Study protocol for comparing the efficacy of left-open single-flap technique versus double-flap technique after proximal gastrectomy: A multicenter randomized controlled trial

Background Proximal gastrectomy has gradually gained more attention due to its superiority in retaining the function of part of the stomach. The inevitable loss of the antireflux barrier and postoperative complications resulting from proximal gastrectomy can severely affect the quality of life. Continuous improvements in digestive tract reconstruction after proximal gastrectomy have yielded the development of a variety of methods with antireflux functions. Recently, our center attempted the left-open single-flap technique and initiated a multicenter, prospective, randomized controlled trial for patients undergoing proximal gastrectomy to reduce the difficulty of surgical anastomosis and the incidence of perioperative complications compared with the double-flap technique. These findings will provide more evidence-based medical research for the development of clinical guidelines. Methods/design This study is a prospective, multicenter, randomized controlled clinical trial. We plan to recruit 250 patients who are eligible for proximal gastrectomy. After informed consent is obtained, patients will be randomly assigned to the trial group (left-open single-flap technique) and the control group (double-flap technique) in a 1:1 allocation ratio. Discussion Increasingly, clinical studies have focused on the improvement of reconstruction modalities after proximal gastrectomy. Among these methods, the double-flap technique is a clinically effective method. The purpose of this study is to establish a prospective randomized controlled trial to compare the efficacy of the left-open single-flap technique versus the double-flap technique after proximal gastrectomy, aiming to provide more evidence-based medical studies for digestive tract reconstruction in proximal gastrectomy. Clinical Trial Registration ClinicalTrials.gov, identifier [NCT05418920].


Introduction
Despite the decreasing incidence and mortality of gastric cancer in recent years, the incidence and proportion of proximal early gastric cancer has markedly increased (1). However, the choice of an appropriate surgical procedure, the only radical treatment for this condition, has been controversial (2). Currently, proximal gastrectomy has gradually gained increasing attention due to its superiority in 1) maintaining the distal gastric volume; 2) preserving the fundic gland area and reducing hormonal and nutritional deficiencies; and 3) ensuring the secretion of internal factors and gastric acid, the absorption of iron ions and vitamin B12, and the maintenance of hemoglobin concentration (3)(4)(5)(6). However, the inevitable a loss of the antireflux barrier and postoperative complications resulting from proximal gastrectomy can severely affect the quality of life (7).
Recently, continuous improvements in digestive tract reconstruction after proximal gastrectomy have yielded the development of a variety of methods with antireflux functions that contribute to retaining the function of the residual stomach and avoiding serious reflux esophagitis (8)(9)(10). Japanese guidelines indicate that popular methods for gastrointestinal reconstruction after proximal gastrectomy include esophagogastrotomy (EG), jejunal interposition (JI), and double-tract reconstruction (DTR) (11)(12)(13). In 2016, Kuroda reported a double-flap technique using the anterior gastric wall plasma muscle flap to cover the anastomosis (14). Its unidirectional flap can reconstruct the "sphincter" and reduce the incidence of reflux esophagitis and the risk of anastomotic fistula.
By comparing p atients wh o u nd e rwe n t di r e ct esophagogastrostomy, jejunal interposition, double tract reconstruction, and the double-flap technique, Shoji Y (15) and Saze Z et al. (16) found that patients undergoing double-flap anastomosis had no reflux esophagitis and a lower incidence of postoperative anastomotic stricture, which improved postoperative serum albumin ratio changes and weight maintenance. Consequently, the double-flap technique is considered to be the most effective technique for proximal gastric reconstruction (17,18).
However, the double-flap technique is associated with shortcomings, such as a more complex suture technique, more difficult operation, longer operation time and higher incidence of postoperative anastomotic stenosis (15,16,19). Therefore, our center attempted the left-open single-flap technique to reduce the difficulty of surgical suturing and the incidence of complications. To further evaluate the therapeutic efficacy of this procedure, we initiated a multicenter, prospective, randomized controlled trial for patients undergoing proximal gastrectomy, which will provide more evidence-based medical research for the development of clinical guidelines.

Trial objectives
This study is a prospective, multicenter, randomized controlled clinical trial. We plan to recruit 250 patients who are eligible for proximal gastrectomy. After informed consent is obtained, patients will be randomly assigned to the trial group (left-open single-flap technique) and the control group (doubleflap technique) in a 1:1 allocation ratio, with the aim of providing more evidence-based medical outcomes for digestive tract reconstruction in proximal gastrectomy. The surgical methods applied in this study are shown in Table 1.
The objectives of this trial are as follows:

Main objective
The main objective is to investigate the incidence of reflux esophagitis after 2 types of anastomosis (

Participant selection
The flow chart of this study is shown in Figure 1. During the routine admission of inpatients, suitable patients will be screened by the study staff according to the inclusion/exclusion criteria. Patients who are successfully selected before formal enrollment will receive study instructions from the investigator with a detailed explanation of the included documents and operations. Participants (or their legally authorized representative) will agree to sign and date the informed consent form after receiving a random serial number. All processes will strictly follow the provisions of the  19) preoperative imaging: regional fusion of enlarged lymph nodes (maximal diameter > 3 cm). Flowchart of the trial. 2) the investigator considers that the patient should stop this study for safety reasons or the benefit of the patient; 3) serious complications or intolerable adverse reactions of the patient; 4) patients may request to withdraw/terminate from the trial at any time after signing the informed consent form.

1) patients with missing main observation indicators and significantly incomplete study data;
2) incomplete follow-up data; 3) patients who failed to follow the study protocol; 4) the study protocol was discontinued after the patient was judged to be a culled case. Follow-up treatment was determined by the investigator according to clinical guidelines. The excluded cases were still subject to follow-up and were included in the study analysis.

Participating entities
As shown in Table 2, this work is a multicenter, large-sample clinical study with six participating medical institutions (Xi-Jing Hospital, Tang-Du Hospital, First Affiliated Hospital Xi'an Jiaotong University, General Hospital of Ningxia Medical University, Henan Provincial People's Hospital, The First Affiliated Hospital of Shanxi Medical University). The mode of enrollment is competitive. All study institutions and personnel were approved by the ethics committee and possessed extensive clinical experience in the treatment of gastric cancer.

Blinding technique and randomization procedure
The study has an open design. Before randomization, the oncologic evaluation will be performed based on relevant clinical parameters (vital signs, serum biochemical tests, tumor markers, CT and/or MRI, ultrasound endoscopy, etc.). Eligible participants will be informed by the investigator and required to sign an informed consent form. Patients will be randomly assigned in a 1:1 ratio to the trial group (left-open single-flap technique) and the control group (double-flap technique). The randomization sequence will be generated by a biostatistician using the SPSS 28.0.1 software. The randomization list will be sealed in an opaque envelope and placed in the custody of a dedicated person.
None of the assistants associated with the randomization process are directly involved in this study to avoid bias.

Perioperative management
1) If the patient's condition deteriorates between enrollment and the date of surgery, the investigator will decide whether to perform the surgery as planned.
If emergency surgery or cancellation is needed, the case will be excluded according to the exclusion criteria.
2) Perioperative enteral/parenteral nutrition support will be allowed for patients with nutritional risk.
3) For high-risk patients (elderly patients, smokers, diabetic patients, obese patients, or patients with a history of chronic cardiovascular or thromboembolic disease), the perioperative administration of low-molecular heparin, lower extremity antithrombotic compression stockings, aggressive lower extremity massage and respiratory function training are recommended as prophylactic measures. Methods for other potentially high-risk complications will be determined by clinical practice routines and specific needs, but all measures need to be documented in the CRF. 5) The principles of prophylactic antibiotic use are as follows: the first intravenous drip is started 30 minutes before surgery, and the recommended choice is cephalosporin II antibiotics. The preparation, concentration, and infusion rate will be in accordance with routine clinical methods. Prophylactic use will last no longer than 3 days after surgery, and the frequency of use will be 1 time/8 hours. In cases of allergy to cephalosporins (including a history of allergy or allergy after use), other types of antibiotics will be selected according to clinical specifics, and the duration of prophylactic use will be the same as before.
6) The patient's preoperative fasting, water fasting, and other anesthetic requirements will be implemented according to the routine anesthetic protocol; 7) The investigator will decide to leave a gastric tube or drainage tube in place based on experience and actual needs;

Treatment protocols and surgical intervention
The mesenterium at the root of the esophagus is fully stripped, and the esophagus is exposed. The location of the tumor is localized according to intraoperative gastroscopy, and the sites of esophageal and gastric body dissection are further clarified (the distances between the cut edges are 5 cm and 3 cm, respectively). The esophagus is dissected, and the stomach is pulled outside the body through an adjuvant incision in the navel or epigastrium. The tumor and remnant stomach are then dissected with linear staplers. Specimens are taken at the cut edge for rapid cytopathological examination.
As shown in Figure 2

Clinical data collection
According to the privacy policy, only the researcher will know the patient's identity and various information. Clinical information will be recorded by the investigators in the case report form and on the web platform (http://www.medresman. org.cn). The patients' clinical data will include general information, previous medical history, previous surgical history, laboratory findings (preoperative and postoperative blood tests, biochemical indicators, and tumor markers), upper gastrointestinal endoscopy, imaging findings, the incidence of postoperative reflux esophagitis, the incidence of anastomotic leakage, the incidence of anastomotic stricture, operative time and intraoperative blood loss. The schedule of data collection in this study is shown in Table 3.

Collection, preservation, and management of biochemical specimens
In this study, blood samples will be collected from subjects to monitor blood biochemical indicators and tumor markers. After testing, all samples will be destroyed in strict accordance with laboratory regulations.

Sample size estimate and statistical analysis
The left-open single-flap technique after proximal gastrectomy is a new and improved procedure in our center, and national or international studies comparing clinical outcomes after reconstruction with the double-flap technique have not been conducted. Kuroda S et al. (22) showed that the incidence of reflux esophagitis, performed by endoscopy at 1.0 years (median) after the double flap technique, was 10.6% for all grades. This finding was considered more in line with "realworld data".
According to the database of this study, we designed a noninferiority study with a noninferiority margin of 10% (a=0.05, b=0.20, d =0.10, 80% power, 10% dropout rate). The test statistic used is the one-sided Z test (unpooled) by PASS 15.0.5 software.
The result is N = 250. Therefore, 125 patients will be enrolled in each of the 2 groups.

Study endpoints
The postoperative complications are classified according to the Clavien-Dindo grading system.

Follow-up
The start time of this study was August 1, 2022. The preliminary completion time is July 31, 2024. Follow-up will be planned for three years, and the study completion time will be July 31, 2027.
Esophagogram fluoroscopy will be performed 6 days after surgery to evaluate anastomotic complications. Subsequent follow-ups will be performed at 1, 3, 6, 12, 24 and 36 months. The follow-up will include questioning, physical examination, gastrointestinal endoscopy, blood examination items (peripheral blood routine, serum iron, vitamin B12, folic acid, blood biochemistry and serum tumor markers), and imaging items (chest imaging, esophagogram fluoroscopy, and whole abdomen √Indicates the need to collect clinical data. enhanced CT). All examinations will be recorded to evaluate the presence of tumor recurrence or metastasis, the survival status of patients and the occurrence of complications. Other assessment tools will be used according to the specific situation, such as color ultrasound of other sites, whole-body bone scan, PET-CT, etc. The follow-up schedule in this study is shown in Table 3.
The diagnosis of postoperative reflux symptoms is based on a combination of symptom presentation, endoscopic evaluation of esophageal mucosa, reflux monitoring, and response to therapeutic intervention (23)(24)(25). Heartburn and regurgitation remain the typical symptoms of postoperative reflux symptoms. The control steps of postoperative reflux symptoms are shown in the Table 4.
In this study, the patients should be reexamined at the hospital where the surgery was performed, but cases of outside hospital examination will not be excluded (outside hospital reexamination should be conducted at a tertiary care hospital). A follow-up specialist will follow up and record the results of each examination.
All patients refuse to be followed up according to the above protocol will be recorded as lost cases and analyzed together with cases meeting the study criteria at the end of the study.

Written informed consent forms
The informed consent process was approved by the internal review board/independent ethics committee. If any changes occur during the study, they will be resubmitted for review.
Informed consent procedures will be implemented in strict compliance with relevant Chinese laws. Original informed consent will be retained in writing by the investigator.
We will rigorously protect patient privacy: The collection, transmission, process and storage of participant data will comply with data security and privacy protection regulations.

Monitoring of the study
The study protocol, which was submitted to the ethical review committee of the health administration department, is in line with the relevant regulations in China and the Measures for Ethical Review of Biomedical Research Involving Human Beings (2007).
We will retain video recordings and unedited image files of all patients throughout the surgery. The organizers will review and monitor the quality of the surgery. The main objectives will be performed for these purposes: 1) to confirm the rationality of the surgical approach, the extent of lymph node dissection and the minimally invasive nature of the incision; 2) to verify the original data of all subjects to confirm consistency with the CRF; and 3) to regularly assess the progress of the study at each center to ensure that it was carried out according to the plan.

Patient and public involvement
Patients and the public will not be involved in our process of design, recruitment, clinical treatment, measurement of outcomes and analysis of the data.

Discussion
For patients diagnosed with Siewert III esophagogastric junction adenocarcinoma and early-stage upper gastric cancer, current clinical guidelines recommend proximal gastrectomy (17,18). Compared with total gastrectomy, proximal gastrectomy can maintain part of the storage and digestive function of the stomach, which has greater advantages for nutrient absorption and weight maintenance (5)(6)(7)(8). Therefore, this approach is more commonly used in East Asia.
Unavoidably, patients' postoperative quality of life is severely affected by postoperative complications (7). Wang S et al. (8) found that proximal gastrectomy is also associated with many complications, most notably reflux esophagitis, which causes heartburn, chest pain, acid reflux, and anorexia. These postoperative complications can severely reduce the quality of life after surgery.
Consequently, the choice of a reasonable approach to reconstruct the digestive tract after proximal gastrectomy and addressing complications, such as reflux esophagitis, remain a challenge for clinicians (10-13). Therefore, an increasing number of clinical studies have focused on improving reconstruction modalities after proximal gastrectomy, such as esophagogastrotomy (EG), jejunostomy (JI), jejunal pouch placement (JPI) and double tract reconstruction (DTR).
Among various gastrointestinal reconstruction methods, the double-flap technique is clinically effective, wrapping around and increasing the pressure of anastomosis through a unidirectional flap. This structure is similar to the "reconstructed cardia" structure, which can improve the antireflux effect. Saze Z et al. (16) found that the double-flap technique did not result in postoperative reflux esophagitis and had the smallest postoperative weight change ratio and the lowest prevalence of gastric residual at 12 months after surgery compared with direct esophagogastrostomy, jejunostomy and double tract reconstruction.
However, double-flap technique is also associated with shortcomings, such as a complicated surgical suture technique, difficult operation, strict surgical indications and high incidence of postoperative anastomotic stenosis (26)(27)(28).  To address the shortcomings of the above procedure, we established a multicenter, prospective, randomized controlled trial to modify the flap-making procedure for the double-flap technique: a left-open single flap will be used instead of a double flap to cover the anastomosis, acting as a "sphincter" and providing a tunneling effect. Preliminary data from our center showed that patients have excellent postoperative results. We will explore and summarize our initial clinical experience and apply it to the development of the treatment protocol. If this study meets the expected results of the trial protocol, it will bridge the gap between the complicated operative procedure and longer operative time of the double-flap reconstruction style and further improve the postoperative quality of life of patients. These outcomes will be landmark improvements in patient prognosis and provide additional high-level research evidence for the standardization of gastrointestinal reconstruction protocols after proximal gastrectomy.Strengths and limitations of this study Strengths: This was a prospective, large sample, multicenter randomized controlled trial that systematically compared the efficacy of 2 methods of gastrointestinal reconstruction after proximal gastrectomy. In previous studies, the left-open singleflap technique had not been reported.
Limitations: Japanese guidelines recommended that the common methods of gastrointestinal reconstruction after proximal gastrectomy include esophagogastrotomy (EG), jejunostomy placement (JI), jejunal pouch placement (JPI) and double-tract reconstruction (DTR). Nevertheless, we compared only 2 of these reconstruction methods in our study.

Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Ethics statement
The studies involving human participants were reviewed and approved by Chinese Ethics Committee of Registering Clinical Trials. The patients/participants provided their written informed consent to participate in this study.

Surgery
Patients with Los Angeles grade C or D esophagitis.