RandomizedControlledTrialsonLaparoscopic Spleen ...

Study protocol No. of edition: V1.2

Date of edition: 2014.12.22

I

Randomized Controlled Trials on Laparoscopic

Spleen-Preserving Splenic Hilar Lymphadenectomy during Total

Gastrectomy forAdvanced Proximal Gastric Cancer (FUGES-02)Study protocol

Research center: 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

E-mail: [email protected]

No. of edition: V1.2




II

Summary

Protocol

Title

Randomized Controlled Trials on Laparoscopic Spleen-Preserving Splenic

Hilar Lymphadenectomy During Total Gastrectomy for Advanced

Proximal Gastric Cancer

Protocol

Version

V1.2

PI Chang-Ming Huang

Research

Centers

Fujian Medical University Union Hospital

IndicationsPatients with locally advanced proximal gastric adenocarcinoma not

invading greater curvature

Research

purpose

To compare the short-term and long-term outcomes between

laparoscopy-assisted total gastrectomy (LATG) with D2 lymphadenectomy

(D2 Group) and D2 minus No.10 lymph node (D2- Group) for advanced

proximal gastric cancer not invading greater curvature

Research

Design

Single center, prospective, open-label, randomized controlled

Case

Grouping

Group A (Study Group): LATG with D2 lymphadenectomy (D2 group)

Group B (Control Group): LATG with D2-No.10 lymphadenectomy (D2-

group)

Determinati

on of

Sample

Size

The projected 3-year disease free survival (DFS) rate of the D2 and D2-

groups were 61.6% and 53.7% respectively. According to the noninferiority

design, this analysis was based on an α of 0.025, a power of 90%, and a

margin delta of 7.2%, revealing that at least 224 patients would be

necessary per group. Considering an expected dropout rate of 20%, it was

determined that each group needed at least 268 patients. The sample size

was calculated by using nQuery Advisor 7.0 (Statistical Solutions, Cork,

Ireland).

Inclusion

Criteria

Age between 18 and 75 years

Endoscopic biopsy confirmed primary gastric adenocarcinoma

(including pap, tub, muc, sig, and por) of the proximal stomach not

invading the greater curvature



III

cT2-4a, N0/+, M0 at preoperative evaluation according to the

American Joint Committee on Cancer (AJCC) Cancer Staging Manual,

7th Edition

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 breast-feeding or pregnancy

Severe mental disorder

Previous upper abdominal surgery (except laparoscopic

cholecystectomy)

Previous gastrectomy, endoscopic mucosal resection, or

endoscopic submucosal dissection

Other malignant disease within the past 5 years

Enlarged or bulky regional lymph node (diameter over 3cm) supported by preoperativeimaging including enlarged or bulky No.10 lymph nodes

Previous neoadjuvant chemotherapy or radiotherapy

Unstable myocardial infarction, angina, or cerebrovascular

accident within the past 6 months

History of continuous systematic administration of corticosteroids

within one month

Forced expiratory volume in one second (FEV1) ＜ 50% of

predicted values

Requirement of simultaneous surgery for other disease

Emergency surgery due to complication (bleeding, obstruction or

perforation) caused by gastric cancer

Withdraw

Criteria

Patients intraoperatively/postoperatively confirmed as M1:

preoperative examination revealed no evidence of distant metastasis

but intraoperative exploration/postoperative pathological examination

confirmed distant metastases (liver, peritoneum, pelvic metastasis, and

distant lymph node metastasis, among others); the peritoneal lavage

cytological examination result is positive after the operation



IV

Patients intraoperatively/postoperatively confirmed as T4b

Patients intraoperatively confirmed as unable to complete D2 or D2-

lymph node dissection/R0 resection due to tumor: unable to complete

R0 resection due to regional lymph node integration into a mass or

surrounded with important blood vessels that cannot be resected

Intraoperative spleen and spleen vessels have obvious tumor

infiltration requiring combined splenectomy

Simultaneous surgical treatment of other diseases

After enrollment, a serious comorbidity (unable to tolerate surgery or

anesthesia) occurred before surgery, and the treatment plan for the

study is not suitable or could not be implemented as planned

Patients confirmed to require emergency surgery by attending

physicians due to changes in the patient's condition after inclusion in

this study

Patient requested to withdraw or suspend treatment for personal

reasons at any stage after the patient enrolled the study

Treatment implemented is proven to violate study protocol

Interventio

n

For patients who are assigned to D2 group, LATG with D2 lymph node

dissection (including spleen-preserving No. 10 lymph node dissection) will

be performed

Endpoints

Primary Outcome Measures:

3-year disease-free survival rate

Secondary Outcome Measures:

Postoperative morbidity and mortality in 30 days

Intraoperative morbidity rate

Number of retrieved LNs

Number of retrieved No. 10 LN

Metastasis rate of No. 10 LN

3-year overall survival rate

3-year recurrence pattern

Rate of splenectomy

Postoperative recovery course

Postoperative nutritional status and quality of life



V

Inflammatory and immune response

Technical performance

The Surgery Task Load Index (SURG-TLX)

LN noncompliance rate

Statistical

Considerati

ons

Statistical analysis will be performed using SPSS 18.0 statistical software.

In addition to the non-inferiority validation of the primary efficacy and

safety indicators, other analyses used a differential test. All statistical tests

will be performed using a two-sided test. The statistically significant test

level is set at 0.05, and the interval of the parameters is estimated to be a

95% confidence interval. Baseline data and validity analyses will be

performed using a modified intent-to-treat (MITT) analysis. The main

efficacy indicators are simultaneously analyzed by a per-protocol (PP)

basis, but the conclusions of the MITT analysis are the main ones. The

safety evaluation will be analyzed by Safety Analysis Population (SAP).

Missing data are not filled. Quantitative data are analyzed by t test,

ANOVA, ANCOVA, and nonparametric tests; qualitative data are

analyzed by Pearson X2 test, CMH test, logistic regression, etc.; grade data

are analyzed by a rank-based nonparametric method; survival data are

analyzed by the KM method and Cox model. Sensitivity analysis is

performed on extreme outlier data. Subgroup analysis are performed in

specific situations



VI

Table of Contents

1. Background---------------------------------------------------------------------------------1

2. Purpose--------------------------------------------------------------------------------------2

3. Study Design--------------------------------------------------------------------------------3

4. Study objects--------------------------------------------------------------------------------3

4.1 Inclusion Criteria-----------------------------------------------------------------------4

4.2 Exclusion Criteria----------------------------------------------------------------------4

4.3 Withdrawal Criteria -------------------------------------------------------------------5

4.4 Selection of Subjects------------------------------------------------------------------6

5. End Point -----------------------------------------------------------------------------------7

5.1 Primary Outcome Measures----------------------------------------------------------7

5.2 Secondary Outcome Measures-------------------------------------------------------7

6. Diagnostic Criteria of This Study--------------------------------------------------------8

7. Qualification of the Participating Surgeons---------------------------------------------9

8. End Point Definition and Relevant Results--------------------------------------------11

9. Standard Operation Procedures (SOPs) -----------------------------------------------16

10. Statistical Analysis ----------------------------------------------------------------------66

11. Data Management -----------------------------------------------------------------------69

12. Relevant Provisions on Adverse Events ----------------------------------------------70

13. Ethical Considerations ------------------------------------------------------------------76

15. References---------------------------------------------------------------------------------81

16. Annex--------------------------------------------------------------------------------------84

16.1 Informed Consent Form-------------------------------------------------------------84



1

1. Background

Worldwide, gastric cancer (GC) is the fourth most common cancer and the

second-leading cause of cancer-related death. Tumor radical surgical resection is the

only treatment possibility to cure gastric cancer patients. The splenic hilar lymph node

(No. 10 LN) is an important station of LNs in the perigastric lymphatic drainage. The

No.10 LN dissection has been admitted for patients with advanced proximal gastric

cancer (APGC) invading the greater curvature according to the Japanese treatment

guidelines for gastric cancer. However, it is still controversial for patients with APGC

not invading the greater curvature.

Previous studies reported that the metastasis rate of the No. 10 LN in APGC is

ranged 8.4%～ 20.9%, and the dissection of No.10 LN was closely related to the

long-term survival. Chikara found that the 5-year survival rate of the No. 10 and No. 11

LN positive was significantly lower than that of the negative (23.8% vs. 41.4%,

P<0.05). Therefore, it is necessary to dissect No. 10 LN of locally advanced GC

through radical D2 surgery. Splenectomy was once performed simultaneously for

achieving No. 10 LN dissection. However, a series of prospective randomized

controlled trial (RCT) have confirmed that splenectomy should be avoided as it

increases operative morbidity and mortality without improving survival compared to

spleen preservation surgery. Therefore, spleen-preserving No. 10 LN dissection has

been accepted by more and more surgeons. However, due to the deep position and

narrow anatomical space, it is difficult to obtain a well vision during open surgery for

No.10 lymphadenectomy. Additionally, factors such as: variation of splenic vessels,



2

multiple splenic lobe of vessels branches, adhesion of omentum and spleen, making the

spleen-preserving No.10 lymphadenectomy (SPL) surgery difficult, and injury of the

spleen or splenic vessel occur frequently. Therefore, how to perform SPL safely and

effectively is one of the focuses of current research.

Because of the development of laparoscopic surgical equipment and the

improvement of surgeons’ skills, laparoscopic gastrectomy (LG) involves no more work

or stress than open gastrectomy (OG) for surgeons in East Asian countries, such as

Korea, Japan, and China, which are endemic areas of gastric cancer. Surgeons in South

Korea and Japan first performed laparoscopic spleen-preserving No. 10 LN dissection

(LSPL) for PGC and determined that the operation was safe and feasible. Subsequently,

studies have confirmed the safety, feasibility and oncological efficacy of LSPL. Our

center proposed a new technique named Huang’s three-step maneuver for LSPL, which

simplifies the No.10 lymphadenectomy, and makes it more safety and easier to learn.

Therefore, since there was no consensus on whether No.10 LN dissection is

needed for APGC without greater curvature invaded during D2 lymphadenectomy, we

designed a prospective, randomized trial to compare the surgical outcomes between

laparoscopy-assisted total gastrectomy (LATG) with D2 lymphadenectomy (D2 Group)

and D2- No.10 LN (D2- Group) for APGC not invading greater curvature.

2. Purpose

To compare the short-term and long-term outcomes between LATG with D2

lymphadenectomy (D2 Group) and D2-No.10 LN (D2- Group) for advanced proximal

gastric cancer (cT2-4a, N0/+, M0) not invading greater curvature.



3

3. Study Design

Prospective, single center, open, parallel assignment, randomized controlled

3.1 Single center

Department of gastric surgery in Fujian Medical University Union Hospital

3.2 Case group

Group A (Study Group): LATG with D2 lymphadenectomy (D2 group)

Group B (Control Group): LATG with D2-No.10 lymphadenectomy (D2- group)

3.3 Estimate sample size

The projected 3-year disease free survival (DFS) rate of the D2 and D2- groups

were 61.6% and 53.7% respectively. According to the noninferiority design, this

analysis was based on an α of 0.025, a power of 90%, and a margin delta of 7.2%,

revealing that at least 224 patients would be necessary per group. Considering an

expected dropout rate of 20%, it was determined that each group needed at least 268

patients. The sample size was calculated by using nQuery Advisor 7.0 (Statistical

Solutions, Cork, Ireland).

3.4 Blind method：This research adopts an open design

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 3 years after

the enrollment of the last case.

Estimated time: 2015.01-2019.01（ to complete enrollment） - 2022.01（ to

complete follow-up）

4. Study objects



4

After clinical staging, 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 between 18 and 75 years

(2) Endoscopic biopsy confirmed primary gastric adenocarcinoma (including pap, tub,

muc, sig, and por) of the proximal stomach not invading the greater curvature

(3) cT2-4a, N0/+, M0 at preoperative evaluation according to the AJCC Cancer Staging

Manual, 7th Edition

(4) No distant metastasis, no significantly enlarged lymph nodes around abdominal

main artery, no direct invasion of pancreas, spleen or other adjacent organs in the

preoperative examinations

(5) Performance status of 0 or 1 on ECOG scale

(6) ASA class I, II, or III

(7) Written informed consent

4.2 Exclusion Criteria

(1) Women during breast-feeding or pregnancy

(2) Severe mental disorder

(3) Previous upper abdominal surgery (except laparoscopic cholecystectomy)

(4) Previous gastrectomy, endoscopic mucosal resection, or endoscopic submucosal

dissection

(5) Other malignant disease within the past 5 years

(6) Enlarged or bulky regional lymph node (diameter over 3cm) supported by



5

preoperative imaging including enlarged or bulky No.10 lymph nodes

(7) Previous neoadjuvant chemotherapy or radiotherapy

(8) Unstable myocardial infarction, angina, or cerebrovascular accident within the past

6 months

(9) History of continuous systematic administration of corticosteroids within one month

(10) FEV1＜50% of predicted values

(11) Requirement of simultaneous surgery for other disease

(12) Emergency surgery due to complication (bleeding, obstruction or perforation)

caused by gastric cancer

4.3 Withdraw Criteria

(1) Patients intraoperatively/postoperatively confirmed as M1: preoperative

examination revealed no evidence of distant metastasis but intraoperative

exploration/postoperative pathological examination confirmed distant metastases (liver,

peritoneum, pelvic metastasis, and distant lymph node metastasis, among others); the

peritoneal lavage cytological examination result is positive after the operation;

(2) Patients intraoperatively/postoperatively confirmed as T4b

(3) Patients intraoperatively confirmed as unable to complete D2 or D2- lymph node

dissection/R0 resection due to tumor: unable to complete R0 resection due to regional

lymph node integration into a mass or surrounded with important blood vessels, which

cannot be resected;

(4) Intraoperative spleen and spleen vessels have obvious tumor infiltration requiring

combined splenectomy



6

(5) Simultaneous surgical treatment of other diseases

(6) After enrollment, a serious comorbidity (unable to tolerate surgery or anesthesia)

occurred before surgery, and the treatment plan for the study is not suitable or could not

be implemented as planned

(7) Patients confirmed to require emergency surgery by attending physicians due to

changes in the patient's condition after inclusion in this study

(8) Patients who request to withdraw or suspend treatment for personal reasons at any

stage after the patient is enrolled the study

(9) Treatment implemented is proven to violate study protocol

4.4 Selection of subjects

After clinical staging, all patients who meet the inclusion criteria and do not

conform to the exclusion criteria are qualified for this study.

(1) Patients should meet the following conditions when they are admitted to the hospital

and undergo physical examination: age >18 and <75 years; preoperative ECOG

performance score of 0/1; non-pregnant or lactating women; no serious mental illness;

no history of abdominal surgery (except for laparoscopic cholecystectomy); no history

of gastric surgery (including ESD/EMR for gastric cancer); no other malignant disease

history within five years; no history of unstable angina or myocardial infarction within

six months; no history of sustained systemic corticosteroid therapy within one month;

no requirement for simultaneous surgical treatment of other diseases; pulmonary

function test with FEV1 ≥50% of the expected value; and no history of cerebral

infarction or cerebral hemorrhage within six months.



7

(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 is performed on the patient,

and no enlarged lymph nodes (maximum diameter ≥ 3 cm) are 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 is found in the spleen

and spleen vessels.

(3) Patient is explicitly diagnosed with APGC, has a preoperative staging assessment of

T2-4a, N0-3, M0 not invading the greater curvature.

(4) Patients do not require neoadjuvant chemoradiotherapy or chemotherapy and the

attending doctor does not recommend that they receive neoadjuvant chemoradiotherapy

or chemotherapy.

(5) Patient's ASA score is I-III.

(6) Patient does not require emergency surgery.

(7) At this time, the patient becomes potentially eligible.

5. End Point

5.1 Primary Outcome Measures

3-year disease-free survival rate

5.2 Secondary Outcome Measures

Postoperative morbidity and mortality in 30 days



8

Intraoperative morbidity rate

Number of retrieved LNs

Number of retrieved No. 10 LN

Metastasis rate of No. 10 LN

3-year overall survival rate

3-year recurrence pattern

Rate of splenectomy

Postoperative recovery course

Postoperative nutritional status and quality of life

Inflammatory and immune response

Technical performance

The Surgery Task Load Index (SURG-TLX)

LN noncompliance rate

6. Diagnostic Criteria for This Study

(1) The AJCC-7th 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).

(3) Definition of advanced stage: tumor infiltration of the stomach wall reaches or

exceeds the inherent muscular layer (T2); T2, T3, and T4a patients will be included as



9

study subjects, whereas T4b patients will not.

(4) Definition of upper gastric cancer: According to "Japanese classification of gastric

carcinoma: 3rd English edition", the stomach is anatomically divided into three portions,

the upper (U), middle (M), and lower (L) parts, by the lines connecting the trisected

points on the lesser and greater curvatures. Proximal gastric cancer is defined as: the

tumor center is located in the upper or middle part of the stomach (U/M), and the upper

edge of the tumor does not involve the esophagus (bounded by the dentate line

connecting the esophagus and the stomach), as shown in Fig. 1.

Fig. 1. The three portions of the stomach. U upper third, M middle third, L lower

third, E esophagus, D duodenum.

(5) No. 10 LN definition: According to "Japanese classification of gastric carcinoma:

3rd English edition", No. 10 LNs are defined as: splenic hilar LNs, including those

adjacent to the splenic artery distal to the pancreatic tail, those on the roots of the short

gastric arteries and those along the left gastroepiploic artery proximal to its 1st gastric

branch.



10

7. Qualifications of the participated Surgeons

7.1 Basic principle

All candidate surgeons in our study met the following criteria:

Performed at least 50 LATG.

Pass the blind surgical video examination.

7.2 Checklist for determination of success about D2 lymphadenectomy

Scoring Method for D2 Lymph Node Dissection Complete Incomplete None

10 5 0

1. Properly full omentectomy

2. Ligation of right gastroepiploic artery at origin

3. Full exposure of common hepatic artery

4. Ligation of right gastric artery at origin

5. Exposure of portal vein

6. Exposure of splenic artery to branch of posterior gastric artery

7. Ligation of left gastric artery at origin

8. Ligation of left gastroepiploic artery at origin

9. Ligation of all posterior and short gastric artery at origin

10. Exposure of gastroesophageal junction

□ □ □

□ □ □

□ □ □

□ □ □

□ □ □

□ □ □

□ □ □

□ □ □

□ □ □

□ □ □

1. Properly full omentectomy

a. Omentectomy was performed close to transverse colon

b. Omentectomy was performed from hepatic flexure to splenic flexure

c. Anterior layer of transverse colonic mesentery and pancreatic anterior peritoneum



11

was dissected.

4. Full exposure of common hepatic artery

a. More than half of anterior part in the common hepatic artery were exposed.

7. Exposure of splenic artery

a. Anterior part in splenic artery was exposed.

b. Splenic artery was exposed from celiac trunk to the terminal branch of the splenic

artery

10. Exposure of gastroesophageal junction

a. Anterior, posterior, left and right side of the abdominal esophagus were exposed.

- D2 lymphadenectomy was accepted if all randomly assigned three investigators rated

85 points and more regarding checklists in unedited video review.

8. End Point Definition and Relevant Results

8.1 Incidence of Operative Complications

8.1.1 Postoperative Complication Rate

The number of patients undergoing surgery is the denominator, and the number of

patients with any of the following postoperative complications is calculated as the

numerator.

Postoperative overall complication rate: Postoperative complications are based on

early surgical complications as mentioned in the postoperative observation program.

The time is defined as within 30 days after surgery, or if the postoperative hospital stay

is >30 days, as the date of the first hospital discharge.

8.1.2 Intraoperative Complications Rate



12

With the number of patients undergoing surgery as the denominator, the number of

patients with any of the following intraoperative complications is calculated as

numerator. Intraoperative complications are based on the intraoperative complications

mentioned in the intraoperative observations

8.1.3 Splenectomy Rate

The number of patients undergoing surgery is the denominator, and the number of

patients who had undergone splenectomy due to intraoperative vascular injury or spleen

injury is calculated as the numerator.

8.1.4 Surgical Mortality

The number of all patients receiving surgery is the denominator, and the number of

patients in any of the following situations is the numerator; the denominator and

numerator are used to calculate proportions. This proportion indicated the operative

mortality ratio.

Situations: patients whose death is identified according to documented

intraoperative observation items, including patients who died within 30 days after the

surgery (including 30 days) regardless of the causality between the death and the

surgery, and patients who died more than 30 days after the surgery (whose death is

proven to have a direct causal relationship with the first operation).

8.2 Overall Survival Time

Overall survival is calculated from the day of surgery until death or until the final

follow-up date, whichever occurs first. For surviving subjects, the end point is the last

confirmed date of survival. If loss to follow-up occurs, the end point is the final date



13

that survival can be confirmed.

8.3 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 any one image examination (X-ray, ultrasound, CT,

MRI, PET-CT, endoscope, etc.) and, if a variety of imaging examinations are performed,

the results without contradiction determine "recurrence". The earliest date that

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 clinical history and physical

examination is defined as the "recurrence date".

(3) For cases without imaging or a 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 cannot be diagnosed as a

relapse.

8.4 Disease-free Survival: DFS

Disease-free survival is calculated from the day of surgery to the day of recurrence

or death. In the event that neither death nor recurrence of the tumor are observed, the

end point is the final date that a patient is confirmed as relapse-free.

8.5 Determination of Surgical Results

8.5.1 Time of operation: from the beginning of the skin incision to the completion of



14

suturing.

8.5.2 Postoperative Rehabilitation Indicators

8.5.2.1 Time to step out of bed, start bowel function, and restore liquid food and

semi-liquid food

Starting from postoperative day 1 to the first postoperative discharge, with initial

recognition of the earliest time for ambulation and the start of bowel function

(flatulence/bowel movement), to restoration of a fluid/semi-fluid diet; records are made

hourly.

Flatulence/bowel movement on the day of surgery is excluded.

In case of no ambulation/flatulence/bowel movement/restoration of a

liquid/semi-liquid diet before the first postoperative discharge, the discharge time

should be recorded as the time of ambulation/flatulence/bowel movement/restoration of

a liquid/semi-liquid diet.

The initial time of ambulation/flatulence/bowel movement/restoration of a

liquid/semi-liquid diet is per patient report.

8.6 Ratio of Conversion to Open Surgery

Ratio, expressed as a percentage, of conversion to open surgery will be calculated

with the number of patients converting to open surgery from a laparoscopy surgery for

any reason as the numerator and the number of patients undergoing laparoscopic

surgery treatment as per protocol among all patients receiving surgical treatment as the

denominator.

An incision length of > 10 cm is defined as a case of conversion to open surgery in



15

this study.

8.7 Technical performance

Technical performance was assessed by the Objective Structured Assessments of

Technical Skills (OSATS) and the Generic Error Rating Tool (GERT).

Detailed global 5-point rating scale for OSATS was shown inPlease rate the performance of surgeon on the following scale:

Respect for tissue

1 2 3 4 5

Frequently used unnecessary

force on tissue or caused

damage by inappropriate use

of instruments.

Careful handling of tissue but

occasionally caused inadvertent

damage.

Consistently handled tissues

appropriately with minimal

damage.

Time and motion

1 2 3 4 5

Many unnecessary moves. Efficient time/motion but some

unnecessary moves.

Economy of movement and

maximum efficiency.

Instrument handling

1 2 3 4 5

Repeatedly makes tentative or

awkward moves with

instruments.

Competent use of instruments

although occasionally appeared stiff

or awkward.

Fluid moves with instruments and

no awkwardness.

Knowledge of instruments

1 2 3 4 5

Frequently asked for the wrong

instrument or used an

inappropriate instrument.

Knew the names of most

instruments and used appropriate

instrument for the task.

Obviously familiar with the

instruments required and their

names.

Use of assistants

1 2 3 4 5

Consistently placed assistants

poorly or failed to use

assistants.

Good use of assistants most of the

time.

Strategically used assistant to the

best advantage at all times.

Flow of operation and

forward planning

1 2 3 4 5

Frequently stopped operating

or needed to discuss next

move.

Demonstrated ability for forward

planning with steady progression of

operative procedure.

Obviously planned course of

operation with effortless flow

from one move to the next.

Knowledge of specific

procedure

1 2 3 4 5

Deficient knowledge. Needed

specific instruction at most

operative steps.

Knew all important aspects of the

operation.

Demonstrated familiarity with all

aspects of the operation.

8.8 The Surgery Task Load Index

Surgeons were asked to complete one Surg-TLX questionnaire for each procedure in

both studies after surgery, consisting of 6 subscales addressing mental, physical, and



16

temporal demands, task complexity, situation, and distrations. All questions were rated

on a 20-point scale (0 = low, 20 = high).

8.9 Lymph node noncompliance rate

Lymph node noncompliance was defined as the absence of lymph nodes that

should have been excised from more than 1 lymph node station. Major lymph node

noncompliance was defined as more than 2 intended lymph node stations that were not

removed.

9. Standard Operating Procedures (SOPs)

9.1 Case Selection

9.1.1 Selection of Assessment Items



17

Clinical examination data of patients conducted from hospital admission to

enrollment into this study (time period is usually 1 week) will be considered baseline

data and must include:

(1) Systemic status: ECOG score, height, weight

(2) Peripheral venous blood: hemoglobin (Hb), red blood cell count (RBC), white blood

cell count (WBC), lymphocyte count (LYM), neutrophils (NEU), neutrophil percentage

(NEU%), platelet count (PLT), monocytes (MONO)

(3) Blood biochemistry: albumin, prealbumin, total bilirubin, indirect bilirubin,

bilirubin direct, AST, ALT, cholesterol, creatinine, urea nitrogen, fasting glucose, K, Ca,

Cl, Na, CRP

(4) Serum tumor markers: CEA, CA19-9, CA72-4, CA12-5, AFP

(5) Full abdominal CT (slice thickness of 10 mm or less; in case of allergy to the

contrast agent, only CT horizontal scanning is allowed)

(6) Upper gastrointestinal endoscopic ultrasonography (EUS) and biopsy. If EUS is not

possible, ordinary upper gastrointestinal endoscopy and biopsy will be used 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



18

accepted.

9.2 Preoperative Management

After eligibility is obtained, surgery should be performed within two weeks

(including the 14th day).

In the case of any deterioration of clinical conditions from the selection time to the

expected day of surgery, whether to undergo the elective surgery as planned should be

decided in accordance with the judgment of the doctor in charge. If an emergency

surgery is required, the case should be withdrawn from the PP set according to 4.3

Withdrawal Criteria.

For patients with nutritional risks, preoperative enteral/parenteral nutritional

support is allowed.

For elderly patients, smokers, and high-risk patients with diabetes, obesity, or a

past history of chronic cardiovascular/cerebrovascular or thromboembolic problems,

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 can decide on

the most appropriate approach according to clinical practice and should record the

approach in the CRF.

Preoperative fasting, water deprivation and other before-anesthesia patient

requirements should follow the conventional anesthesia program of the research center,

which are not specified in this study.



19

For prophylactic antibiotics, the first intravenous infusion should begin 30 minutes

prior to 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 time period mentioned.

Patient data to be collected during the preoperative period also includes C-reactive

protein (CRP).

9.3 Standardization of Surgical Procedures

9.3.1 Principle of Surgical Treatments for both group

9.3.1.1 Anesthesia

Surgery is performed with endotracheal intubation under general anesthesia; the

decision to use epidural-assisted anesthesia depends on the anesthetist and is not

regulated in this study.

9.3.1.2 Acquisition of Peritoneal Lavage Cytological Specimens

After laparotomy, peritoneal lavage cytological specimens will be taken first for

postoperative examination (specific method: draw ascites if they are found; if no ascites

are found, 100 ml of physiological saline will be slowly injected into the abdominal

cavity; the irrigation sample will be collected at the pouch of Douglas for examination).

9.3.1.3 Intraoperative Exploration



20

After acquiring peritoneal lavage cytological specimens, explore the abdominal

cavity for any peritoneal, hepatic, pelvic, or mesenteric metastases and gastric serosal

invasion.

9.3.1.4 Gastrectomy Regulations

Follow the Japanese Gastric Cancer Treatment Guideline (fourth edition for

physicians, May. 2014) to perform total gastrectomy under the premise of satisfying the

oncological principles.

9.3.1.5 Regulations Regarding Greater Omentum Resection

This study protocol requires total greater omentum resection.

9.3.1.6 Regulations Regarding Digestive Tract Reconstruction

The digestive tract reconstruction method is determined by the surgeon according to

his own experience and the specific intraoperative situation. If instrumental

anastomosis is used, the surgeon determines whether manual reinforced stitching of the

anastomotic stoma is to be performed; the study protocol does not specify.

9.3.1.7 Regulations Regarding Surgery-related Equipment and Instruments

The energy equipment, vascular ligation method, digestive tract cutting closure,

and digestive tract reconstruction instruments are determined by the surgeon

responsible for surgery based on experience and actual needs and are not specified in

this study protocol.

9.3.1.8 Regulations Regarding Gastric Canal and Peritoneal Drainage Tube

Whether the gastric canal or peritoneal drainage tube is left after surgery is

determined by experience and actual needs and is not specified in this study protocol.



21

9.3.1.9 Regulations Regarding Concurrent Surgical Treatments

If another organ/system disease is present, the responsible surgeon and the relevant

department consultants will jointly decide whether a concurrent operation is required

and can be performed. The order is determined according to the clinical routine, but

these cases will be excluded from the PP set according to the Exclusion Criteria.

9.3.1.10 Regulations Regarding the Processing of Excluded Patients Identified

Intraoperatively

If the patient is judged to meet the exclusion requirements during the operation,

the study approach will be suspended, and the responsible surgeon will decide upon the

subsequent treatment according to the clinical practice of the research center (the

therapeutic decision, such as whether to excise the gastric primary focus or metastases,

is determined by the responsible surgeon). Data collection and follow-up are still

necessary for the excluded subject and should be incorporated into the ITTP analysis.

9.3.1.11 Regulations Regarding Photography/Imagery

Use a digital camera (at least 8 megapixels) to take pictures; the photo content

required is as follows (see example):

(1) Field of lymph node dissection (6 pictures)

Inferior pylorus region (1 picture); the right gastroepiploic arteriovenous cut site

should be included.

Right-side area of the superior margin of the pancreas (1 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.



22

Left-side region of the superior margin of the pancreas (1 picture); the left gastric

arteriovenous cut position, celiac arterial trunk and proximal splenic artery should be

included.

Right side of the cardia and lesser gastric curvature side (1 picture).

Left gastroepiploic vessel dividing position (1 picture); the cut site of the left

gastroepiploic artery and vein should be included.

Splenic hilus region (1 picture); the cut sites of the distal splenic artery and short

gastric vessel should be included.

(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

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).



23

Fig. 2-1 Inferior pylorus area (no. 6 lymph node)

Fig. 2-2 Right-side area of the superior margin of the pancreas (no. 5, no. 8a and no.

12a lymph node)



24

Fig. 2-3 Left-side area of the superior margin of the pancreas (no. 7, no. 9 and no. 11p

lymph nodes)

Fig. 2-4 Right side of the cardia and lesser gastric curvature side (the no. 1 and no. 3

lymph node)



25

Fig. 2-5 Cut site of the left gastroepiploic vessel (no. 4 sb lymph nodes)

Fig. 2-6 Splenic hilus area (no. 11d and no. 10 lymph nodes)



26

Fig. 2-7 Incision appearance (mark the incision length)

Fig. 2-8 Specimen observation (before dissection)



27

Fig. 2-9 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)

Fig. 2-10 Specimen observation (the distance between the tumor edge and the proximal

incisional margin)



28

Fig. 2-11 Specimen observation (the distance between the tumor edge and the distal

incisional margin)

9.3.1.12 Regulations Regarding Photo/Image Naming and Privacy Protection

(1) No image data shall disclose the personal information of patients.

(2) When the photos/images are viewed or reviewed, personal information must be

processed with mosaics or be covered.

(3) The photographed parts should be marked with a unified Chinese name: inferior

pylorus area; left gastroepiploic vessel cut site; right-side area of superior margin of the

pancreas; left-side area of superior margin of the pancreas; right side of the cardia and

lesser gastric curvature side; splenic hilus area; 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).



29

For example:

Photo Name: [D2 group-subject's random number - Inferior pylorus area]/ [D2-

group-subject's random number - Inferior pylorus area]

Folder name: [D2 group-subject's random number]/ [D2- group-subject's random

number]

9.3.1.13 Basis for Confirming the Quality of Surgery

To confirm the appropriateness of the surgical procedure, surgery quality,

(auxiliary) incision length and specimen integrity will be assessed using the

photographs saved (as stated above). The whole laparoscopic surgery procedure will be

videotaped, and the unclipped image files will be saved.

9.3.1.14 Storage of Image 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 Regarding Laparoscopy Surgery

9.3.2.1 Regulations Regarding Pneumoperitoneum

Carbon dioxide will be used to maintain the pressure of the pneumoperitoneum at 12-13

mmHg.



30

9.3.2.2 Regulations Regarding Punctures andAuxiliary Incision

The positions of punctures and the 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 must be less than 10 cm in normal cases. However, if

the body mass index (BMI) of the patient is greater than 25, the length of the incision

should be less than 13 cm.

If the auxiliary small incision needs to be longer than 10 cm (patients with a

BMI>25 and an incision greater than 13 cm), the surgeon in charge should indicate this

specification and record the reasons in the CRF.

9.3.2.3 Definition of the Laparoscopic Approach

Operations within the abdominal cavity must be performed with laparoscopic

instruments with the support of a camera system.

Perigastric disassociation, greater omentum excision, omental bursa excision,

lymph node dissection, and vessel handling are completed under laparoscopic guidance.

Procedures for gastrectomy and digestive tract reconstruction performed outside

the abdomen through small auxiliary incisions are allowed.

9.3.2.4 Regulations Regarding Laparoscopic No. 10 Lymph Node Dissection with

Spleen Preservation

Dissection of the No. 10 lymph nodes should be performed under laparoscopic

guidance. The LN dissection extent of D2 group includes No. 1, 2, 3, 4, 5, 6, 7, 8a, 9,

10, 11 and 12a LN, while the LN dissection extent of D2- group includes 1, 2, 3, 4, 5, 6,



31

7, 8a, 9, 11 and 12a.

9.3.2.5 Regulations Regarding 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 anesthesiologists and surgeons 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 convert the operation to laparotomy due to other

technical or equipment problems and record the reasons.

There is no limit to the length of the incision for conversion to open surgery in

this study.

The reasons for the conversion to open surgery shall be clearly recorded in the

CRF.

Cases for which the length of the auxiliary incision is more than 10 cm (or for

cases of patients with a BMI≥25 and an incision greater than 13 cm) will be regarded as

conversion to open surgery.

9.3.2.6 Subsequent Treatment of Patients Excluded from the Laparoscopic Group

Whether to proceed with laparoscopic surgery or convert to laparotomy will be

determined by the surgeon in charge according to clinical experience.

9.3.3 Observation Items during Surgery

The research assistant should fill in the appropriate content on the day of surgery.



32

The specific items include the following:

(1) Name of surgeon in charge

(2) Operation duration (min)

(3) Operation type, extent of lymph node dissection, reconstruction method,

intraoperative injury

(4) Incision length (cm)

(5) Whether the operation will be converted to laparotomy and the reasons

(6) Estimation of intraoperative blood loss [ml; from skin cutting to stitching,

intraoperative blood loss = [postoperative gauze weight (mg) - preoperative gauze

weight (mg)] * 1 ml/mg + suction drainage fluid (ml).

(7) Blood transfusion (ml): the blood transfusion event is defined as component

transfusion (ml) or whole blood transfusion (ml) in this study

(8) Tumor location (U/M) and position (lesser curvature, anterior wall/posterior wall,

whether tumor surrounds the whole wall)

(9) Tumor size (maximum diameter, in mm)

(10) Tumor invasion depth, total number of dissected lymph nodes, number of dissected

lymph nodes of each group, distant metastasis (position)

(11) Length of proximal margin (mm), length of distal margin (mm), radical degree of

operation (R0/R1/R2)

(12) Intraoperative complications (occurring during the time period from skin cutting to

completion of skin stitching):

Intraoperative complications are defined as follows:



33

A. Vessel injury: vessel injury is defined when the bleeding should be controlled by

vascular clip or titanium clip and intraoperative vascular ligation or other method.

B. Injury of other organs: includes the following types: phrenic injury, esophageal

injury, duodenal injury, colon injury, small intestine injury, spleen injury (excluding

ischemia of less than 1/3 of the spleen), hepatic injury, pancreatic injury, gallbladder

injury and renal injury.

C. Pneumoperitoneum-related complication: hypercapnia, pneumomediastinum,

subcutaneous emphysema, aeroembolism and respiratory and circulatory disfunction

caused by the pressure of pneumoperitoneum, etc.

D. Anesthetization-related complication: anaphylaxis

(13) Intraoperative death (occurring during the time period from skin cutting to

completion of skin stitching) for any reason

(14) Whether the spleen has been resected and the reasons for dissection

9.4 Postoperative Management

9.4.1 Preventive Use of Analgesics

Continuous postoperative prophylactic intravenous analgesia is allowable but not

mandatory within postoperative 48 hours; which 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 surgery, unless it is judged necessary.

9.4.2 Fluid Replacement and Nutritional Support

Postoperative fluid infusion (including glucose, insulin, electrolytes, vitamins, etc.)



34

or nutritional support (enteral/parenteral) will be performed based on doctor's

experience and routine clinical practice; there is no specified regulation in this study.

After oral feeding, it is allowable to stop or gradually reduce fluid

infusion/nutritional support.

9.4.3 Postoperative Rehabilitation Management

Management methods for 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 Patient Discharge Standards

Patients should meet the following criteria for discharge: 1) satisfactory intake of a

soft diet for two meals; 2) limited self-care ability; and 3) absence of complications by

routine clinical examinations.

Discharge shall be recorded in the CRF.

9.4.5 Postoperative Observation Items

Definition of "postoperative day n": A day is from 0:00 to 24:00. Up to 24:00 after

surgery is "postoperative day 0"; the next day from 0:00 up to 24:00 is “postoperative

day 1"; and so on.

From the first postoperative day until hospital discharge, the research assistant

should fill in the following items in a timely manner:

(1) Pathological Results:

Original lesion tissue typing (papillary adenocarcinoma [pap], tubular



35

adenocarcinoma [tub], mucinous adenocarcinoma [muc], signet ring cell

carcinoma [sig], and poorly differentiated adenocarcinoma [por])

Tumor invasion depth

Distant metastasis, and position (including intraperitoneal exfoliative cytology)

Histological grading (G1/G2/G3/G4/Gx)

Radical surgery degree (R0/R1/R2)

(2) Postoperative complications:

Postoperative complications divided into early postoperative complications and

postoperative complications. Time definition of "Early stage": Within 30 days after

surgery, or if the postoperative hospital stay is >30 days, it is the first hospital discharge

time. Time definition of "Late stage": 30 days after surgery or above, or after the first

discharge (postoperative days > 30 days) to 3 years after surgery. The diagnostic criteria

for complications are as follows:

Classification and name of

complications

Diagnostic criteria

Abdominal hemorrhage Intra-abdominal hemorrhage requires blood transfusion,

emergency endoscopy or surgical intervention to rule out

anastomotic hemorrhage

Anastomotic hemorrhage After the operation, the gastrointestinal decompression tube

continues to have bright red blood flow, and hemoglobin drops

more than 1 g/dL per day.

Gastrointestinal Gastrointestinal angiography shows that the contrast agent has



36

anastomosis leaked from the anastomosis or oral Meilan and shows the blue

drainage fluid of the drainage tube, excluding the duodenal

stump and intestinal fistula.

Duodenal stump Gastrointestinal angiography shows contrast agent leaking from

the duodenal stump, excluding anastomotic leakage and intestinal

fistula

Intestinal fistula Digestive tract angiography shows effusion fluid leakage or oral

Meilan shows blue drainage fluid outflow, excluding anastomotic

leakage and the duodenal stump

Anastomotic stenosis Endoscopic examination via 9.2-mm endoscopy cannot pass the

anastomosis; rule out tumor recurrence

Entering jejunal obstruction Abdominal pain, bloating, vomiting and other symptoms,

combined with abdominal plain film to show a dilated intestinal

fistula in the right upper abdomen, and there is a liquid level, or

barium meal examination finds that the input of the jejunum is

greatly expanded to confirm the diagnosis.

Postoperative intestinal

obstruction

Abdomen X-ray plain film shows multiple fluid levels, indicating

fluid accumulation in the intestinal lumen, and can visualize an

isolated, fixed, and swollen intestinal fistula. Total abdominal CT

shows intestinal wall edema, thickening, adhesion, intestinal

effusion, uniform dilatation of the intestine and exudation in the

abdominal cavity



37

Early dumping syndrome Combined with sweating, heat, weakness, dizziness, palpitations,

heart fullness, vomiting, abdominal cramps or diarrhea,

tachycardia, slightly elevated blood pressure, slightly faster

breathing, etc., within 15 to 30 minutes after eating. At the same

time, a solid phase radionuclide gastric emptying scan indicates

that the stomach is rapidly emptied.

Late dumping syndrome Feeling of hunger, palpitations, and sweating 2-3 hours after a

meal. Blood sugar at the time of onset is less than 2.9 mmol/L,

excluding other diseases that cause hypoglycemia

Intestinal ischemic necrosis Digestive endoscopy shows mucosal congestion, edema,

ecchymosis, submucosal hemorrhage, dark red mucosa,

disappearance of the vascular network, and partial mucosal

necrosis, followed by mucosal shedding, ulcer formation,

ring-shaped, longitudinal, serpentine and scattered ulcers

Guilty Postoperative CT shows cyst or cystic mass, intestinal

aggregation, stretching, displacement, abnormal mesenteric

movement, vascular filling thickening

Alkaline reflux esophagitis 1. Upper gastrointestinal endoscopy and biopsy show evidence of

mucosal inflammation and gastrointestinal metaplasia; 2. CT

scan and gastrointestinal barium meal examination show no input

sputum dilatation or obstruction.

Disruption of wound Including partial slitting and full-layer splitting



38

Abdominal wall incision When standing or exerting force, there is a lump in the scar area

or abdominal wall bulging. CT sees continuous interruption of

the anterior wall of the abdomen.

Incision infection The soft tissue is thickened at the incision, and gas is

accumulated in or out of the incision. The incision is red or

swollen or pus is squeezed out from the incision, or secretion

cultures indicate pathogenic bacteria.

Pulmonitis Meets one of the following two diagnostic criteria: 1.

Auscultation voice/percussion voiced sound + one of the

following: new appearance of sputum or sputum trait changes;

blood culture (+); bronchoalveolar lavage fluid, anti-pollution

sample brush, cultured biopsy specimens indicate pathogenic

bacteria. 2. Chest radiographs suggest new or progressive

infiltration + one of the following: new appearance of sputum or

sputum trait changes; blood culture (+); bronchoalveolar lavage

fluid, anti-pollution sample brush, biopsy specimens that produce

pathogenic bacteria; isolation of virus or detection of respiratory

virus IgM, IgG (+)

Acute pancreatitis Dysphoria, abdominal pain, rebound pain, fever, leukocytosis,

increased serum amylase, diagnosed by B ultrasound or CT

within 3 days after operation.

Acute cholecystitis Serum bilirubin more than 85 μmol/l, B ultrasound shows



39

gallbladder enlargement, wall thickness, cholelithiasis and

acoustic shadow, deposition in bile, gallbladder dyskinesia.

Pleural effusion/infection CT scan shows a localized low-density area of the thoracic

cavity, which can be accompanied by gas accumulation and

secretion of pathogenic bacteria in the thoracic secretions.

Abdominal infection Within 30 days after the operation, the abdominal cavity has at

least one of the following evidences: 1. drainage of pus, a/no

microbiological examination, 2. microbiological culture, 3.

exploration, pathology, and imaging findings can also be

diagnosed.

Pelvic infection Symptoms of systemic infection or rectal irritation, combined

with rectal examination to touch the tender mass or posterior

hernia puncture for to extract purulent fluid married women,

allow diagnosis

Pyemia There are two simultaneous conditions: 1. There is evidence of

active bacterial infection, but blood culture does not necessarily

have pathogenic bacteria; 2. also meets 2 of the following 4: (1)

body temperature > 39.0 ℃ or < 35.5 ℃ for more than 3 days;

(2) heart rate > 120 beats/min; (3) total number of leukocytes >

12.0 × 10 ~ 9/l or < 4.0 × 10 ~ (9)/l, neutrophil > 0.80, or

infantile granulocyte > 0.10; (4) respiratory frequency > 28/min;

Urinary tract infection Frequent urination, urgency, dysuria and other symptoms, and in



40

the absence of antibiotics, urine bacterial culture colony count

1000 ~ 100,000/ml; or no frequent urination, urgency, dysuria

and other symptoms, urine bacterial culture colony count ≥

100,000/ml

Pancreatic fistula The level of amylase in the drainage fluid is more than three

times higher than the normal value of serum.

Bile fistula Abdominal distension, abdominal pain, tenderness, rebound

tenderness, muscle tension, abdominal puncture or drainage fluid

for bile

Chylous fistula The drainage fluid is milky white and >200 mL/d, no reduction

for 48 hours, positive chyme qualitative test, and triglyceride

level >110 mg/dL

Nutritional disorders after

gastrectomy

Patient has weight loss, anemia, malnutrition bone disease,

vitamin A deficiency, etc.; laboratory tests suggest abnormal

intestinal absorption function test; exclude other causes of

nutritional disorders

Metabolic bone diseases

after gastrectomy

There are symptoms of low back pain, shortened length,

hunchback, fracture, etc., and bone density decreases. Combined

with elevated alkaline phosphatase, decreased serum calcium,

serum 25-(O1)D3 and 1,25-(O1)2D3, the concentration of serum

parathyroid hormone increases. Exclude bone diseases caused by

other causes.



41

Subcutaneous emphysema In a flat-position X-ray examination, an irregular spot shadow of

subcutaneous light can be seen.

Mediastinal emphysema In a posterior-anterior-position X-ray examination, there is a

narrow gas shadow that rises along the mediastinum side to the

soft tissue of the neck to form a thin line-like dense shadow. In a

lateral-position X-ray examination, a clear translucent band is

visible between the front of the heart and the sternum. If

necessary, CT examination shows a line of dense gas around the

mediastinum, and the mediastinal pleura moves in the direction

of the lung field.

Postoperative cardiac

dysfunction

No symptoms before surgery, postoperative sinus tachycardia,

sinus bradycardia, supraventricular tachycardia, ventricular

tachycardia and other arrhythmias, or heart failure; exclude the

above symptoms caused by other reasons

Hepatic dysfunction No symptoms before surgery, postoperative bilirubin rise and

AST, ALT > 5 times or more

Renal Failure Postoperative progressive renal insufficiency, serum creatinine

increased by 2 mg/dL, or acute renal failure requires dialysis

treatment.

Cerebral embolism The onset is acute, and there are focal neurological deficits such

as hemiplegia and aphasia. Twenty-four to forty-eight hours after

onset, there is a low-density infarction in the embolization site,



42

the boundary is not clear and there is no obstruction.

Pulmonary embolism Difficulty breathing, chest pain, syncope, shortness of breath,

right heart dysfunction and hypotension, pulmonary angiography

showing filling defects

Lower limb venous

thrombosis

Local tenderness, swelling, purple skin color, combined with

venography to show filling defects.

Mesenteric artery

embolization

Acute abdominal pain, vomiting, diarrhea, abdominal X-ray

findings or intestinal flatness, abdominal angiography allow

filling defects to be diagnosed

DIC 1. There are basic diseases apt to cause DIC. 2. There are more

than 2 clinical manifestations: (1) severe or multiple bleeding

tendency, (2) microcirculatory disorder or shock that cannot be

explained by primary disease, (3) extensive skin mucosal

embolism, focal ischemic necrosis, shedding and ulceration, or

unexplained lung, kidney, brain and other organ failure, (4)

anticoagulant therapy is effective. 3. Laboratory testing meets the

following conditions: (1) there are at least three of the following

experimental abnormalities: platelet count, prothrombin time,

activated partial thromboplastin time, thrombin time, fibrinogen

level, D-dimer, etc., (2) special inspections for difficult or special

cases.

others Complications other than those described above that did not exist



43

before surgery

The severity of complications is graded according to the Clavien–Dindo Complications

Scoring System, and grade IIIA and above are serious complications.

Ⅰ: Postoperative complications of unwanted medication, surgery, endoscopy, and reflex

intervention, but including drug treatments for antiemetics, antipyretics, analgesics,

diuretics, electrolytes, physiotherapy, and wound infections at the bedside;

Ⅱ: Need medication for patients who do not include stage 1 medication, incision

infection requires antibiotic treatment, blood transfusion and total parenteral nutrition

are included;

Ⅲ: Need surgery, endoscopy, radiotherapy

Ⅲa: No need for general anesthesia

Ⅲb: Need general anesthesia

Ⅳ: Life-threatening complications (including central nervous system complications)

require IC (intermittent monitoring) or ICU (intensive care) treatment

Ⅳa: An organ dysfunction (including dialysis)

Ⅳb: Multiple organ dysfunction

Ⅴ: death

(3) Blood test items (days 1, 3, and 5 after surgery):

Peripheral blood routine: Hb, RBC, WBC, LYM, NEU, NEU%, PLTMONO

Blood biochemistry: albumin, prealbumin, total bilirubin, AST, ALT, creatinine, urea

nitrogen, fasting blood glucose, potassium, sodium, chloride, calcium

Immune index: CRP



44

(4) Postoperative rehabilitation evaluation project:

First time to get out of bed (hour)

First anal exhaust/defecation/bowel sound time (hour)

Restore full-flow, half-feed time (hour)

The highest daily body temperature after surgery to discharge (℃)

Time of removal of gastric tube (d), daily gastric drainage (ml)

Time of removal of abdominal drainage tube (d), daily drainage (ml)

Postoperative blood volume before discharge (ml): In this study, the transfusion

event is defined as the input of red blood cell suspension (ml) or whole blood (ml)

Postoperative hospital stay (d): Surgery until the first discharge

9.5 Follow-up

9.5.1 Follow-up cycle and precautions

The study centers have arranged follow-up specialists to follow up all of the subjects

enrolled in the study. Follow-up every 3 months within 2 years after surgery; follow-up

every 6 months after 2 years (i.e., patients are followed up at 1, 3, 6, 9, 12, 15, 18, 21,

24, 30, and 36 months after surgery). This study suggests that the above examinations

should be conducted at the research center where the patient is undergoing surgery, but

a review of an external hospital is not excluded. For review of an external hospital, it is

recommended that the hospital be reviewed as a tertiary hospital, and the follow-up

commissioner will track and record the results of each inspection. The results of each

examination will be combined to assess and record the postoperative survival status of

all patients and whether there is tumor recurrence or metastasis. If the patient refuses to



45

follow up according to the abovementioned protocol, they will be recorded as a lost

subject and analyzed together with the subjects that meet the research criteria at the end

of the study.

9.5.2 Inspection items during follow-up

(1) Full physical examination:

The exam should be carried out by a competent doctor at the time of regular follow-up.

It is necessary to understand the superficial lymph nodes, abdomen and signs of

metastases, etc.

(2) Blood test items:

Peripheral blood routine: Hb, RBC, WBC, LYM, NEU, NEU%, PLT, MONO

Blood biochemistry: albumin, prealbumin, total bilirubin, indirect bilirubin, Direct

bilirubin, AST, ALT, creatinine, urea nitrogen, total cholesterol, triglycerides, fasting

blood glucose, potassium, sodium, chloride, calcium, serum tumor markers: CEA,

CA19-9, CA72-4, CA12-5, AFP

(3) Imaging examination project:

Total abdominal (including pelvic) CT (thickness of 10 mm or less, CT autopsy or

MRI only when allergic to contrast agent), upper gastrointestinal endoscopy

(pathological histological biopsy and endoscopic ultrasound if necessary), chest film

(positive side): lung field condition.

Other assessment methods: gastrointestinal angiography, other parts of color

ultrasound, whole-body bone scan, PET-CT, etc., when the competent doctor thinks it is

necessary.



46

9.5.3 Follow-up procedure

9.6 Postoperative adjuvant therapy

9.6.1 Indications for postoperative adjuvant chemotherapy

After completion of the surgical treatment, according to the postoperative

Postoperative 1

mont

h

3

month

s

6

month

s

9

month

s

12

month

s

15

month

s

18

month

s

21

month

s

2

years

2 and

a half

years

3

years

Actual visit date

Physical

examination

Blood routine

Blood chemistry

Tumor markers

Chest film

Upper

gastrointestinal

endoscopy

Abdominal CT

Full belly color

Other(if

necessary)



47

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 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.



48

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.

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:

Peripheral venous blood assessment: Hb, RBC, WBC, LYM, NEU, NEU%, PLT,

MONO.

Blood biochemistry: albumin, prealbumin, total bilirubin, AST, ALT, creatinine,



49

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

Tumorm

arkers

Electrocardiogram,respiratory

function

Uppergastrointestinalendoscopy

ChestX

-ray,fullabdominalC

TOrultrasound

Eligibilityconfirm

ationnotice

Preoperative,postoperativecom

plications

Adverse

chemotherapy

events

CRF-Preoperative

CRF-Intraoperative

CRF-Postoperative

CRF-treatm

entend

CRF-follow

-upobservation

surgery

Selection Application ○ ○ ○ ○ ○ ○

After selection and

prior to surgery

○ ○

Intraoperative period ○ ○

Early postoperative ○ ○ ○



50

period

Before postoperative

first chemotherapy

○ ○ ○ ○

Regular chemotherapy ○ ○ ○ ○

Follow-up

periodPostoperative

advancedstage

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

○ ○ ○ ○ ○ ○



51

year (±15 days)

At

postoperative

15 months (±15

days)

○ ○ ○ ○ ○

At

postoperative

18 months (±15

days)

○ ○ ○ ○ ○ ○

At

postoperative

21 months (±15

days)

○ ○ ○ ○ ○

At

postoperative 2

years (±15

days)

○ ○ ○ ○ ○ ○

At

postoperative 2

years (±15

days)

○ ○ ○ ○ ○ ○

At ○ ○ ○ ○ ○ ○



52

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 patient's 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 house work, 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 ASAClassification



53

The American Society of Anesthesiologists (ASA) has categorized patients into 5 levels

(I-V levels) according to their physical status and surgical risk before anesthesia as

follows:

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%.

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 an elective surgery.



54

9.8.3 Oncology-related Definitions

In this study, tumor staging is based on AJCC-7; surgical treatment follows the

Japanese Gastric Cancer Treatment Guidelines, Physicians Edition, 4rd Edition, 2014. ,

and other writing and recording principles follow the Japanese Gastric Cancer Statute

14th.

9.8.3.1 Primary Focus Location and Position

The greater and lesser curvature of the stomach are 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. The tumor position

is defined as tumor epicenter located as follow: the stomach’s cross-sectional

circumference is divided into four equal parts: the lesser (Less) and greater (Gre)

curvatures, and the anterior (Ant) and posterior (Post) walls, more than two parts were

defined multiple parts.

Fig. 3. Division of the Three Areas of the Stomach



55

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 lymph node) and M (distant metastasis), which

are expressed in Arabic 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)



56

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) Lymph node metastasis:

NX: Number of lymph node metastases is unknown

N0: No lymph node metastasis

N1: Lymph node metastasis of 1-2 areas

N2: Lymph node metastasis of 3-6 areas

N3: Lymph node metastasis of 7 and more areas

N3a: Lymph node metastasis of 7-15 areas

N3b: Lymph node metastasis of 16 and more areas

Lymph node numbers are defined as follows:

No. Name Definition

1 Cardia right Lymph nodes around the gastric wall first branch (cardia

branch) of ascending branches of the left gastric artery and

those at the cardia sides

2 Cardia left Lymph nodes at the left side of the cardia and those along the

cardia branch of the lower left diaphragmatic artery esophagus



57

3a Lesser gastric

curvature

(along the

left gastric

artery)

Lymph nodes at the lesser curvature side along the left gastric

artery branch, below the cardia branch

3b Lesser gastric

curvature

(along the

right gastric

artery)

Lymph nodes at the lesser curvature side along the right gastric

artery branch, partial left side of the 1st branch in the lesser

curvature direction

4sa Left side of

the greater

gastric

curvature

(short gastric

artery)

Lymph nodes along the short gastric artery (excluding the

root)

4sb Left side of

the greater

gastric

curvature

(along the left

gastroepiploic

Lymph nodes along the left gastroepiploic artery and the first

branch of the greater curvature (refer to the definition of No.

10)



58

artery)

4d Right side of

The greater

gastric

curvature

(along the

right

gastroepiploic

artery)

Lymph nodes at the partial left side of the first branch in the

greater gastric curvature direction along the right

gastroepiploic artery

5 Superior

pylorus

Lymph nodes along the right gastric artery and around the first

branch in the lesser gastric curvature direction

6 Inferior

pylorus

Lymph nodes from the root of the right gastroepiploic artery to

the first branch in the greater gastric curvature direction and

those at the junction of the right gastroepiploic veins and

superior anterior pancreaticoduodenal veins (including the

junction portion)

7 Left gastric

artery trunk

Lymph nodes from the root of the left gastric artery to the

branch portion of the ascending branches

8a Anterior upper

part

of the

common

Lymph nodes at the anterior upper part of the common hepatic

artery (from the branch portion of the splenic artery to the

branch portion of the gastroduodenal artery)



59

hepatic

artery

8p Posterior part

of the

common

hepatic

artery

Lymph nodes at the posterior part of the common hepatic

artery (from the branch portion of the splenic artery to the

branch portion of the gastroduodenal artery)

9 Surrounding

of the celiac

artery

Lymph gland that is in the surroundings of the celiac artery or

that is a part of each root of the left artery of the stomach,

common hepatic artery and splenic artery as well as that

related to the celiac artery

10 Splenic hilum Lymph gland that is in the surroundings of the celiac artery

and splenic hilum far away from the end of the pancreas,

including the first greater gastric curvature in the root of the

short gastric artery and the left gastroepiploic artery

11p Splenic artery

proximal

Lymph gland at the splenic artery proximal (in a location that

divides the distance between the root of the splenic artery and

the end of the pancreas into two equal parts, including the

proximal side)

11d Splenic artery

distal

Lymph gland at the splenic artery distal (in a location that

divides the distance between the root of the splenic artery and

the end of the pancreas into two equal parts, inclining to the



60

end of the pancreas)

12a Within the

hepatoduoden

al

ligament

(along the

proper hepatic

artery)

Lymph gland that is below a location that divides the height of

the confluence portions of the left and right hepatic ducts and

the bile duct in the upper margin of the pancreas into two

equal parts and is along the proper hepatic artery (as stated in

No. 12a2 of the regulations for bile duct carcinoma)

12b Within the

hepatoduoden

al ligament

(along the bile

duct)





No. 12b2 of the regulations for bile duct carcinoma)

12p Within the

hepatoduoden

al ligament

(along the

portal vein)





No. 12p2 of the regulations for bile duct carcinoma)

13 Back of the

pancreatic

head

Lymph gland adjacent to the head of the duodenal papilla at

the back of the pancreatic head (No. 12b in the surroundings of

the hepatoduodenal ligament)

14v Along the Lymph gland that is in the front of the superior mesenteric



61

superior

mesenteric

vein

vein, with the inferior margin of the pancreas on the upper

side, the right gastroepiploic vein and confluence portion of

the superior pancreaticoduodenal vein to the right, the left

margin of the mesenteric vein to the left and the branch of the

middle colic vein in the lower margin

14a Along the

superior

mesenteric

artery

Lymph gland along the superior mesenteric artery

15 Surroundings

of the colon

middle artery

Lymph gland that is in the surroundings of the colon middle

artery

16a1 Surroundings

of the

abdominal

aorta a1

Lymph gland that is in the surroundings of the aorta gap (4 to

5 cm wide in the surroundings of the medial crus of the

diaphragm)

16a2 Surroundings

of the

abdominal

aorta a2

Lymph gland that is in the surroundings of the aorta from the

upper margin of the abdominal artery root to the lower margin

of the left renal vein

16b1 Surroundings

of the


lower margin of the left renal vein to the upper margin of the



62

abdominal

aorta b1

inferior mesenteric artery root

16b2 Surroundings

of the

abdominal

aorta b2


upper margin of the inferior mesenteric artery root to the

branch of aorta

17 Front of the

pancreatic

head

Lymph gland that is in the front of the pancreatic head, next to

the pancreas and under the pancreatic capsule

18 Below the

pancreas

Lymph gland that is in the lower margin of the pancreas

19 Below the

diaphragm

Lymph gland that is in the cavity of the diaphragm and along

the lower side of the diaphragmatic artery

20 Hiatal part of

the gullet

Lymph gland that connects the hiatal part of diaphragm to the

gullet

110 Beside the

lower gullet

Lymph gland that departs from the diaphragm and is next to

the lower gullet

111 Above the

diaphragm

Lymph gland that is in the cavity of the diaphragm and departs

from the gullet (No. 20 that connects to the diaphragm and

gullet)

112 Posterior

mediastinum

Lymph gland of the posterior mediastinum departed from the

gullet and its hiatal portion



63

Fig. 4. Lymph node grouping

(2) Distant metastasis



64

M0: No distant metastasis outside of the regional lymph nodes

M1: Distant metastasis outside of the regional lymph nodes

MX: Presence of distant metastasis is unclear

Record the specific sites under the M1 condition: peritoneum (PER), liver (HEP),

lymph node (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

N0 N1 N2 N3 M1

T1a,T1b IA IB IIA IIB

T2 IB IIA IIB IIIA

T3 IIA IIB IIIA IIIB

T4a IIB IIIA IIIB IIIC

T4b IIIB IIIB IIIC IIIC

Any T/N Ⅳ

9.8.3.3 Pathologic Types and Classifications

9.8.3.3.1 Type

Papillary adenocarcinoma

Tubular adenocarcinoma

Mucinous adenocarcinoma



65

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)

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.



66

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 Set for Statistical Analysis

(1) Intent-to-treat Population (ITTP): Subjects that expressed intention to participate in

the study and signed an informed consent form.

(2) Modified Intent-to-treat Population (MITTP, modified intent-to-treat population):

Subjects that underwent randomization and laparoscopic surgical treatment or

conventional laparotomy, with data records from at least one valid efficacy evaluation

after intervention.

(3) Per-protocol Population (PPP): Subjects complying with the study protocol, with

good compliance and a completed CRF, allowing statistical analysis of the efficacy. The

main analytical results are consistent with those of the MITT analysis.

(4) Safety Analysis Population (SAP): All subjects that underwent randomization and

laparoscopic surgical treatment or conventional laparotomy, with safety evaluation data

records after intervention constituting a safety analysis population of this study,

allowing the statistical description and analysis of safety indicators and the incidence of

adverse reactions.

10.2 Statistical Analysis Plan



67

Statistical software: We will use Epidata3.0 to establish a database and to input

data，and we will use SPSS 18.0 software to perform statistical analyses.

Basic principle: A significance test method is used. All statistical tests used cases

with post-intervention safety evaluation data, which constitute the safety analysis

population of this study, and analyze 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 and analysis of shedding rate due to adverse

events.

Statistical analysis of Population Division: Analyses of baseline data and validity

analyses will be conducted with a modified intent-to-treat (MITT) analysis. The main

efficacy indicators are the incidence of adverse reactions and use of SAP as the

denominator.

Method for the Determination of Outliers: Any observed value that is lower or

higher than the lowest (P25) or highest (P75) interquartile range will be considered an

outlier. In the process of analysis, a sensitivity analysis of the outlier data will be

performed, and the effects of retention and the elimination of outliers will be analyzed;

in the case of no contradictions, the data shall be retained; in the case of any

contradictions, a decision shall be made depending on individual cases.

Descriptive Statistics: The measurement variables are the mean, standard deviation

and confidence interval, and if necessary, the minimum, maximum, P25, median and

P75; the paired measurement variables also consist of the mean and standard deviation



68

of the difference; when using a non-parametric method, the median and average rank

should be shown. Counting variables are the frequency distribution and the

corresponding percentage. Ranked variables are the frequency distribution and the

corresponding percentage, as well as the median and average rank. Qualitative variables

are the positive rate, the number of positives, and the denominator cases. Survival time

data are the number of events and censored numbers, the median survival time, and the

survival rate.

Subgroup analysis: Prognostic factors are analyzed according to the specific

circumstances of the data.

Missing value processing: this study does not fill in missing values.

Effectiveness analysis: Survival data (time and rate) will be analyzed using a log

rank test. Multi-variable and central effect analysis will be conducted using Cox's

proportional hazards model. Quantitative variables are analyzed using Student's t-test or

another t-test (when the variance is not uniform), and categorical variables are analyzed

with the χ2 test. Ranked variables are analyzed with the Wilcoxon rank sum test.

Safety analysis: The incidence of adverse reactions, incidence of adverse events,

and a list of adverse events occurring in this study are collected; describing either

laboratory test results before and after the study to identify normal/abnormal changes or

the relationships between abnormal changes and drugs in the study, and listing the

"normal/abnormal" changes that occurred in this study; the results of laboratory tests

before and after the study of normal/abnormal changes and identification of the

relationship between the drug and these results when abnormal changes occurred. More



69

detailed statistical analysis descriptions can be found 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 prior to surgery (time frame of three days)

(2) Enrolling: submitted to the data center one day prior to 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

11.1.2 CRF Transmittal Methods

In this study, the paper CRF form are used for information and data transmittal.

11.1.3 CRFAmendment

After the start of the study, if the CRF is found to lack items that are deemed

pertinent, under the premises of ensuring that amendment of the CRF does not cause

medical and economic burden and increased risks to the selected patients, the CRF can

be modified after adoption by the Research Committee via discussion at a meeting. If

amendment of the CRF requires no changes to the study protocol, the latter will not be

modified.

11.2 Monitoring and Supervision

To assess whether study implementation follows the protocol and data are being

collected properly, monitoring should be conducted every two months during the



70

follow-up period. Surveillance is completed by visiting the hospital and comparison

with the original data through hospital visits.

11.2.1 Monitoring Items

Data Collection Completion Status:

Eligibility: No eligible patients/potentially ineligible patients

Different end of treatment, the reasons for suspension/end of the study protocol

Background factors, pretreatment report factors, post-treatment report factors when

selected for registration

Severe adverse events

Adverse events/adverse reactions

Proportion of conversion to laparotomy

Protocol deviation

Disease-free survival/overall survival

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 are partly dependent on the qualifications of the participating

research hospitals and their staff; a rate of over 3% is considered unacceptable.

12 Relevant Provisions on Adverse Events

12.1 Surgery-related Adverse Events

See the adverse events mentioned for surgical complications in Definition of the

study endpoint.



71

12.2 Adverse Events Caused byWorsening Primary Diseases

Adverse events related to various forms of deterioration in primary diseases should

be recorded according to the Short Name of CTCAEv3.0, including:

(1) Adverse events caused by deterioration of the primary lesions and peritoneal

disseminated lesions: Gastrointestinal adverse events: loss of appetite, constipation,

dehydration, abdominal fullness, heartburn, nausea, gastrointestinal occlusion [stomach,

duodenum, ileum, colon, small intestine - cannot be broken down], gastrointestinal

perforation [stomach, duodenum, jejunum, ileum, colon], digestive tract stenosis

[stomach, duodenum, jejunum, ileum, colon], vomiting, hyponatremia, gastrointestinal

bleeding [stomach, duodenum, jejunum, ileum, colon]

(2) Adverse events caused by the deterioration of liver metastases: Abnormal

metabolism/laboratory test values: AST, ALT, bilirubin, alkaline phosphatase

(3) Adverse events caused by the deterioration of lung metastases: Lung/upper

respiratory tract: atelectasis, dyspnea, hypoxemia, airway occlusion [bronchial]

(4) Adverse events caused by the deterioration of other focus metastases: Pain: pain

[metastasis sites], hypercalcemia

(5) Adverse events caused by the deterioration of systemic status:

Systemic status: fatigue, weight loss, cachexia quality

Blood/bone marrow: hemoglobin, platelet

Cardiovascular system: hypotension

Lymphatic system: edema: head and neck, limbs, trunk/genitalia, viscera

Metabolic/clinical laboratory values: low albumin, AST, ALT, acidosis, creatinine,



72

hyperglycemia, hypoglycemia, hypernatremia, hyponatremia, hyperkalemia,

hypokalemia, other electrolyte disturbances

Lung/upper respiratory tract: pleural effusion (non-malignant), dyspnea,

hypoxemia, pulmonary infections

Renal/genitourinary system: cystitis, renal failure, oliguria/anuria

12.3 Evaluation of Adverse Events

Evaluation of adverse events/adverse reactions is based on the [Accordion Severity

Grading System] and [CTCAE v3.0]; for more comprehensive detail, refer to sources

for the latter.

Adverse events will be graded 0 ~ 4 as per the 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 the 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 Events" are“all observed, unexpected bad

signs, symptoms and diseases (abnormal value of clinical examination are also included)

in treatment or disposal, regardless of a causal relationship with treatment or handling,

including determining whether there is a causal relationship or not".

Therefore, even if events are "obviously caused by primary disease (cancer)”or



73

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 occurring within 30 days of 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) For adverse events within 31 days of the last treatment day of the study regimen

treatment (protocol treatment), only those determined (adverse reactions, adverse

drug reactions) to have a causal relationship (any definite, probable, possible) with

the protocol treatment will be collected.

12.4 Reporting of Adverse Events

When “severe adverse events” or “unexpected adverse events” occur, the Research

Responsible Person 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



74

medical institutions at the same time. The person in charge of research should hold

accountability and responsibility for the emergency treatment of patients with any

degree of adverse events to ensure patient safety.

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 of the last

treatment day regardless of the presence or absence of a causal relationship with the

study regimen treatment. Additionally, cases of discontinuation of treatment, even if

within 30 days of the last treatment day, 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 are emergent reporting objects.

12.4.1.2 Adverse Events with Regular Reporting Obligations

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).

(3) Unexpected grade 3 adverse events: grade 3 adverse events are not recorded in 12.1



75

expected adverse events.

(4) Other significant medical events: adverse events that the study group deems

important and potentially permanent, with a significant impact on offspring (MDS

myelodysplastic syndrome, except for secondary cancer)

Adverse events among those listed above (2)-(4), determined to have a causal

relationship (any of definite, probable, or possible) with the study regimen, are regular

reporting objects.

12.4.2 Reporting Procedure

12.4.2.1 Emergency Reporting

In the case of any adverse event or emergency study reporting objects, the doctor

in charge will quickly report the event or object to the Research Responsible Person of

the participating research hospitals. When the Research Responsible Person of the

hospital cannot be contacted, the coordinator or the doctor in charge of the hospital

must assume responsibility on behalf of the Research Responsible Person of the

hospital.

First Reporting: Within 72 hours after the occurrence of the adverse event, the

Research Responsible Person should complete the “AE/AR/ADR first emergency

report” and send it to the Research Committee.

Second Reporting: The Research Responsible Person completes the “AE/AR/ADR

Report” and a more detailed case information report (A4 format) and then send them to

the Research Committee within 15 days after the occurrence of the adverse event. If

there is an autopsy examination, the autopsy results report should be submitted to the



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Research Committee.

12.4.2.2 General Reports

The Research Responsible Person completes the "AE/AR/ADR report" and then

send it to the Research Committee within 15 days after the occurrence of the adverse

event.

12.5 Responsibilities and Obligations of the Research Responsible

Person/Research Committee

12.5.1 Judgment of Study Discontinuation and Necessity for Sending an

Emergency Notice to the Hospital

After receipt of the report from the Research Responsible Person, the Research

Committee replies to the Research Responsible Person for confirmation and negotiation

and then jointly determines the urgency and importance of reporting events; if

necessary, the Committee can temporarily stop the study and to take emergency

notification countermeasures.

12.6 Review of the 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 Investigators



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The 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

specially 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. To obtain 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 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 the 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 where the investigator is located and must be properly and

safely kept for future review at any time during audit and inspection throughout the



78

inspection period. Before participating in the study, subjects should be provided a copy

of 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 approved revised information will be provided to each subject

participating in the study. The researchers will explain the changes made to the previous

version of the 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 for 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 the research data of the subjects to themselves through the identification table kept

at the research center after authorization; 2) during onsite auditing of raw data by the

supervisors of this study, as well as relevant inspection and inspection visits by

supervising departments, the personnel engaging in the above activities may view the

original medical information of the subjects, which will be kept strictly confidential.

Collection, transmission, handling and storage of data on study subjects will

comply with data protection and privacy regulations. This information will be provided



79

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 Board

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 investigator.

Before beginning the study, the investigator 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, amendments to the study protocol will

be submitted to the IEC/IRB prior to performing the study. In the course of the study,

relevant safety information will be submitted to the IEC/IRB in accordance with

national regulations and requirements.

13.5 Regulatory Authority

The study protocol and any relevant documents (for example, the study protocol,

the subject's informed consent form) will be submitted according to the Ethical Review

Approach of Biomedical Research Involving Human Beings (Trial) (2007) and the



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applicable regulatory requirements of our country, or the ethical review guidance

counseling organization of the provincial health administrative department will be

notified.

14 Organizations and Responsibilities of Study

14.1 Research Committee

Responsible for developing the 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 the Research Committee: Chang-Ming Huang (Gastric Surgery,

Union Hospital, Fujian Medical University)

Address: Department of Gastric Surgery, Fujian Medical University Union

Hospital, No. 29 Xinquan Road, Fuzhou, Fujian Province, China. Postcode:

350001, China; 0591-83357896-8011; Fax: 0591-83363366; Mobile: 13805069676;


Chief Statistical Expert of the Research Committee: Zhi-Jian Hu (Department of

Preventive Medicine Statistics, School of Public Health, Fujian Medical

University)

Secretary: Mi Lin

Address: Department of Gastric Surgery, Fujian Medical University Union

Hospital, Fuzhou, China; Postcode: 350001

Tel: 0591-83357896-8011, Mobile: 13459152658 (Mi Lin)



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14.2 Efficacy and Safety Evaluation Committee

Responsible for the supervision/monitoring of treatment safety and efficacy of this

study.

The principal of the Efficacy and Safety Evaluation Committee: Chang-Ming

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.

The Independent Ethics Committee/Institutional Review Board (IEC/IRB) is

responsible for the ethics review.

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16 Annex



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16.1 Informed Consent Form

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