Safety of OGT-assisted Overlap Esophagojejunostomy Versus Traditional Overlap Method

Methods Objectives This CLASS15-01 trial is a prospective, multicenter trial for OGT-assisted overlap esophagojejunostomy and traditional overlap method during totally laparoscopic total gastrectomy for Siewert III/II esophagogastric junction cancer and gastric cancer. The primary purpose of this study is to evaluate the early operative morbidity and mortality and determine the safety of OGT method compared with traditional overlap method for Siewert III/II esophagogastric junction cancer and gastric cancer. The second purpose is to evaluate the success rate of inserting anvil fork into esophageal lumen at first attempt, attempts of inserting anvil fork into esophagus, time of esophagojejunostomy,recovery course and compare the postoperative hospital stay of the patients enrolled in this study.

Study design This CLASS15-01 trial is a prospective, multicenter, randomized, controlled, open, and non-inferiority trial comparing the safety of OGT method during TLTG for Siewert III /II esophagogastric junction cancer and gastric cancer compared with traditional overlap method .

Participating surgeons To participate in this CLASS15 trial, the responsible surgeons should meet the following qualifications: first, completing at least 50 cases of TLTG with D2 lymphadenectomy;second, passing the blind review of surgery video. Briefly, the applicants should provide the videos of TLTG with traditional overlap and OGT method in recent 3 months (three cases each) to the CLASS Research Council.CLASS Research Council will select two videos of traditional overlap and OGT method separately, and randomly appoint three experts to peer review blindly. When three experts unanimously approved it, the applicant will be permitted to participate in this study as a researcher.

Sample size calculation This is a non-inferiority verification study on clinical safety, with the early operative morbidity and mortality rate as the main index for safety evaluation. According to the previous reports, the morbidity and mortality rate for TLTG with traditional overlap is about 29%. Setting α=0.025, β = 0.2, and the noninferiority margin δ = 5%, the sample size required for each group is 148 cases. Considering that the dropout rate for this clinical study is about 5%, the sample size is determined as 156 cases in each group.

Inclusion criteria Aged 18-80 years; Primary lesion is pathologically diagnosed as gastric adenocarcinoma; Expected to live more than 1 year; Tumor located located in gastroesophageal junction (GEJ) involve esophagus no more than 2cm, or in the upper, upper to middle, or entire stomach, and intend to perform laparoscopic total gastrectomy with D2 lymphadenectomy No history of upper abdominal surgery (except for laparoscopic cholecystectomy); Preoperative performance status (ECOG, Eastern Cooperative Oncology Group) of 0 or 1; Preoperative ASA (American Society of Anesthesiologists) scoring: I-III; Sufficient organ functions; Written informed consent.

Exclusion criteria Women during pregnancy or breast-feeding; Body temperature ≥ 38 °C before surgery or infectious disease with a systemic therapy indicated; Severe mental disease; Confirmed stage IV (AJCC 8th) during surgery Severe respiratory disease; Severe hepatic and renal dysfunction; Unstable angina pectoris or history of myocardial infarction within 6 months; History of cerebral infarction or cerebral hemorrhage within 6 months; Gastric cancer complications (bleeding, perforation, obstruction) that requiring emergency surgery.

Randomized grouping In this study, the central dynamic, stratified randomization method is adopted, and the factors including age, TNM stage, tumor location, neoadjuvant, BMI, and investigators, are considered. After each case is enrolled, the research center will arrange the research assistant to send the information of included cases (age,TNM stage, tumor location, neoadjuvant, and BMI) to the data center. After analyzing the case information by the center randomization department, the case grouping will be determined.

Quality control To ensure the rationality of the ESJ procedure, a series of photographs of ESJ (traditional and OGT) are taken for assessment. All photographs will be saved and submitted to CLASS data center within 1 week after the operation. The CLASS Research Committee will monitor and review regularly to ensure the quality of operation.

Outcome measurements Primary endpoint The primary endpoint of the CLASS15 trial is noninferiority in the early operative morbidity and mortality, which are defined as the event observed within 30 days following surgery. The postoperative complications are defined and graded according to the grading system of

Clavien-Dindo Classification. To measure this endpoint, the criteria are suggested in details as follows:

Intraoperative complications

1. Surgery-related complications: intraoperative hemorrhage (≥400 ml) and injury;
2. Pneumoperitoneum-related complications: hypercapnia, mediastinal emphysema, subcutaneous emphysema, aeroembolism, and respiratory and circulatory instability caused by pneumoperitonum;
3. Anesthesia-related complication.

Early postoperative complications

1. Surgery-related complications: wound complications (infection, effusion, dehiscence,poor healing), intra-abdominal active bleeding,digestive tract active bleeding, anastomotic leakage, anastomotic stenosis, intestinal fistula, pancreatic fistula, chylous fistula, intra-abdominal abscess formation, gastroparesis, intestinal paralysis, intestinal obstruction, cholecystitis, pancreatitis, etc.
2. System-related complications: pneumonia, pleural effusion, pulmonary embolism, cardiocerebrovascular complications, deep venous thrombosis, urinary tract complications,catheter-related complications, condition of pain,etc.;

Secondary endpoint The secondary endpoint of this study is the time of oesophagojejunostomy, the success rate of inserting anvil fork into oesophagal lumen at first attempt, the number of attempts to insert anvil fork into oesophagus and postoperative recovery course, which is assessed by time to first ambulation, flatus, liquid diet, soft diet, etc. In addition, the length of postoperative hospital stay will be recorded.

Follow-up The patients in both groups will be followed up 6 months after operation. A physical examination, a complete blood count, blood biochemical examination (albumin, prealbumin, total bilirubin, direct bilirubin, AST, ALT, creatinine, blood urea nitrogen, and blood glucose), and serum tumor markers (AFP, CEA, CA19-9, CA12-5, and CA72-4) analyses will be performed. In addition, imageological examination (total abdominal and pelvic enhanced CT, chest X-ray, upper gastrointestinal tract iodine imaging, gastroscopy, ultrasonography, whole body bone scan, PET-CT, etc.) will also be performed if needed. All the results will be recorded and evaluated by the specialist.

Statistical analysis Statistical analysis will be performed with SPSS 25.0 (SPSS Inc., Chicago, IL, USA). Continuous variables with normal distribution are expressed as the mean ± standard deviation, and continuous variables with a skewed distribution are expressed as the median (interquartile range [IQR]) and were compared across groups using. Continuous variables were compared across groups using the independent t-test or Mann-Whitney U test if the data were highly skewed. Categorical variables are expressed as the number and percentage and were compared with the chi-square test or Fisher's exact test(if a variable's exact theory frequency was less than 1). P \< 0.05 was considered statistically significant.