relevance judgement 
Determining the correlation between adverse events and surgical interventions will be 
made by researchers subjectively. 
10. Data processing and storage 
 
All relevant clinical data including demographic and medical information will be collected 
from the electronic medical record. The collected data will be encoded to protect the privacy of 
all participants and then be entered into an electronic case report forms (eCRFs) by trained 
research assistants in each sub-center. Double data entry will be performed to ensure that the 
data collected are accurate and verifiable from source documents. Input rules including field 
and range checks will also be set to minimize data entry errors. The research coordinator will 
periodically check the data distribution, verify outliers, and track missing data to improve data 
integrity and data validation. Data storage and backup will be managed by the edocdata 
platform (https://jlcrc.edocdata.com/), which will track all changes to the data and retains a 
history for each variable. Unauthorized persons or institutions will not be able to access any 
data stored on this server. When the trial is completed, the data will be locked and stored on 
edocdata platform, after which the researchers can no longer modify the data. Both paper and 
electronic documents will be preserved for at least 5 years after publication. 
11. Quality management 

 
 
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Research center participation criteria: Surgeons involved in this study must complete at 
least 100 cases of laparoscopy-assisted left colectomy and have a minimum of 20 cases of 
intraoperative anastomosis in laparoscopy-assisted left colectomy. This study establishes a trial 
steering committee (TSC). The TSC is composed of surgeons with at least 10 years of 
experience in colorectal cancer surgery. Before enrolling in the research center, participating 
centers should provide surgical videos of two consecutive IA cases and two EA cases by the 
same operator recently to determine if the surgery quality meets expectations and if they can 
qualify as enrolment units. The evaluation method is the Delphi method. 
Evaluation of surgical quality during research: Surgery quality is assessed using videos 
and photographs. Surgical teams are required to take photographs of the laparoscopic 
investigation of the tumor site, surgical area after lymph node removal, and the anastomosis. 
The TSC evaluates the videos and photographs to assess surgical quality and ensure compliance 
with the allocated intervention. Any surgical procedures deviating from the randomized 
allocation plan are documented. If participating centers cannot obtain imaging data, they must 
document the reason for not being able to leave a video or photo. 
Surgeons participating in the trial are required to record the surgical procedure and explain 
any surgical procedures that deviate from standardized procedures. The trial steering committee 
will evaluate the enrollment situation and quality of enrolled cases at each center every half a 
year and supervise and control the quality of enrolled cases at each center. 
12. Statistical analysis 
12.1 Method for determining sample size 
This study is a multicenter, randomized, controlled, noninferiority trial specifically 
designed for patients within the age range of 18 to 80 years old who are diagnosed with left-
sided colon cancer. We adjusted the sample size according to our latest published multicenter 
retrospective data(19). We expected that the incidence of overall surgical site infection 
following extracorporeal anastomosis left colon cancer surgery stands at 13.3%, while the 
incidence of SSI after intracorporeal anastomosis is 8.0%. When there is an absolute risk 
difference in the SSI rate of more than 5% within 30 days after surgery, intracorporeal 

 
 
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anastomosis is regarded as inferior to extracorporeal anastomosis. Consequently, the sample 
size for this study is calculated based on non-inferiority, considering an absolute risk 
difference of 5%, a one-sided level of significance of 0.025, a ratio of 1:1, a power of 0.80, 
and a 20% drop-out rate. In total, 350 patients are required for this study, with 175 patients in 
the experimental group and an equal number of 175 patients in the control group. 
12.2 Analytical population 
12.2.1 Full analysis set 
The primary outcome will be comparatively analyzed based on “modified intention-to-
treat (mITT)”. In the mITT analysis, patients will be analyzed according to their randomization 
allocations. If patients randomly assigned to the IA group actually receive EA during surgery, 
they will be analyzed according to the IA group in mITT analysis. If patients randomly assigned 
to group EA actually receive IA during surgery, they will be analyzed according to group EA. 
Patients who meet the exit criteria after randomization will not be included in the mITT 
population. 
12.2.2 Per-protocol analysis 
In per-protocol (PP) analysis, only cases treated strictly in accordance with random groups 
and assigned treatment plans will be included. Patients who haven't been treated with a 
randomly assigned protocol will be excluded from the per-protocol analysis. 
12.2.3 As-treated analysis set 
In the as-treated (AT) analysis set, we'll analyze patients according to the actual treatment 
they received instead of the allocated plan for random groups. 
12.3 Effect analysis and statistical method 
12.3.1 primary endpoint analysis 
In analyzing the primary outcomes, the rate of overall SSI will be reported as frequencies 
and percentages. We will calculate the absolute risk differences and the corresponding 95% 
confidence interval (CI) between two groups. If the absolute risk differences and the 
corresponding 95% CI are within the non-inferiority margin (<5%), non-inferiority is 
established. If not, IA is not non-inferior to EA. The analysis of the primary endpoint will be 
carried out in the mITT population, the PP population, and the AT population. 

 
 
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The independent risk factor of the primary endpoint will be analyzed in the AT population. 
High-risk variables identified through univariable analysis and clinical experience will be 
included in the multivariable analysis. Multivariable logistic regression will be employed to 
identify independent risk factors for SSI. The effect size will be estimated using odds ratios 
(ORs) with 95% confidence intervals.  
12.3.2 Secondary endpoint analysis 
The analysis of the secondary endpoints will be carried out in the mITT population. In the 
analysis of secondary endpoints, categorical variables will be reported as frequencies and 
percentages. Groups will be compared using the χ2 test or Fisher’s exact test. Absolute risk 
differences and the corresponding 95% CI will be calculated. Continuous variables will be 
described as mean ± standard deviation or median (quartile). Groups will be compared using 
the t-test or Mann-Whitney U test, as appropriate. Hodges-Lehmann method will be used to 
calculate the difference in median and the corresponding 95% CI. 
The comparison of 3-year DFS and 3-year OS between the two groups will utilize the 
Kaplan–Meier curve and the Cox proportional risk model. Relevant risk factors will be adjusted 
in Cox proportional risk model.  
The missing data in this trial is expected to be minimal. If it occurs, it will be treated as 
censored data and not imputed. All statistical tests were 2-sided, and statistical significance was 
set at P <0.05. All statistical analyses were performed using R or SPSS. 
12.4 Interim analysis  
There will be no interim analysis for this study 
12.5 Terminal analysis 
We will conduct an analysis of the main endpoints of the study and publish the relevant 
findings after all patients have completed the first month of follow-up after surgery. After all 
patients have completed 5 years of follow-up, we will analyze results involving survival data, 
and publish relevant research results. 
12.6 Data Monitoring Committee 
The data and safety monitoring board (DSMB) was composed of senior surgeons, ethicists, 
and statistical analysts. Each member of the DSMB is independent of this trial and is not likely 

 
 
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to affect the competitive interests of the trial. The DSMB will receive and review the safety 
data for this trial. If the DSMB believes the number of adverse events in the trial is biased 
between groups, they will notify the chair of the trial steering committee. 
There will be no interim analysis for this project. However, once the study begins, the 
DSMB will evaluate the results of the study every year. The assessment included primary and 
secondary endpoint records, adverse events, and loss of study samples. It also assesses 
differences with expectations, and potential conflicts with new findings and/or developments 
in the field of colon cancer. DSMB members are not allowed to share confidential information 
with anyone outside of the DSMB, with the exception of the trial steering committee. 
The techniques used in this research institute are all techniques currently used in surgical 
treatment of colon cancer, and patients are not at higher risk. Therefore, this study did not set 
suspension parameters for the entire project. However, if in the DSMB's regular assessments, a 
center shows a huge difference in safety indicators compared to other centers and is 
significantly worse than the current international level, then the DSMB will submit its 
recommendations in writing to the trial steering committee, requesting that the trial plan be 
revised, or the quality of cases in the corresponding center be re-evaluated, or even suspended 
or terminated the clinical trial enrollment of the corresponding center. 
At the discretion of the DSMB during the trial process, the DSMB may decide to meet 
early to discuss testing procedures together about adverse events and promptly clarify any 
issues with key investigators. 
13. Data collection and management 
13.1 Electronic Case Report Form 
An electronic case report form (eCRF) is developed by the lead investigator. The CRF 
table includes the primary endpoint and Secondary endpoints. Additionally, general baseline 
data on patients will be included. 
All relevant clinical data including demographic and medical information will be collected 
from the electronic medical record. The collected data will be encoded to protect the privacy of 
all participants and then be entered into an eCRF by trained research assistants in each sub-

 
 
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center. Double data entry will be performed to ensure that the data collected are accurate and 
verifiable from source documents. Input rules including field and range checks will also be set 
to minimize data entry errors. The research coordinator will periodically check the data 
distribution, verify outliers, and track missing data to improve data integrity and data validation.  
13.2 Data management 
Data 
storage 
and 
backup 
will 
be 
managed 
by 
the 
edocdata 
platform 
(https://jlcrc.edocdata.com/), which will track all changes to the data and retains a history for 
each variable. Unauthorized persons or institutions will not be able to access any data stored on 
this server. When the trial is completed, the data will be locked and stored on edocdata platform, 
after which the researchers can no longer modify the data. Both paper and electronic documents 
will be preserved for at least 5 years after publication. 
14. Ethics 
14.1 Ethics Committee 
This trial has been approved by the Ethics Review Committee of the First Hospital of Jilin 
University (Approval number: 19K135-001). Each sub-center must conduct an ethical 
application before participating in this trial. 
14.2 Patients information and informed consent 
Eligible patients should receive in-person notification from the treating surgeon and 
written information about the trial. Each patient should provide informed consent in accordance 
with local ethics committee guidelines before entering the random allocation of studies. 
 
The informed consent procedure should be carried out by the doctors of each centre. 
Information provided to patients with informed consent includes: 1) a statement about the study 
involved in the trial; 2) a full and fair explanation of the procedures to be followed; 3) a full 
explanation of the nature, anticipated length, and purpose of the study; 4) a description of any 
risk or discomfort that the patient can reasonably anticipate; 5) a description of any benefits 
that can be reasonably anticipated; 6) a statement that patient data will be treated with care and 
confidentiality and that the data will be kept for 15 years; 7) a statement about the patient's 
physical material will be kept for 15 years; 8) a statement about voluntary participation, where 

 
 
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the statement will state the refusal Participation in the trial does not involve any punishment or 
loss of benefits the patient is entitled to, and patients can stop participating at any time without 
being penalized or losing benefits, in which case the patient will receive standard treatment 
with the same level of care. 
15. Definition of Study Completion 
The completion of the study was defined as all enrolled patients completed 5 years of 
follow-up. Follow-up outcomes include disease-free survival, recurrence survival, death, or loss 
of visits. 
16. Study organizational structure 
This study includes several medical centers. The research initiation center is First Hospital 
of Jilin University. Participating centers in clinical research include: Peking Union Medical 
College Hospital, Fudan University Cancer Hospital, Ruijin Hospital Affiliated to Shanghai 
Jiao Tong University School of Medicine, Beijing Friendship Hospital Affiliated to Capital 
Medical University, Chinese People's Liberation Army General Hospital, Daping Hospital 
Affiliated to Army Military Medical University, Shengjing Hospital Affiliated to Chinese 
Medical University, Chinese Academy of Medical Sciences Cancer Hospital, China - Japan 
Union Hospital of Jilin University, First Affiliated Hospital of China Medical University, 
Southern Medical University Southern College. The members of the TSC are heads of the 
corresponding departments of the above centers: Wang Quan, Lin Guole, Li Xinxiang, Feng 
Bo, Zang lu, Yao Hongwei, Du Xiaohui, Tong Weidong, Zhang Hong, Liu Qian, Xie Zhongshi, 
Wu Aiwen, and Deng Haijun. The members of the trial guidance team are attending physicians 
and above in the corresponding medical teams of each center. The DSMB is comprised of senior 
surgeons, ethicists, and statistical analysts. Each member of the DSMB is independent of this 
trial and is not likely to affect the competitive interests of the trial. 
17. Confidentiality and Data Security 
Participants are given a unique code to maintain their anonymity. Personal information 
documents are stored separately from assessment data in locked cabinets. Only the authorized 

 
 
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research assistants and DSMB can access to the dataset. Unless there is an institutional or 
regulatory requirement, nobody else can access it. DSMB members can know the patient 
allocation and be aware of accumulated data. The DSMB will discuss the relevant data results 
with the TSC. DSMB members are not allowed to share confidential information with anyone 
outside the DSMB. The fully anonymized experimental data is stored on secure servers of Jilin 
University First Hospital. 
18. Insurance and Compensation 
Enrolled patients have all purchased medical commercial insurance jointly offered by our 
hospital and insurance companies before surgery. This insurance covers surgery-related 
complications and deaths. This study was funded by the Development Center for Medical 
Science & Technology, National Health Commission of the People’s Republic of China 
(W2017ZWS01 and WA2021RW19). The funder had no role in the study's design and will not 
have any role in data collection, analysis, interpretation, or manuscript writing. 
19. Publication notes 
No relevant data for this study will be published until the collection of primary outcomes 
is completed. We will conduct an analysis of the primary endpoints of the study and publish 
the relevant findings after all patients have completed the first month of follow-up after 
surgery. After all patients complete 5 years of follow-up, the results involving survival data 
will be analyzed again, and the relevant research results will be published. 
20. References 
1. 
Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002 Oct 10;101(5):403–
8.  
2. 
Lee MS, Menter DG, Kopetz S. Right Versus Left Colon Cancer Biology: Integrating the 
Consensus Molecular Subtypes. J Natl Compr Canc Netw. 2017 Mar;15(3):411–9.  
3. 
Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N. Is there a difference in survival 
between right- versus left-sided colon cancers? Ann Surg Oncol. 2008 Sep;15(9):2388–94.  
4. 
Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: 
selecting optimal treatments for individual patients. J Clin Oncol. 2015 Jun 1;33(16):1787–
96.  
5. 
Hawkins AT, Ford MM, Geiger TM, Hopkins MB, Kachnic LA, Muldoon RL, et al. Neoadjuvant 
radiation for clinical T4 colon cancer: A potential improvement to overall survival. Surgery. 

 
 
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2019 Feb;165(2):469–75.  
6. 
Mohamed F. Colon cancer surgery: is it what you do, or the way you do it that matters? 
Lancet Gastroenterol Hepatol. 2017 Apr;2(4):237–8.  
7. 
Liu ZH, Wang N, Wang FQ, Dong Q, Ding J. Oncological outcomes of laparoscopic versus 
open surgery in pT4 colon cancers: A systematic review and meta-analysis. Int J Surg. 2018 
Aug;56:221–33.  
8. 
Park JH, Park HC, Park SC, Sohn DK, Oh JH, Kang SB, et al. Laparoscopic approach for left-
sided T4 colon cancer is a safe and feasible procedure, compared to open surgery. Surg 
Endosc. 2019 Sep;33(9):2843–9.  
9. 
Kitano S, Inomata M, Mizusawa J, Katayama H, Watanabe M, Yamamoto S, et al. Survival 
outcomes following laparoscopic versus open D3 dissection for stage II or III colon cancer 
(JCOG0404): a phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol. 2017 
Apr;2(4):261–8.  
10. 
Yamaguchi S, Tashiro J, Araki R, Okuda J, Hanai T, Otsuka K, et al. Laparoscopic versus open 
resection for transverse and descending colon cancer: Short-term and long-term outcomes 
of a multicenter retrospective study of 1830 patients. Asian J Endosc Surg. 2017 
Aug;10(3):268–75.  
11. 
Zywot A, Lau CSM, Stephen Fletcher H, Paul S. Bundles Prevent Surgical Site Infections After 
Colorectal Surgery: Meta-analysis and Systematic Review. J Gastrointest Surg. 2017 
Nov;21(11):1915–30.  
12. 
Olguín Joseau S, Bollati NP, Reimondez S, Signorini F, Rossini AM, Maldonado PS, et al. Risk 
factors for surgical site infection in colon surgery in our population. Rev Fac Cien Med Univ 
Nac Cordoba. 2018 Nov 14;75(4):229–33.  
13. 
Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of 
Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital 
Infection Control Practices Advisory Committee. Am J Infect Control. 1999 Apr;27(2):97–
132; quiz 133–4; discussion 96.  
14. 
Ban KA, Minei JP, Laronga C, Harbrecht BG, Jensen EH, Fry DE, et al. American College of 
Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update. J 
Am Coll Surg. 2017 Jan;224(1):59–74.  
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Murray ACA, Pasam R, Estrada D, Kiran RP. Risk of Surgical Site Infection Varies Based on 
Location of Disease and Segment of Colorectal Resection for Cancer. Dis Colon Rectum. 
2016 Jun;59(6):493–500.  
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Caroff DA, Chan C, Kleinman K, Calderwood MS, Wolf R, Wick EC, et al. Association of Open 
Approach vs Laparoscopic Approach With Risk of Surgical Site Infection After Colon Surgery. 
JAMA Netw Open. 2019 Oct 2;2(10):e1913570.  
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Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal 
with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 
Aug;240(2):205–13.  
18. 
West NP, Morris EJ, Rotimi O, Cairns A, Finan PJ, Quirke P. Pathology grading of colon cancer 
surgical resection and its association with survival: a retrospective observational study. 
Lancet Oncol. 2008 Sep;9(9):857–65.  
19. 
Guo Y, Li K, He L, Tong W, Chen Y, Wu B, et al. Surgical site infection after intracorporeal and 

 
 
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extracorporeal anastomosis in laparoscopic left colectomy for colon cancer: a multicenter 
propensity score-matched cohort study. Surg Endosc. 2023 May 11;  
  
 
 

 
 
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21. Attachments 
Attachment 1: Definition and classification of SSI according to CDC 
Surgical site infection (SSI) can be subdivided into infections of the subcutaneous tissue 
(superficial SSI), deep soft tissues such as fascial and muscle layers (deep SSI) and infections 
of organs or spaces (organ/space SSI) that occur within 30 days after surgery. 
Superficial 
Incisional SSI 
Infection occurs within 30 days after the operation and infection 
involves only skin or subcutaneous tissue of the incision and at least 
one of the following: 
1. Purulent drainage, with or without laboratory confirmation, from 
the superficial incision. 
  2. Organisms isolated from an aseptically obtained culture of fluid 
or tissue from the superficial incision. 
  3. At least one of the following signs or symptoms of infection: 
pain or tenderness, localized swelling, redness, or heat and 
superficial incision is deliberately opened by surgeon, unless incision 
is culture-negative. 
  4. Diagnosis of superficial incisional SSI by the surgeon or 
attending physician. 
  **Notes**: Do not report the following conditions as SSI: 
  1. Stitch abscess (minimal inflammation and discharge confined to 
the points of suture penetration). 
Deep Incisional SSI 
Infection occurs within 30 days after the operation and the infection 
appears to be related to the operation and infection involves deep soft 
tissues (e.g., fascial and muscle layers) of the incision and at least 
one of the following: 

 
 
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  1. Purulent drainage from the deep incision but not from the 
organ/space component of the surgical site. 
  2. A deep incision spontaneously dehisces or is deliberately opened 
by a surgeon when the patient has at least one of the following signs 
or symptoms: fever (>38°C), localized pain, or tenderness, unless site 
is culture-negative. 
  3. An abscess or other evidence of infection involving the deep 
incision is found on direct examination, during reoperation, or by 
histopathologic or radiologic examination. 
  4. Diagnosis of a deep incisional SSI by a surgeon or attending 
physician. 
  **Notes**: 
  1. Report infection that involves both superficial and deep incision 
sites as deep incisional SSI. 
  2. Report an organ/space SSI that drains through the incision as a 
deep incisional SSI. 
Organ/Space SSI 
Infection occurs within 30 days after the operation and the infection 
appears to be related to the operation and infection involves any part 
of the anatomy (e.g., organs or spaces), other than the incision, which 
was opened or manipulated during an operation and at least one of 
the following: 
  1. Purulent drainage from a drain that is placed through a stab 
wound into the organ/space. 
  2. Organisms isolated from an aseptically obtained culture of fluid 
or tissue in the organ/space. 

 
 
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  3. An abscess or other evidence of infection involving the 
organ/space that is found on direct examination, during reoperation, 
or by histopathologic or radiologic examination. 
  4. Diagnosis of an organ/space SSI by a surgeon or attending 
physician. 
 
   
 
 
 
 
 
 

 
 
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Attachment 2: ASA Classification Criteria 
It refers to the six levels into which patients are classified by the American Society of 
Anesthesiologists (ASA) prior to anesthesia based on their physical condition and risk to 
surgery. 
classification condition 
Level I 
Physical health, good development and nutrition, and 
normal functioning of organs. 
Level II 
In addition to surgical disease, there is mild coexisting 
disease with sound functional compensation. 
Level III 
Coexisting conditions are severe and physical activity 
is limited, but can still manage daily activities. 
Level IV 
Severe coexisting conditions, loss of ability to 
perform daily activities, and frequent life-threatening 
situations. 
Level V 
Dying patients who have difficulty sustaining life for 
24 hours, with or without surgery. 
Level VI 
Confirmed brain death and his organs are intended for 
organ transplantation. 
 
 
 

 
 
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Attachment 3: ECOG Physical Fitness Assessment Criteria 
Physical condition 
Grading 
Normal activity 
0 
Mild symptoms, comfortable living, able to do light physical activities 
1 
Can withstand the symptoms of the tumor and take care of one's own life, but 
not spend more than 50% of the time in bed during the day 
2 
The symptoms are severe. You spend more than 50% of your time in bed 
during the day, but you can still get up and stand, so you can take care of 
yourself for part of your life 
3 
Sick and unable to stay bedridden 
4 
Death 
5 
 
 
 
 

 
 
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Attachment 4: Postoperative Complications Clavien-Dindo System Grading 
Grading 
Definition 
I 
There are complications of unnecessary medication, surgery, 
laparoscopic, and reflex intervention after surgery, but they include 
medications for antiemetics, fever-reducing drugs, pain relievers, 
diuretics, dielectrics, and physiotherapy, as well as incision infections 
opening at the bedside; 
II 
Patients requiring medication not including phase 1 medication, 
incisional infections require antibiotic treatment, blood transfusions, 
and parenteral nutrition included 
III. 
Surgical, laparoscopic, and interventional radiological treatment is 
required 
 
IIIa 
Does not require general anesthesia 
IIIb 
General anesthesia required 
IV 
Life-threatening complications (including central nervous system 
complications) that require IC (intermittent monitoring) or ICU 
treatment 
 
iVa 
Insufficiency of one organ (including dialysis) 
ivB 
multiple organ dysfunction 
V 
Death 
 
 
 

 
 
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Attachment 5: TNM Stages of Colon Cancer (AJCC, 8th Edition, 2018) 
Primary tumors: 
Tx: the primary tumor cannot be evaluated; 
T0: no evidence of primary tumor; 
Tis: Carcinoma in situ, intramucosal cancer (the tumor invades the lamina propria of the 
mucosa but does not break through the myofascial layer); 
T1: The tumor invades the submucosal layer (the tumor invades the submucosal layer but 
does not involve the intrinsic muscle layer); 
T2: the tumor invades the intrinsic muscle layer; 
T3: the tumor penetrates the intrinsic muscle layer to the peri-colorectal tissue; 
T4: the tumor invades the sublayer of the peritoneum or invades or adheres to nearby organs 
or structures; 
T4a: Tumor penetrates the mesenteric peritoneum (including intestinal perforation at the 
tumor site visible to the naked eye, and continuous infiltration of the tumor through the 
inflamed area to the surface of the peritoneum layer); 
T4b: Tumor directly invades or attaches to neighboring organs or structures. 
regional lymph nodes (N) 
Nx: regional lymph nodes cannot be evaluated; 
N0: no regional lymph node metastasis; 
N1: There are 1-3 regional lymph node metastases (tumor diameter in the lymph nodes is 
greater than 0.2 mm), or no regional lymph node metastasis, but there are any number of 
tumor nodules; 
N1a: there is 1 regional lymph node metastasis; 
N1b: There are 2-3 regional lymph node metastases; 
N1c: no regional lymph node metastasis, but tumor nodules in subserous, mesenteric, or 
peri-peritoneal tissues; 
N2: There are 4 or more regional lymph node metastases; 
N2a: There are 4-6 regional lymph node metastases; 

 
 
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N2b: There are more than 7 regional lymph node metastases. 
Distant Metastasis (M) 
Mx: distant transfers cannot be evaluated; 
M0: no distant metastasis on imaging, that is, there is no evidence of metastatic tumors in 
distant sites and organs (this classification should not be determined by pathologists); 
M1: the presence of metastases in one or more distal parts, organs, or peritoneum; 
M1a: distant metastases are limited to a single distant site or organ, but there is no peritoneal 
metastasis; 
M1b: Distal metastases distributed to two or more distant sites or organs, no peritoneal 
metastases; 
M1c: Peritoneal metastases, with or without other site or organ metastases. 
 
 
 

 
 
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Attachment 6: The VAS pain score 
It is a straight line about 10 centimeters long. One end of the line is marked as "0", 
representing no pain, and the other end is marked as "10", representing the most severe pain 
imaginable. There are no other scale marks on the line, maintaining a simple visual 
presentation. 
Self - assessment by the Patient: The patient marks a point on the line according to his or 
her current pain experience to represent the degree of pain. This process is completely 
completed by the patient independently to fully reflect his or her subjective pain experience. 
For example, if the patient feels mild pain, he or she may mark a point closer to the "0" end; 
if the pain is very severe, the mark will be closer to the "10" end. 
Degree of Pain 
VAS Score Range 
Description 
No Pain - Mild 
Pain 
0 - 3 points 
A score of 0 represents no pain at all; a score of 1 - 3 
indicates mild pain, which has a relatively minor 
impact on daily life and generally does not require 
strong painkillers. 
Moderate Pain 
4 - 6 points 
The pain begins to have a certain impact on daily 
life, intensifies during daily activities, and may 
require relief measures such as rest and the use of 
over-the-counter painkillers. 
Severe Pain 
7 - 10 points 
Unbearable pain that has a severe impact on the 
quality of life, greatly interfering with daily 
activities, sleep, and emotions, and requires strong 
painkillers. 
 
 
 

 
 
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Attachment 7 Completeness of Specimens 
Grading 
Descriptions 
Mesocolic plane 
Smooth intact mesocolic excision. 
Intramesocolic plane 
The excision disrupts the mesocolon but do not reach down to the 
muscularis propria. 
Muscularis propria plane 
The excision disrupts the mesocolon and exposed the muscularis propria. 
 

 CSP amendments summary 
 
Amendments in Version 2.0 
Title 
Change the title to "A Multicenter Randomized Clinical Trial Comparing Surgical Site 
Infection after Intracorporeal Anastomosis and Extracorporeal Anastomosis for Left 
Colon Cancer (STARS)" 
Exclusion criteria 
Change "planned synchronous abdominal organ resections;" to "Patients who need to 
undergo combined organ resection or robot-assisted colectomy". 
 
Change "metastatic or multiple carcinoma" to "Have a history of malignant colorectal 
tumor or have metastatic or multiple carcinoma".  
 
Add "Patients who are receiving preoperative neoadjuvant therapy." 
 
Add "ASA grade ≥ IV and/or ECOG performance status score > 2". 
 
Add "Patients with other clinical and laboratory conditions that are considered by 
researchers as inappropriate for participating in this trial." 
 
Delete " end-to-end anastomosis." 
Exit criteria 
Delete "Serious adverse events occurred preoperatively (according to the Common 
Terminology Criteria for Adverse Events, CTCAE version 5.0). " 
 
Add "Patients with other non-tumor diseases that prevent them from continuing to 
receive this treatment regimen." 
 
Add "Patients who request to withdraw from this study cohort for various reasons 
after being enrolled in the study, or who cannot complete the study plan and follow-up 
for various reasons." 
Experimental Group 
Procedure 
Add a statement: "Note that only these three anastomotic methods are allowed in 
intracorporeal anastomosis. If the anastomosis was completed by inserting the circular 
stapler through the anus after patients were assigned to the IA group, it is considered a 
conversion to EA. This is because the surgeons had to make an incision and insert the 
circular stapler anvil into the proximal colon with the abdomen open. In these cases, 
the anastomosis was not completed under laparoscopy." 
Control Group 
Procedures 
Add a statement: "The method of anastomosis is at the surgeon's discretion. A side-to-
side anastomosis (including antiperistaltic, isoperistaltic, or overlapping anastomosis) 
is recommended. Side-to-end or end-to-end anastomosis (sewn by hand or by inserting 
a circular stapler through the anus or proximal colon) is also allowed". 
 
Add figures and figure legends to explain the details of side-to-end anastomosis and 
end-to-end anastomsis 
Analytical population 
Add as-treated analysis set 
Primary endpoint 
analysis 
Add univariable analysis and multivariable analysis of SSI in as-treated population. 
 
Amendments in Version 2.1 
Method for 
determining sample 
size 
Re-estimate the sample size 

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Statistical analysis plan (SAP) 
SAP version 1.0 (2023.12.05) 
TABLE OF CONTENTS 
1 Introduction ............................................................................................................... 3 
2 Study design and objectives ..................................................................................... 3 
3 Sample size ................................................................................................................. 3 
4 Statistical methods .................................................................................................... 4 
4.1 General calculation rules .................................................................................... 4 
4.2 Analysis populations ............................................................................................ 5 
4.2.1 Modified intention-to-treat (mITT) population ............................................. 5 
4.2.2 Per-protocol (PP) population ......................................................................... 5 
4.2.3 As-treated (AT) population ............................................................................ 5 
4.3 Analysis of endpoints ........................................................................................... 5 
4.4 Baseline Characteristics ...................................................................................... 6 
4.5 Primary endpoint ................................................................................................. 7 
4.6 Secondary endpoints ........................................................................................... 8 
4.7 Subgroup analysis ............................................................................................... 9 
5 Missing data ............................................................................................................. 10 
6 Interim analyses ...................................................................................................... 10 
7 Timing of analysis ................................................................................................... 10 
Reference .................................................................................................................... 10 
 

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LIST OF ABBREVIATIONS 
SSI 
Surgical site infection 
IA 
Intracorporeal anastomosis 
EA 
Extracorporeal anastomosis 
SAP 
Statistical analysis plan 
mITT 
Modified intention-to-treat 
PP 
Per-protocol 
AT 
As-treated 
CI 
Confidence intervals 
ORs 
Odds ratios 
HR 
Hazard ratio 
DFS 
Disease-free survival 
OS 
Overall survival 
VAS 
Visual analog score 
 
 
 

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1 Introduction 
The STARS trial is a multicenter, randomized, single-blind, non-inferiority study 
designed to compare the incidence of surgical site infection (SSI) following 
intracorporeal anastomosis (IA) versus extracorporeal anastomosis (EA) in patients 
undergoing surgery for left colon cancer. The primary objective of this trial is to 
determine whether IA is non-inferior to EA in terms of SSI rates within 30 
postoperative days. While the aims, hypotheses, and design of the STARS trial have 
been detailed elsewhere, this statistical analysis plan (SAP) will focus on the 
forthcoming analysis and presentation of the trial data. This SAP is conducted based 
on the study protocol version 2.1. The comprehensive study design, including the 
primary and secondary endpoints, along with the methods for determining sample size 
and the approach to data management, are integral to the SAP and are critical for 
understanding the trial's methodology and interpretation of results. 
2 Study design and objectives 
This is a prospective, multicenter, non-inferiority, two-arm, single-blind, randomized 
controlled study. The study aims to investigate the effects of intracorporeal 
anastomosis and extracorporeal anastomosis in laparoscopic-assisted radical left 
hemicolectomy on surgical site infection. It also examines the difference in 
postoperative recovery, safety, oncology outcomes and survival. The trial was 
prospectively registered in clinicaltrial.gov (NCT04201717) and the study protocol 
(version 1.0) has been previously published,(1) and minor revisions has been made in 
study protocol version 2.0 and version 2.1. Details of exclusion criteria and study 
treatments can be found in study protocol version 2.1. 
3 Sample size 
The sample size is determined based on the rate of SSI. Based on our multicenter 
retrospective data,(2) we estimated the incidence of overall SSI following EA in 
laparoscopic left hemicolectomy stands at 13.3%, while the incidence of SSI after IA 
is 8.0%. When there is an absolute risk difference in the SSI rate of more than 5% 

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within 30 days after surgery, IA is regarded as inferior to EA. Consequently, the 
sample size for this study is calculated based on non-inferiority, taking into account an 
absolute risk difference of 5%, a one-sided level of significance of 0.025, a ratio of 
1:1, a power of 0.80, and a 20% drop-out rate. In total, 350 patients are required for 
this study, with 175 patients in the IA group and an equal number of 175 patients in 
the EA group. 
4 Statistical methods 
4.1 General calculation rules 
All statistical tests were 2-sided, and statistical significance was set at P <0.05. All 
statistical analyses were performed using R or SPSS. P-values will be quoted to three 
decimal places. Confidence intervals (CI) will be two-sided and 95%. CI will also be 
quoted to one decimal place.  
Categorical variables will be reported as frequencies and percentages. Percentages 
will be quoted to one decimal place. Chi-square tests in contingency tables will be 
replaced by Fisher’s exact tests if any expected cell frequency is less than five. 
Absolute risk differences and the corresponding 95% CI will be calculated.  
Continuous data with normal distribution were presented as mean (standard deviation) 
and analyzed by Student’s t-test. Continuous variables with non-normal distribution 
were reported as medians (quartile) and compared using the Mann–Whitney U test. 
Hodges-Lehmann method will be used to calculate the difference in median and the 
corresponding 95% CI. Data will be quoted to one decimal place. 
Survival data between two groups will be compared using a two-sided log-rank test 
stratified by pathological TNM (0–I, II, III) and age (≤65 years and >65 years). The 
hazard ratio (HR) for disease recurrence or death will be estimated using the stratified 
Cox proportional hazards model, including strata of pathological TNM (0–I, II, III) 
and age (≤65 years and >65 years). The 95% confidence interval for the HR will be 
constructed. Results from an unstratified analysis will also be provided. The Kaplan-

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Meier methodology will be applied to estimate the median disease-free survival 
(DFS) and overall survival (OS) for each treatment arm. Kaplan-Meier curves will be 
developed. 
4.2 Analysis populations 
4.2.1 Modified intention-to-treat (mITT) population 
In the mITT analysis, patients will be analyzed based on their randomization 
allocations. If patients randomly assigned to the IA group receive EA during surgery, 
they will be analyzed within the IA group in the mITT analysis. If patients randomly 
assigned to group EA receive IA during surgery, they will be analyzed according to 
group EA. Patients who meet the exit criteria after randomization won't be included in 
the mITT population.  
4.2.2 Per-protocol (PP) population 
In PP analysis, only cases treated strictly in accordance with random groups and 
assigned treatment plans will be included. Patients who haven't been treated with a 
randomly assigned protocol will be excluded from the per-protocol analysis. 
4.2.3 As-treated (AT) population 
In the AT analysis, we'll analyze patients according to the actual treatment they 
received instead of the allocated plan for random groups. 
4.3 Analysis of endpoints 
The analyses of primary endpoint and secondary endpoints will be conducted in mITT 
population, PP population and AT population.  
Analyses for the primary outcome variable will be unadjusted. In analyzing the 
primary outcomes, the rate of overall SSI will be reported as frequencies and 
percentages. We will calculate the absolute risk differences and the corresponding 
95% confidence interval (CI) between two groups. If the absolute risk differences and 
the corresponding 95% CI are within the non-inferiority margin (<5%), non-
inferiority is established. If not, IA is not non-inferior to EA. 

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The independent risk factor of the primary endpoint will be analyzed in the AT 
population. High-risk variables identified through univariable analysis and clinical 
experience will be included in the multivariable analysis. Multivariable logistic 
regression will be employed to identify independent risk factors for SSI. The effect 
size will be estimated using odds ratios (ORs) with 95% confidence intervals. 
4.4 Baseline Characteristics 
The following baseline characteristics will be presented in mITT, PP and AT 
polulation: 
l 
Sex, categorical variable; 
l 
Age, continuous variable, measured in years; 
l 
Body Mass Index, continuous variable, measured in kg/m2; 
l 
American Society of Anesthesiologists grading, categorical variable 
l 
Eastern Cooperative Oncology Group performance status score, categorical 
variable; 
l 
Tumor site, categorical variable, classified as distal transverse colon (distal 1/2 of 
transverse colon), splenic flexure of colon (junction of transverse colon and 
descending colon), descending colon (descending colon and the junction of 
sigmoid colon and descending colon), and proximal sigmoid colon (proximal 1/3 
of sigmoid colon); 
l 
NRS2002 score, continuous variable, measured in points 
l 
Parenteral prophylactic antibiotics, categorical variable; 
l 
Mechanical bowel preparation, categorical variable; 
l 
Oral antibiotic bowel preparation, categorical variable;  
l 
Postoperative antibiotic use time, categorical variable, divide by ≥3 days and <3 
days; 
l 
Clinical T stage, categorical variable; 
l 
Clinical N stage, categorical variable; 
l 
Clinical TNM stage, categorical variable; 

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4.5 Primary endpoint 
The primary endpoint in this trial is surgical site infection (SSI) within 30 
postoperative days. Cases that fail to complete the 30-day follow-up are treated as 
missing data. The SSI will be compared between groups in the mITT population, PP 
population, and AT population. 
l 
Overall SSI, Categorical variable. The absolute risk differences and the 
corresponding 95% CI between two groups will be calculated. The 95% CI will 
be compared with the non-inferiority margin (5%). 
The subtypes of SSI (Superficial or deep incisional SSI, and Organ/space SSI) will 
also be compared between the two groups. However, their 95% confidence interval 
will not be compared with the non-inferiority margin. 
The independent risk factors for overall surgical site infection (SSI) will be analyzed 
in the AT population. In univariable analysis, continuous variables will be converted 
to categorical variables. Chi-square tests or Fisher’s exact tests will be employed. The 
key variables are as follows. 
l 
Sex (male, female); 
l 
Age (≤65 years,>65 years); 
l 
Body Mass Index (≤24kg/m2, >24kg/m2); 
l 
American Society of Anesthesiologists grading (I, II, III); 
l 
Eastern Cooperative Oncology Group performance status score (0, 1, 2); 
l 
Tumor site (distal transverse colon, splenic flexure of colon, descending colon, 
and proximal sigmoid colon); 
l 
NRS2002 score (≤2 points, > 2 points);  
l 
Parenteral prophylactic antibiotics (Yes, No); 
l 
Mechanical bowel preparation (No, only enema, only oral laxative, enema plus 
oral laxative); 
l 
Oral antibiotic bowel preparation (Yes, No);  
l 
Postoperative antibiotic use time(≥3 days, <3 days); 

5 Dec 2023                                                                     SAP version 1.0 
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l 
Pathological TNM stage (0, I, II, III); 
l 
Overflow of intestinal contents during anastomosis (Yes, No); 
l 
Operating time (≤180mins, >180mins); 
l 
Blood loss during operation(≤100ml, >100ml); 
l 
Blood transfusion during operation (Yes, No); 
l 
Prophylactic enterostomy (Yes, No); 
l 
Anastomosis methods (Side-to-side anastomosis, End-to-side anastomosis, End-
to-end anastomosis) 
l 
Intervention (intracorporeal anastomosis, extracorporeal anastomosis) 
Factors clinically relevant to SSI after univariable analysis will be included in 
multivariable analysis. Logistic regression will be used in multivariable analysis to 
identify independent risk factors for SSI. The effect size will be estimated using odds 
ratios (ORs) with 95% confidence intervals.  
4.6 Secondary endpoints 
The secondary endpoints will be compared between groups in the mITT population, 
PP population, and AT population. 
l 
Operating time, continuous variable, measured in minutes; 
l 
Total blood loss during operation, continuous variable, measured in milliliters; 
l 
Conversion to open surgery, categorical variable; 
l 
Postoperative complications, categorical variable. It will be analyzed according 
to the overall occurrence. The occurrence of its subtype (anastomotic leakage, 
bowel obstruction, etc.) will also be analyzed. Additionally, Clavien–Dindo 
classification will be analyzed (≤grade II, ≥grade III). (3) 
l 
Completeness of specimens, categorical variable. It is evaluated according to the 
West classification (mesocolic plane, intramesocolic plane, and muscularis 
propria plane).(4)  
l 
Number of lymph nodes dissected, continuous variable.  
l 
The pathological TNM stage (as per the American Joint Committee on Cancer 

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Cancer Staging Manual, 8th edition), categorical variable. The T stage, N stage, 
and TNM stage will be analyzed separately.  
l 
Postoperative recovery, continuous variable. It includes the time to first flatus, the 
time to first defecation, the time to start food intake, and the postoperative 
hospital stay. Additionally, the time to first ambulation and the time to remove the 
abdominal drainage tube, which are not included in the study protocol's design, 
will also be analyzed. These are measured in days. 
l 
Length of incision, continuous variable. It is measured in millimeters. 
l 
Visual analog score (VAS) of pain, it will be analyzed as categorical variable: no 
to mild pain (0–3 points); moderate pain (4–6 points) ,and severe pain (7–10 
points).  
l 
3-year DFS: DFS is defined as the time from randomization until the occurrence 
of local recurrence, distant metastasis, or death from the tumor, whichever comes 
first. It is measured in months. For patients who are lost to follow-up, DFS will 
be censored at the time of the last available tumor assessment before the missing 
assessments. 
l 
5-year OS: OS was defined as the time from randomization to death due to any 
cause. It is measured in months. For patients lost to follow-up, OS will be 
censored at the time of the last available follow-up prior to the missing 
assessments. 
4.7 Subgroup analysis 
The subgroup analysis will be carried out only if the primary endpoint in the mITT 
population do not reach the non-inferiority margin. If the 95% CI of SSI is not within 
the non-inferiority margin, the primary endpoint will be summarized within the 
following subgroups.  
l 
Sex (male, female); 
l 
Age (≤65 years,>65 years); 
l 
Body Mass Index (≤24kg/m2, >24kg/m2); 
l 
Tumor site (distal transverse colon or splenic flexure of colon, descending colon, 

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proximal sigmoid colon); 
l 
NRS2002 score (≤2 points, > 2 points);  
l 
Mechanical bowel preparation (Yes, No); 
l 
Oral antibiotic bowel preparation (Yes, No);  
l 
Postoperative antibiotic use time(≥3 days, <3 days); 
l 
Operating time (≤180mins, >180mins); 
Subgroup analyses will be performed using mITT population. If intracorporeal 
anastomosis is proven to be noninferior to extracorporeal anastomosis regarding SSI, 
subgroup analysis will not be performed.  
5 Missing data 
Missing primary endpoint data will be treated as censored data and won't be imputed 
during analysis. Other missing data won't be imputed either. The missing data will be 
stated in the tables.  
6 Interim analyses 
No interim analyses are planned in this study. 
7 Timing of analysis 
We will conduct an analysis of the study's primary endpoint and publish the relevant 
findings after enrollment is completed and all patients have completed the first month 
of follow-up after surgery. When all patients complete 5 years of follow-up, the 
results involving survival data will be analyzed again, and the relevant research 
results will be published. 
Reference 
1. 
He L, Li M, Zhang J xin, Tong W hua, Chen Y, Wang Q. Surgical site infection after 
intracorporeal anastomosis for left-sided colon cancer: study protocol for a non-

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inferiority multicenter randomized controlled trial (STARS). Trials. 2022 Nov 
22;23(1):954.  
2. 
Guo Y, Li K, He L, Tong W, Chen Y, Wu B, et al. Surgical site infection after 
intracorporeal and extracorporeal anastomosis in laparoscopic left colectomy for 
colon cancer: a multicenter propensity score-matched cohort study. Surg 
Endosc. 2023 May 11;  
3. 
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a 
new proposal with evaluation in a cohort of 6336 patients and results of a survey. 
Ann Surg. 2004 Aug;240(2):205–13.  
4. 
West NP, Morris EJ, Rotimi O, Cairns A, Finan PJ, Quirke P. Pathology grading of 
colon cancer surgical resection and its association with survival: a retrospective 
observational study. Lancet Oncol. 2008 Sep;9(9):857–65.