Advantages of Hao’s esophagogastrostomy by fissure technique: study protocol for a prospective clinical trial

Abstract

Introduction

In the past, total gastrectomy (TG) was the most common surgical method, but now proximal gastrectomy (PG) has gradually become an alternative surgical method for proximal gastric and esophagogastric junction cancer. However, there is no recognized preferred anastomosis method after PG. In view of this, Hao’s esophagogastrostomy by fissure technique (HEFT) proposed by the author’s team can reduce the difficulty of the operation and the occurrence of postoperative complications. 13 cases that underwent this technique were free of complications during postoperative follow-up, and the intraoperative anastomosis time was significantly shorter than that reported in the literature for Double-flap technique (45 min vs. 79–114 min).

Methods and Analysis

This is a single-center, single-arm, prospective clinical study. We will recruit 30 eligible patients consecutively to undergo HEFT. The primary objective is to assess perioperative safety. The secondary objectives: (1) Incidence of postoperative reflux esophagitis and anastomotic stenosis; (2) Assess the quality of life at 3 Months Postoperatively by EORTC QLQ-C30 and EORTC QLQ-STO22 scales. Measurement data will be presented as mean ± standard deviation ($\overline{\mathrm{x}}\hspace{0.17em}\pm \text{\hspace{0.17em}s}$). Count data will be presented as rates (%).

ARTICLE HIGHLIGHTS

Background

• PG is increasingly being used for upper gastric cancer or esophagogastric junction cancer, but there is no consensus on the optimal anastomosis method.

• HEFT demonstrates promising applicability in PG. Preliminary retrospective studies confirm its advantages over existing anastomotic techniques

• This single-center, single-arm prospective cohort study aims to further validate the safety and efficacy of HEFT.

Study design

• This study plans to enroll 30 gastric cancer patients meeting PG criteria.

• This study adheres to the IDEAL Framework guidelines for evaluating innovative surgical techniques.

• Perioperative data and 30-day postoperative complication rates will be collected. QOL assessments will commence at 3 months postoperatively and continue through the first postoperative year.

Outcomes measures

• The primary objective is incidence of complications related to surgery and anastomosis (including bleeding, anastomotic leakage, obstruction, infection) within 1 month postoperatively.

• Secondary objectives are categorized as follows: (1) incidence of postoperative reflux esophagitis and anastomotic stenosis within 1 month postoperatively; (2) Quality of life at 3 months postoperatively assessed by EORTC QLQ-C30 and EORTC QLQ-STO22 scales, To dynamically assess postoperative quality of life, questionnaire follow-up will be conducted at 6 months and 12 months postoperatively.

1. Introduction

1.1. Background

China has the highest incidence of gastric cancer globally [1]. Particularly, the incidence of proximal gastric cancer and esophagogastric junction cancer is showing a significant upward trend. In the past, treatment for such cancers mainly relied on total gastrectomy (TG) [2]. However, with the increasing focus on postoperative quality of life (QOL), TG cannot meet the urgent need for precision treatment. Numerous studies indicate that proximal gastrectomy (PG) is not only comparable to TG in terms of tumor safety but also has the potential to improve nutritional absorption, maintain weight, and offer a better QOL by preserving partial gastric function [3,4]. Currently used PG anastomosis methods in clinical practice can be classified into 2 main categories: (1) Esophagogastrostomy (EG); (2) Esophagojejunostomy (EJ) [5]. PG-EJ methods, represented by double tract reconstruction (DTR) and jejunal interposition, effectively resist reflux but exist the problem of underused remnant stomach and a high rate of missed diagnoses during follow-up examinations [6,7]. PG-EG anastomosis, which is most in line with physiology and has the greatest potential to improve patient QOL, suffers from a high incidence of reflux esophagitis with traditional EG anastomosis. Improved gastric tube reconstruction shows some improvement but sacrifices remnant stomach capacity [8]. In recent years, the double-flap technique (DFT) proposed by Kamikawa has become a research hotspot in PG anastomosis [9]. It is an improved PG-EG method characterized by enhanced anti-reflux design, and its safety and anti-reflux efficacy have been confirmed by multiple studies [10]. However, DFT has several shortcomings: (1) It requires high surgical skills; (2) It is time-consuming, with the average surgery duration exceeding 6 hours; (3) Due to the need for flap creation, DFT is difficult and time-consuming to perform entirely laparoscopically. Additionally, it is worth noting that almost all studies mention a higher incidence of anastomotic stenosis in DFT-type EG anastomosis, requiring early postoperative endoscopic intervention [11]. Therefore, we need a simpler, more efficient innovative PG anastomosis method.

1.2. Institutional data

Our institution is one of the leading institutions in Shanghai, China affiliated to Fudan University. We initiated totally laparoscopic PG surgery in 2014, having attempted nearly all kinds of intracorporeal PG anastomosis, and reported totally laparoscopic PG-EJ double-tract reconstruction by using linear stapler. In the practical process, we deeply realized that anti-reflux in PG-EG needs to be achieved by reconstructing the cardia, involving the reconstruction of the “pseudo-fundus” and the formation of the anastomotic valve membrane [12,13]. Based on these theoretical considerations and continuous clinical exploration, we introduced the “Hao’s Esophagogastrostomy by Fissure Technique” (HEFT) as an innovative method.

1.3. Advantages of HEFT

Since 2021, investigator’s group have been applying the HEFT method, continuously refining it, and finalized it in 2022. This method, compared to traditional approaches, saves consumables, reduces clinical costs, and is relatively simple in operation compared to DFT. It eliminates the need for complex flap creation, reduces a significant number of intracavitary suturing steps, leading to a significant reduction in surgical time (average 220 vs. 360 minutes). Moreover, it can be simply performed intracorporeally. In addition, HEFT not only shows no significant reflux esophagitis but may also have an advantage over DFT in reducing the occurrence of anastomotic stenosis. So far, all 13 patients who underwent HEFT surgery achieved satisfactory treatment outcomes, with only one patient experiencing postoperative mild dysphagia after 3 months of eating and subsequently receiving endoscopic dilation treatment (anastomotic stenosis rate 1/13 vs. 4.7–29.1%) [14]. Compared with DTR, HEFT reduces the use of staplers, thereby significantly lowering patient costs. Theoretically, a higher number of anastomoses may lead to increased anastomosis-related complications such as anastomotic leakage. Compared with total gastrectomy (TG), PG has a relatively higher incidence of remnant gastric cancer. Although DTR has relatively reliable anti-reflux effects, during postoperative follow-up, endoscopists without relevant experience may miss examining the remnant stomach. Moreover, in most cases, DTR cannot achieve 100% utilization of the remnant gastric function. Mechanistically, as a direct esophagogastric anastomosis, HEFT has corresponding advantages regarding these issues [15–17].

2. Methods and analysis

2.1. Patient and public involvement

Patients and the public were not involved in the design and conduct of the trial. The results of the study will be disseminated through a peer-reviewed journal. Study participants will not be individually informed of study results.

2.2. Trail design

This study adopts a prospective, single-center, single-arm clinical research method. The study will use the AJCC-8th TNM tumor staging system for strict preoperative and postoperative TNM staging of tumors. Figure 1 shows an overview of the trial design, and each aspect of the trial is introduced in detail below.

Figure 1.

Flowchart of patient enrollment and follow-up.

2.3. Inclusion criteria

(1) Age between 18 and 75. (2) Pathologically confirmed adenocarcinoma. (3) Primary tumor located in the upper 1/3 of the stomach or esophagogastral junction (Siewert II or III) [18]. (4) For upper gastric adenocarcinoma, cT1N0M0 should be met. (5) For esophagogastral junction adenocarcinoma, cT1-2N0M0 should be met, and clinical judgment should indicate no distant lymph node metastasis around the stomach. (6) Bilateral resection margins should be greater than 2 cm, and more than half of the residual stomach should be preserved. (7) No history of upper abdominal surgery (excluding laparoscopic cholecystectomy). (8) No preoperative comprehensive treatments such as chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc. (9) Preoperative ECOG (Eastern Cooperative Oncology Group) score of 0/1. (10) Preoperative ASA (American Society of Anesthesiologists) score I-III. (11) Good function of important organs. (12) Signed informed consent.

2.4. Exclusion criteria

(1) Preoperative assessment indicating cT4b or Bulky lymph node enlargement or possible distant lymph node metastasis. (2) Pregnant or lactating women. (3) Patients with severe mental illness. (4) Preoperative temperature ≥ 38 °C or infectious diseases requiring systemic treatment. (5) Severe respiratory diseases, FEV1 < 50% of predicted value. (6) Occurrence of other malignant tumors in the past 5 years. (7) Severe liver or kidney dysfunction. (8) Unstable angina or myocardial infarction within the last 6 months. (9) Stroke or history of cerebral hemorrhage within the last 6 months (excluding old infarcts). (10) Systemic use of glucocorticoids in the last 1 month. (11) Emergency surgery required for complications of gastric cancer (bleeding, perforation, obstruction). (12) Patients who have participated in or are currently participating in other clinical studies within the last 6 months.

2.5. Treatment

2.5.1. Proximal gastrectomy

Laparoscopic proximal gastrectomy is performed for each patient with D1+/D2 lymphadenectomy, preserving residual stomach with 1/2–2/3 volume of the distal end, and incisal margin of both sides of the tumor is confirmed to be more than 2 cm. If necessary, confirm the margins are negative by intraoperative frozen section pathology examination.

2.5.2. Reconstruction of anastomosis

Firstly, create a fissure in the anterior wall of the stomach, by vertically cutting the muscular layer of the anterior wall of the remnant stomach, about 2–5 cm from the central portion of the remnant end (approximately 3 cm long). Preserve the mucosa intact and only incise the serosa and muscular layers, without requiring lateral expansion of the fissure (no width requirements, just open it). Connect the lower end of esophagus to the lower end of the fissure in stomach wall through a single-layer continuous anastomosis, utilizing the mucosa of the fissure’s stomach wall adhering to the posterior wall of the esophagus to form a valve membrane. Next, fold the “pseudo-fundus” (remnant stomach body) 270 degrees, wrapping it around the lower end of the esophagus to block the anterior wall of the esophagus. After completion of the entire surgical procedure, as visible in the schematic diagram, the esophagus is fixed to the anterior gastric wall in a tension-free anastomosis. Combined with well-preserved blood supply to both the esophagus and stomach, this ensures anastomotic safety. Furthermore, the fissure functions as a valve and is enclosed by surrounding sutures. Therefore, even if there are minor imperfections or tears during creation, or if fissure recurrence occurs postoperatively, it will not affect the overall anti-reflux structure or pose additional risks (Figures 2 and 3).

Figure 2.

Surgical steps diagram for HEFT. (a) The position of the fissure in anterior wall of stomach, the fixed position of the esophagus and stomach, and the position for full-thickness incision of gastric wall at the distal end of the fissure. (b) Single layer continuous suture of esophageal posterior wall and gastric mucosa. (c) Single layer continuous suture between the anterior wall of esophagus and the entire layer of stomach to reconstruct “pseudo-fundus.” (d) Fold the “pseudo-fundus” 270 degrees and rotate it around the lower end of the esophagus.

Figure 3.

Intraoperative diagram for HEFT. (a) Complete lymphadenectomy and transect the gastric body (preserving 1/2–2/3 of the distal stomach). Identify the anastomotic site 2–5 cm from the gastric remnant using a calibrated ruler. (b) Create a 3-cm longitudinal seromuscular fissure along the anterior midline (incising serosa and muscular layers while preserving intact mucosa). (c) Suture the esophageal stump, leaving 3–4 cm of thread for traction. Mark the esophageal posterior wall 4–5 cm oral to the closure line. (d) Fix the marked muscular layer to the seromuscular layer of the gastric wall at the cephalic end of the fissure. (e) Make a 1.8–2.5 cm full-thickness transverse incision at the caudal end of the fissure (adjusted to esophageal diameter). (f) Resect esophageal staples and open the lumen. Submit resection margins for intraoperative frozen section pathology. By using absorbable barbed sutures, continuously suture the fullthickness esophageal posterior wall to the mucosal edge of the gastric incision’s superior aspect and the fullthickness esophageal anterior wall to the full-thickness gastric wall of the incision’s inferior aspect. (g) Embed 270° of the distal esophageal circumference. (h) Complete the anastomosis.

2.6. Outcomes

Primary outcome is to assess perioperative safety by incidence of complications related to surgery and anastomosis (including bleeding, anastomotic leakage, obstruction, infection) within 1 month postoperatively. Secondary outcomes include: (1) incidence of postoperative reflux esophagitis and anastomotic stenosis within 1 month postoperatively; (2) Quality of life at 3 months postoperatively assessed by EORTC QLQ-C30 and EORTC QLQ-STO22 scales, To dynamically assess postoperative quality of life, questionnaire follow-up will be conducted at 6 months and 12 months postoperatively [19,20].

2.7. Adverse events

Adverse events (AEs) are any disadvantageous or uncertain events that affect the subject, regardless of its association to the treatment procedure. Adverse event/adverse reaction evaluation will refer to the Accordion Severity Grading System and CTCAEv3.0. When grading adverse events, categorization will be based on the definitions closest to Grade 0–4. Deaths related to treatment are categorized as Grade 5 in the original CTCAE [21].

2.8. Sample size

HEFT is still in the developmental stage as a surgical innovation. Due to the current selection of patients with strong indications for PG, including upper third early gastric cancer and some esophagogastral junction cancers, the expected number of cases for inclusion is low (estimated 20 cases per year). Additionally, based on the preliminary research experience, the effectiveness of HEFT expected to be significantly superior to traditional methods and DFT anastomosis (cost savings, reduced surgical difficulty, shortened surgical time). As an innovative surgical technique, we strictly adhere to the IDEAL Framework and Recommendations proposed by the IDEAL Collaboration. Our current study is in Stage 2a. According to the latest 2019 IDEAL Framework and Guidelines, studies at this stage should be small-sample, single-center, single-arm prospective studies with no more than 30 cases. Considering the actual patient enrollment pace achievable at our center, we set the sample size to 30 cases [22].

2.9. Data collection

Data collection will be performed by trained professionals via paper-form datasheets from inpatient and outpatient records until 1 year after the surgery. All relevant data will remain anonymous and will only be accessible to relevant researchers and statisticians.

2.10. Follow-up records

The follow-up medical history and physical examination, adjuvant therapy and completion, questionnaire results, laboratory results, imaging and endoscopic examination results are recorded.

Patient follow-up in the outpatient clinic abided by postoperative standards. The follow-up period and parameters were in Table 1.

Table 1.

Follow-up arrangements.

Items	Observation period
	Preoperative	5 days after surgery	1 month after surgery	3 month after surgery
weight
BMI
Blood routine test
CRP
Liver function test
Abdomen Routine Enhanced Scan
gastroscopy
Drainage fluid amylase
EORTC QLQ-C30 scale
QLQ-STO22 scale

2.11. Data analysis

Measurement data will be presented as mean ± standard deviation ($\overline{\mathrm{x}}\hspace{0.17em}\pm \text{\hspace{0.17em}s}$). Count data will be presented as rates (%). Data processing of QoL scale: (1) Raw Score (RS)=(Q1 + Q2 + Q?)/n, (Q: score of each item; n: number of all items). (2) Functional field: standard score (SS)= [1-(RS-1)/R(Range)] × 100. (3) Symptom field and general health field: SS = [(RS-1)/R(Range)] × 100.

2.12. Patient informed consent

All participants should sufficiently understand the instructions detailed in the written informed consent form (supplemental material 1). All patients will be given the opportunity to ask questions and be provided with a comprehensive response. Patients may choose not to participate in the study or withdraw at any time after notifying the researchers to ensure that patient rights to treatment will not be affected. All participants are required to provide written informed consent before participating in the trial.

2.13. Data monitoring and interim analysis

Data monitoring and interim analysis will be conducted annually by a specialist committee organized by the Hospital Institutional Review Board (HIRB) of Huashan Hospital. An independent statistician will be invited to evaluate study outcomes after enrollment of over 60% participants. If the perioperative safety and postoperative quality of life related indicators of HEFT are significantly inferior to those of existing techniques, the institution Hospital Institutional Review Board will be notified to determine whether early termination is necessary.

2.14. Modification of the protocol

Any protocol modification that could affect study implementation, potential patient benefit, or potentially affect patient safety, including changes in study objectives, study design, patient population, sample size, study procedures, or significant management, would require formal protocol modification. Such amendments need to be jointly decided by all members of the study group and approved by the Hospital Institutional Review Board (HIRB) of Huashan Hospital, Fudan University before implementation and notified to the health authorities in accordance with local regulations.

Funding Statement

This study is supported by the Shanghai ShenKang Hospital Development Center [No. SHDC2020CR3038B].

Author contributions

H-KH and JH initiated the study design and JW, M-YM helped with implementation. W-LC and Z-QW performed acquisition, analysis and interpretation of data; W-LC and JH drafted the manuscript; L-CH, H-KH and Y-PW provided critical revision of the manuscript; all authors have reviewed and approved of the final version manuscript for submission.

Ethical approval

This study has been approved by the Hospital Institutional Review Board (HIRB) of Huashan Hospital, Fudan University (2023-1058). On completion of the study, the results of the primary study will be published in a peer-reviewed journal.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Registration

This study has been registered on ClinicalTrails.gov (NCT06300879).