Comparison of Submucosal and Subserosal Approaches Toward Optimized Indocyanine Green Tracer-Guided Laparoscopic Lymphadenectomy for Patients With Gastric Cancer: The FUGES-019 Randomized Clinical Trial
Phase: PHASE3
Conditions: Indocyanine Green, Gastric Cancer, Injection Site
Sponsor: Fujian Medical University

   Study protocol                                     
Submucosal versus Subserosal Approaches of Indocyanine Green Tracer-Guided 
Lymphadenectomy for Gastric Cancer: A Randomized Clinical Trial 
Study Protocol 
 
Bidding party: Fujian Medical University Union Hospital 
 
Principle Investigator: 
Prof. Chang-Ming Huang, M.D.  
Department of Gastric Surgery, Fujian Medical University Union Hospital,  
Address: No. 29 Xinquan Road, Fuzhou 350001 Fujian Province, China.  
Telephone: +86-591-83363366, Fax: +86-591-83363366 
 
No. of edition: V2.1 
 
The date of the edition: 2023.09.30 
 
 

   Study protocol                                     
I 
Summary 
Scenario 
Title 
Comparison of Submucosal and Subserosal Approaches Toward 
Optimized 
Indocyanine 
Green 
Tracer-Guided 
Laparoscopic 
Lymphadenectomy for Patients with Gastric Cancer: The FUGES-019 
Randomized Clinical Trial 
Scenario 
Version 
V2.1 
Sponsor 
Chang-Ming Huang 
Research 
Center 
Fujian Medical University Union Hospital 
Indications 
Patients with potentially resectable gastric adenocarcinoma (cT1-4a, 
N0/+, M0) 
Purpose of 
research 
To compare the efficacy and cost-effectiveness of the submucosal 
approach (SMA) and subserosal approach (SSA) of ICG injection for 
lymph node (LN) tracing during radical gastrectomy in patients with 
gastric cancer. 
Research 
design 
Investigator-initiated, single-center, parallel, noninferiority, open-label, 
randomized controlled 
Case 
grouping 
Group A (Study Group): Laparoscopic gastrectomy with submucosal 
injection of indocyanine green tracer group (SMA group)  
Group B (Control Group): Laparoscopic gastrectomy with subserosal 
injection of indocyanine green tracer group (SSA group)  
The basis 
for 
determining 
the sample 
size 
This study is a noninferiority test (bilateral), whose primary outcome 
measure is the total number of retrieving LNs. According to the previous 
study results, the total number of LNs retrieved in the control group was 
about 50.5 with a standard deviation was 15.9. A sample size of 111 
patients per group was calculated as necessary for 80% power to detect a 
noninferiority margin of 6 with a 1-sided α of 0.025. Assuming an 
expected dropout rate of 20%, each group needed to include at least 133 
patients, for a total of 266 cases. 
Inclusion 
criteria 
⚫ Age from 18 to 75 years (not including 18 and 75 years old) 
⚫ Primary gastric adenocarcinoma (papillary, tubular, mucinous, signet 
ring cell, or poorly differentiated) confirmed pathologically by 
endoscopic biopsy 
⚫ A tumor stage of T1-4a (cT1-4a), N0/+, M0 at preoperative 
evaluation according to the American Joint Committee on Cancer 
(AJCC) Cancer Staging Manual Eighth Edition 
⚫ No distant metastasis, no direct invasion of pancreas, spleen, or other 

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II 
 
organs nearby in the preoperative examinations 
⚫ Performance status of 0 or 1 on Eastern Cooperative Oncology Group 
scale (ECOG) 
⚫ American Society of Anesthesiology score (ASA) class I, II, or III 
⚫ Written informed consent 
Exclusion 
criteria 
⚫ Women during pregnancy or breast-feeding  
⚫ Severe mental disorder  
⚫ History of previous upper abdominal surgery (except laparoscopic 
cholecystectomy)  
⚫ History of previous gastrectomy, endoscopic mucosal resection, or 
endoscopic submucosal dissection 
⚫ Rejection of laparoscopic resection  
⚫ History of allergy to iodine agents  
⚫ Enlarged or bulky regional LN diameter over 3cm by preoperative 
imaging  
⚫ History of other malignant diseases within the past five years  
⚫ History of previous neoadjuvant chemotherapy or radiotherapy  
⚫ History of unstable angina or myocardial infarction within the past 
six months  
⚫ History of a cerebrovascular accident within the past six months 
⚫ History of continuous systematic administration of corticosteroids 
within one month  
⚫ Requirement of simultaneous surgery for other diseases  
⚫ Emergency surgery due to complication (bleeding, obstruction, or 
perforation) caused by gastric cancer  
⚫ Forced expiratory volume in 1 second (FEV1)＜50% of predicted 
values  
⚫ Linitis plastica, Widespread 
Rejection 
criteria 
⚫ M1 tumor confirmed intraoperatively or postoperatively: distant 
metastasis only found by intraoperative exploration or postoperative 
pathological biopsy or a positive postoperative peritoneal lavage 
cytology examination;  
⚫ Patients intraoperatively/postoperatively confirmed as T4b, or tumor 
invading the duodenum; 
⚫ Patients intraoperatively confirmed as unable to complete D2 LN 
dissection/R0 resection due to tumor: unable to complete R0 
resection due to regional LN integration into a mass or surrounded 
with important blood vessels, which cannot be resected;  

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⚫ Patients requiring simultaneous surgical treatment of other diseases;   
⚫ Patients with sudden severe comorbidities (cannot tolerate surgery or 
anesthesia) or in whom the procedure was unable to be implemented 
as planned after being selected;    
⚫ Patients confirmed to require emergency surgery by attending 
physicians due to changes in the patient’s condition after inclusion in 
this study;  
⚫ Patients who voluntarily quit or discontinued treatment for personal 
reasons at any stage after inclusion in this study;  
⚫ LNs that were indistinguishable from ICG-stained soft tissue under 
NIR imaging due to ICG contamination; 
⚫ Treatment implemented that was proven to violate study protocol. 
Intervention 
⚫ For patients who were assigned to the SSA group, after preoperative 
exploration, the indocyanine green powder (Dandong Yichuang 
Pharmaceutical Co) is dissolved in 0.5 mg/ml of sterile water and the 
prepared solution (1.5 ml for each point) is injected along the 
subserosal of the stomach at 6 specific points along the lesser and 
greater curvature of the stomach. 
⚫ For patients who were assigned to the SMA group, submucosal 
injection of indocyanine green One day before surgery, 1.25 mg/ml 
indocyanine green (Dandong Yichuang Pharmaceutical Co) was 
prepared in sterile water and 0.5 ml of the solution was injected into 
the submucosal layer at 4 quadrants around the primary tumor, 
amounting to 2.5 mg of indocyanine green. 
Outcome 
Measures 
Primary Outcome Measures:  
⚫ Total number of retrieved LNs  
Secondary Outcome Measures:  
⚫ Total number of fluorescent LNs in groups A and B 
⚫ True positive rate 
⚫ False positive rate 
⚫ True negative rate 
⚫ False negative rate 
⚫ Number of metastasis LNs 
⚫ Metastasis rate of LN 
⚫ Morbidity and mortality rates 
⚫ 3-year overall survival rate 
⚫ 3-year disease free survival rate 
⚫ 3-year recurrence pattern 

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⚫ Time to first ambulation  
⚫ Time to first flatus 
⚫ Time to first liquid diet, 
⚫ Time to first soft diet 
⚫ Duration of postoperative hospital stay 
⚫ The variation of BMI 
⚫ The variation of weight 
⚫ Intraoperative morbidity rates 
⚫ The variation of album 
⚫ The variation of white blood cell count 
⚫ The variation of hemoglobin 
⚫ The variation of C-reactive protein 
⚫ LN noncompliance rate 
⚫ Modified EORTC cancer in-patient satisfaction with care measure 
(EORTC IN-PATSAT14) 
⚫ The Surgery Task Load Index (SURG-TLX) 
Statistical  
consideratio
ns  
All data analyses will be performed using the SPSS statistical software 
(version 22.0; SPSS Inc.) and R software (version 3.6.1; R Foundation for 
Statistical Computing).  
The noninferiority analysis for the primary endpoint of the total number 
of retrieving LNs will be conducted, while the test method of difference 
for secondary endpoints. All the statistical tests were tested by two sides. 
A p-value <0.05 is considered statistically significant. The confidence 
interval of the parameters is estimated with a 95% confidence interval. 
Baseline data and validity analyses will be conducted on a modified 
intent-to-treat (MITT) and per-protocol (PP) basis. SAP analysis is used 
for safety assessment, and this study does not fill in missing values. 
Normally distributed continuous variables will be presented as mean and 
standard deviation and compared using the t-test if normally distributed, 
or as median and interquartile range and compared using the Wilcoxon 
rank-sum test if non-normally distributed; while categorical data will be 
presented as number and percentages and compared using the Pearson χ2 
test or the Fisher exact test, as appropriate. Survival data will be analyzed 
using the Kaplan-Meier method and Cox's proportional hazards model. 
Sensitivity analysis is used for extreme outlier data. The subgroup 
analysis is conducted according to the specific situation. Interim analysis 
will not be conducted in this study. 
 

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1. Research background 
Since Kitano1 in Japan first reported laparoscopic distal gastrectomy for GC in 1994, 
after more than 20 years of development, laparoscopic radical gastrectomy has been 
widely used in clinical practice.2-4 Nowadays, lymphadenectomy is often performed 
under the naked eye according to the surgeon's experience. However, due to the 
complex vascular anatomy and lymphatic drainage around the stomach, it remains a 
huge challenge for surgeons, especially young surgeons, to dissect enough lymph nodes 
(LNs) efficiently and accurately without increasing operate-related complications. 
Therefore, with the advent of the era of precision minimally invasive surgery, 
laparoscopic surgeons are still exploring how to perform convenient and accurate 
real-time LN navigation under laparoscope, to perform systematic, accurate, and 
sufficient LN dissection. As a new surgical navigation technique, indocyanine green 
(ICG) near-infrared (NIR) fluorescent imaging has achieved relatively positive results 
in the localization of sentinel LN in breast cancer, non-small-cell lung cancer, and other 
cancers.5-8 With the successful application of ICG fluorescence imaging technology in 
laparoscopic devices, scholars have found that NIR imaging has better tissue 
penetration and can better identify LNs in hypertrophic adipose tissue than other dyes 
in visible light.9,10 It has important research value, good application prospect, and broad 
development space, which has attracted wide attention, so that ICG fluorescence 
imaging-guided minimally invasive treatment such as laparoscopic or robotic radical 
resection of GC has become a new exploration direction.11 Our randomized controlled 
trial 
(RCT) 
confirmed 
that 
ICG 
fluorescent 
lymphography‑guided 
lymphadenectomy can help surgeons harvest more LNs than conventional LN 
dissection and reduce LN noncompliance in patients with gastric cancer who undergo 
D2 lymphadenectomy, and indocyanine green fluorescence imaging can be used for 
routine lymphatic mapping during laparoscopic gastrectomy, especially total 
gastrectomy.  
However, at present, the application of ICG in laparoscopic lymphadenectomy for 
patients with gastric cancer is in the preliminary stages. In particular, there is no unified 
standard for ICG injection. At present, there are great differences in the preoperative 
submucosal or intraoperative subserosal injection methods in each center. Different 
methods of ICG injection used in different studies are also important reasons for the 
inconsistent results of ICG related clinical studies. Some scholars12-14 believe that 
compared with intraoperative subserosal injection of ICG, preoperative submucosal 

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injection of ICG under endoscopic guidance one day before surgery was easier to 
control and saved time, and it was less likely to cause intraoperative leakage of ICG 
into the surgical field or to interfere with the operation by straying into blood vessels. 
Some studies15,16 have shown that the injection under the serosa is easier for surgeons 
to control and the injection time can be easily unified.  
Therefore, there is still a lack of high-level evidence-based large sample RCT to 
compare the safety, efficacy, and feasibility of preoperative submucosal or 
intraoperative subserosal injection of ICG on LN tracing and its economic and social 
benefits in laparoscopic radical gastrectomy worldwide. So, Fujian Medical University 
Union Hospital Gastric Surgery Study Group (FUGES) first conduct this RCT to assess 
LN harvest and perioperative safety during laparoscopic ICG-guide radical gastrectomy 
for GC patients by comparing the preoperative submucosal approach (SMA) and the 
intraoperative subserosal approach (SSA) of ICG injection at a tertiary referral teaching 
hospital.  
2. Objective 
The purpose of this study was to compare the effect of submucosal or subserosal 
injection of ICG on LN tracing and its economic and social benefits in laparoscopic 
radical gastrectomy. 
3.  Research design 
Investigator-initiated, single-center, prospective, noninferiority, open-label, phase 3, 
parallel assignment, randomized controlled. 
3.1 Single center 
Department of Gastric Surgery, Fujian Medical University Union Hospital 
3.2 Case group 
Group A (Study Group): Laparoscopic gastrectomy with subserosal injection of 
indocyanine green tracer group (SMA group)  
Group B (Control Group): Laparoscopic gastrectomy with submucosal injection of 
indocyanine green tracer group (SSA group) 
3.3 Estimate Sample Size 
This study is a noninferiority test (bilateral), whose primary outcome measure is 
the total number of retrieving LNs. According to the previous study results, the total 
number of LNs retrieved in the control group was about 50.5 with a standard deviation 
was 15.9. A sample size of 111 patients per group was calculated as necessary for 80% 
power to detect a noninferiority margin of 6 with a 1-sided α of 0.025. Assuming an 
expected dropout rate of 20%, each group needed to include at least 133 patients, for a 
total of 266 cases. 

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3.4 Blind method: This research adopts an open design. Although it is not feasible to 
blind the surgeons and participants, the pathologists are unaware of the intervention 
received by the patients. The researcher performing statistical analyses after recruitment 
is blinded to patient group allocation. 
3.5 Research cycle 
Estimated enrollment cycle: complete enrollment within 4 years 
Follow-up period: begin at the enrollment of the first case and end 1 month after 
the enrollment of the last case. 
Estimated time: 2019.12-2020.12 (to complete enrollment) - 2023.12 (to complete 
follow-up) 
4. Study objects 
All patients who meet the inclusion criteria and do not conform to the exclusion 
criteria are qualified for this study. 
4.1 Inclusion criteria  
(1) Age from 18 to 75 years   
(2) Primary gastric adenocarcinoma (papillary, tubular, mucinous, signet ring cell, or 
poorly differentiated) confirmed pathologically by endoscopic biopsy  
(3) A tumor stage of T1-4a (cT1-4a), N0/+, M0 at preoperative evaluation according to 
the American Joint Committee on Cancer (AJCC) Cancer Staging Manual Eighth 
Edition. Preoperative staging was made by conducting mandatory computed 
tomography (CT) scans and an optional endoscopic ultrasound  
(4) No distant metastasis, no direct invasion of pancreas, spleen, or other organs nearby 
in the preoperative examinations  
(5) Performance status of 0 or 1 on Eastern Cooperative Oncology Group scale (ECOG)  
(6) American Society of Anesthesiology score (ASA) class I, II, or III  
(7) Written informed consent  
4.2 Exclusion criteria 
(1) Women during pregnancy or breast-feeding  
(2) Severe mental disorder  
(3) History of previous upper abdominal surgery (except laparoscopic cholecystectomy)  
(4) History of previous gastrectomy, endoscopic mucosal resection, or endoscopic 
submucosal dissection 
(5) Rejection of laparoscopic resection  
(6) History of allergy to iodine agents  
(7) Enlarged or bulky regional LN diameter over 3cm by preoperative imaging  
(8) History of other malignant diseases within the past five years  
(9) History of previous neoadjuvant chemotherapy or radiotherapy  
(10) History of unstable angina or myocardial infarction within the past six months  
(11) History of a cerebrovascular accident within the past six months 

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(12) History of continuous systematic administration of corticosteroids within one 
month  
(13) Requirement of simultaneous surgery for other diseases  
(14) Emergency surgery due to complication (bleeding, obstruction, or perforation) 
caused by gastric cancer  
(15) Forced expiratory volume in 1 second (FEV1)＜50% of predicted values  
(16) Linitis plastica, Widespread 
4.3 Rejection criteria 
⚫ M1 tumor confirmed intraoperatively or postoperatively: distant metastasis only 
found by intraoperative exploration or postoperative pathological biopsy or a 
positive postoperative peritoneal lavage cytology examination;  
⚫ Patients intraoperatively/postoperatively confirmed as T4b, or tumor invading the 
duodenum; 
⚫ Patients intraoperatively confirmed as unable to complete D2 LN dissection/R0 
resection due to tumor: unable to complete R0 resection due to regional LN 
integration into a mass or surrounded with important blood vessels, which cannot 
be resected;  
⚫ Patients requiring simultaneous surgical treatment of other diseases;    
⚫ Patients with sudden severe comorbidities (cannot tolerate surgery or anesthesia) or 
in whom the procedure was unable to be implemented as planned after being 
selected;    
⚫ Patients confirmed to require emergency surgery by attending physicians due to 
changes in the patient’s condition after inclusion in this study;  
⚫ Patients who voluntarily quit or discontinued treatment for personal reasons at any 
stage after inclusion in this study;  
⚫ LNs that were indistinguishable from ICG-stained soft tissue under NIR imaging 
due to ICG contamination; 
⚫ Treatment implemented that was proven to violate study protocol. 
4.4 Case screening 
(1)  When Patients admitted to hospital should meet the following criteria: Age 
between 18 and 75 years old；Performance status of 0 or 1 on the ECOG scale；
None-pregnant or no lactating women；Not suffering from a severe mental disorder；
No history of previous upper abdominal surgery (except for laparoscopic 
cholecystectomy)；No history of previous gastric surgery (including ESD/EMR for 
gastric cancer)；No History of other malignant diseases within the past five years；
No history of unstable angina or myocardial infarction within the past six months; 

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No history of continuous systematic administration of corticosteroids within one 
month；No requirement of simultaneous surgery for another disease；FEV1≥50% of 
the predicted values；No history of a cerebrovascular accident within the past six 
months. 
(2) Endoscopic examination of the primary lesion in the patient (recommended 
endoscopic ultrasound endoscopy, EUS) and histopathological biopsy showed 
gastric adenocarcinoma (papillary adenocarcinoma [pap], tubular adenocarcinoma 
[tub], mucinous adenocarcinoma [muc], signet ring cell carcinoma [sig], and 
poorly differentiated adenocarcinoma [por]). Total abdominal CT was performed 
on the patient, and no enlarged LNs (maximum diameter ≥ 3 cm) were found in 
the periplasmic area, including significant enlargement or merging of the No. 10 
LNs into a group or local invasion/distance metastasis. No obvious tumor 
infiltration was found in the spleen and spleen vessels. 
(3)  Patient is explicitly diagnosed with upper third gastric cancer, has a preoperative 
staging assessment of T1-4a, N0-3, M0 and is expected to undergo total 
gastrectomy and D2 LN dissection to obtain R0 surgical results (also indicated for 
multiple primary cancer). 
(4)  Patients do not require neoadjuvant chemoradiotherapy or chemotherapy and the 
attending doctor does not recommend that they receive neoadjuvant 
chemoradiotherapy or chemotherapy. ASA class I to III. 
(5)   No requirement for emergency surgery. 
(6)   Patient does not require emergency surgery. 
(7)  At this point the patient becomes a potential selected case and enters the 9.1 case 
selection procedure 
5.  Outcome Measures 
5.1 Primary Outcome Measures 
⚫ Total number of retrieved LNs  
5.2 Secondary Outcome Measures 
⚫ Total number of fluorescent LNs in groups A and B 
⚫ True positive rate 
⚫ False positive rate 
⚫ True negative rate 
⚫ False negative rate 
⚫ Number of metastasis LNs 
⚫ Metastasis rate of LN 
⚫ Morbidity rates 
⚫ Mortality rates 

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⚫ 3-year overall survival rate 
⚫ 3-year disease free survival rate 
⚫ 3-year recurrence pattern 
⚫ Time to first ambulation  
⚫ Time to first flatus  
⚫ Time to first liquid diet  
⚫ Time to first soft diet  
⚫ Duration of postoperative hospital stay 
⚫ The variation of BMI 
⚫ The variation of weight 
⚫ Intraoperative morbidity rates 
⚫ The variation of album 
⚫ The variation of white blood cell count 
⚫ The variation of hemoglobin 
⚫ The variation of C-reactive protein 
⚫ LN noncompliance rate 
⚫ Modified EORTC cancer in-patient satisfaction with care measure (EORTC 
IN-PATSAT14) 
⚫ The Surgery Task Load Index (SURG-TLX) 
6．Diagnostic criteria for this study 
(1) The AJCC-8th TNM tumor staging system will be used for this study. 
(2) Diagnostic criteria and classification of gastric cancer: According to the 
histopathological international diagnostic criteria, classification will be divided into 
papillary 
adenocarcinoma 
(pap), 
tubular 
adenocarcinoma 
(tub), 
mucinous 
adenocarcinoma (muc), signet ring cell carcinoma (sig), and poorly differentiated 
adenocarcinoma (por). 
7 Qualifications of the participated Surgeons  
7.1 Basic principle  
All candidate surgeons in our study met the following criteria: 
Performed at least 100 laparoscopic radical gastrectomy. 
Pass the blind surgical video examination. 
 
 
 
 
 
 

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7.2 Checklist for Determining the Success of D2 Lymphadenectomy 
Scoring Method for D2 Lymph Node Dissection  
Complete   Incomplete    None 
10           5          0 
1. Properly full omentectomy  
2. Ligation of the left gastroepiploic artery at origin  
3. Ligation of the right gastroepiploic artery at origin 
4. Full exposure of the common hepatic artery 
5. Ligation of the right gastric artery at origin 
6. Exposure of the portal vein 
7. Exposure of the splenic artery  
8. Identification of the splenic vein 
9. Ligation of the left gastric artery at origin 
10. Exposure of the gastroesophageal junction 
□          □          □ 
□          □          □ 
□          □          □ 
□          □          □ 
□          □          □ 
□          □          □ 
□          □          □ 
□          □          □ 
□          □          □ 
□          □          □ 
1. Properly full omentectomy  
a. Omentectomy was performed close to the transverse colon 
b. Omentectomy was performed from hepatic flexure to splenic flexure 
c. The anterior layer of the transverse colonic mesentery and anterior pancreatic peritoneum were dissected.  
2. Ligation of the left gastroepiploic artery at origin 
3. Ligation of the right gastroepiploic artery at origin 
4. Full exposure of common hepatic artery 
a. More than half of the anterior part of the common hepatic artery was exposed. 
5. Ligation of the right gastric artery at origin  
6. Exposure of the portal vein  
7. Exposure of the splenic artery 
a. The anterior part in the splenic artery was exposed 
b. The splenic artery was exposed from the celiac trunk to the posterior gastric artery (distal gastrectomy) 
c. The splenic artery was exposed from the celiac trunk to the terminal branch of the splenic artery (total gastrectomy) 
8. Identification of the splenic vein  
9. Ligation of the left gastric artery at origin 
10. Exposure of the gastroesophageal junction 
a. The anterior and right side of the abdominal esophagus were exposed (distal gastrectomy) 
b. The anterior, posterior, left, and right sides of the abdominal esophagus were exposed (total gastrectomy) 

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- D2 lymphadenectomy was accepted if all three randomly assigned investigators rated ≥85 points regarding checklists in the 
unedited video review. 
8. End point and definition of related result determination 
8.1 Definition of recurrence and recurrence date 
The following situations are regarded as "recurrence" and should be recorded as 
evidence of "recurrence" in the CRF. 
(1)  Recurrence identified by anyone image examination (X-ray, ultrasound, CT, MRI, 
PET-CT, endoscope, etc.) and, if there are a variety of imaging examinations, 
results without contradiction determined "recurrence". The earliest date that the 
recurrence is found is defined as the "recurrence date". 
(2)  For cases that lack the use of imaging or a pathological diagnosis, the date we 
diagnose the occurrence of clinical recurrence based on the clinical history and 
physical examination is defined as the “recurrence date”. 
(3)  For cases without imaging or clinical diagnosis but with a cytology or tissue 
biopsy pathological diagnosis of recurrence, the earliest date confirmed by 
cytology or biopsy pathology is considered the "recurrence date". 
(4)  A rise in CEA or other associated tumor markers alone could not be diagnosed as 
a relapse. 
8.2 Incidence of intraoperative complications 
8.2.1 Incidence of postoperative complications 
The number of all patients treated with surgery as the denominator and the number 
of patients with any intraoperative and postoperative complications as the numerator is 
used to calculate the proportions.  
8.2.2 Incidence of overall postoperative complications 
The postoperative complication criteria refer to short-term complications after 
surgery in the postoperative observation project (see 9.4.5). The time is defined as 
within 30th after surgery, or the first discharge time if the days of hospital stay more 
than 30 days. 
8.2.3 Incidence of postoperative major complications  
The standard for postoperative major complications refers to the short-term 
complications in the postoperative observation project (see 9.4.5) according to the 
Clavien–Dindo grade, IIIA level and above for serious complications, and when 
multiple complications occur simultaneously, the highest-ranked complication is the 
subject. 
8.3 Incidence of operative complications 
The number of all patients treated with surgery as the denominator and the number 
of patients with any intraoperative and postoperative complications as the numerator is 
used to calculate the proportions. The criteria for the intraoperative complications refer 

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to the descriptions of intraoperative complications in the observation project (in 9.3.3). 
8.4 Mortality 
The number of all the patients receiving surgery as the denominator and the 
number of patients in any of the following situations as the numerator is used to 
calculate proportions. This proportion indicated the operative mortality ratio. 
Situations: patients whose death was identified according to documented 
intraoperative observation items, including patients who die within 30 days after the 
surgery (including 30 days) regardless of the causality between the death and the 
surgery, and patients who die more than 30 days after the surgery (whose death is 
proved to have a direct causal relationship with the first operation). 
8.5 Disease-free survival 
Disease-free survival is calculated from the day of surgery to the day of recurrence 
or death (When the specific date of recurrence of the tumor is unknown, the endpoint is 
the date of death due to tumor causes). If neither death nor recurrence of the tumor is 
observed, the endpoint is the final date that a patient is confirmed as relapse-free. (The 
final date of DFS: The last date of the outpatient visit day or the date of acceptance of 
the examination). (Follow-up cycle and required examinations are shown in the 
follow-up process 9.5.3). 
8.6 Overall survival time 
The overall survival is calculated from the day of surgery until death or until the 
final follow-up date, whichever occurs first. For survival cases, the endpoint is the last 
date that survival was confirmed. If the loss to follow-up occurred, the endpoint is the 
final date that survival could be confirmed. 
8.7 Determination of surgical outcomes 
8.7.1 Operative time: from skin incision to the skin being sutured 
8.7.2 Postoperative recovery indexes 
8.7.2.1 Time to ambulation, flatus, recovery of liquid diet, and semi-liquid diet. 
 
During the day of surgery to the first discharge, the initial time to ambulation, 
flatus, liquid diet, and semi-liquid diet during the postoperative hospitalization is 
recorded by the day. 
 
Flatus on the operation day should be excluded. 
 
If flatus or resumption of liquid and semi-liquid diet does not occur before hospital 
discharge, the discharge time should be recorded as the corresponding time. 
 
The initial time to ambulation, flatus, liquid diet and semi-liquid diet should be 
recorded according to patients’ reports. 
8.7.2.2 The maximum temperature 
The highest value of body temperature measured at least 3 times a day from the 
first day to the eighth day after the operation is documented. 

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8.7.3 Percentage of conversion to laparotomy 
Among all the patients who underwent surgery, the number of patients planning to 
receive a laparoscopic surgery per-protocol is used as the denominator, while the 
number of the patients who receive a conversion to open surgery is considered the 
numerator. The proportion calculated is regarded as the rate of transfer laparotomies. In 
this study, if the length of the auxiliary incision is more than 10 cm, it is considered a 
conversion to open surgery. 
8.8 Fluorescent station and fluorescent LN 
After fluorescent lymphography-guided lymphadenectomy, each LN station was 
first separated ex vivo from the resected specimen in accordance with the definitions of 
the Japanese classification of gastric carcinoma.17 Thereafter, LN stations and LNs were 
examined for fluorescence directly through near-infrared imaging. LNs were classified 
as “fluorescent” if they were stained with ICG and “nonfluorescent” if they were not 
stained with ICG. Stations containing fluorescent LNs were classified as “fluorescent” 
stations, while those without fluorescent LNs were classified as “non-fluorescent” 
stations.  
 
8.9 Diagnostic test 
The presence and absence of fluorescent staining were subsequently matched with 
the results of histopathological analysis. True-positive (TP) stations were defined as 
fluorescent stations observed through near-infrared imaging, which contained 
metastatic LNs on histopathological analysis. False-negative (FN) stations were defined 
as non-fluorescent stations observed through near-infrared imaging, which contained 
metastatic LNs on histopathological examination. True-positive LNs were defined as 
fluorescent LNs observed through near-infrared imaging, which were metastatic on 
histopathological assessment. False-positive (FP) LNs were defined as fluorescent LNs 
observed 
through 
near-infrared 
imaging, 
which 
were 
not 
metastatic 
on 

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histopathological assessment. False-negative LNs were defined as non-fluorescent LNs 
observed through near-infrared imaging, which were metastatic on histopathological 
examination.  
The sensitivity, specificity, false-negative rate, negative predictive value (NPV), 
and positive predictive value (PPV) of fluorescent lymphography for detecting LN 
metastases based on stations and LNs were evaluated. These proportions were 
determined by matching the presence or absence of fluorescence staining in stations or 
LNs with the results of histopathological analysis. First, the sensitivity of fluorescent 
lymphography was determined from the total number of patients with LN metastases. 
Therefore, the diagnostic value of ICG fluorescent lymphography was determined on 
the basis of the total number of stations and LNs. Sensitivity (TP rate) was determined 
by dividing the number of TP stations or LNs by the number of TP plus FN stations or 
LNs [TP / (TP + FN)]. Specificity (true-negative rate) was determined by dividing the 
number of TN stations or LNs by the number of TN plus FP stations or LNs [TN / (TN 
+ FP)]. The FP rate of fluorescent stations or LNs was determined by dividing the 
number of FP stations or LNs by the number of FP plus true-negative (TN) stations or 
LNs [FP / (FP + TN)]. The FN rate of fluorescent stations or LNs was determined by 
dividing the number of FN stations or LNs by the number of FP plus TP stations or LNs 
[FN / (FN + TP)]. PPV was determined by dividing the number of TP stations or LNs 
by the number of TP plus FP stations or LNs [TP / TP + FP]. NPV was determined by 
dividing the number of TN stations or LNs by the number of TN plus FN stations or 
LNs [TN / (TN + FN)]. 
8.10 The Surgery Task Load Index 
Surgeons were asked to complete one Surg-TLX questionnaire for each procedure 
in both studies after surgery18, consisting of 6 subscales addressing mental, physical, 
and temporal demands, task complexity, situation, and distrations. All questions were 
rated on a 20-point scale (0 = low, 20 = high).  

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12 
 
 
8.11 LN noncompliance rate 
Within the scope of D2 dissection, LN noncompliance was defined as the absence 
of LNs that should have been excised from more than 1 LN station. Major LN 
noncompliance was defined as more than 2 intended LN stations that were not 
removed. 
8.12 Patient satisfaction with care 
Patient satisfaction with care was measured before their discharge from 
hospital by the Modified EORTC IN-PATSAT14 scale. The Modified EORTC 
IN-PATSAT14 was conceptualized as containing five multi-item and three single-item 
scales.19 All scores are linearly transformed to a 0–100 scale. A higher score reflects a 
higher level of satisfaction. 
 
 

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13 
 
The modified EORTC IN-PATSAT14 Questionnaire 
We are interested in your experience of the care received during your hospital stay. Please answer all the questions yourself by circling the 
number that best applies to you. There are no “right” or “wrong” answers. The information that you provide will remain strictly confidential. 
Thank you very much. 
 
During your hospital stay, how would you rate doctors, in terms 
of 
Poor 
Fair 
Good 
Very good 
Excellent 
1 
Their knowledge and experience of your illness? 
1 
2 
3 
4 
5 
2 
The treatment and medical follow-up they provided? 
1 
2 
3 
4 
5 
3 
Their willingness to listen to all of your concerns? 
1 
2 
3 
4 
5 
4 
The information they gave you about your illness, medical tests, 
and treatment? 
1 
2 
3 
4 
5 
5 
The frequency of their visits/consultations? 
1 
2 
3 
4 
5 
6 
The time they devoted to you during visits/consultations? 
1 
2 
3 
4 
5 
 
During your hospital stay, how would you rate services in terms 
of 
Poor 
Fair 
Good 
Very good 
Excellent 
7 
The information provided on your admission to the hospital? 
1 
2 
3 
4 
5 
8 
The information provided on your discharge from the hospital? 
1 
2 
3 
4 
5 
9 
The kindness and helpfulness of the technical, reception, 
laboratory personnel? 
1 
2 
3 
4 
5 
10 
The waiting time for obtaining results of medical tests?  
1 
2 
3 
4 
5 
11 
The speed of implementing medical tests and/or treatments? 
1 
2 
3 
4 
5 
 
Special item 
Quite a lot 
Serious 
Moderate 
Middle 
Not at all 
12 
Was any discomfort caused by the examination or treatment 
during the hospitalization period? 
1 
2 
3 
4 
5 
13 
Is there any examination or treatment that you think is repeated 
and bother you? 
1 
2 
3 
4 
5 
 
Overall 
Poor 
Fair 
Good 
Very good 
Excellent 
14 
How would you rate the care received during your hospital stay? 
1 
2 
3 
4 
5 
The modified EORTC IN-PATSAT14 contains five multi-item and three single-item scales. These include 
the doctors’ technical skills (items 1 and 2), interpersonal skills (item 3), information provision (item 4), 
availability (items 5 and 6) scales; other hospital staff interpersonal skills and information provision scale 
(items 7–9); waiting time scale (items 10 and 11); comfort special-item scale (items 12 and 13); and 
general satisfaction single-item scale (item 14).  
 
9 Standard operating procedures (SOP)  
9.1 Case selection 
9.1.1 Selection assessment items 
Clinical examination data of patients conducted from hospital admission to 
enrollment into this study (time period is usually 2 week) will be considered baseline 
data, and must include: 
(1) Systemic status: ECOG PS score, height, weight 
(2) Peripheral  venous  blood:  Hb、RBC、WBC、LYM、NEU、NEU%、PLT、

Study protocol              
14 
 
MONO 
(3) Blood biochemistry: albumin, total bilirubin, indirect bilirubin, direct bilirubin, AST, 
ALT, creatinine, urea nitrogen, total cholesterol, triglycerides, fasting glucose, 
potassium, sodium, chlorine, calcium 
(4) Serum tumor markers: CEA、CA19-9、CA72-4、CA12-5、AFP 
(5) Full abdominal (slice thickness of 10mm or less, in case of allergy to the contrast 
agent, CT horizontal scanning is allowed only) 
(6) Upper gastrointestinal endoscopic ultrasonography (EUS) and biopsy, if no EUS, 
select ordinary upper gastrointestinal endoscopy and biopsy instead 
(7) Chest X-ray (AP and lateral views): cardiopulmonary conditions 
(8) Resting 12-lead ECG 
(9) Respiratory function tests: FEV1, FVC  
9.1.2 Selection application  
For cases that meet all inclusion criteria and none of the exclusion criteria, talk to 
patients and their families, and sign informed consent. Application and confirmation of 
eligibility should be completed preoperatively; postoperative applications will not be 
accepted. 
9.2 Preoperative management 
After the eligibility is obtained, surgery should be performed within two weeks 
(including the 14th day)  
⚫ In case of any deterioration of the clinical conditions from the selected time to the 
expected day of surgery, whether to undergo an elective surgery as planned should be 
decided under the judgment of the doctor in charge; if emergency surgery is required, 
the case should be withdrawn from PP set according to 4.3 Withdrawal Criteria;  
⚫ For patients with nutritional risks, preoperative enteral/parenteral nutritional 
support is allowed.  
⚫ For elderly, smokers, high-risk patients with diabetes, obesity, and chronic 
cardiovascular/cerebrovascular 
or thromboembolic history, among 
others, 
perioperative 
low-molecular-weight 
heparin 
prophylaxis, 
lower-limb 
antithrombotic massage, active lower limb massage, training in respiratory function, 
and other preventive measures are recommended. For other potentially high-risk 
complications not specified in this study protocol, the doctor in charge of the 
research center can decide on the most appropriate approach according to clinical 
practice and should record it in the CRF.  
⚫ For the operative approach of the surgeries in this study should be selected by the 
doctor in charge according to his/her experience and the specific intraoperative 
circumstances. 
⚫ Preoperative fasting and water deprivation and other before-anesthesia 

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15 
 
requirements on patients should follow the conventional anesthesia program of the 
research center, which is not specified in this study.  
⚫ For prophylactic antibiotics, the first intravenous infusion should begin 30 minutes 
before surgery. It is recommended to select a second-generation cephalosporin 
(there are no provisions on specific brands in this study); the preparation, 
concentration, and infusion rate should comply with routine practice; and 
prophylaxis should not exceed postoperative three days at a frequency of one 
infusion every 12 hours. If the patient is allergic to cephalosporins (including a 
history of allergy or allergy after cephalosporin administration), other types of 
antibiotics are allowed according to the specific clinical situation and when used 
over the same period mentioned.  
⚫ Patient data to be collected during the preoperative period also includes CRP 
⚫ For patients who were assigned to the SSA group, after preoperative 
exploration, the indocyanine green powder (Dandong Yichuang Pharmaceutical Co) 
is dissolved in 0.5 mg/ml of sterile water and the prepared solution (1.5 ml for each 
point) is injected along the subserosal of the stomach at 6 specific points along the 
lesser and greater curvature of the stomach. If the tumor invades one or more of the 
six injection points, subserosal injection of ICG will be conducted at the tumor 
non-invasive sites along the greater or lesser curvature of the stomach next to the 
established injection point. 
⚫ 
 
⚫ For patients who were assigned to the SMA group, submucosal injection of 
indocyanine green One day before surgery, 1.25 mg/ml indocyanine green 
(Dandong Yichuang Pharmaceutical Co) was prepared in sterile water and 0.5 ml 
of the solution was injected into the submucosal layer at 4 quadrants around the 
primary tumor, amounting to 2.5 mg of indocyanine green. 

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16 
 
 
 
Figure 1. Endoscopic submucosal injection of ICG one day before surgery. 
 
Figure 2. Laparoscopic subserosal injection of ICG at the begning of surgery 
9.3 Standardization of surgical practice 
9.3.1 Handling practices followed by both groups 
9.3.1.1 Anesthesia 
The operation is to be carried out with endotracheal intubation under general 
anesthesia; whether epidural assisted anesthesia is applied or not is left at the discretion 
of the anesthetist and is not specified in this study protocol. 
9.3.1.2 Intraoperative exploration 
Explore the abdominal cavity for any hepatic, peritoneal, mesenteric, or pelvic 
metastases and gastric serosal invasion 
9.3.1.3 Regulations on the extent of the gastrectomy 
If the oncological principles first can be satisfied, it is determined by the surgeon 
according to his experience and the specific circumstances of the operation. 
9.3.1.4 Regulations on digestive tract reconstruction  
The digestive tract reconstruction method is to be determined by the surgeon 
according to his/her own experience and the intraoperative situation. If instrumental 
anastomosis is used, whether the manual reinforced stitching is to be performed or not 
on anastomotic stoma is determined by the surgeon and not specified in this study 
protocol. 
9.3.1.5 Regulations on surgery-related equipment and instruments  
We used the NOVADAQ Fluorescence Surgical System (Stryker, US) equipped 
with the fluorescence mode to acquire NIR fluorescent images. A simple finger click 
can change a visible light into NIR fluorescent images (NIR imaging, green 
fluorescence, and color-segmented fluorescence) without the need to change any 

Study protocol              
17 
 
equipment, because the surgical system contains a module for fluorescence imaging, 
the surgeon could turn on the NIR fluorescent mode during the LN dissection. 
Energy equipment, vascular ligation method, digestive tract cutting closure, and 
digestive tract reconstruction instruments are determined by the surgeon in charge of 
the operation according to his/her own experience and actual needs and are not 
specified in this study protocol.  
9.3.1.6 Regulations on ICG-guide LN dissection  
Sequences of LN dissection were routinely performed as follow20,21: (1) for total 
gastrectomy: No. 6 → No.7, 9, 11p → No. 8a, 12a, 5 → No. 1 → No. 4sb → No. 4sa, 
11d → No. 2; and for (2) distal gastrectomy: No. 6 → No. 7, 9, 11p → No. 3, 1 → No. 
8a, 12a, 5 → No. 4sb.  
No.10 LNs were performed a selective dissection when the primary tumor was 
located in the upper-middle part of the stomach and invading the greater curvature or 
preoperative imaging suggests splenic LN enlargement or No.10 LNs emitted 
fluorescence under the NIR mode.22-25 
For patients in the ICG group, after finished the all LNs dissection, routine 
imaging of the surgical area was performed to determine whether there is residual 
fluorescent LN. When residual LNs containing fluorescence were detected in the 
dissected area, we performed complementary dissection of these LNs. Also, if 
fluorescent LNs were detected outside the planned dissection area (No. 10, and 14v), 
excessive dissection beyond the scope of D2 LN dissection was performed.  
9.3.1.6 Regulations on the gastric canal and peritoneal drainage tube 
Whether an indwelling gastric canal or peritoneal drainage tube is left or not after 
the operation is determined by the surgeon according to his/her own experience and 
actual needs and are not specified in this study protocol.  
9.3.1.7 Regulations on simultaneous surgery for other diseases 
If any other system/organ disease is found during surgery, the responsible surgeon 
and the consultants of relevant departments should jointly determine the performance of 
a concurrent operation if there is such necessity. The priority of operations is 
determined according to clinical routine; the patients meeting Exclusion Criteria will be 
excluded from the PP Set.  
9.3.1.8 Regulations on the handling of excluded patients as identified 
intraoperatively 
If the surgeon in charge judges and determines that the patient undergoing surgery 
belongs to the exclusion case group, then the research approach is suspended and the 

Study protocol              
18 
 
surgeon will follow the routine clinical practice to decide subsequent treatment 
(therapeutic decisions as to whether to excise gastric primary focus and metastases are 
made by the surgeon in charge); whether to proceed with laparoscopic surgery or 
convert it to laparotomy will be determined by the surgeon in charge. The excluded 
cases still need to complete data collection and follow-up and included in the analysis 
study (ITTP population). 
9.3.1.9 Regulations on imagery/photographing 
A laparoscopic/digital camera (8 million pixels at least) will be used to take pictures 
should contain the following contents (see the example below): 
(1) Field of LN dissection (15 or 17 pictures)  
 
Inferior pylorus region (2 picture): The right gastroepiploic arteriovenous cut site 
should be included. Another screenshot in NIR fluorescent mode should be saved. 
 
Right-side area of the superior margin of the pancreas (2 picture): The front top of 
the entire common hepatic artery, the half front of the inferior proper hepatic artery, 
and the cut site of the right gastric artery should be included. Another screenshot in 
NIR fluorescent mode should be saved. 
 
Left-side region of the superior margin of the pancreas (2 picture): The left gastric 
arteriovenous cut position, celiac arterial trunk, and proximal splenic artery should 
be included. Another screenshot in NIR fluorescent mode should be saved. 
 
The right side of the cardia and lesser gastric curvature side (2 picture). Another 
screenshot in NIR fluorescent mode should be saved. 
 
Left gastroepiploic vessel dividing position (2 picture): The cut site of the left 
gastroepiploic artery and vein should be included. Another screenshot in NIR 
fluorescent mode should be saved. 
 
Splenic hilus region (2 picture, if applicable); the cut sites of the distal splenic 
artery and the short gastric vessel should be included. Another screenshot in NIR 
fluorescent mode should be saved. 
(2) After the skin incision is closed (1 picture, measuring scale serving as a reference 
object). 
(3) Postoperative fresh specimens (4 pictures, measuring scale serving as a reference 
object); 1 picture before and 3 pictures after dissection (mark focus size; 1 picture each 
of distal and proximal incisional margins). After the specimen is cut open along the 
greater gastric curvature, a measuring scale is placed as a reference object before taking 
pictures to record the following items: the distance between the tumor edge and the 

Study protocol              
19 
 
proximal incisional margin (1 picture), the distance between the tumor edge and the 
distal incisional margin (1 picture), and the focus size and appearance of the mucosal 
face after the specimen is unfolded (1 picture).  
 
Figure 3-1-1. Inferior pyloric area (no. 6 LNs) under a natural light mode 
 
Figure 3-1-2. Inferior pyloric area (no. 6 LNs) under a NIR fluorescent light mode 

Study protocol              
20 
 
 
Figure 3-2-1. Right-side area of the superior margin of the pancreas (no. 5, no. 8a, and no. 12a LNs) 
under a natural light mode 
 
Figure 3-2-2. Right-side area of the superior margin of the pancreas (no. 5, no. 8a, and no. 12a LNs) 
under a NIR fluorescent light mode 

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21 
 
 
Figure 3-3-1. Left-side area of the superior margin of the pancreas (no. 7, no. 9, and no. 11p LNs) 
under a nature light mode 
 
Figure 3-3-2. Left-side area of the superior margin of the pancreas (no. 7, no. 9, and no. 11p LNs) 
under a NIR fluorescent light mode 
 

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22 
 
 
Figure 3-4-1. Right side of the cardia and lesser gastric curvature side (the no. 1 and no. 3 LNs) 
under a nature light mode 
 
 
Figure 3-4-2. Right side of the cardia and lesser gastric curvature side (the no. 1 and no. 3 LNs) 
under a NIR fluorescent light mode 

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23 
 
 
Figure 3-5-1. Cut site of the left gastroepiploic vessel (no. 4 sb LNs) under a nature light mode 
 
Figure 3-5-2. Cut site of the left gastroepiploic vessel (no. 4 sb LNs) under a NIR fluorescent light 
mode 

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24 
 
 
Figure 3-6-1. Splenic hilus area (no. 11d and no. 10 LNs) under a nature light mode 
 
Figure 3-6-2. Splenic hilus area (no. 11d and no. 10 LNs) under a NIR fluorescent light mode 

Study protocol              
25 
 
 
Figure 3-7. Incision appearance (mark the incision length) 
 
Figure 3-8. Specimen observation (before dissection) 

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26 
 
 
Figure 3-9. Specimen observation (focus size; the dissection is made along the greater gastric 
curvature, and the focus and incisional margin on the mucosal face are observed; if the tumor is 
located at the greater gastric curvature, then the dissection is made along the lesser curvature)
 
Figure 3-10. Specimen observation (the distance between the tumor edge and the proximal 
incisional margin)

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27 
 
 
Figure 3-11. Specimen observation (the distance between the tumor edge and the distal incisional 
margin) 
9.3.1.10 Regulations on the photo/ image privacy protection and naming 
No image data shall disclose the personal information of patients. 
When the photos/images are viewed or reviewed, the personal information must be 
processed with mosaics or be covered.  
The photographed parts should be marked with unified Chinese name: inferior 
pylorus area (nature light/fluorescent light); left gastroepiploic vessel cut site (nature 
light/fluorescent light); right-side area of the superior margin of the pancreas (nature 
light/fluorescent light); left-side area of the superior margin of the pancreas (nature 
light/fluorescent light); right side of the cardia and lesser gastric curvature side (nature 
light/fluorescent light); splenic hilus area (nature light/fluorescent light); incision 
appearance; specimen observation (before dissection); specimen observation (focus 
size); specimen observation (the distance between the tumor edge and the proximal 
incisional margin); and specimen observation (the distance between the tumor edge and 
the distal incisional margin). 
 For example: 
 Photo Name: [SMA-subject's random number - Inferior pylorus area]/ 
[SMA-subject's random number - Inferior pylorus area] 
 Folder name: [SSA-subject's random number]/ [SSA-subject's random number] 
9.3.1.11 Criteria for confirming operation quality 
To confirm the appropriateness of the surgical procedure, surgery quality, 
(auxiliary) incision length and specimen integrity will be assessed in the photographs 
saved (as stated above) The whole laparoscopic surgery procedure will be videotaped, 

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28 
 
and the unclipped image files will be saved. 
9.3.1.12 Saving of imaging data 
All photographs and data will be saved in the hard disk or portable digital carrier 
in digital form, and the surgical video required a specific hard drive to be saved for at 
least 3 years. 
If failure to provide the complete photo according to “Regulations on 
imagery/photographing” is confirmed, the Research Committee will judge and record 
the surgery quality as unqualified; however, the case will remain in the PP set data of 
this study.  
9.3.2 Regulations on laparoscopy 
9.3.2.1 Regulations on pneumoperitoneum 
      Carbon dioxide pneumoperitoneum will be used to maintain the pressure at 
12-14 mmHg. 
9.3.2.2 Regulations on punctures and auxiliary incision 
The positions of punctures and auxiliary small incision are not specified; the 
number of punctures should not exceed 5. There should be only one auxiliary small 
incision whose length shall not exceed the maximum tumor diameter and necessarily 
will be less than 10 cm in normal cases. If the auxiliary small incision needs to be 
longer than 10 cm, the surgeon in charge should make a decision and record the reasons 
in the CRF.  
9.3.2.3 Definition of laparoscopic approach 
The operations within the abdominal cavity must be performed using laparoscopic 
instruments with the support of a camera system. Peri-gastric disassociation, greater 
omental excision, omental bursa excision, LN dissection, and blood vessel handling 
should be completed under laparoscopic guidance. For gastrectomy and digestive tract 
reconstruction, the use of auxiliary small incisions is allowed and can be completed 
with an open abdomen. 
9.3.2.4 Regulations on conversion to laparotomy 
When 
intra-abdominal 
hemorrhage, 
organ 
damage 
and 
other 
serious/life-threatening complications that are difficult to control occur during 
laparoscopic surgery, it is necessary to actively convert to laparotomy. If the 
anesthesiologist and surgeon consider that intraoperative complications caused by 
carbon dioxide pneumoperitoneum may threaten the patient’s life, it is necessary to 
actively convert to open surgery. The surgeon in charge can decide to convert to 
laparotomy driven by other technical or equipment reasons and will record said reasons. 
The reasons for conversion to open surgery must be clearly recorded in the CRF. The 
incision length of > 10 cm is defined as a case of conversion to open surgery in this 
study. 

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29 
 
9.3.2.5 Subsequent treatment of excluded patients from the laparoscopic surgery 
Whether the patients continue to undergo surgery under laparoscopy or are 
converted to open surgery should be at the surgeon’s discretion according to his or her 
clinical experience. 
9.3.3 Operative parameters (same for both groups) 
Completed by the research assistant on the day of the operation. specific projects 
include: 
(1) Name of responsible surgeons 
(2) Operation time (min) 
(3) Type of operation, digestive tract reconstruction, intraoperative damage and whether 
the tumor was ruptured during surgery (intact rupture of the capsule)  
(4) Length of incision (cm) 
(5) Conversion to open surgery or not and the reasons for this decision 
(6) Intraoperative estimated blood loss (ml; from skin cutting to stitching, intraoperative 
blood loss = (postoperative gauze weight, grams - preoperative gauze weight, 
grams) *1ml/g+ suction fluid, ml) 
(7) Blood transfusion (ml):  in this study, the blood transfusion event is defined as 
transfusion of red cell suspension (ml) or whole blood (ml)  
(8) Tumor location  
(9) Tumor size (maximum tumor diameter, mm) 
(10) Distant metastasis (location) 
(11) 
Proximal 
resected 
margin 
(mm), 
distal 
resected 
margin 
(mm), 
radicality(R0/R1/R2) 
(12) Intraoperative complications (occurring from skin incision to skin closure) 
including:  
surgery-related complications: intraoperative hemorrhage and injury: A. Vascular 
injury: A vascular injury is defined as a blood vessel with either a blood vessel clamp or 
a titanium clamp closure and an intra-cavity suture or any other method to control the 
bleeding. B. Organ damage: maybe including diaphragmatic injury, esophageal injury, 
duodenal injury, colon injury, small intestine injury, spleen injury (excluding <1/3 
spleen ischemia), liver injury, pancreatic injury, gallbladder injury, kidney damage etc. 
C. Tumor rupture: tumor envelope Integrity damage 
air 
abdominal-related 
complications: 
high-blood 
carbonate, 
mediastinal 
emphysema, subcutaneous emphysema, air embolism, respiratory circulation instability 
caused by abdominal pressure. 
Anesthesia-related complications: Allergic reactions. 
(13) Intraoperative death (occurring during the time period from skin cutting to skin 
stitching completion) regardless of reason.  

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30 
 
9.3.4 Postoperative LN harvest 
LN–bearing soft tissue was separated from the resected specimens in 
vitro in accordance with the definitions of the Japanese classification 
guidelines.17 Fluorescent LNs were retrieved from each station directly 
through NIR imaging. LNs emitted fluorescence were classified as 
fluorescent LNs. Stations containing fluorescent LNs were classified as 
fluorescent stations. Surgeons examined all specimens, which were 
immediately 
sent 
to 
the 
pathology 
department. 
All 
pathological 
examinations were performed in a standard manner.17 
 
 
Figure 4. Postoperative LN sorting (fluorescent LNs and non-fluorescent LNs) 
9.4 Postoperative management (same for both groups)  
9.4.1 The use of prophylactic analgesics 
Continuous postoperative prophylactic intravenous analgesia is allowable but not 
mandatory within postoperative 48 hours; its dose, type, and rate of infusion should be 
determined by the anesthesiologist according to clinical practices and specific patient 
conditions. The repeated use of prophylactic analgesics is not allowed beyond 48 hours 
after the end of the surgery unless it is judged necessary 
9.4.2 Fluid replacement and nutritional support 
Postoperative fluid infusion (including glucose, insulin, electrolytes, vitamins, etc.) 
or nutritional support (enteral/parenteral) will be performed based on the doctor’s 

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31 
 
experience and routine clinical practices and is not specified in this study. After oral 
feeding, it is allowable to stop or gradually reduce fluid infusion/nutritional support.  
9.4.3 Post-operative rehabilitation management 
Management methods of incision, stomach, and abdominal drainage tube: Follow 
regular diagnosis and treatment approaches. Eating recovery time, diet transition 
strategies: Follow regular diagnosis and treatment approaches.  
9.4.4 Discharge standard 
Patients needed to meet the following criteria for discharge: 1) satisfactory intake 
of a soft diet. 2) move around their bed. and 3) absence of complications by routine 
clinical examinations. This information will be recorded in the CRF. 
9.4.5 Postoperative observation items 
Definition of “postoperative day n”: One day from 0:00 to up to 24:00. Up to 
24:00 on the day of surgery is “postoperative day 0;” the next day from 0:00 to up to 
24:00 is “postoperative day 1;” and so on. From the first postoperative day until 
hospital discharge, the research assistant should timely fill in the following items and 
specific observation items including: 
(1) Pathologic results:  
Original lesion tissue typing, Distant metastasis, and parts, NIH Hazard grading, 
Radical surgery degree (R0/R1/R2) 
(2) Postoperative complications:  
Postoperative complications are divided into and short-term complications after surgery 
and long-term complications after surgery. Short-term is defined as within 30 days of 
surgery or the first discharge if the hospital days > 30 days. Long-term is defined as the 
period from 30 days or more after the operation, or the first discharge (the hospital days 
after surgery >30 days) to 3 years after the operation. 
Classification and name of 
complication 
Diagnostic criteria 
  Abdominal bleeding 
Intra-abdominal hemorrhage requires a blood transfusion, emergency 
endoscopy, or surgical intervention to eliminate anastomotic bleeding. 
  Anastomotic bleeding 
The postoperative gastrointestinal decompression tube continued to 
have fresh red blood outflow; the hemoglobin drops more than 1g/dl. 
  Gastrointestinal anastomotic 
stoma Fistula 
Using gastrointestinal angiography to see contrast agent leak out from 
the anastomosis, or the blue drainage outflow through tube after oral 
Methylene blue to eliminate the possibility duodenal stump fistula and 
intestinal fistula. 
  Duodenal Stump Fistula 
Using gastrointestinal angiography to see contrast agent leak out from 
the duodenal stump to eliminate the anastomotic fistula or intestinal 

Study protocol              
32 
 
fistula. 
  Intestinal fistula 
Using gastrointestinal angiography to see the blue drainage outflow 
through tube after oral Methylene blue to eliminate anastomotic fistula 
and duodenal stump fistula. 
  Stenosis of Anastomosis 
Endoscopic examination with a 9.2-mm endoscopy not passing through 
the anastomosis to eliminate recurrence of tumors. 
  Input jejunal loop obstruction  Abdominal pain, abdominal distension, vomiting, and other symptoms. 
Abdominal flat to see the right upper abdomen expansion of the 
intestinal loop, and there is a liquid plane or a visible input loop 
jejunum giant expansion by barium meal examination. 
  Intestinal obstruction after the 
operation 
Abdominal X-ray shows a plurality of liquid planes and the 
phenomenon of intestinal effusion with visible isolated, fixed, swelling 
of the intestinal loop. Total Abdominal CT showed edema, thickening, 
adhesion of intestinal wall, accumulation of gas in the intestinal cavity, 
uniform expansion of bowel, and intra-abdominal exudation. 
  Early dumping syndrome  
Combined the symptoms of sweating, heat, weakness, dizziness, 
palpitations, heart-swelling feeling, vomiting, abdominal colic or 
diarrhea with the signs of tachycardia, blood pressure micro-rise, 
breathing a little faster sign after meal 15-30 minutes, and solid-phase 
radionuclide gastric emptying scanning tips stomach quickly emptying. 
  Late dumping syndrome  
Feeling hungry, flustered, out of sweating 2-3 hours after the meal. 
Blood sugar is less than 2.9mmol/L, excluding other diseases that 
cause hypoglycemia. 
  Intestinal 
ischemia 
and 
necrosis 
Under the digestive endoscopy, the intestinal mucosa congestion, 
edema, bruising, mucosal hemorrhage, the mucous membrane being 
dark red, the vascular network disappearing, can have part mucosal 
necrosis, following with mucosal shedding, ulcer formation with 
annular, longitudinal, snake and scattered in the ulcer erosion. 
  Internal hernia 
Postoperative CT findings of cystic or cystic and solid mass, and 
intestinal aggregation, stretching, translocation, abnormal mesenteric 
movement, and thickening of the blood vessel. 
  Alkaline reflux esophagitis 
1. Endoscopic examination and biopsy of the upper gastrointestinal 
tract showed evidence of inflammation of the mucous membranes and 
gastrointestinal metaplasia; 2. CT scan and gastrointestinal barium 
meal examination showed no expansion or obstruction of the input 
loop. 
  Incision splitting 
Including partial dehiscence of the incision and full-layer dehiscence. 
  Incisional 
hernia 
of 
the 
abdominal wall 
The swelling tumor showing in the surgical scar area or abdominal 
wall swelling when standing or force. CT shows ventral wall continuity 
interruption and hernia content extravasation. 
  Incision infection 
Thickening of the soft tissue at the incision, in or below the incision of 
gas, exudation, swelling of the incision or pus from the incision 

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extrusion, or secretion culture of pathogenic bacteria. 
Lymphatic leakage 
A chyle test when abdominal drainage ﬂuid exceeded 300 ml/day for 5 
consecutive days after postoperative day 3. 
Pneumonia 
Complies with one of the following two diagnostic Criteria: 1. 
Auscultation/percussion voiced + one of the following: fresh sputum or 
sputum character changes; blood culture (+); bronchoalveolar lavage 
fluid, anti-pollution sample brush, biopsy specimens cultured 
pathogenic bacteria. 2. Chest film hints of new or progressive 
infiltration + one of the following: fresh sputum or sputum character 
changes, blood culture (+), bronchoalveolar lavage fluid, anti-pollution 
sample brush, biopsy specimens cultured pathogenic bacteria; isolate 
the virus or detect IgM, IgG (+) of respiratory viral. 
  Acute pancreatitis 
Irritability, abdominal pain, anti-jumping pain, fever, leukocyte 
increase, and blood amylase increased occurring and diagnosed by 
ultrasound or CT within 3 days after surgery. 
  Acute cholecystitis 
Serum bilirubin exceeding 85μmol/l and ultrasound examination shows 
gallbladder enlargement, wall thickness, signal and sound shadow of 
gallbladder stone, bile internal sediment, gallbladder contraction bad, 
etc. 
  Pleural effusion/infection 
CT scan showed the localized fluid low density area of the thoracic 
cavity, which could accompany with gas, and culture pathogenic 
bacteria in thoracic endocrine. 
  Abdominal infection 
There is at least one of the following evidence in the abdominal cavity 
within 30 days after operation: 1. discharge of pus, with/without 
microbiological examination; 2. bacterial culture positive; 3. diagnosed 
by detection, pathology, imaging findings. 
  Pelvic infection 
Symptoms of systemic infection or rectal irritation, combined with a 
rectal finger examination and touching tenderness, or a married woman 
with a posterior vault to extract pus-based fluid. 
  Sepsis 
The following two conditions are available: 1. There is evidence of 
active bacterial infection, but the blood culture does not necessarily 
appear pathogenic bacteria; 2. meeting two of the following four items 
at the same time: (1). body temperature >39. 0℃ or ＜35.5 ℃ for 3 
consecutive days, (2). heart rate > 120 times/min; (3). total white blood 
cells >12. 0*109/L or <4.0*109/l, wherein neutrophils >0. 80, or naïve 
granular cells >0. 10; (4). Respiratory frequency > 28 times/min. 
  Urinary system infection 
Symptoms of urine frequency, urgency and urine pain, etc. and urine 
bacteria culture colony count 1000~10 million/ml in the absence of 
antibiotics; No symptoms of urine frequency, urgency and urine pain, 
etc, urine bacterial culture colony count ≥ 100,000/ml. 
  Pancreatic fistula 
The level of amylase in the drainage fluid is more than three times the 

Study protocol              
34 
 
normal level. 
  Bile fistula 
Symptoms of abdominal distension, Abdominal pain, tenderness, 
anti-jumping pain, muscle tension, abdominal puncture, or drainage 
fluid for bile. 
  Celiac fistula 
The drainage fluid is milky white, and more than 200ml/d and does not 
decrease for 48 hours, the celiac qualitative test is positive, and the 
level of triglyceride >110 mg/dL at the same time. 
  Nutritional 
disorder 
after 
gastrectomy 
In the presence of weight loss, anemia, malnutrition bone disease, 
vitamin A deficiency, and other symptoms, laboratory tests suggest that 
the intestinal absorption function test is abnormal, excluding other 
causes of nutritional disorders. 
  Bone 
disease 
after 
gastrectomy 
Lumbar back pain, length shortening, kyphosis, bone fractures, and 
other symptoms. Bone density decreased combining with elevated 
alkaline phosphatase and serum calcium reduction, the concentration of 
serum 25-(O1) D3 and 1,25-(O1) 2D3 increasing and the serum 
parathyroid hormone increasing. Exclusion of bone disease caused by 
other causes.  
  Subcutaneous emphysema 
visible the irregular speckle shadow under the skin in the horizontal 
flat sheet. 
  Mediastinal emphysema 
In the posterior and anterior flat fame, a long narrow gas shadow rises 
to the neck soft tissue along the mediastinal side, forming a thin-line 
dense shadow. In the lateral flat, there was a visible and clear band 
between the heart and the sternum. The CT examination, if necessary, 
shows a gas density line-like shadow around the mediastinal and 
mediastinal pleura closing to the direction of the lung field. 
Postoperative hemorrhage 
An amount of hemorrhage exceeding 300 ml. 
Postoperative 
cardiac 
dysfunction 
The symptom of sinus tachycardia, sinus bradycardia, supraventricular 
tachycardia, ventricular tachycardia, and other arrhythmias, or heart 
failure preoperatively non-existing and postoperatively appearing, and 
other causes of the above-mentioned manifestations are excluded. 
Hepatic dysfunction 
Bilirubin increasing and the levels of AST and ALT >5 times after 
operation and these symptoms no existing before surgery.  
Kidney function failure 
Postoperative continuing renal function insufficiency, blood creatinine 
rising 2mg/dl, or acute renal failure needing dialysis treatment. 
Cerebral embolism 
Acute onset, hemiplegia, aphasia, and other focal neurological function 
deficits. Embolism site has low-density infarction, of which border is 
not clear and no obstructions performance within 24-48 hours after the 
onset. 
Pulmonary embolism 
Characteristics of dyspnea, chest pain, syncope, shortness of breath, 
right 
ventricular 
insufficiency 
and 
hypotension, 
pulmonary 
angiography revealed a filling defect. 

Study protocol              
35 
 
Venous thrombosis of lower 
extremities 
Local tenderness, swelling, purple skin color, combined with 
intravenous angiography to show the filling defect. 
Mesenteric 
arterial 
embolization 
For patients with acute abdominal pain, vomiting, diarrhea, and 
abdominal x-ray of intestinal tract filling with gas or existing liquid 
level, abdominal angiography revealed a filling defect. 
DIC 
1.There are basic diseases easily leading to DIC, 2. There are more 
than two clinical performances: (1) severe or multiple bleeding 
tendencies; (2) Microcirculation disorder or shock cannot be explained 
by the original disease. (3) Extensive skin mucosal embolism, focal 
ischemic necrosis, shedding and ulcer formation, or unexplained lung, 
kidney, brain, and other organ failure. (4)  anticoagulant treatment.is 
effective. 3. The laboratory meets the following conditions: (1) there 
are 3 or more experimental abnormalities: platelet count, prothrombin 
time, activated partial coagulation enzyme time, thrombin time, 
fibrinogen level, D-two poly, and (2) difficult or special cases for a 
special examination. 
Other 
Complications are other than the above complications, which do not 
exist before surgery but appear after surgery. 
The severity of complication is graded according to Clavien–Dindo complication 
scoring system,26 
IIIa level and above are defined as a serious complication  
Ⅰ: Any deviation from the normal postoperative course without the need for 
pharmacologic treatment or surgical, endoscopic, and radiologic interventions. Allowed 
therapeutic regimens are drugs as antiemetics, antipyretics, analgesics, and diuretics, 
and electrolytes and physiotherapy. This grade also includes wound infections opened 
at the bedside. 
Ⅱ: Requiring pharmacologic treatment with drugs other than such allowed for grade I 
complications. Blood transfusions and total parenteral nutrition are also included. 
Ⅲ: Requiring surgical, endoscopic, or radiologic intervention. 
Ⅲa: Intervention not under general anesthesia. 
Ⅲb: Intervention under general anesthesia. 
Ⅳ: Life-threatening complication (including CNS complications) requiring IC 
(intermediate care) / ICU (intensive care unit) management. 
Ⅳa: Single organ dysfunction (including dialysis). 
Ⅳb: Multiple organ dysfunction. 
Ⅴ: Death as a result of complications. 
(3)  Blood test items (At postoperative day 1, 3, 5) 
Peripheral blood routine assessment: Hb, RBC, WBC, LYM, NEU, NEU%, and 
PLT、MONO. Blood biochemistry: albumin, total bilirubin, AST, ALT, creatinine, urea 
nitrogen, fasting blood glucose, potassium, sodium, chlorine, calcium, and CRP.  
(4)  Postoperative rehabilitation evaluation:  
Time to first ambulation (hours), time to first flatus (hour), time to a liquid diet, 

Study protocol              
36 
 
time to semi-liquid diet (hour), daily body temperature maximum from surgery to 
out-patient (℃), time to removal of a gastric tube (d), the daily volume of gastric 
drainage (ml), time to removal of the abdominal drainage tube (d), the daily volume of 
drainage (ml). Blood transfusion volume (ml) from the end of surgery to postoperative 
discharge: a transfusion event is defined as an infusion of the red blood cell suspension 
(ml) or whole blood (ml). Postoperative hospital stays (days): periods form surgery day 
to first discharge day 
9.5 Follow-Up 
9.5.1 Follow-up Period and strategy 
Follow-up visits will be completed by special persons for all cases selected in this 
study. All patients are followed up with every 3 months during the first 2 years and then 
every 6 months beyond the third year (1、 3、 6、 9、 12、 15、18、21、24、30 and 
36 months after the operation). This study suggests that the above examinations should 
be conducted in the patient's primary surgical research center, but does not exclude 
outer court review. For Outer Court review, it recommended that visiting the hospital as 
a three-level hospital, and this information will be recorded by the follow-up specialist. 
The occurrence of tumor recurrence or metastasis and the survival status of all patients 
are evaluated and recorded according to the results of the various examinations. 
Patients who refuse to follow the protocol should be recorded as lost to follow-up, and 
at the end of the study, these cases should be analyzed together with cases lost to 
follow-up in line with the criteria of this study. 
9.5.2 Assessment items during the follow-up 
(1) Systematic physical examination:  
The doctor in charge will regularly conduct a systematic physical examination at the 
time of each follow-up, giving particular attention to superficial LNs, abdomen, and 
signs of metastases, among others. 
(2)  Blood test items: 
 
Peripheral blood routine assessment: Hb、RBC、WBC、LYM、NEU、NEU%、
PLT、MONO 
 
Biochemistry: Albumin, total bilirubin, indirect bilirubin, direct bilirubin, AST, 
ALT, creatinine, urea nitrogen, total cholesterol, triglycerides, fasting blood 
glucose, potassium, sodium, chlorine, calcium, serum tumor markers: CEA、
CA19-9、CA72-4、CA12-5、AFP 
(3)  Imaging items:  
 
Whole abdomen (including cavity) CT (thickness of 10 mm or less, in case of 
contrast agent allergy, CT horizontal scanning is only allowable or conversion to 
MRI). Upper gastrointestinal endoscopy (histopathological biopsy, endoscopic 
ultrasonography when necessary). Chest X-ray (AP and lateral views): lung field 
condition. 
Other 
means 
of 
evaluation: 
gastrointestinal 
radiography, 
ultrasonography of other organs, whole-body bone scanning, and PET-CT, among 
others used at physician’s discretion. 
9.5.3 Follow-up process 
 

Study protocol              
37 
 
Postoperative 
3 
month
s 
6 
month
s 
9 
month
s 
12 
month
s 
15 
month
s 
18 
month
s 
21 
month
s 
2 
years 
2 
years 
and a 
half 
3 
years 
Date 
of 
the 
actual visit 
  
  
  
  
  
  
  
  
  
  
Physical 
examination 
  
  
  
  
  
  
  
  
  
  
Blood Routine 
  
  
  
  
  
  
  
  
  
  
Blood 
biochemistry 
  
  
  
  
  
  
  
  
  
  
Tumor Markers 
  
  
  
  
  
  
  
  
  
  
Chest slices 
  
  
  
  
  
  
  
  
  
  
Upper digestive 
tract endoscopy 
  
  
  
  
  
  
  
  
  
  
Abdominal CT 
  
  
  
  
  
  
  
  
  
  
Full abdominal 
ultrasound 
 
 
 
 
 
 
 
 
 
 
Other 
(if 
necessary) 
 
 
 
 
 
 
 
 
 
 
 
9.6 Post-operative adjuvant therapy 
9.6.1 Indications for postoperative adjuvant chemotherapy 
 
After completion of the surgical treatment, according to the postoperative 
pathological results, subjects among the R0 resection cases that are stage II and 
above are administered postoperative adjuvant chemotherapy according to the 
provisions of this program. 
 
For cases of non-R0 resection or recurrence after R0 resection, this study does not 
stipulate the follow-up treatment plan; the research center decides on the action to 
be taken according to the clinical treatment routine. 
9.6.2 Postoperative adjuvant chemotherapy 
 
This study uses a combination of chemotherapy based on 5-FU (5-fluorouracil) and 
recommends the SOX regimen. 
 
The adjuvant chemotherapy cycle is half a year (6 months postoperatively). 
 
In cases of good physical and tolerable conditions, chemotherapy is first started 
within 8 weeks after surgery and then according to the regularity of the 
chemotherapy cycle. 
 
During the chemotherapy period, tumor recurrence should be assessed according to 

Study protocol              
38 
 
the follow-up plan. 
 
When tumor recurrence occurs during chemotherapy, the adjuvant chemotherapy 
regimen of this study is discontinued. The follow-up treatment is decided by the 
research center according to the clinical treatment routine. This study does not 
make regulations, but the cause and follow-up treatment plan should be recorded in 
the CRF. 
 
If there is no recurrence during chemotherapy, adjuvant chemotherapy is 
terminated after 6 months, and the follow-up plan continues. 
 
Adjuvant chemotherapy requires written approval from the patient. 
 
Subjects that refuse postoperative adjuvant chemotherapy or do not complete the 
adjuvant chemotherapy are not excluded from this study, but the cause is marked 
and recorded in the CRF. 
 
For elderly patients (70 years and older), considering differences in the physical 
fitness of the elderly and ensuring the safety of patients, the research center decides 
according to the clinical treatment routine. This study does not recommend or 
stipulate any chemotherapy regimen for patients of this age.  
 
Patients who choose adjuvant chemotherapy, irregular chemotherapy, or a 
non-first-line regimen are not excluded from the study, but the FUGES-019 
Efficacy and Safety Evaluation Committee is obliged to monitor patient safety 
during follow-up. The patient's chemotherapy medication must be recorded in the 
CRF. 
 
The principles of processing in terms of the method of administration of adjuvant 
chemotherapy, toxic reactions, and dose adjustment with intolerance are 
implemented according to the original literature on drug toxicity and dose 
adjustment for each chemotherapy regimen. This study does not regulate these 
principles. 
9.6.3 Safety Evaluation Indicators of Postoperative Adjuvant Chemotherapy  
The safety evaluation indicators for patients enrolled in the study should be 
immediately filled out by the investigators before and after each postoperative adjuvant 
chemotherapy cycle, with specific items including the following:  
(1) Performance Status (ECOG)  
(2) Subjective and objective status (according to the records of CTCAE v3.0 Short 
Name)  
(3) Blood tests:  

Study protocol              
39 
 
 
Peripheral venous blood assessment: Hb, RBC, WBC, LYM, NEU, NEU%, PLT, 
MONO. 
 
Blood biochemistry: albumin, total bilirubin, AST, ALT, creatinine, urea nitrogen, 
fasting blood glucose, serum tumor markers (CEA, CA19-9, CA72-4, CA12-5, 
AFP) 
(4) Safety evaluation items to be implemented during chemotherapy when necessary 
(refer to CTCAE v3.0):  
 
Neurotoxicity  
 
Cardiovascular system (cardiac toxicity, ischemic heart disease, etc.)  
 
Bone marrow suppression and infections due to immune dysfunction  
 
Others  
9.7 Study calendar 
Observation  
Stage  
Performance Status 
Blood biochemistry 
Tumor markers 
Electrocardiogram, respiratory function 
Upper gastrointestinal endoscopy  
Chest X-ray, full abdominal CT Or ultrasound  
Eligibility confirmation notice  
Preoperative, postoperative complications  
Adverse chemotherapy events  
CRF- Preoperative  
CRF-Intraoperative  
CRF- Postoperative 
CRF- treatment end  
CRF- follow-up observation surgery  
Selection Application 
○ 
○ 
○ 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
After selection and 
prior to surgery  
 
 
 
 
 
 
○ 
 
 
○ 
 
 
 
 
Intraoperative period  
 
 
 
 
 
 
 
○ 
 
 
○ 
 
 
 
Early postoperative 
period  
 
 
 
 
 
 
 
○ 
 
 
 
○ 
○ 
 

Study protocol              
40 
 
Before postoperative 
first chemotherapy  
○ 
○ 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
Regular chemotherapy  ○ 
○ 
○ 
 
 
 
 
 
○ 
 
 
 
 
 
Follow-up period Postoperative advanced stage 
At postoperative 1 
month (±7 days) 
○ 
○ 
○ 
 
 
○ 
 
○ 
 
 
 
 
 
○ 
At postoperative 3 
months (±15 days) 
○ 
○ 
○ 
 
 
 
 
○ 
 
 
 
 
 
○ 
At postoperative 6 
months (±15 days) 
○ 
○ 
○ 
 
 
○ 
 
○ 
 
 
 
 
 
○ 
At postoperative 9 
months (±15 days) 
○ 
○ 
○ 
 
 
 
 
○ 
 
 
 
 
 
○ 
At postoperative 1 
year (±15 days) 
○ 
○ 
○ 
 
 
○ 
 
○ 
 
 
 
 
 
○ 
At postoperative 15 
months (±15 days) 
○ 
○ 
○ 
 
 
 
 
○ 
 
 
 
 
 
○ 
At postoperative 18 
months (±15 days) 
○ 
○ 
○ 
 
 
○ 
 
○ 
 
 
 
 
 
○ 
At postoperative 21 
months (±15 days) 
○ 
○ 
○ 
 
 
 
 
○ 
 
 
 
 
 
○ 

Study protocol              
41 
 
At postoperative 2 
years (±15 days) 
○ 
○ 
○ 
 
 
 
○ 
○ 
 
 
 
 
 
○ 
At postoperative 2.5 
years (±15 days) 
○ 
○ 
○ 
 
 
 
○ 
○ 
 
 
 
 
 
○ 
At postoperative 3 
years (±15 days) 
○ 
○ 
○ 
 
 
 
○ 
○ 
 
 
 
 
 
○ 
○: must do 
9.8 Definitions involved in SOP 
9.8.1 ECOG performance status score 
According to the simplified performance status score scale developed by the ECOG, the 
patients’ performance status can be classified into 6 levels, namely 0-5, as follows:   
0: Fully active, able to carry on all pre-disease performance without restriction  
1: Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light housework, office work  
2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours  
3: Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours  
4: Completely disabled. Cannot carry on any self-care. In total, confined to bed or chair  
5: Dead  
Patients at levels 3, 4, and 5 are generally considered to be unsuitable for surgical 
treatment or chemotherapy. 
9.8.2 ASA classification 
According to the patients' physical status and surgical risk before anesthesia, the American 
Society of Anesthesiologists (ASA) has categorized patients into 5 levels (I-V levels): 
 
Class I: Well-developed patients with physical health and normal function of various 
organs, with a perioperative mortality rate of 0.06% -0.08%.  
Class II: Patients with mild complications and good functional compensation in addition to 
surgical diseases, with a perioperative mortality rate of 0.27% -0.40%.  
Class III: Patients with severe complications and restricted physical activity but still 
capable of coping with day-to-day activities, with a perioperative mortality rate of 1.82% 
-4.30%.  

Study protocol              
42 
 
Class IV: Patients with serious complications who have lost the ability to perform 
day-to-day activities, often have life-threatening conditions, and a perioperative mortality rate 
of 7.80% -23.0%.  
Class V: Moribund patients either receiving surgery or not, have little chance for survival, 
and a perioperative mortality rate of 9.40% -50.70%.  
Generally, Class I/II patients are considered good for anesthesia and surgical tolerance, 
with a smooth anesthesia process. Class III patients are exposed to some anesthesia risks; 
therefore, good preparations should be fully made before anesthesia, and effective measures 
should be taken to prevent potential complications during anesthesia. Class IV patients are 
exposed to the most risks, even if good preoperative preparations are made, and have a very 
high perioperative mortality rate. Class V patients are moribund patients and should not 
undergo elective surgery. 
9.8.3 Oncology-related definitions 
In this study, tumor staging is based on AJCC-8th; surgical treatment follows the Japanese 
gastric cancer treatment guidelines 2018 (5th edition), and other writing and recording 
principles follow the Japanese classification of gastric carcinoma: 3rd English edition. 
9.8.3.1 Primary focus location 
The greater and lesser curvature of the stomach is divided into three equal parts, the U (upper), 
M (middle), and L (lower) areas, connected to the corresponding points. Esophagus and 
duodenum infiltration are recorded as E (esophagus), and D (duodenum), respectively. If the 
lesions are located in two or more adjacent areas, they should be recorded in the order of the 
main portions of the lesions.  
 
Figure 5. Division of the Three Areas of the Stomach  
9.8.3.2 Tumor staging record 
9.8.3.2.1 Recording principle  
The two staging records for clinical classification and pathological classification involve T 
(invasion depth), N (regional LN), and M (distant metastasis), which are expressed in Arabic 

Study protocol              
43 
 
numerals and denoted as x if indefinite.  
Clinical classification 
Pathological classification  
Physical examination X-ray, endoscopy, 
diagnostic imaging  
laparoscopy, 
intraoperative 
observations 
(laparotomy/laparoscopy), biopsy, cytology, 
biochemistry, biology examination  
Pathological diagnosis of the  
endoscopic/surgical specimens  
Intraperitoneal exfoliative cytology  
9.8.3.2.2 Records of tumor invasion depth  
Tumor invasion depth is defined as follows: 
 
TX: Unknown cancer invasion depth  
 
T0: No cancer found  
 
T1: Cancer invasion is only confined to the mucosa (M) or the submucosal tissue (SM)  
◆ 
T1a: Cancer invasion is only confined to the mucosa (M)  
◆ 
T1b: Cancer invasion is confined to the submucosal tissue (SM)  
 
T2: Cancer invasion exceeds the submucosal tissue but is only confined to the inherent 
muscular layer (MP)  
 
T3: Cancer invasion exceeds the inherent muscular layer (MP) but is only confined to the 
subserosal tissue (SS)  
 
T4: Cancer invasion involves the serosa (SE) or direct invasion of adjacent structures (SI)  
◆ 
T4a: Cancer invasion involves only the serosa (SE)  
◆ 
T4b: Cancer directly invades the adjacent structures (SI) 
9.8.3.2.3 Records of tumor metastasis 
(1) LN metastasis:  
 
NX: Number of LN metastases is unknown  
 
N0: No LN metastasis  
 
N1: LN metastasis of 1-2 areas  
 
N2: LN metastasis of 3-6 areas  
 
N3: LN metastasis of 7 and more areas  
◆ 
N3a: LN metastasis of 7-15 areas  
◆ 
N3b: LN metastasis of 16 and more areas  
Anatomical definitions of LN stations 
No.  
Name   
Definition  
1  
Right paracardial LNs 
LNs including those along the first branch of the ascending 
limb of the left gastric artery 

Study protocol              
44 
 
2  
Left paracardial LNs (along the 
left gastric artery) 
LNs including those along the esophago-cardiac branch of 
the left subphrenic artery 
3a  
Lesser curvature LNs  
LNs along the branches of the left gastric artery 
3b  
Lesser curvature LNs (along 
the right gastric artery)  
LNs along the 2nd branch and distal part of the right gastric 
artery 
4sa  
Left greater curvature LNs 
(short gastric artery)  
LNs along the short gastric arteries (peri-gastric area) 
4sb  
Left greater curvature LNs 
(along the left gastroepiploic 
artery)  
LNs along the left gastroepiploic artery (peri-gastric area) 
4d  
Right greater curvature LNs 
(along the right gastroepiploic 
artery)  
LNs along the 2nd branch and distal part of the right 
gastroepiploic artery 
5  
Supra-pyloric LNs 
LNs along the 1st branch and proximal part of the right 
gastric artery 
6  
Infra-pyloric LNs 
LNs along the first branch and proximal part of the right 
gastroepiploic artery down to the confluence of the right 
gastroepiploic 
vein 
and 
the 
anterior 
superior 
pancreatoduodenal vein 
7  
Left gastric artery trunk LNs 
LNs along the trunk of left gastric artery between its root and 
the origin of its ascending branch 
8a  
Anterosuperior part of the 
common hepatic artery LNs 
Anterosuperior LNs along the common hepatic artery 
8p  
Posterior part of the common 
hepatic artery LNs 
Posterior LNs along the common hepatic artery 
9  
Celiac artery LNs  
Celiac artery LNs 
10  
Splenic hilar LNs 
Splenic hilar LNs including those adjacent to the splenic 
artery distal to the pancreatic tail, and those on the roots of 
the short gastric arteries and those along the left 
gastroepiploic artery proximal to its 1st gastric branch 
11p  
Proximal splenic artery LNs 
LNs from its origin to halfway between its origin and the 
pancreatic tail end 
11d  
Distal splenic artery LNs 
LNs from halfway between its origin and the pancreatic tail 
end to the end of the pancreatic tail 

Study protocol              
45 
 
12a  
Hepatoduodenal ligament LNs 
(along 
the 
proper 
hepatic 
artery)  
LNs along the proper hepatic artery, in the caudal half 
between the confluence of the right and left hepatic ducts and 
the upper border of the pancreas 
12b  
Hepatoduodenal ligament LNs 
(along the bile duct)  
LNs along the bile duct, in the caudal half between the 
confluence of the right and left hepatic ducts and the upper 
border of the pancreas 
12p  
Hepatoduodenal ligament LNs 
(along the portal vein)  
LNs along the portal vein in the caudal half between the 
confluence of the right and left hepatic ducts and the upper 
border of the pancreas 
13  
LNs on the posterior surface of 
the pancreatic head cranial 
LNs on the posterior surface of the pancreatic head cranial to 
the duodenal papilla 
14v  
LNs 
along 
the 
superior 
mesenteric vein 
LNs along the superior mesenteric vein 
15  
LNs along the middle colic 
vessels 
LNs along the middle colic vessels 
16a1  Paraaortic LNs a1  
Paraaortic LNs in the diaphragmatic aortic hiatus 
16a2  Paraaortic LNs a2  
Paraaortic LNs between the upper margin of the origin of the 
celiac artery and the lower border of the left renal vein 
16b1  Paraaortic LNs b1  
Paraaortic LNs between the lower border of the left renal 
vein and the upper border of the origin of the inferior 
mesenteric artery 
16b2  Paraaortic LNs b2 
Paraaortic LNs between the upper border of the origin of the 
inferior mesenteric artery and the aortic bifurcation 
17  
LNs on the anterior surface of 
the pancreatic head 
LNs on the anterior surface of the pancreatic head beneath 
the pancreatic sheath 
18  
Below the pancreas  
LNs along the inferior border of the pancreatic body 
19  
Infra-diaphragmatic LNs 
Infra-diaphragmatic LNs predominantly along the subphrenic 
artery 
20  
Para-esophageal LNs 
Para-esophageal LNs in the diaphragmatic esophageal hiatus 
110  
Para-esophageal LNs in the 
lower thorax 
Para-esophageal LNs in the lower thorax 
111  
Supradiaphragmatic LNs 
Supradiaphragmatic LNs separate from the esophagus 
112  
Posterior mediastinal LNs 
Posterior mediastinal LNs separate from the esophagus and 

Study protocol              
46 
 
the esophageal hiatus  
 
 
 
 
Figure 6. Lymph node station  
(2) Distant metastasis  
 
M0: No distant metastasis outside of the regional LNs  
 
M1: Distant metastasis outside of the regional LNs  

Study protocol              
47 
 
 
MX: The Presence of distant metastasis is unclear 
Record the specific sites under the M1 condition: peritoneum (PER), liver (HEP), distant 
LN (LYM), skin (SKI), lung (PUL), bone marrow (MAR), bone (OSS), pleura (PLE), brain 
(BRA) and meninges (MEN), intraperitoneal exfoliated cells (CY), and others (OTH). Note: A 
positive examination result for intraperitoneal exfoliated cells is recorded as M1.  
9.8.3.2.4 Tumor Staging 
 
9.8.3.3 Pathologic types and classifications 
9.8.3.3.1 Type 
 
Papillary adenocarcinoma 
 
Tubular adenocarcinoma 
 
Mucinous adenocarcinoma 
 
Signet ring cell carcinoma 
 
Poorly differentiated carcinoma 
9.8.3.3.2 Grading  
 
GX classification is not possible to assess  
 
G1 well-differentiated  
 
G2 moderately differentiated  
 
G3 poorly differentiated  
 
G4 undifferentiated  
9.8.3.4 Evaluation of Radical Level (Degree)  
9.8.3.4.1 Recording the Presence or Absence of Cancer Invasion on the Resection Stump 
(1) Proximal incisional margin (PM: proximal margin)  
 
PM (-): No cancer invasion found on the proximal incisional margin  
 
PM (+): Cancer invasion found on the proximal incisional margin  
 
PM X: Unknown cancer invasion on the proximal incisional margin  
(2) Distal incisional margin (DM: distal margin)  

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 
DM (-): No cancer invasion found on the distal incisional margin  
 
DM (+): Cancer invasion found on the distal incisional margin  
 
DM X: Unknown cancer invasion on the distal incisional margin  
9.8.3.4.2 Radical Records 
Postoperative residual tumor, denoted with R (residual tumor): R0: curative resection; R1, R2: 
non-curative resection.  
 
RX: cannot be evaluated  
 
R0: no residual cancer  
 
R1: microscopic residual cancer (positive margins, peritoneal lavage cytology positive)  
 
R2: macroscopic residual cancer  
10 Statistical analysis 
10.1 Definition of the population 
(1) ITTP, intent-to-treat population 
(2) MITTP, modified intent-to-treat population 
(3) PPP, per-protocol population 
(4) SAP, safety analysis population 
10.2 Statistical analysis plan 
Statistical software: We will use Epidata3.0 to establish a database and to input data，
and we will use the SPSS statistical software, version 22.0 (SPSS Inc) and the 
R software environment, (R Foundation for Statistical Computing) to perform statistical 
analyses. 
 Basic principle: The method of differential testing was adopted. The safety population 
of the study consists of the patients who receive safety evaluation data after the 
intervention. Descriptive statistics and two-sided tests were conducted for the safety 
indicators and the incidence of adverse reactions. A p-value <0.05 is considered 
statistically significant. The confidence interval of the parameters is estimated with a 95% 
confidence interval. 
Shedding analysis: Total shedding rate of two groups and loss rate due to adverse 
events will be compared using pearsonχ2 test 
Statistical analysis of population division: baseline data and effective analysis using 
MITT analysis. The main therapeutic indicators are analyzed using both MITT and PP 
analysis. But based on the conclusion of MITT analysis. If MITT analysis and PP 
analysis of the conclusions are consistent, it can increase the credibility of the 
conclusion. The data of laboratory examination, adverse events, and adverse reactions 
were analyzed by SAP. The incidence rate of adverse reactions uses SAP as the 
denominator. 

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49 
 
Method of outlier determination: the observation value is greater than P75 or less than 
P25, and the exceed value more than 3 times of the quartile spacing (=p75-p25), which 
will be sentenced to outlier data. During the analysis, the sensitivity analysis is used for 
outlier data, namely analyzing outcomes including or excluding, outlier data. and if the 
results are not contradictory, the data is retained; if the contradiction, it depends on the 
specific circumstances. 
Descriptive statistics: The measurement data gives the mean, the standard deviation, 
and the confidence interval, and the minimum value, the maximum value, the P25, the 
median, and the P75 are given when necessary; matched data also gives the mean and 
standard deviation of the gap-value, and the median and average rank of the 
Non-parametric method. The nominal-scale data gives the frequency distribution and 
the corresponding percentages. The level data gives the frequency distribution and the 
corresponding percentages, as well as the median and the average rank. Qualitative data 
give a positive rate, positive number, and denominator numbers. The survival data gives 
the number of events, the number of deletions, the median survival time, and the 
survival rate. 
Subgroup analysis: Sub-group analysis is to find the factors that may affect prognostic 
according to the specific circumstances of the data。 
Missing values handling: This study does not fill in missing values 
Effective analysis: Using Log-rank test for single-factor analysis of Survival Time 
Data, using Cox regression model Analysis for multi-factor analysis. Quantitative data 
using t-test or t' Test (variance is not homogeneous), qualitative data using Pearson c2 
test, grade data using Wilcoxon rank test. 
Safety analysis: counting adverse response incidence and incidence of adverse events 
and make a list to describe the adverse events occurring in the study. describe the 
results of the laboratory tests before and after the normal/abnormal changes and the 
relationship between the abnormal changes and drugs in the research, and make a list of 
the "normal/abnormal" changes that occurred in the study. More detailed statistical 
analysis is shown in the statistical analysis plan. 
11 Data management 
11.1 Case Report Form (CRF) 
11.1.1 CRF Types and Submission Deadline 
CRFs used in this study and their submission deadlines are as follows: 
(1) Case Screening: 7 days before surgery (time frame of three days) 
(2) Enrolling: submitted to the data center two days before surgery  
(3) Surgery: within 1 day after surgery  
(4) Postoperative discharge: within three days after the first discharge  
(5) Follow-up records: 7 days after each specified follow-up time point   

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11.1.2 Method of transmission of CRF 
In this study, the paper CRF form is used for information and data transmittal. 
11.1.3 Revision of CRF 
 After the start of the study, if the CRF is found to lack items that are then deemed 
pertinent, under the premises of ensuring the amendment of the CRF does not cause 
medical and economic burden and increased risks to the selected patients, the CRF can 
be modified after the Research Committee adopt it through discussion at the meeting. If 
the amendment of the CRF requires no changes to this study protocol, the latter will not 
be modified. 
11.2 Monitoring and Supervising 
To assess whether study implementation follows protocol and data are being 
collected properly, monitoring should be conducted every February during the 
follow-up period. Monitoring is to complete through visiting a hospital and comparing 
the original Data. 
11.2.1 Monitoring item 
⚫ Data Collection Completion Status: By selected registration numbers (cumulative 
and for each period)  
⚫ Eligibility: Not eligible patients/potentially ineligible patients 
⚫ Different end of treatment, the reasons for the suspension/end of the study protocol  
⚫ Background factors, pre-treatment report factors, post-treatment report factors 
when selected for registration 
⚫ Severe adverse events 
⚫ Adverse events/adverse reactions  
⚫ Laparoscopic surgery completion percentage  
⚫ Proportion of conversion to laparotomy 
⚫ Protocol deviation  
⚫ Disease-free survival /overall survival (all enrolled patients) 
⚫ Progress and safety of the study, other issues 
11.2.2 Acceptable range of adverse events 
Treatment-related death and life-threatening complications caused by surgeries 
occur relatively rarely and partly are dependent on the qualifications of the research 
participating hospitals and their staff; a rate of over 3% is considered unacceptable. If 
treatment-related death is suspected or non-hematologic Grade 4 toxicity having a 
causal relationship with the surgery is determined, adverse events should be reported to 
the Efficacy and Safety Evaluation Committee. If the number of treatment-related 
deaths or the number of patients with determined non-hematologic Grade 4 toxicity 
having a causal relationship with the surgery reached 9, the final incidence proportion 
of adverse events would be expected to exceed 3%, and therefore the inclusion of 
patients must be immediately suspended. Whether the study can continue should be 

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determined by the Efficacy and Safety Evaluation Committee. 
12 Relevant Provisions on adverse events 
12.1 Surgery-related adverse events 
See the adverse events mentioned for surgical complications in 8.3Definition of the 
study endpoint.  
12.2 Various forms of adverse events caused by original incidence 
Adverse events relating to various forms of deterioration in primary diseases should be 
recorded according to the short name of CTCAEv3.0. 
12.3 Evaluation of adverse events 
Evaluation of adverse event/adverse reaction is based on [Accordion Severity Grading 
System] and [CTCAE v3.0]. 
•Adverse events will be graded 0 ~ 4 as per definition. For treatment-related death, fatal 
adverse events are classified as Grade 5 in the original CTCAE. 
•Toxicity items specified in the [surgery-related adverse events], Grade, and the 
discovery date of Grade should be recorded in the treatment process report. For other 
toxicity items observed, observed Grade 3 toxicity items are only recorded in the 
freedom registration column of the treatment process report, as well as Grade and the 
discovery date of Grade.  The grade recorded in the treatment process report must be 
recorded in the case report form. 
•CTCAE v3.0, the so-called “Adverse Event”, “all observed,  unexpected bad signs, 
symptoms and diseases (abnormal value of clinical examination are also included) in 
the treatment or disposal, regardless of a causal relationship with the treatment or 
handling, including determining whether there is a causal relationship or not”. 
•Therefore, even if events were “obviously caused by primary disease (cancer)” or 
caused by supportive therapy or combination therapy rather than the study regimen 
treatment (protocol treatment), they are “adverse events”. 
•For adverse event data collection strategy, the following principles should be complied 
with in this study:1) Adverse events within 30 days from the last treatment day of the 
study regimen treatment (protocol treatment), regardless of the presence or absence of a 
causal relationship should be completely collected. (When adverse events are reported, 
the causality and classification of adverse events are separately discussed)2) Adverse 
events within 30 days from the last treatment day of the study regimen treatment 

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(protocol treatment), regardless of the presence or absence of a causal relationship 
should be completely collected. (When adverse events are reported, the causality and 
classification of adverse events are separately discussed). 
12.4 Reporting of Adverse Events 
 
When “severe adverse events” or “unexpected adverse events” occur, the Research 
Responsible Person of the research participating unit should report them to the 
Research Committee (Chang-Ming Huang). 
 
Based on the relevant laws and regulations, adverse events should be reported to 
the province (city) Health Department at the location of the research center. Severe 
adverse events based on clinical research-related ethical guidelines should be 
reported to the person in overall charge of the medical institution. The appropriate 
reporting procedures should be completed in accordance with the relevant 
provisions of all medical institutions at the same time. The person in charge of the 
research should hold accountability and responsibility for the emergency treatment 
of patients with any degree of adverse events to ensure patient safety.  
2) Adverse events within 30 days from the last treatment day of the study regimen 
treatment (protocol treatment), regardless of the presence or absence of a causal 
relationship should be completely collected. (When adverse events are reported, the 
causality and classification of adverse events are separately discussed). 
12.4.1 Adverse Events with Reporting Obligations  
12.4.1.1 Adverse Events with Emergency Reporting Obligations 
Any of the following adverse events should be reported on an emergent basis:  
 
All patients who die during the course of treatment or within 30 days from the last 
treatment day, regardless of the presence or absence of a causal relationship with 
the study regimen treatment. Also, cases of discontinuation of treatment, even if 
within 30 days from the last treatment day, those patients are also emergent 
reporting objects. (“30 days” refers to day 0, the final treatment day, 30 days 
starting from the next day). 
 
Those patients with unexpected Grade 4 non-hematologic toxicity (CTCAE v3.0 
adverse events other than the blood/bone marrow group), having a causality of 
treatment (any of definite, probable, possible) who emergent reporting objects are.  
12.4.1.2 Adverse Events with Regular Reporting Obligations  
One of the following adverse events are regular reporting objects:  
(1) After 31 days from the last treatment day, deaths for which a causal relationship 
with treatment cannot be denied, including suspected treatment-related death; death due  
to obvious primary disease is included.  
(2) Expected Grade 4 non-hematologic toxicity (CTCAE v3.0 adverse events other than  
the blood/bone marrow group).   

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(3) Unexpected Grade 3adverse events: Grade 3 adverse events are not recorded in the  
12.1 expected adverse events.   
(4) Other significant medical events: adverse events that the study group deems cause 
important and potentially permanent, significant impact on their offspring (MDS 
myelodysplastic syndrome, except for secondary cancer) Adverse events among above 
(2)-(4), determined to have a causal relationship (any of definite, probable, possible) 
with the study regimen is regular reporting objects. 
12.4.2 Reporting Procedure   
12.4.2.1 Emergency Reporting  
 
In case of any adverse event on emergency study reporting objects, the doctor in 
charge will quickly report it to the Research Responsible Person of the research 
participating hospitals. When the Research Responsible Person of the hospital 
cannot be contacted, the coordinator or the doctor in charge of the hospital must 
assume the responsibility on behalf of the Research Responsible Person of the 
hospital.  
 
First Reporting: Within 72 hours after the occurrence of adverse events, the 
Research Responsible Person of the hospital should complete the “AE/AR/ADR 
first emergency report” and send it to the Research Committee by email and 
telephone.   
 
Second Reporting: The Research Responsible Person of the research participating 
hospital completes the “AE/AR/ADR Report” and a more detailed case 
information report (A4 format) and then faxes the two reports to the Research 
Committee within 15 days after the occurrence of adverse events. If any autopsy 
examination, the autopsy result report should be submitted to the Research 
Committee.  
12.4.2.2 General Reports  
 
The Research Responsible Person of the research participating hospital completes 
the “AE/AR/ADR report”, and then faxes it to the Research Committee within 15 
days after the occurrence of adverse events.  
12.5 Review of Efficacy and Safety Evaluation Committee   
The Efficacy and Safety Evaluation Committee reviews and discusses the report in 
accordance with the procedures recorded in the Clinical Safety Information 
Management Guideline, and makes recommendations in writing for the Research 
Responsible Person, including whether to continue to include study objects or to 
modify the study protocol. 
13 Ethical Considerations 
13.1 Responsibilities of researchers  
The investigators are responsible for the conduction of this study. The 

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investigators will ensure the implementation of this study in accordance with the study 
protocol and in compliance with the Declaration of Helsinki, as well as domestic and 
international ethical guiding principles and applicable regulatory requirements. It is 
especially noted that the investigators must ensure that only subjects providing 
informed consent can be enrolled in this study.  
13.2 Information and Informed Consent of Subjects  
An unconditional prerequisite for subjects to participate in this study is his/her 
written informed consent. The written informed consent of subjects participating in this 
study must be given before study-related activities are conducted. Therefore, before 
obtaining informed consent, the investigators must provide sufficient information to the 
subjects. In order to obtain the informed consent, the investigators will provide the 
information page to subjects, and the information required to comply with the 
applicable regulatory requirements. While providing written information, the 
investigators will orally inform the subjects of all the relevant circumstances of this 
study. In this process, the information must be fully and easily understood by 
non-professionals, so that they can sign the informed consent form according to their 
own will on the basis of their full understanding of this study.  
The informed consent form must be signed and dated personally by the subjects 
and investigators. All subjects will be asked to sign the informed consent form to prove 
that they agree to participate in the study. The signed informed consent form should be 
kept at the research center and must be properly safe kept for future review at any time 
during audit and inspection throughout the inspection period. Before participating in the 
study, the subjects should provide a copy of the signed and dated informed consent 
form.  
At any time, if important new information becomes available that may be related 
to the consent of the subjects, the investigators will revise the information pages and 
any other written information which must be submitted to the IEC/IRB for review and 
approval. The revised information approved will be provided to each subject 
participating in the study. The researchers will explain the changes made to the previous 
version of ICF to the subjects. 
13.3 Identity and Privacy of Subjects 
After obtaining an informed consent form, each selected subject is assigned a 
subject number (Allocation Number). This number will represent the identity of the 
subject during the entire study and for the clinical research database of the study. The 
collected data of subjects in the study will be stored in the ID.  
Throughout the entire study, several measures will be taken to minimize any 
breaches of personal information, including 1) only the investigators will be able to link 
to the research data of the subjects to themselves through the identity table kept at the 
research center after authorization; 2) during onsite auditing of raw data by the 

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supervisors of this study, as well as relevant inspection and inspection visits by the 
supervision departments, the person engaging in the above activities may view the 
original medical information of subjects that will be kept strictly confidential.  
Collection, transmission, handling, and storage of data on study subjects will 
comply with the data protection and privacy regulations. This information will be 
provided to the study subjects when their informed consent is being obtained for 
treatment procedures in accordance with national regulations. 
13.4 Independent Ethics Committee or Institutional Review Committee  
Before beginning the study, the research center will be responsible for submitting 
the study protocol and relevant documents (informed consent form, subject information 
page, CRF, and other documents that may be required) to the Independent Ethics 
Committee (IEC)/ Institutional Review Board (IRB) to obtain their favorable 
opinion/approval. The favorable opinions/approval documents of the IEC/IRB will be 
archived in the research center folders of the investigators. 
Before beginning the study at the center, the investigators must obtain written 
proof of favorable opinions/approval by the IEC/IRB and should provide written proof 
of the date of the favorable opinions/approval meeting, written proof of the members 
presenting at the meeting, and voting members, written proof of recording the reviewed 
study, protocol version, and Informed Consent Form version, and if possible, a copy of 
the minutes.  
In the case of major revisions to this study, the amendment of the study protocol 
will be submitted to the IEC/IRB prior to performing the study. In the course of the 
study, the relevant safety information will be submitted to the IEC/IRB in accordance 
with national regulations and requirements.  
13.5 Supervising 
The research approach of the authorities and any associated files (such as the 
research protocol, subjects’ informed consent) will be in accordance with the 
requirements of the ethical review board of biomedical research involving humans 
(Trial) (2007) and the applicable Chinese laws and regulations. Studies should provide 
the main references or inform the ethics review guidance advisory organization of the 
provincial health administrative department in the province the research center is in. 
14 Organizations and Responsibilities of Study 
14.1 Research Committee  
⚫ Responsible for developing study protocol, auditing eligibility for inclusion, and 
guiding the interpretation of informed consent; also responsible for the collection 
of adverse event reports, guiding the clinical diagnosis and treatment of such events, 
and the emergency intervention of serious adverse events.  
⚫ Person in Charge of Research Committee: Changming Huang (Department of 

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Gastric Surgery, Fujian Medical University Union Hospital) 
Add: Department of Gastric Surgery, Fujian Medical University Union Hospital, 
No.29 Xinquan Road, Fuzhou 350001, Fujian Province, China.; Post code: 350001; 
Tel: 0591-83357896-8011 ；Fax: 0591-83363366 ；Mobile: +8613805069676; 
E-mail:hcmlr2002@163.com 
Central Contact Backup: Qi-Yue Chen, PhD, Telephone: +8615980235636. Email:  
690934662@qq.com   
⚫ Chief Statistical Expert of Research Committee: Zhijian Hu (Department of 
Preventive Medicine statistics, School of Public health, Fujian Medical University) 
14.2 Efficacy and Safety Evaluation Committee 
Responsible for the supervision/monitoring of treatment safety and efficacy of this 
study.  
⚫ Person in Charge of Efficacy and Safety Evaluation Committee: Changming Huang 
(Department of Gastric Surgery, Fujian Medical University Union Hospital) 
14.3 Independent Ethics Committee/Institutional Review Board (IEC/IRB)  
⚫ 
Responsible for evaluating this study to determine if risks to which subjects are 
exposed have been duly minimized and whether these risks are reasonable 
compared to expected benefits. 
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