The trial protocol is identified as version 2.0 of 27 December 2022. This protocol has been drafted in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). The SPIRIT checklists can be found as Additional file 1.
Study Design
This study was a prospective, single-blind, noninferiority randomized controlled trial and a multicenter study conducted at hospitals in Korea. In this study, we enrolled patients with histologically diagnosed gastric cancer of clinical stage I, II, or III who underwent Roux-en-Y or B- II gastrojejunostomy anastomosis after laparoscopic gastrectomy. Patients who met the inclusion criteria were randomly assigned to two groups: a CLOSURE group that underwent Petersen's defect closure method and a MEFIX group that underwent the mesenteric fixation method. Computed tomography (CT) was performed every 6 months for the first 3 years after surgery, and outpatient follow-up was performed every 1 year for the next 2 years. A history of outpatient or emergency department visits for symptoms of internal hernia, such as vomiting and abdominal pain, or emergency surgery for internal hernia and the presence of Petersen’s hernia by CT were examined (Figs. 2 and Table 1).
Table 1
Timetable of the study period.
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STUDY PERIOD
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Enrolment
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Allocation
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Post-allocation (months)
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Close-out
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Time point
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Surgery
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6
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12
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18
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24
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30
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36
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48
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60
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5 years after surgery
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ENROLMENT:
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Eligibility screen
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x
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Informed consent
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x
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Allocation
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x
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INTERVENTIONS:
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x
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x
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ASSESSMENT:
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Evaluation of
Petersen' s hernia
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x
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x
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x
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x
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x
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x
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x
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x
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x
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Participants
This study is aimed at patients with gastric cancer of clinical TNM stage I, II, or III who were diagnosed by methods such as preoperative biopsy, endoscopic ultrasonography, or CT. Laparoscopic or robot-assisted total or distal gastrectomy was performed.
Eligibility criteria
Inclusion criteria
a) histologically confirmed primary gastric adenocarcinoma
b) no evidence of other distant metastasis
c) underwent laparoscopic total or distal gastrectomy
d) underwent robotic total or distal gastrectomy
e) reconstructed by Roux-en-Y reconstruction or the Billroth II procedure
f) aged 20 or older
g) patients with appropriate activity conditions; 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
h) patients who had not previously received abdominal chemotherapy or radiation treatment
i) patients who signed the consent form
Exclusion criteria
a) active double cancer (i.e., synchronous and metachronous double cancer within 5 disease-free years), carcinoma in situ (i.e., lesions suggestive of intraepithelial or intramucosal cancer),
b) gastric cancer recurrence
c) a history of abdominal surgery, with the exception of laparoscopic appendectomy, gallbladder resection, laparoscopic gynecologic surgery for benign neoplasms, and cesarean section.
d) patients in whom other organs must be coordinated during the preoperative examination (however, laparoscopic cholecystectomy is included in the selection criteria due to gallbladder polyps and gallbladder disease)
e) pregnant or lactating women
f) diagnosed with mental illness in the medical records
g) patients taking whole-body corticosteroids, including herbal medicines
h) an uncontrolled history of angina or myocardial infarction within 6 months before the study period
i) uncontrolled hypertension
j) patients suffering from severe respiratory disease requiring continuous oxygen therapy
Elimination criteria
a) If a patient has expressed an intention to discontinue participation in the study before or after the study has begun.
b) Serious violation of research protocol
Recruitment
The clinical tester or authorized personnel should be able to explain the purpose and treatment of the test and show that they are aware of the benefits and risks of the test in this process. Subjects should also be aware that participation in the exam is voluntary and that they can be eliminated without any problems at any time. The subjects should have enough time to think about their participation before the ICF sign and discuss it with their families. The documentation of the discussion and the date of the prior consent shall be recorded in the source documentation. Subjects must write a written consent form. If the hospital that manages the subject's informed consent does not have the same guidelines, the guidelines that manage the informed consent should be followed equally in all hospitals
Sample Size
Sample size calculation was based on an assumed proportion of Petersen’s hernia of approximately 1.15% for the conventional close method compared with the 2.58% for the MEFIX surgical method [9]. Furthermore, we set the inferiority threshold at 2%. Therefore, if the proportion of Petersen’s hernia of the MEFIX method is less than 3.15%, the MEFIX method is not considered inferior to the conventional close method.
A sample size of 192 per arm is required for a proportion test with a one-sided significance level of 0.025 and power of 80% with a non-inferiority margin for the MEFIX method of 2%. Further, we decided to increase the sample size by 10% to cover possible dropouts. Consequently, 426 participants were included per group. This calculation was performed using the PASS software 13.0 (NCSS, LLC., Kaysville, Utah, USA).
Statistical analysis
All outcomes are assessed using an intention-to-treat analysis that included all patients who were randomly assigned.
Demographic data and baseline characteristics of all randomized participants were pooled. Data was analyzed using R version 4.2.1 (R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria). Continuous variables are presented as mean and standard deviation or median and interquartile range. Categorical variables are described as frequencies and percentages. The baseline characteristics of patients were compared using the chi-square test, Fisher's exact test, Student's t test (two samples), or Mann–Whitney U test, as appropriate.
To assess the non-inferiority of the MEFIX method compared with the conventional close method, the primary endpoint, i.e., bowel obstruction due to Petersen’s hernia, will be compared between the two groups using the difference in proportions and hazard ratios during the follow-up period. The primary analysis of the primary endpoint is performed without adjustment for imbalance in baseline covariates. Additionally, secondary dichotomous endpoints will be compared between the two groups using adjusted and unadjusted hazard ratios and assessed for non-inferiority of the MEFIX method. Unadjusted analyses of time to event for primary and secondary endpoints were presented using Kaplan-Meier curves and analyzed for non-inferiority of median time to event using the log-rank test.
Randomization
Patients were randomly assigned in a 1:1 ratio to the MEFIX or conventional close group. Allocation was conducted by computer-generated permuted random blocks (size four) stratified by 12 hospitals. Block randomization was performed by an independent statistician using R software. An independent investigator retained the random assignment tables from each hospital. When eligible patients were recruited from each hospital, they were directed to that hospital. The randomization R code can be found as Additional file 2.
Intervention description
This study is aimed at patients with gastric cancer of clinical TNM stage I, II, or III who were diagnosed by methods such as preoperative biopsy, endoscopic ultrasonography, or CT. Laparoscopic or robot-assisted total or distal gastrectomy was performed. Partial omentectomy and D1 + lymph node resection were performed for early gastric cancer (EGC), while total omentectomy and D2 lymph node resection were performed for advanced gastric cancer (AGC). The lymph node resection zone followed the Japanese Classification of Gastric Carcinoma published in 2011 [12]. Roux-en-Y or Billroth II reconstruction was performed using intracorporeal and antecolic methods. Isoperistaltic or antiperistaltic anastomosis was performed differently depending on the preference of the technician. All technicians sent surgical videos to the principal investigator (PI) before patient registration to verify quality control.
Operative Methods For Petersen’s Defect Closure (Closure Group)
To prevent the occurrence of Petersen’s hernia, the Petersen’s defect, which occurs between the mesentery of the jejunum and transverse colon, was sutured with a non-absorbable suture after a gastro-jejunal or esophageal-jejunal anastomosis. First, a traction suture was performed between the jejunum and transverse colon, and Petersen's defect was closed continuously using a non-absorbable barbed suture V-LocTM 3 − 0 (Medtronic VR, Minneapolis, MN, USA). Leaving the tip of the barbed suture can cause bowel obstruction; thus, at the last suturing step., backward suture with the V-Loc 3 − 0 was performed 2 to 3 times, and subsequently, the tip was cut short after anchoring (Fig. 3).
Operative Methods For Mesentery Fixation (Mefix Group)
The purpose of the MEFIX method is to allow small bowel herniation by fixing the jejunal mesentery to the transverse mesocolon or mesenteric peritoneum and prevent whole bowel ischemia by preventing the twisting of the small bowel mesentery.
The arcade artery (blue area, jejunal side) and transverse mesocolon (purple area, colonic side) have relatively few blood vessels under the vasa recta of the jejunal mesentery within 30 cm distal to the jejunojejunostomy site (Fig. 4a). A traction suture was performed at the suture origin, and the mesentery of the jejunum was fixed to the transverse mesocolon with a non-absorbable barbed V-LocTM 3 − 0 suture (Medtronic VR, Minneapolis, MN, USA). It was sutured from the inferior arcade artery to the mesenteric root, which was present in approximately 2/3 of the mesentery of the small intestine. Similarly, in the final suturing step, the reverse suture was performed 2 to 3 times with the V-Loc 3 − 0 and the tip was cut short after anchoring. (Fig. 4b)
Assessment of outcomes
Primary Outcome
The number of patients who underwent surgery within 3 years after laparoscopic gastrectomy for bowel obstruction caused by Peterson’s hernia.
Secondary Outcomes
The following secondary outcomes were examined: duration of procedures (minutes), bleeding, hospital stay, occurrence of postoperative small bowel obstruction within 30 days after surgery, short-term complications within 30 days after surgery, occurrence of Petersen’s hernia in relation to the use of anti-adhesive agents and anastomosis methods, and comparison between the CLOSURE or MEFIX methods in relation to the condition of the previous surgical suture, the degree of hernia, and the condition of the bowel (i.e., strangulation, perforation) at the time of emergency surgery for the treatment of Petersen’s hernias.
Data collection
All data were recorded accurately according to the appropriate format in the case report form. The central research center evaluated the completeness and accuracy of the data collected and submitted at each center. The data collected were as follows:
A. Clinical observations
(1) The patient's health status before surgery (i.e., underlying disease, ECOG score, and clinical stage of gastric cancer)
(2) Surgical method: extent of gastric resection, lymph node dissection, reconstruction method, total operation time, CLOSURE or MEFIX procedure time, bleeding, use of anti-adhesion agents during surgery, hospital stay, and postoperative complications.
B. Complications that occur during the postoperative hospitalization period
(1) Initial complications were defined within the financial period and within 30 days after surgery and were classified and recorded according to the Clavien–Dindo classification.
(2) Post-discharge investigations and long-term complications were as follows:
- Long-term complications were defined as those occurring 30 days postoperatively.
- Outpatient follow-up: symptoms of Peterson's hernia and hernia, other long-term complications, and incidence of reentry.
- Occurrence of Peterson’s hernia: Peterson's hernia requires reoperation. Therefore, Peterson's hernia was confirmed by repeat surgical findings (i.e., preoperative hernia was suspected, but hernias in other areas were diagnosed as internal hernias, not Peterson's hernia). The diagnosis of Peterson hernia before surgery is a case in which the patient has abdominal pain and is confirmed as a Peterson hernia by radiologic examination. CT is usually recommended for radiographic examinations. Ultrasonography is possible, but superior mesenteric vessel rotation must be confirmed.
Data monitoring, auditing, and interim analysis
This study was conducted with respect for the rights and welfare of patients, and it was monitored whether the reported data related to the clinical research were accurate, complete, and verifiable compared with the evidence document, and whether the clinical research was conducted in accordance with the approved plans and relevant regulations. The patients' original records, medical records, and data repositories (i.e., research files) were reviewed every 6 months. All personal data will be stored in password-protected program, only authorized coordinator can access. The progress of clinical research was also reviewed and any violations or non-compliance were reported according to the institutional bioethics committee reporting procedure.
For safety and efficiency reasons, interim analyses were performed after 33% (first interim analysis) and 66% (second interim analysis) of the sample size had been recruited and their results had occurred. The O'Brian-Fleming stopping rule was applied to ensure efficacy and safety. If the primary outcome of the MEFIX method was superior to that of the conventional close method with a p value of less than 0.0005 (at the first interim analysis) or 0.014 (at the second interim analysis), consideration was given to terminating the study early to assess the efficacy of the MEFIX method. There was no predefined stopping rule for safety related to complications. Any significant potential harm or serious adverse events (AEs) related to the procedures were considered grounds for stopping the trial.
This clinical trial is an Intention to treat (ITT) analysis study, and after random assignment, the subjects who have been dropped out will be treated as missing and included in the analysis.
This study was a prospective, multi-institutional clinical study, evaluation of the safety of the research was conducted periodically, and the results of the evaluation were reported to the Research Safety Monitoring Committee and the Steering Committee. The safety of the research was assessed by the research safety monitoring committee in the following cases.
1) The case of surgery due to Peterson's hernia, which is the primary endpoint of this study, does not fall under the safety evaluation. During the interim analysis, if the upper margin of 9.7% of the incidence of Peterson's hernia known through the existing references is exceeded, the research safety monitoring committee evaluates the safety of the study.
2) During the interim analysis, evaluation is conducted if complications suspected to have a strong relationship with the surgical method of this study occur significantly higher in the experimental group
Adverse event
An AE is an inappropriate medical occurrence in patients that is not necessarily associated with treatment and causation. Thus, an abnormal reaction is an unwanted and unintended symptom (e.g., abnormal laboratory test results), symptom, or illness that occurs transiently, independent of surgery and causality. The severity of the AEs was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, and detailed information was recorded in the patient record.
Serious AE was defined as a critical anomaly response if:
All deaths within 30 days of surgery were reported as significant AEs, regardless of the causality of the surgery. The following items were reported when a causal relationship was present in the study within 30 days of surgery (i.e., causal relationships were reported separately as defined, probable, and passive): hospitalization due to severe complications or an extended hospitalization period after surgery. If re-operation was required after surgery (i.e., surgery requiring general anesthesia in the operating room), permanent or significant impairment that cannot be denied its relevance to surgery, including brain lesions with permanent after-effects associated with surgery, were reported.
If severe or medically significant clinical AEs or laboratory test numbers occurred during or after the clinical trial period, the investigator shall report them to the PI and Clinical Trial Institutional Review Board (IRB) of the testing hospital, regardless of the treatment the patient received. The critical AEs were then reported by the PI to each responsible researcher at the participating institution, who subsequently reported them to the IRB of the affiliated institution.
Ethics
Our study was conducted in accordance with the recent Declaration of Helsinki as amended by the 64th World Congress of Fortaleza, Brazil, 2013. In addition, clinical research plans and related documents were submitted to the institutional bioethics committee before clinical research was conducted in accordance with national laws and regulations. Clinical research was initiated after approval, and all individuals involved in the research below the researcher-in-charge adhered to good clinical practice (GCP). The study protocol was registered at ClinicalTrials.gov as NCT05105360.