Comparative Study on the Efficacy of Lobaplatin and Paclitaxel in the Treatment of Advanced Gastric Cancer Patients With D2 Surgery Combined With Hyperthermic Intraperitoneal Chemotherapy
Phase: PHASE2
Conditions: Gastric Cancer, Chemotherapy Effect, Surgery, Metastasis, Survival
Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

 
1 
 
 
 
 
 
Comparative Study on the Efficacy of Lobaplatin and 
Paclitaxel in the Treatment of Advanced Gastric Cancer 
Patients with D2 Surgery Combined with Hyperthermic 
Intraperitoneal Chemotherapy 
Version:  
V1.0  
Date:  
2021.02.09  
Acronym:  
NCT Number: 
WUHIPEC01  
XXX 
Organization:  
Wuhan Union Hospital, Tongji Medical 
College of HUST  
 
 

 
2 
 
Protocol Synopsis  
Title  
Comparative Study on the Efficacy of Lobaplatin and Paclitaxel 
in the Treatment of Advanced Gastric Cancer Patients with D2 
Surgery 
Combined 
with 
Hyperthermic 
Intraperitoneal 
Chemotherapy  
Version.  
1.0  
Main inclusion 
criteria  
Initial treatment,. Intraoperative judgment showed that the 
patient's T stage was T3 and above, without distant metastasis, D2 
radical gastrectomy was feasible, the function of major organs 
was normal, and the patient was pathologically diagnosed with 
gastric adenocarcinoma Male or female, 18-75 years of age.  
Objectives  
1. Main objectives: To evaluate and compare the peritoneal 
metastasis rate and overall survival rate between lobaplatin 
and paclitaxel;  
2. secondary objectives: comparison of immune status and 
perioperative safety assessment between lobaplatin and 
paclitaxel.  
Design  
a single-center prospective randomized controlled phase II 
clinical study.  
Planned scale 
231 cases  
Organization 
Wuhan Union Hospital, Tongji Medical College of HUST  
Criteria  
Inclusion criteria:  
1. age 18-75 years;  
2. male or non-pregnant or lactating women;  
3. pathological diagnosis of gastric malignant tumor;  
4. intraoperative judgment of patients requiring hyperthermic 
intraperitoneal chemotherapy (HIPEC);  
5. normal function of major organs, that is, meeting the following 
criteria:  
routine blood tests should meet the following criteria:  
A. HB ≥ 90 g/L;  
B. ANC ≥ 1.5 x 10 9 /L;  
C. PLT ≥ 125 × 10 9 /L;  
Chemistry panel meeting the following criteria:  
A. TBIL < 1.5ULN;  
B. ALT and AST < 2.5 ULN;  
C. Serum Cr ≤ 1.25 ULN or endogenous creatinine clearance > 
50 ml/min (Cockcroft-Gault formula);  
D. ALB ≥ 30 g/L  
6. ECOG score 0-1;  
7. voluntarily sign the informed consent form.  
Exclusion Criteria:  

 
3 
 
1. the patient has a history of other malignancies within 5 years;  
2. allergy to paclitaxel, lobaplatin and other related 
chemotherapeutic drugs;  
3. suffering from epilepsy or other mental illness, unable to 
control behavior;  
4. unable to tolerate surgery due to severe cardiac, pulmonary and 
vascular diseases;  
5. pregnant or lactating women.  
Interventions 
Drug group 1: D2 surgical resection + HIPEC (paclitaxel) + 
systemic chemotherapy for 8 cycles  
Drug group 2: D2 surgical resection + HIPEC (lobaplatin) + 
systemic chemotherapy for 8 cycles  
Control group: D2 surgical resection + hyperthermic 
intraperitoneal therapy (HIPET) + systemic chemotherapy 
for 8 cycles  
Primary study 
endpoint  
overall survival (OS) and peritoneal metastasis-free survival 
(pRFS) observed for 3 years  
Secondary study 
endpoints  
Incidence of postoperative adverse reactions (referring to CTCAE 
5.0 (including blood routine, liver and kidney function, patient 
response to HIPEC, adverse events), completed when the patient 
is discharged. ( Immunology, ascites)  
Safety indicators  Vital signs, laboratory parameters, adverse events (AEs), serious 
adverse events (SAEs)  
Additional Data 
Analysis  
Radiographic data analysis  
 
 

 
4 
 
Study Flow Chart  
"×" indicates the examination currently required to be completed  
 
Item  
Before 
randomiz
ation  
Surgery 
HIPEC  
Post-op  
Discharge  
Day 1  
Day 3  
Day 5  Day 7  
Informed Consent 
Form  
×  
 
 
 
 
 
 
 
Physical examination  
×  
 
 
 
 
 
 
 
ECOG score  
×  
 
 
 
 
 
 
 
Tumor markers  
×  
 
 
 
 
 
 
 
Chest CT/X-ray  
×  
 
 
 
 
 
 
 
Enhanced CT/MRI of 
whole abdomen  
×  
 
 
 
 
 
 
 
Colonoscope  
×  
 
 
 
 
 
 
 
Cytological 
examination of 
washing fluid  
 
×  
 
 
 
 
 
 
Blood routine, liver 
and kidney function  
×  
 
×  
×  
×  
×  
×  
×  
Plasma concentration  
 
 
 
×  
×  
 
 
 
Electrocardiogram  
×  
 
 
 
 
 
 
 
Pregnancy test  
When 
necessary  
 
 
 
 
 
 
 
Quality of Life 
Questionnaires  
×  
 
 
 
 
 
 
×  
In-hospital adverse 
events  
 
 
 
 
 
 
 
×  

 
5 
 
List of abbreviations and definitions of terms  
Abbreviations and Special 
Terms  
Explanation  
AE  
Adverse events  
ALB  
Albumin  
ALT  
Alanine aminotransferase  
AST  
Aspartate aminotransferase  
ANC  
Neutrophil count  
CI  
Confidence interval  
Cr  
Creatinine  
CRF  
Case Report Form  
CRS  
Cytoreductive operation  
DRQ  
Question and Answer Sheet  
ECOG PS score  
Eastern Cooperative Oncology Group Body 
Condition Score  
EPIC  
Early 
postoperative 
intraperitoneal 
chemotherapy  
GCP  
Good Clinical Practice  
HB  
Hemoglobin  
HIPEC  
Hyperthermic intraperitoneal chemotherapy  
ICF  
Informed Consent Form  
IPC  
Intraperitoneal chemotherapy  
IRB  
Ethics Committee  
OS  
Overall survival  
PC  
Peritoneal cancer  
PFS  
Progression-free survival  
PLT  
Platelet count  
PR  
Partial response  
SAE  
Serious adverse event  
TBIL  
Total bilirubin  

 
1 
 
CONTENTS  
1. Research Background ........................................................................................ 4 
1.1 Gastric Cancer .......................................................................................... 4 
1.2 Hyperthermic Intraperitoneal Chemotherapy .......................................... 4 
1.3 Expected accomplishments of the study .................................................. 6 
1.4 Risk/Benefit Assessment .......................................................................... 6 
1.4.1 Potential Risks .............................................................................. 6 
1.4.2 Potential Benefits .......................................................................... 6 
2. study objectives .................................................................................................. 7 
2.1 Primary Objectives................................................................................... 7 
2.2 Secondary Objectives............................................................................... 7 
Design of the study ................................................................................................ 7 
3.1 Overall Design ......................................................................................... 7 
3.2 Endpoints ................................................................................................. 7 
3.3 Sample Size .............................................................................................. 8 
4. Subjects .............................................................................................................. 9 
4.1 Inclusion criteria ...................................................................................... 9 
4.2 Exclusion Criteria .................................................................................... 9 
4.3 Recruitment ............................................................................................ 10 
4.4 Method of Randomization ..................................................................... 10 
5. Intervention ...................................................................................................... 10 
5.1 Administer Study Intervention ............................................................... 10 
5.1.1 Description of Study Intervention ............................................... 10 
5.1.2 Dosage and Administration ......................................................... 15 
5.2 Preparation/Handling/Storage/Responsibility of Durgs ........................ 15 
5.2.1 Responsibilities ........................................................................... 15 
5.2.2 Drug composition, appearance, packaging and labeling ............ 15 
5.2.3 Product Storage and Stability...................................................... 15 
5.2.4 Preparation .................................................................................. 16 

 
2 
 
5.3 Measures to Reduce Bias: Randomization and Blind ............................ 16 
5.4 Follow-up and Compliance .................................................................... 16 
5.5 
Dose 
Modifications 
and 
Concomitant 
Medications 
During 
Chemotherapy ...................................................................................................... 16 
5.6 Study Intervention Commitment............................................................ 19 
6. discontinuation of study intervention and discontinuation/withdrawal of study 
subjects ......................................................................................................................... 19 
6.1 Discontinuation of Study Intervention ................................................... 19 
6.2 Discontinuation/withdrawal of study subjects ....................................... 19 
6.3 Drop Out ................................................................................................ 20 
7. Evaluation of Study Outcomes ........................................................................ 20 
7.1 Evaluation of Primary and Secondary Outcomes .................................. 20 
7.2 Safety and Other Evaluations................................................................. 21 
7.3 Performance Status and Quality of Life Scoring Tables ........................ 21 
7.3.1 Evaluation of ECOG Performance Status ................................... 21 
7.3.2 Quality of life score .................................................................... 21 
8. safety evaluation .............................................................................................. 26 
8.1 Observation of Adverse Events .............................................................. 26 
8.2 Assessment and Treatment of Adverse Events....................................... 27 
8.3 Reporting and Handling of Serious Adverse Events.............................. 28 
9. data management ............................................................................................. 29 
9.1 Completion and Transfer of Case Report Forms (CRFs)....................... 29 
9.2 Data entry and modification................................................................... 30 
9.3 Data Lock ............................................................................................... 30 
9.4 Data Processing ...................................................................................... 30 
10. statistical analysis methods ............................................................................ 30 
11. ethical requirements ....................................................................................... 31 
12. Quality Control and Quality Assurance of Clinical Trials ............................. 32 
13. Data Retention ............................................................................................... 33 
14. Summary work ............................................................................................... 34 

 
3 
 
14.1 Acceptance Criteria for Case Report Forms ........................................ 34 
14.2 Retention of Case Report Forms .......................................................... 34 
14.3 Summary of Case Report Forms .......................................................... 34 
15. Duties assumed by all parties and provisions for publication of papers ........ 35 
15.1 Responsibilities .................................................................................... 35 
15.2 Provisions for Publication .................................................................... 35 
References ............................................................................................................ 36 
 
 
 

 
4 
 
1. Research Background  
1.1 Gastric Cancer  
Although the prevalence and mortality of gastric cancer have a gradual decline, 
the mortality rate of gastric cancer (GC) is still ranked second among all kinds of 
tumor in the world (736,000 per year) [1, 2]. According to the latest data from the 
National Cancer Registry [3], the incidence and death of GC cases made up 42.6-45.0% of 
the global incidence and death in China. The incidence rate of china is the fifth and the 
mortality rate is the sixth among 183 countries in the world. In 2015, there were about 
679,000 new GC cases of GC in China, including 478,000 males and 201,000 females; 
there were about 498,000 deaths, including 339,000 males and 159,000 females. 
Further, the number of patients and deaths ranked the second in all malignant tumors 
in China, and many patients have arrived advanced status at the time of diagnosis. A 
survey by the American Academy of Surgery showed that the 5-year overall survival 
(OS) rate of patients undergoing gastrectomy for GC was 14% [4]. In recent years, 
although surgical mortality and complications have been reduced with the 
improvement of diagnostic methods, surgical skills, perioperative care and treatment 
of GC, the 5-year OS rate of patients with GC is still low even after receiving 
standard treatment (< 40% in McDonald and Magic trials) [5, 6]. Further, the recurrence 
rate also remains high for advanced GCs. Therefore, it is necessary to develop more 
effective therapeutic measures to reduce the recurrence rate of advanced GC and 
mortality in addition to standard R0 resection, D2 surgery, and adjuvant therapy [7-9].  
1.2 Hyperthermic Intraperitoneal Chemotherapy  
Hyperthermic intraperitoneal chemotherapy (HIPEC) is traditionally applied to 
treat peritoneal cancer with cytoreductive surgery (CRS). In terms of GC treatment, 
there have been multiple randomized clinical trials assessing the efficacy of surgery + 
HIPEC for the treatment of locally advanced GC [11-13]. However, to date, there are 
still are not clearly concluded with HIPEC drugs and doses, time, combinations of 
drugs. Meanwhile, the standardized clinical application of intraperitoneal medication 

 
5 
 
has become an international concern. HIPEC drugs should meet the following 
characteristics: first, effective drugs for systemic chemotherapy of GC; second, in line 
with the characteristics of intraperitoneal chemotherapy, drugs must be able to 
effectively kill tumor cells through their own or other metabolites, higher abdominal 
concentration, lower abdominal permeability, less peritoneal irritation, and tumor 
tissue penetration ability [14]. Therefore, it is important to eplore the safety and 
efficacy of different chemotherapeutic drugs for HIPEC treatment of GC for 
improving the survive and life quality of patients with advanced GC.  
Paclitaxel is a broad-spectrum anti-tumor drug that can fight with tumors through 
multiple anti-cancer mechanisms. The NCCN guidelines regard paclitaxel-based 
two-drug or three-drug combination as the recommended protocol for advanced GCs. 
In recent years, paclitaxel has been proved effective in advanced GCs combined with 
HIPEC, and China clinical expert consensus of HIPEC in GCs has listed it as one of 
infusion drugs [15]. In the HIPEC-01 clinical trial, paclitaxel was used as a HIPEC 
infusion drug to compare its safety and efficacy with CRS+ HIPEC. It is expected that 
the test results will bring more evidence-based evidence. 
Platinum drugs are non-specific cell cycle anti-tumor drugs that act on the 
chemical structure of DNA. Oxaliplatin is unstable in sodium chloride solution. The 
perfusion fluid generally uses the mixture of glucose or glucose distilled water. 
However, recent studies have shown that glucose used for intraperitoneal 
hyperthermic infusion chemotherapy can increase the risk of intraoperative 
hyperglycemia and postoperative infection [16]. Lobaplatin is a third-generation 
platinum drug. It has no obvious nephrotoxicity, ototoxicity, neurotoxicity, mild 
gastrointestinal toxicity, and no cross-resistance with other platinum drugs, and its 
perfusion fluid can be normal saline. Wu et al. enrolled 50 patients of GC with 
peritoneal metastasis who underwent radical gastrectomy combined with 
hyperthermic perfusion therapy and used lobaplatin and paclitaxel in a clinical study. 
The results suggest that this treatment plan can improve OS [17].  

 
6 
 
There is no prospective randomized controlled clinical study on the choice of 
lobaplatin and paclitaxel in HIPEC of advanced GC patients in the nation. Based on 
the widely use of HIPEC among prevention and treatment of peritoneal cancer after 
surgery in the early stage，we carried out a prospective, single-center, randomized 
controlled clinical trial to explore the efficacy, perioperative safety and immune status 
evaluation of different infusion drugs in D2 surgery combined with HIPEC in the 
treatment of advanced GC patients. Further, this study provides clinical evidence for 
the clinical development of the best comprehensive treatment plan. 
1.3 Expected accomplishments of the study  
To evaluate the peritoneal metastasis rate, survival rate, perioperative safety and 
immune status of lobaplatin and paclitaxel in patients with advanced GC treated with 
D2 surgery + HIPEC + intravenous chemotherapy.  
1.4 Risk/Benefit Assessment  
1.4.1 Potential Risks  
The main chemotherapeutic drugs used in this study were paclitaxel, lobaplatin 
and capecitabine. The hematological adverse reactions of these chemotherapeutic 
drugs were mainly anemia, leukopenia, granulocytopenia and thrombocytopenia; the 
non-hematological adverse reactions were mainly nausea, vomiting and diarrhea; the 
neurological toxicity was mainly manifested as peripheral neuritis, sometimes with 
spasm and sensory disturbance around the oral cavity, upper respiratory tract and 
upper gastrointestinal tract. The HIPEC treatment group must use dedicated thermal 
perfusion pipeline components with the risks of anastomotic leakage, delayed exhaust, 
intestinal adhesion, intestinal obstruction, tumor recurrence or metastasis. 
1.4.2 Potential Benefits  
Anticipated benefits of the Study to provide comparative results on efficacy, 
perioperative safety, immune effects, and reduction of cancer cell positive rate of 
different perfusion drugs in patients with advanced GC treated with D2 surgery + 
HIPEC + systemic chemotherapy. Further demonstrate the feasibility of HIPEC in 

 
7 
 
patients with advanced GC, take active treatment measures to reduce the length of 
hospital stay and costs, reduce mortality, improve survival outcomes, and provide 
real-world data for clinical practice. 
2. study objectives  
2.1 Primary Objectives  
A prospective randomized controlled study was designed to compare the 
incidence of perioperative adverse reactions, overall survival rate, peritoneal 
metastasis-free survival rate and other indicators of different chemotherapeutic drugs 
(paclitaxel, lobaplatin) for intraperitoneal hyperthermic perfusion chemotherapy in 
patients with GC, and to evaluate its safety and efficacy  
2.2 Secondary Objectives  
Blood routine, biochemical, immunological parameters and ascites related tests 
were compared before and after HIPEC to analyze the value of relevant laboratory 
test results in the evaluation of HIPEC in patients with GC  
Design of the study  
3.1 Overall Design  
Design type: This study is a prospective, randomized, single-center clinical trial, and 
Union Hospital, Tongji Medical College of Huazhong University of Science and 
Technology is the organizational unit.  
Test group 1: D2 surgery + HIPEC (paclitaxel) + systemic intravenous chemotherapy 
Test group 2: D2 surgery + HIPEC (lobaplatin)+ systemic intravenous chemotherapy  
Control group: D2 surgery + hyperthermic intraperitoneal therapy + systemic 
intravenous chemotherapy  
3.2 Endpoints  
The study endpoint is reached if the subjects complete all stages of study or follow-up 
or withdraw the informed consent form according to the study protocol.  

 
8 
 
3.3 Sample Size  
In a study of 1035 patients with II-IIIB GC treated with D2 surgery combined with 
capecitabine and adjuvant chemotherapy with oxaliplatin, patients were randomly 
divided into surgery alone combined with drug chemotherapy group. The 3-year PFS 
was 71% and 85% in stage II patients, 51% and 66% in stage IIIa patients, and 33% 
and 61% in stage IIIb patients, respectively. The 3-year overall survival rate in the 
surgery-only group was 78% (risk coefficient 0.72). Among the relevant western 
studies, MacDonald and Magic had the highest 5-year survival rates of 42% and 36%, 
respectively. In our recent study, the 5-year survival of Asian patients with T3 and T4 
GC after treatment in the United States was 34% and 18%, respectively. We expect 
that the 3-year survival rate of patients with stage T3-4 GC treated with D2 radical 
resection combined with hyperthermia alone and systemic chemotherapy can reach 
50%, and the 3-year survival rate of patients with stage T3-4 GC treated with D2 
radical resection combined with HIPEC and systemic chemotherapy can reach 70%, 
and the 3-year survival rate is increased by 20%. This study is expected to complete 
all surgical treatments in 1 year, with an annual dropout rate of 5%. The total sample 
size calculated by long-rank test is 231 (77 cases in each group). The annual number 
of advanced GC surgeries in our center is about 300, and the study is expected to be 
completed in 1 year.  
Steps for sample size calculation:  
（1） The survival rate was 0.50 in the control group and 0.70 in the intervention 
group, and an alpha level of 0.1 and a beta of 0.2 were set to give a power (1 − β) of 
90%.  
（2） P 0 = 0.50, P 1 = 0.70, test Z Alpha Is 1.645, Z Beta 0.842, 𝑃= (0.50 +
0.70)/2 = 0.6Input Formula  
 
𝑁=
[1.645√2 ∗0.6 ∗0.4 + 0.842√0.7 ∗(1 −0.7) + 0.5 ∗(1 −0.5)]
2
(0.70 −0.50)2
= 73 

 
9 
 
Theoretical total sample size 219 (73 per arm)  
（3） Consider dropout 5%  
219 * 1.05 = 231  
231 in total  
4. Subjects  
4.1 Inclusion criteria  
1.1. GC patients treated with no chemoradiotherapy or other anti-tumor therapy 
before surgery; 
1.2. Aged 18-75 years;  
1.3. Male or non-pregnant or lactating women;  
1.4. Pathological diagnosis of gastric adenocarcinoma;  
1.5. Patients with T stage of T3 or above without distant metastasis who can be given 
D2 radical resection (AJCC Version 8, 2018);  
1.6. Normal function of major organs, i.e. meeting the following criteria:  
Routine blood tests should meet the following criteria:  
A. HB ≥ 90 g/L;  
B. ANC ≥ 1.5 x 10 9 /L;  
C. PLT ≥ 125 × 10 9 /L;  
Chemistry panel meeting the following criteria:  
A. TBIL < 1.5ULN;  
B. ALT and AST < 2.5ULN; ALB > 30 g/L  
C. serum Cr ≤ 1.25 ULN or endogenous creatinine clearance > 50 ml/min  
(Cockcroft-Gault formula);  
1.7. ECOG score 0-1;  
1.8. Voluntarily signed informed consent form.  
4.2 Exclusion Criteria  
2.1. Patients with a history of other malignant tumors within 5 years;  
2.2. Distant metastasis was found during surgery;  
2.3. Allergic to paclitaxel, lobaplatin and other related chemotherapeutic drugs;  

 
10 
 
2.4. Suffering from epilepsy or other mental illness, unable to control behavior;  
2.5. Inability to tolerate surgery due to severe cardiac, pulmonary and vascular 
disease;  
2.6.Pregnant or lactating women.  
2.7. Receiving anticancer drug therapy from other clinical trials.  
4.3 Recruitment  
Source of study subjects: Inpatients.  
Recruiting place: Union Hospital, Tongji Medical College of HUST  
Planned Recruitment Plan: Conversation prior to surgery.  
4.4 Method of Randomization 
The patients were coded by "001", "002" and "003" in turn, and randomly assigned by 
a scheme of generating binary categorical variables using random numbers.  
5. Intervention  
5.1 Administer Study Intervention  
5.1.1 Description of Study Intervention  
Study Intervention: Paclitaxel and lobaplatin. See Annex 1 and Annex 2 for the 
relevant safe use instructions.  
Study Intervention Program:  
1. patient screening and evaluation  
Patients will be screened strictly according to the inclusion and exclusion criteria 
above in this study protocol.  
Admission 1:  
(1) Perfect medical history and physical examination  
(2) Blood routine, biochemical, immunological indicators, CRP/PCT and tumor 
markers  
(3) B ultrasound, electrocardiogram, chest radiography and gastric CT/MRI  

 
11 
 
(4) Gastroscopy  
2. D2 Surgery  
Surgical method: Open surgery or laparoscopic surgery  
The steps are as follows: anesthesia → blood sampling → abdominal exploration and 
evaluation → intraoperative lottery if the criteria are met → preoperative peritoneal 
lavage → standard D2 surgery → cancer, paraneoplastic and normal tissue samples 
are obtained → the surgical area needs photography (proven as D2 surgery) → 
postoperative peritoneal lavage. In the abdominal exploration, "evaluation of lesion 
infiltration area", "evaluation of tumor size" and "intraoperative staging" were 
performed, and whether the patients had peritoneal cancer was decided by whether 
they had peritoneal cancer or not and drawing lots, and the category of the 
experimental group and the control group was determined.  
(1) Extent of surgical resection: The distance from the gastric resection margin of 
localized GC to the tumor should be more than 3–4 cm, and the distance from 
infiltrating GC should be more than 5 cm. For esophagogastric junction cancer, the 
distance from the esophageal resection margin to the tumor should be more than 3 cm, 
and frozen pathological section examination should be performed when suspicious. 
For tumors invading the pyloric canal, the duodenal resection margin should be more 
than 3 cm from the tumor. A sufficient extent of lymph nodes was removed according 
to the GC staging method.  
(2) Principle of tumor-free operation: First ligate veins and arteries at the root of the 
blood vessel, and at the same time sweep the lymph nodes, then separate and resect 
the specimen. The operation should be gentle, more sharp separation and less blunt 
separation. The tumor could not be directly touched to avoid the damage to the lymph 
nodes which can cause cancer cells to spread and local implantation. The serosal layer 
can be protected by covering method or applying various glues 
(3) Remove the specimen and protect the incision to prevent tumor cell implantation 
in the incision.  

 
12 
 
(4) Intraoperative cytology  
Before and after the resection of the primary cancer, rinse the attachment area of the 
primary cancer with more than 1000ml of normal saline, collect more than 500ml of 
rinsing solution, and send it to the pathology department for centrifugation at 
1000g ,10min. Collect nucleated cell smears for HE staining microscopy. We get two 
chief physicians and above pathologists using HE staining method to detect tumor 
cells. When two pathologists dispute the conclusion, consult the deputy chief 
physician and above pathologists to confirm the diagnosis.  
(5) Abdominal lavage after the operation: After the operation, lavage of the 
abdominal cavity should be performed to remove free cancer cells in the abdominal 
cavity as much as possible. The lavage fluid should be normal saline.  
(6) After the operation is completed, take photos or videos for archive. Photo or video 
must cover the following organizations: 
Distal subtotal gastrectomy It shows left gastroepiploic artery ligation point, 
common hepatic artery, proper hepatic artery, left gastric artery ligation point, left and 
right gastric vein ligation point, splenic artery, right sub-pyloric artery and vein 
ligation point, bare lesser curvature  
Gastrectomy The ligation point of left gastric artery and stump of coronary vein, 
common hepatic artery, splenic artery, celiac trunk and splenic hilum were shown.  
Total gastrectomy It shows the ligation points of left gastric artery and vein, right 
gastric artery and vein, common hepatic artery, celiac trunk, splenic hilum, splenic 
artery, proper hepatic artery, right gastroepiploic artery and vein, and sub-pyloric 
artery and vein.  
(7) The collection of pathological tissue samples, peripheral blood samples and lavage 
fluid samples should be completed during surgery, and photographs of each sample 
should be taken and archived.  
3. Hyperthermic intraperitoneal chemotherapy (HIPEC) (with paclitaxel drugs)  

 
13 
 
The location of the drainage tube: The two drainage tubes with the tube opening in the 
upper abdomen are used as perfusion tubes. The tube openings are placed under the 
left side of the diaphragm and the liver and kidney recesses. After HIPEC is 
completed, the left side of the diaphragm can be used as a postoperative abdominal 
drainage tube. Two drainage tubes with nozzles located in the lower abdomen are 
used as outflow tubes, and the nozzles are placed on both sides of the pelvic floor. 
Each drainage tube is generally placed on the plane of the anterior axillary line, and 
the perfusion tube should be placed near the tumor as much as possible, while the 
outflow tube should be placed away from the tumor area. 
Temperature Setting: 43 ± 1.0 ℃.  
Priming time: 60 min.  
Dosage of perfusion fluid: The perfusion fluid is based on the principle of filling the 
abdominal cavity and unobstructed circulation.  
Choice of perfusate: Normal saline.  
Drug selection and dosage: Paclitaxel 75 mg/m 2 .  
Timing of treatment: Performed intra-operatively  
Treatment course: the first time after surgery, the second time 48h after first time. 
Intraoperative medication: give intravenous sedatives during treatment when the 
patient is intolerant, adjust the dose according to the patient's response, and give fluids 
according to the monitoring of vital signs. 
Cytological examination: Before and after the resection of the primary cancer, rinse 
the attachment area of the primary cancer with more than 1000ml of normal saline, 
collect more than 500ml of rinsing solution, and send it to the pathology department 
for centrifugation at 1000g ,10min. Collect nucleated cell smears for HE staining 
microscopy. We arrange two chief physicians and above pathologists using HE 
staining method to detect tumor cells. When two pathologists dispute the conclusion, 
consult the deputy chief physician and above pathologists to confirm the diagnosis. 

 
14 
 
Immunological examination: After HIPEC, collect patient blood samples and 5mL 
the above-mentioned flushing fluid samples for immunological indicators such as 
CD3, CD4 and CD8 lymphocyte population; IL-2, 4, 8, 10, etc. 
Intraoperative monitoring: During HIPEC treatment, monitor blood pressure, body 
temperature, pulse, urine output, respiration, blood oxygen saturation, whether the 
perfusion tube is blocked and whether the outflow is smooth. If there is profuse 
sweating, if the heart rate is faster than 100 beats/minute etc. It is necessary to 
strengthen fluids after eliminating the cause of hypovolemia. If abnormalities such as 
breathing and blood oxygen saturation occur, pay attention to the number of 
anesthetics and perfusion fluid, and stop treatment if necessary. 
Judgment on postoperative complications: Intra-abdominal bleeding, infection, 
peritonitis, anastomotic leakage, intestinal obstruction, intestinal perforation, 
intestinal necrosis, death and other complications (refer to CTCAE v5.0) and 
unplanned second surgery; 
4.Postoperative systemic adjuvant chemotherapy regimen (SOX/XELOX 
regimen)  
After the patient's condition recovered 4-6 weeks after surgery, 8 cycles of 
postoperative systemic adjuvant chemotherapy were started. SOX/XELOX regimen 
was used for chemotherapy regimen  
SOX regimen: Oxaliplatin 130 mg/m2 IV d1 + Tegafur capsules: body surface area < 
1.25m 2 40 mg/time, bid; 1.25 m2 ≤ body surface area < 1.5m 2 60 mg/time, twice a 
day; body surface area ≥ 1.5 m 2 Those, 60 mg/time, twice a day, d1-14, q3w, 4-8 
cycles.  
XELOX regimen: Oxaliplatin 130 mg/m 2 IV d1 + Capecitabine 1000 mg/m 2 Po bid 
d1-14, q3w, 4-8 cycles  
Eight-cycle chemotherapy monitoring: Laboratory tests were performed once 
before and after chemotherapy, including blood routine tests (hemoglobin Hb, red 

 
15 
 
blood cell count RBC, white blood cell count WBC, platelet count Plt, neutrophil 
count NEUT), routine biochemical parameters such as liver and kidney function 
(glutamate aminotransferase ALT, aspartate aminotransferase AST, γ-glutamyl 
transferase γ-GT, lactate dehydrogenase LDH, alkaline phosphatase ALP, total 
protein TP, albumin ALB, albumin/globulin ratio A/G, blood urea nitrogen BUN, 
serum creatinine Cr), and tumor marker tests (CEA, CA199, CA724).  
5.1.2 Dosage and Administration  
1) mode of administration: hyperthermic intraperitoneal perfusion (HIPEC)  
2) Drug and dose  
Drug group 1: Paclitaxel 75 mg/m 2  
Drug group 2: Lobaplatin 50 mg/m 2 /time  
The dose of HIPEC was based on the dose of intravenous chemotherapy, and the 
solvent was 0.9% NS (2000 ml/m2 + 500 ml),  
The first time of HIPEC is performed after surgery, and the second time is performed 
48 hours after surgery. The HIPEC interval is not less than 24 hours.  
5.2 Preparation/Handling/Storage/Responsibility of Durgs 
5.2.1 Responsibilities  
The drug will be collected by the hospital pharmacy according to actual needs and 
random results  
5.2.2 Drug composition, appearance, packaging and labeling  
The experimental group lobaplatin (Hainan Chang'an International Pharmaceutical 
Co., Ltd., 50 mg), and paclitaxel (Haikou Pharmaceutical Factory Co., Ltd., 30 mg) 
were provided by the hospital pharmacy  
5.2.3 Product Storage and Stability  
Store the drug at room temperature, protected from light  

 
16 
 
5.2.4 Preparation  
The drug is compatible with normal saline, and is perfused and administered through 
a hyperthermic intraperitoneal perfusion device  
5.3 Measures to Reduce Bias: Randomization and Blind  
The randomization process is performed by the investigator through the software, and 
the subjects are single-blinded  
5.4 Follow-up and Compliance  
• Eight follow-ups were performed at 3, 6, 9, 12, 18, 24, 30, and 36 months after 
surgery, and blood routine, biochemistry, and tumor markers needed to be examined 
during follow-up, and CT was performed once a year after surgery; postgraduates 
were responsible for follow-up.  
5.5 Dose Modifications and Concomitant Medications During 
Chemotherapy  
Other chemotherapy and targeted drugs are not allowed to be used before disease 
progression; liver enzyme inducers such as phenytoin sodium, carbamazepine, rifampicin, 
barbiturates and itraconazole should be used with caution; palliative drugs (such as analgesic, 
antiemetic and bisphosphonates, etc.) to relieve symptoms of traditional Chinese medicine 
are allowed; and leukocyte-elevating therapy can be used according to specific 
circumstances.  
Absolute neutrophil count  
(× 10 
9 /L)  
Platelet count  
(× 10 
9 /L)  
Chemotherapy Dose Modification  
≥ 1.5  
And  
≥ 100  
Continue 100% of the initial dose of 
chemotherapy without delay  
Administration. &#32;  

 
17 
 
① Dose adjustment method at the beginning of each course of treatment: The following 
table shows the dose adjustment when hematological toxicity is produced by the application 
of chemoradiotherapy drugs. If patient has an absolute neutrophil count > 1.5 × 10 prior to 
starting a course 
9 /L and platelet count > 100 × 10 
9 /L, then a new 2-week course may be 
started without dose adjustment. Otherwise, dose modification or treatment delay will occur 
until hematological parameters return to the above levels. If the above hematological 
parameters do not return to the above levels after a 3-week delay, the patient should 
discontinue treatment.  
② Dose adjustment method caused by severe hematological DLT: dose-limiting toxicity 
(DLT), including grade 3 and 4 hematological toxicity, with or without fever. If an 
unscheduled evaluation during a treatment course revealed dose limiting toxicity (DLT), 
capecitabine was discontinued during that course and the dosage of tegafur and oxaliplatin 
was reduced in the next course with the following dose reduction regimen. &#32;  
≥ 1 - < 1.5  
And  
≥ 100  
75% 
of 
the 
initial 
dose 
of 
the 
chemotherapeutic agent was used and the 
administration was delayed. &#32;  
< 1  
And/or  < 100  
Delay dosing until absolute neutrophil count 
recovers to ≥ 1 and platelet count recovers 
to ≥ 100; if absolute neutrophil count 
recovers to ≥ 1 but < 1.5, resume treatment 
at 75% of starting dose of chemotherapeutic 
agents; if absolute neutrophil count recovers 
to ≥ 1.5, then chemotherapeutic agents  
Resume treatment at 100% of the starting 
dose. &#32;  
Dose limiting toxicity  
First occurrence  
Second 
occurrence  
Third issue 
Raw  
Grade 4 neutropenia lasting 
more than 5 days  
75% of initial dose of 
chemotherapy  
50% 
of 
initial dose 
of 
chemothera
py  
Consider 
discontinua
tion  
Grade 4 thrombocytopenia  
50% of initial dose of 
chemotherapy  
Consider 
discontinuation  
  

 
18 
 
③ Dose adjustment methods caused by non-hematological toxicity:  
 
 
Grade 
3 
neutropenic 
fever 
(absolute neutrophil count < 1.0 
and fever ≥ 38.5℃)  
75% of initial dose of 
chemotherapy  
50% 
of 
initial dose 
of 
chemothera
py  
Consider 
discontinua
tion  
  
Grade 4 neutropenic fever 
(absolute neutrophil count < 1.0, 
fever  
≥ 38.5℃ with life-threatening 
failure  
Blood)  
After careful consideration 
by the investigator, the 
initial 
dose 
of 
chemotherapy drugs can be 
used when the toxicity 
recovers to grade 0 – 1  
Of 50%  
Consider 
discontinuation  
  
  
  
  
  
  
Grade 2  
Grade 3  
Grade 4  
First occurrence  
Interrupt treatment 
until toxicity recovers 
to grade 0-1, followed 
by treatment at the 
same dose and, if 
possible, preventive 
measures. &#32;  
Interrupt treatment 
until toxicity resolves 
to grade 0-1, then 
administer 75% of the 
initial dose, with 
precautions if 
possible. &#32;  
Treatment 
discontinuation, 50% 
of the initial dose 
after recovery of 
toxicity to grade 0-1, 
only if the 
investigator believes 
that it is in the best 
interest of the patient 
to continue treatment  
Perform treatment  
Second occurrence of 
same toxicity  
Interrupt treatment 
until toxicity recovers 
to grade 0-1, followed 
by the initial dose  
75% were treated. 
&#32;  
Interrupt treatment 
until toxicity recovers 
to grade 0-1, followed 
by the initial dose  
50% were treated. 
&#32;  
  
Third occurrence of the 
same toxicity  
Interrupt treatment 
until toxicity recovers 
to grade 0-1, followed 
by the initial dose  
50% were treated. 
&#32;  
Discontinue treatment. 
&#32;  
  
Fourth occurrence of 
same toxicity  
Discontinue treatment. 
&#32;  
  
  

 
19 
 
5.6 Study Intervention Commitment  
The investigator screened and communicated with the patient to sign the 
informed consent form. The postgraduate student communicated with the patient 
about the postoperative examination and reminded the patient to follow up. The 
relevant examination results of the patient were recorded by the CRF form.  
6. 
discontinuation 
of 
study 
intervention 
and 
discontinuation/withdrawal of study subjects   
6.1 Discontinuation of Study Intervention  
Criteria for discontinuation of study intervention: the efficacy in the test group is 
equal to or inferior to that in the control group; or the incidence of serious adverse 
reactions is significantly higher than that in the control group, or the overall toxicity 
events are uncontrollable. The rationale for discontinuation of study intervention was 
derived from the interim analysis report and written recommendations from the Data 
Monitoring Committee.  
After the decision to discontinue study intervention is made, each investigator must 
convene all ongoing subjects within a reasonable time, up to 1 month, and instruct the 
subjects to perform safety assessments and complete all case report forms as soon as 
possible.  
6.2 Discontinuation/withdrawal of study subjects  
Discontinuation/Withdrawal Criteria:  
1. withdrawal of informed consent by the subject;  
2. other complications or special physiological changes in subjects during the trial, 
which are not suitable to continue the trial;  
3. During the trial, the subjects need to combine the treatment affecting the efficacy 
determination, and the trial should be discontinued in a timely manner;  
4. in addition to the above conditions, the investigator judges that it is no longer 
suitable to continue this trial.  
For all the suspension/withdrawal cases, it is necessary to record the completion of 

 
20 
 
trial as well as the reasons and time for case suspension/withdrawal and fill the 
obtained information in the record form. Subjects who discontinued/withdrew from 
the trial were required to complete visits according to the schedule of visit procedures, 
and other protocol treatments were given according to the condition.  
• The medical files of the subjects are only used for this study, and only the 
investigators of this trial have access to this data; key new variables, medical coding 
and deprivacy will be generated during data processing.  
6.3 Drop Out 
Patients in this clinical trial will be followed up for 3 years, with a special person for 
follow-up and patient management. In the sample design, it is expected that 5% of the 
patients will drop out, and the sample size will be increased accordingly.  
7. Evaluation of Study Outcomes  
7.1 Evaluation of Primary and Secondary Outcomes  
Primary study endpoints: Overall survival (OS) and peritoneal metastasis-free 
survival (pRFS) observed for 3 years  
1) Peritoneal metastasis-free survival time (pRFS):  
Defined as the time from the date of randomization to the date of first documentation 
of peritoneal metastasis (with or without metastases to other organs), ovarian 
metastasis, malignant ascites, death (from any cause), calculated with earlier 
occurrence.  
2) Disease-free survival (DFS):  
Defined as the time from the date of randomization to the date of first documented 
disease recurrence, metastasis, new GC, death (from any cause), calculated for the 
earlier occurrence.  
3) Overall survival (OS):  
Defined as the time from the date of randomization to the date of patient death (from 
any cause). For patients with no death information collected in the clinical database, 
the latest date last known to be still alive will be used as the cut-off point.  
Secondary observation endpoints: The incidence of postoperative adverse reactions 

 
21 
 
(referring to CTCAE 5.0 (including blood routine, liver and kidney function, patient 
reaction to HIPEC, adverse events)) was completed when the patients were 
discharged. Analysis of immune indicator data: changes in immune indicators 
between groups were analyzed based on immune indicators measured at different time 
points. Analysis of exfoliative cytology data: According to the positive rate of 
exfoliative cytology cancer cells measured at different time points, the difference in 
the positive rate of exfoliative cytology between the groups was analyzed.  
The primary outcome was recorded by 3-year follow-up after surgery, and laboratory 
tests were entered into the CRF form.  
7.2 Safety and Other Evaluations  
Laboratory tests, vital signs recording and assessment of adverse reactions during 
hospitalization  
Laboratory tests during follow-up to assess response to chemotherapy  
7.3 Performance Status and Quality of Life Scoring Tables  
7.3.1 Evaluation of ECOG Performance Status  
7.3.2 Quality of life score  
7.3.2.1 EORTC QLQ-C30 Questionnaire (v3.0)  
We would like to know about you and your health and ask you to answer all of the 
questions below personally. There is no "yes" or "no" answer, just circle the number that best 
Grading 
0  
Freely mobile and able to carry out all pre-disease work without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work.  
2  
Ambulatory and capable of all selfcare but unable to carry out any activity of a 
work nature with activity of 50% or more of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours.  
4  
Completely disabled. Cannot carry on any self-care. Always confined to bed or 
chair.  
5  
Death  

 
22 
 
reflects your condition. The information provided by you will remain strictly confidential.  
Please initial:  
Date of birth: DD MMM YYYY Date: DD MMM YYYY  
No
ne  
A 
litt
le  
Co
mp
ara
ble  
Ve
ry  
1.  
Are you having trouble doing strenuous activities 
like lifting heavy shopping bags or suitcases?  
1  
2  
3  
4  
2.  Are you having trouble walking long distances?  
1  
2  
3  
4  
3.  Do you have trouble walking short distances 
outdoors?  
1  
2  
3  
4  
4.  Do you need to stay in bed or chair during the 
day?  
1  
2  
3  
4  
5.  Do you need help eating, dressing, bathing, or 
using the toilet?  
1  
2  
3  
4  
In the past week:  
No
ne  
A 
litt
le  
Co
mp
ara
ble  
Ve
ry  
6.  Were you limited in your work and daily 
activities?  
1  
2  
3  
4  
7.  Are you limited in your hobbies or leisure 
activities?  
1  
2  
3  
4  
8.  Have you had shortness of breath?  
1  
2  
3  
4  
9.  Have you had pain?  
1  
2  
3  
4  
10. Do you need a break?  
1  
2  
3  
4  
11. Have you had trouble sleeping?  
1  
2  
3  
4  
12. Did you feel weak?  
1  
2  
3  
4  
13. Have you lost appetite (no appetite)?  
1  
2  
3  
4  
14. Did you feel sick?  
1  
2  
3  
4  
15. Have you vomited?  
1  
2  
3  
4  
16. Are you constipated?  
1  
2  
3  
4  
17. Do you have diarrhea?  
1  
2  
3  
4  
18. Were you tired?  
1  
2  
3  
4  
19. Does pain interfere with your daily activities?  
1  
2  
3  
4  

 
23 
 
20. Do you have trouble concentrating on things, like 
reading a newspaper or watching TV?  
1  
2  
3  
4  
21. Did you feel nervous?  
1  
2  
3  
4  
22. Did you feel worried?  
1  
2  
3  
4  
23. Did you feel irritable?  
1  
2  
3  
4  
24. Did you feel depressed (low mood)?  
1  
2  
3  
4  
25. Do you have difficulty remembering?  
1  
2  
3  
4  
26. Does your physical condition or treatment affect 
your family life?  
1  
2  
3  
4  
27. Does your medical condition or treatment affect 
your social activities?  
1  
2  
3  
4  
28. Do your physical condition or treatment make 
you financially difficult?  
1  
2  
3  
4  
For the following questions, please circle the number between 1 and 7 that best 
applies to you.  
29. How would you rate your general health over the past week?  
1 2 3 4 5 6 7  
Very bad Very good  
30. How would you rate your overall quality of life during the past week?  
1 2 3 4 5 6 7  
Very bad Very good  
7.3.2.2 Quality of life scoring methods  
The QLQ-C30 (V3.0) of the EORTC is a core scale oriented to all cancer patients, with a 
total of 30 items. Among them, items 29 and 30 are divided into seven levels, which are 
scored from 1 to 7 according to their response options; other items are divided into four 
levels: not at all, a little, a lot, and very, which are directly scored from 1 to 4.  
Calculation of EOETC QLQ-C30 domain (dimension) score (crude score):  
For the convenience of statistical analysis and application, scales are often divided into 
certain domains. Domain is an aspect of the quality of life component, also known as 
dimension, which is analyzed as an independent variable. 30 items of EOETC QLQ-C30 

 
24 
 
(V3.0), which can be divided into 15 domains and count 5 functional domains  
(physical, role, cognitive, emotional, and social functioning) 3 symptom domains 
(fatigue, pain, nausea and vomiting), 1 global health status/quality of life domain, and 6 
single items (each as a domain). See the table below for classification.  
The score of each domain is obtained by summing the scores of the included items and 
dividing by the number of included items (crude RS, Raw Score), i.e. RS = (Q1 + Q2 +... + 
Qn )/n.  
Calculation of EOETC QLQ-C30 score  
In order to make the scores of each domain compare with each other, the linear 
transformation is further performed using the polarization method to convert the crude score 
into a standardized score (SS) taking values within 0 ~ 100. In addition, the transformation 
has another purpose, that is, to change the direction of the score. Because the QLQ-C30 scale, 
except items 29 and 30, is a reverse item (the worse the quality of life), it is clearly specified 
in the scoring rules that: for the functional domain and overall health status domain scores, 
the better the functional status and quality of life, and for the symptom domain scores, the 
more symptoms or problems (the worse the quality of life). Therefore, it is also necessary to 
change the direction of calculating the standardization timescale of the functional domain. 
Specifically, calculate separately according to the following formula (where R is the full 
distance of scores in each field or item).  
Functional Area: SS = [1- (RS-1)/R] 100  
Symptom domain and global health status domain: SS = [(RS-1)/R] 100  
7.3.2.3 EORTC QLQ-CR29 (v2.1) Questionnaire  
Patients sometimes have the following symptoms or problems. Please indicate 
the level of symptoms or problems you have experienced during the past week and 
circle the number that best reflects your condition.  
In the past week:  
None  
A 
little  
Comp
arable  
Very  
31 Do you have frequent urination during the 
day?  
1  
2  
3  
4  
32 Do you have frequent urination at night?  
1  
2  
3  
4  

 
25 
 
33 Do you have involuntary urine leakage?  
1  
2  
3  
4  
34 Did you feel pain when you urinated?  
1  
2  
3  
4  
35 Have you had abdominal pain?  
1  
2  
3  
4  
36 Have you had pain in your buttocks, near 
your anus, in your rectum?  
1  
2  
3  
4  
37 Have you had abdominal distension?  
1  
2  
3  
4  
38 Did you have blood in your stool?  
1  
2  
3  
4  
39 Do you have mucus in your stool?  
1  
2  
3  
4  
40 What do you think of your mouth?  
1  
2  
3  
4  
41 Have you lost your hair because of a 
disease or treatment?  
1  
2  
3  
4  
42 Do you eat food or drink differently from 
before?  
1  
2  
3  
4  
43 Are you worried about your future health?  
1  
2  
3  
4  
44 Have you ever worried about your weight? 
1  
2  
3  
4  
45 Are you visually less attractive because of 
the disease or treatment?  
1  
2  
3  
4  
46 Do you feel less attractive for women or 
men because of the disease or treatment?  
1  
2  
3  
4  
47 Are you dissatisfied with your physical 
appearance?  
1  
2  
3  
4  
48 Do you have a colostomy bag?  
Yes  
No  
In the past week:  
 
If you have a colostomy bag, please answer the 
following questions:  
None  
A 
litt
le  
Co
mp
ara
ble  
Ve
ry  
49  
Is there involuntary venting of the ostomy bag?  
1  
2  
3  
4  
50  
Have you ever had a bowel movement from your 
ostomy bag?  
1  
2  
3  
4  
51  
Is there pain in the skin around the ostomy bag?  
1  
2  
3  
4  
52  
Do you often change your ostomy bag during the 
day?  
1  
2  
3  
4  
53  
Do you often change your ostomy bag at night?  
1  
2  
3  
4  
54  
Do you feel embarrassed about your ostomy bag?  
1  
2  
3  
4  

 
26 
 
55  
Do you have problems with ostomy care?  
1  
2  
3  
4  
 
If you do not have a colostomy bag, please 
answer the following questions:  
None  
A 
little  
Com
para
ble  
Very  
49 Have you ever had an involuntary fart?  
1  
2  
3  
4  
50 Have you ever had involuntary bowel 
movements?  
1  
2  
3  
4  
51 Have you had pain in the skin around your 
anus?  
1  
2  
3  
4  
52 Do you need to defecate often during the 
day?  
1  
2  
3  
4  
53 Do you need frequent bowel movements 
during the night?  
1  
2  
3  
4  
54 Do you feel embarrassed about having too 
many bowel movements?  
1  
2  
3  
4  
In the past four weeks:  
 
Male responses only:  
None  
A 
little  
Comp
arable  
Very  
56.  
How interested are you in having 
sex?  
1  
2  
3  
4  
57.  
Do you have trouble achieving or 
maintaining an erection?  
1  
2  
3  
4  
 
Female Responses Only:  
None  
A 
little  
Comp
arable  
Very  
58.  
How interested are you in having 
sex?  
1  
2  
3  
4  
59.  
Have 
you 
had 
pain 
during 
intercourse?  
1  
2  
3  
4  
8. safety evaluation  
8.1 Observation of Adverse Events  
An AE is any untoward medical occurrence in a subject or clinical subject and 
which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable or unintended sign (eg, an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. Adverse events that 
occurred before and after treatment were considered as adverse events according to 

 
27 
 
management needs. Therefore, safety monitoring (reporting of adverse events or 
serious adverse events) should be performed from the beginning of the subject until 
the end of the study. Therefore, adverse events that occurred between signing of 
informed consent and initiation of study treatment were also considered as AEs. 
General adverse events: The outcome of the event can be closely continued or the 
corresponding symptomatic treatment can be given according to the trial protocol.  
8.2 Assessment and Treatment of Adverse Events  
① AE grading  
Grade 1: Mild; asymptomatic or mild: clinical or diagnostic findings; treatment 
not indicated.  
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living.  
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
personal activities of daily living  
Grade 4: Life-threatening; urgent intervention indicated.  
Grade 5: Death related to AE.  
② AE recording  
The name, severity, occurrence time, duration, handling measures and outcome 
of various AEs occurred during the trial shall be recorded in detail and truthfully filled 
in the case report form (CRF). Abnormal laboratory test data were recorded in the 
CRF and repeated at least once a week and followed up until recovery or the end of 
the study.  
③ Correlation with study intervention  
Not Related = There is no temporal relationship to hyperthermic perfusion 
chemotherapy, or there is a reasonable causal relationship between the AE and another 
treatment, disease, or setting.  
Unlikely = Temporal relationship with hyperthermic perfusion chemotherapy but 
no reasonable causal relationship between the AE and hyperthermic perfusion 

 
28 
 
chemotherapy  
Possibly = There is a reasonable causal relationship between the AE and the 
hyperthermic perfusion chemotherapy. Failure to stop hyperthermic perfusion 
chemotherapy or unclear.  
Probable = reasonable causal relationship between the AE and the hyperthermic 
chemotherapy and the drug. Discontinuation of hyperthermic perfusion chemotherapy 
has an impact on the response.  
A reasonable causal relationship between AE = hyperthermic perfusion 
chemotherapy 
was 
clearly 
established. 
Stopping 
hyperthermic 
perfusion 
chemotherapy has an impact, and when clinically feasible, if hyperthermic perfusion 
chemotherapy occurs again.  
8.3 Reporting and Handling of Serious Adverse Events  
① Definition of serious adverse event  
An SAE that occurs after patient enrollment but before completion of 
chemotherapy is defined as any untoward medical occurrence that is life-threatening 
or results in death at any dose. Serious "life-threatening" is defined as an adverse 
event in which the subject was at risk of death from the event as it occurred; it does 
not refer to an adverse event that hypothetically might have caused death if it were 
more severe. These generally include: the patient requires hospitalization or 
prolongation of existing time; results in persistent significant incapacity/disability; 
congenital anomaly/birth defect and important medical events, some requiring 
treatment in the emergency room for disability; congenital anomaly/birth defect and 
important medical events, some requiring treatment in the emergency room for 
disability; congenital anomaly/birth defect and important medical events, some 
requiring treatment in the emergency room for important medical events, requiring 
medical and scientific identification to decide whether prompt reporting is appropriate, 
these important medical events may not be immediately life-threatening or result in 
death or require hospitalization, but may jeopardize the subject or may require 
intervention to prevent the occurrence of other outcomes listed above. These should 

 
29 
 
also usually be considered serious.  
② Reporting procedures of serious adverse events  
Serious adverse events were reported from the time a subject signed informed 
consent through 30 calendar days (inclusive) after the last dose of study drug. During 
the trial, any SAE must be reported to the clinical research associate (CRA) and the 
principal investigator within 24 hours. Meanwhile, New Drug Clinical Trial Serious 
Adverse Event (SAE) Reporting Form should be filled in, signed and dated, and 
reported to the sponsor, leading site, ethics committee of the study site, China Food 
and Drug Administration (CFDA) and food and drug administration in the region 
(province or municipality) where the investigator is located immediately by fax.  
During the period of continued administration after the end of the study, the 
occurrence of serious adverse events must be reported to the sponsor within 24 hours. 
Information on all serious adverse events must be recorded on the Serious Adverse 
Event form. Serious adverse events must be reported if they occur during continued 
supply and within 30 days of dosing. Serious adverse events occurring after 
administration of investigational product 30 are not reported unless they are suspected 
to be related to the study drug.  
For serious adverse events, symptoms, severity, occurrence time, treatment time, 
measures taken, follow-up time and method and outcome should be recorded in detail. 
If the investigator considers a SAE to be unrelated to the investigational drug and 
potentially related to the study conditions (e.g. discontinuation of original treatment, 
or comorbidities during the trial), the relationship should be detailed in the narrative 
section of the SAE CRF. If the intensity of an ongoing SAE or its relationship with 
the investigational drug changes, the SAE follow-up report should be submitted to the 
ethics committee immediately. All serious adverse events should be followed up until 
recovery or stabilization.  
9. data management  
9.1 Completion and Transfer of Case Report Forms (CRFs)  
CRFs are completed by the investigator and must be completed for each enrolled 

 
30 
 
case. After review by the investigator and submission to the data manager for data 
entry and management.  
9.2 Data entry and modification  
Data entry and management will be performed by a designated person. In order 
to ensure the accuracy of the data, two data managers independently performed 
double entry, which was checked by computer and manually and then submitted to a 
statistician for blind verification and statistical analysis.  
For any question in the case report form, the data manager will prepare a 
question-answering form (DRQ) and ask the investigator by the CRA. The 
investigator should answer and return as soon as possible. The data manager modifies, 
confirms and enters the data according to the investigator's answers, and may send out 
the DRQ again if necessary.  
9.3 Data Lock  
After blind review and confirmation that the established database is correct, the 
data will be locked by the principal investigator, applicant and statistical analysis 
personnel. The locked data files will not be changed, and the database will be 
submitted to the statistician for statistical analysis according to the requirements of 
statistical analysis plan. Problems found after data locking will be corrected in the 
statistical analysis program after confirmation.  
9.4 Data Processing  
The professional personnel in charge of statistical analysis shall perform 
statistical analysis according to the statistical analysis plan prepared in advance. 
Statistical analysis was performed according to the principle of intention to determine 
the full analysis set and per protocol set. After the completion of statistical analysis, 
the statistical analysis personnel wrote the statistical analysis report and the principal 
investigator of this trial wrote the study report.  
10. statistical analysis methods  
(1) General principles  

 
31 
 
All statistical tests were performed and P < 0.05 was considered statistically 
significant unless otherwise noted.  
Quantitative data: Number of cases, arithmetic mean, standard deviation, median 
and range were used for description. Qualitative data: Described by frequency, 
constituent ratio or percentage.  
Statistical test: Parametric statistical method is considered firstly. If the data 
distribution is quite different from the requirements for testing hypothesis, 
non-parametric statistical method is used.  
Statistical analysis: Statistical software was used for statistical analysis.  
(2) Case characteristics  
Completion of enrollment: The number of subjects who completed enrollment at 
each site was summarized, and a list of drop-out cases was provided.  
Baseline characteristics of general information: Baseline is defined as the data 
obtained during the screening period of the case. The demographic characteristics, 
symptoms and signs, complications, allergic history and medical history of the 
patients were described.  
(3) Safety evaluation  
The postoperative surgical safety evaluation was completed during the first 
postoperative systemic chemotherapy  
Evaluation of adverse reactions during HIIPEC, performed at discharge. For the 
evaluation of adverse events/adverse reactions, refer to CTCAE  
V5.0 Criteria. The evaluation includes:  
(1) Blood routine and liver and kidney function tests  
(2) Patient response to HIIPEC  
(3) Adverse events  
11. ethical requirements  
(1) The trial protocol and the implementation of the trial study are in accordance 
with the requirements of the Declaration of Helsinki and the Good Clinical Practice 
for Drugs.  

 
32 
 
(2) The trial protocol shall be developed before the start of the clinical trial, 
signed and confirmed by the investigator, and reported to the Ethics Committee for 
review and approval before implementation. If the protocol needs to be revised during 
the actual implementation of the clinical trial, it should be reported to the Ethics 
Committee for approval in written form before implementation. If important new 
information involving the study puncture needle is found, the informed consent form 
must be revised in writing and submitted to the Ethics Committee for approval before 
obtaining the consent of the subject again.  
(3) Before the start of the clinical trial, the investigator must provide the subject 
or his/her legal representative (guardian) with details of the clinical trial, including the 
nature of the trial, the purpose of the trial, possible benefits and risks, other treatment 
options available and the rights and obligations of the subject in accordance with the 
Declaration of Helsinki, so that the subject or his/her legal guardian can fully 
understand the clinical trial. The clinical trial can only be initiated after the subject or 
his/her legal guardian has given consent and signed the informed consent form. The 
subject informed consent form was provided in duplicate, with one copy for the 
subject's own storage and one copy for each trial site. Each patient should leave a 
detailed contact address and telephone data. At the same time, the doctor should leave 
his/her contact number for the patient, so that the patient can contact the investigator 
at any time when there is a change in the condition, which is also conducive to the 
investigator to understand the change in the condition at any time.  
(4) If adverse reactions occur during the trial, active treatment should be given to 
the subjects to minimize the pain of the subjects.  
(5) Patients with permanent damage or even death caused by serious adverse 
reactions shall be given appropriate economic compensation by the study party after 
being appraised and recognized by the special institution.  
12. Quality Control and Quality Assurance of Clinical Trials  
The investigator of each center was responsible for the quality control of this 
clinical trial, and the statistical analysts were responsible for the quality control of 

 
33 
 
data and analysis. During the study process, ensure that all contents of the study 
protocol are strictly followed and the study data are correctly filled.  
(1) The trial protocol, CRF and informed consent form shall be submitted to the 
clinical trial ethics committee of each participating unit for review and approval;  
(2) The researchers participating in this trial should earnestly implement the 
standard operating procedures for clinical trials before, during and after the trial;  
(3) Accept the clinical trial institutions of all participating units to monitor the 
correctness and completeness of the data in the CRF during the trial;  
(4) The participating researchers must receive unified training, unified recording 
methods and judgment criteria;  
(5) The whole process of clinical trials should be carried out in a strict screening 
state;  
(6) The investigator should truthfully, detailedly and carefully record the contents 
of CRF according to the requirements for CRF completion, so as to ensure that the 
contents of CRF are true and reliable;  
(7) The abnormal judgment standard of laboratory examination shall be subject 
to the normal reference range of the inspection institution;  
(8) All observations and findings in clinical trials should be verified to ensure 
that the reliability of data and various conclusions in clinical trials are derived from 
raw data. Have corresponding data management measures in the clinical trial and data 
processing stage;  
In view of the possible dropout, take active measures to control the dropout rate 
of cases within 20%.  
13. Data Retention  
The investigator should keep all the study data, including the confirmation of all 
the participating subjects (can effectively check the different record data, such as CRF 
and original hospital record), all the original signed ICFs, detailed records of all the 
CRFs, etc., and ensure the traceability of all the laboratory tests until 5 years after the 
end of the clinical study.  

 
34 
 
14. Summary work  
14.1 Acceptance Criteria for Case Report Forms  
CRF shall be submitted to the principal investigator of the unit for review and 
signature after being completed by the investigator during the trial. The principal 
investigator of each study institution examined the completion of original medical 
records and CRFs according to the requirements of "clinical trial records" and 
reviewed the following items:  
(1) The CRF must be checked with the original medical records. All the contents 
recorded on the CRF should be recorded on the original medical records.  
(2) The name, mailing address and telephone number of the subject on the 
medical record must be filled in to ensure its authenticity.  
14.2 Retention of Case Report Forms  
The CRF was kept in eCRF; the informed consent form was kept in duplicate 
and kept by the subject and the investigator, respectively.  
After all eCRFs are statistically processed, a clinical trial summary report will be 
written and archived. The original medical records of the trial are kept in the medical 
record room of each hospital or the archive room of the clinical trial institution.  
14.3 Summary of Case Report Forms  
The investigator shall be responsible for establishing the database of clinical data 
and making statistics respectively for the data of each study institution and integrating 
all the data. Each study site should draft "Summary Table of Clinical Trial Sub-sites", 
which should be stamped and submitted to each site in one copy. The statistical unit 
shall be responsible for completing the "Clinical Trial Summary Report", affixing a 
seal on it and submitting it to each participant.  

 
35 
 
15. Duties assumed by all parties and provisions for 
publication of papers  
15.1 Responsibilities  
The sponsor of clinical study shall assume its responsibilities in accordance with 
the corresponding provisions of Good Clinical Practice.  
15.2 Provisions for Publication  
As study results, all the relevant information obtained from this study will be 
considered confidential. Until the principal investigator completes and reviews the 
data analysis, these study results can be published and demonstrated with the 
authorization and consent of the principal investigator, but confidential or proprietary 
information cannot be disclosed.  
 

 
36 
 
 
References  
[1] Organization WH. Cancer, sheet Fact N ° 297 [D], World Health Organization 
Media centre, Published 2009. Reviewed January 2013.  
[2] Jemal A, Siegel R, Xu J, et al. Cancer statistics [M], 2010. CA Cancer J Clin 
60.277-300, 2010  
[3] Peng Zhi. Interpretation of GLOBCAN Gastric Cancer Epidemiological Data [J]. 
Electronic Journal of Comprehensive Cancer Therapy, Vol. 4, No. 4, 2018  
[4] Wanebo HJ, Kennedy BJ, Chmiel J, et al. &#32; Cancer of the stomach. A patient 
care study by the American College of Surgeons [J]. Ann Surg 218.583-92, 1993  
[5] Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery 
compared with surgery alone for adenocarcinoma of the stomach or 
gastroesophageal junction [J]. NEngl J Med 345.725-30, 2001  
[6] Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy 
alone versus surgery for gastroresectable esophageal cancer [J]. N Engl J Med 
355.11-20, 2006  
[7] Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for 
gastric cancer after D2 gastrectomy (CLASSIC). a phase 3 open-label, 
randomised controlled trial [J]. Lancet 379.315-21, 2012  
[8] Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric 
cancer with S-1, an oral fluoropyrimidine [J]. N Engl J Med 357.1810-20, 2007  
[9] Sasako M, Sano T, Yamamoto S, et al. D2 lymphadenectomy or with para-nodal 
aortic dissection alone for gastric cancer [J]. N Engl J Med 359.453-62, 2008  
[10] Kuramoto M, Shimada S, Ikeshima S, et al. Extensive intraoperative peritoneal 
lavage as a standard prophylactic strategy for peritoneal recurrence in patients 
with gastric carcinoma [J]. Ann Surg 250.242-6, 2009  

 
37 
 
[11] Yonemura 
Y, 
de 
Aretxabala 
X, 
Fujimura 
T, 
et 
al. 
Intraoperative 
chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer. final 
results of a randomized controlled study [J]. Hepatogastroenterology 48.1776-82, 
2001  
[12] Hamazoe R, Maeta M, Kaibara N. Intraperitoneal thermochemotherapy for 
prevention of peritoneal recurrence of gastric cancer. Final results of a 
randomized controlled study [J]. Cancer 73.2048-52, 1994  
[13] Fujimoto S, Takahashi M, Mutou T, et al. Successful intraperitoneal 
hyperthermic chemoperfusion for the prevention of postoperative peritoneal 
recurrence in patients with advanced gastric carcinoma [J]. Cancer 85.529-34, 
1999  
[14] Yan T D, Cao C Q, Munkholm-Larsen S. A pharmacological review on 
intraperitoneal chemotherapy for peritoneal malignancy [J]. World Journal of 
Gastrointestinal Oncology, 2010 (02): 109.  
[15] Professional Committee of Peritoneal Tumor, Chinese Anti-Cancer Association, 
Professional Committee of Tumor Hyperthermia, Guangdong Anti-cancer 
Association. Chinese Expert Consensus on Clinical Application of Hyperthermic 
Intraperitoneal Chemotherapy (2019 Edition) [J]. Chinese Medical Journal, 2020, 
100 (2). 89-96. &#32; DOI.10.3760/cma.j.issn .0376-2491.2020.02.003.  
[16] Torphy Robert J, Stewart Camille, Sharma Piyush et al. Dextrose-Containing 
Carrier Solution for Hyperthermic Intraperitoneal Chemotherapy. Increased 
Intraoperative Hyperglycemia and Postoperative Complications. [ J]. Ann. Surg. 
Oncol., 2020.  
[17] Zhong-He Ji, Kai-Wen Peng, Yang Yu, et al. Current Status and Future Prospects 
of Clinical Trials on CRS + HIPEC for Gastric Cancer Peritoneal Metastases [J]. 
Int J Hyperthermia, 2017 Aug; 33 (5). 562-570.  

 
38 
 
[18] Fujimoto S, Takahashi M, Mutou T et al. Improved JUST ACCEPTED mortality 
rate of gastric carcinoma patients with peritoneal carcinomatosis treated with 
intraperitoneal hyperthermic chemoper fusion combined with surgery [J]. Cancer 
1997; 79.884-91  
[19] Shen P, Stewart JHT, Levine EA et al. Cytoreductive surgery and intraperitoneal 
hype rthermic chemotherapy for peritoneal surface malignancy. Non-colorectal 
indicatiions [J]. Curr Probl Cancer 2009; 33. 168-93.  
[20] Glehen O, Schreiber V, Cotte E et al. Cytoreductive surgery and intraperitoneal 
hyperthermia for peritoneal carcinomatosis arising from gastric cancer [J]. Arch 
Surg 2004; 139. 20-6