Study Protocol for Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Gastric Cancer after Laparoscopic or Robotic Gastrectomy with D2 Lymphadenectomy: A Phase III Multicentre Prospective Randomized Controlled Clinical Trial (HIPEC-09)

Study Protocol for Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Gastric Cancer after Laparoscopic or Robotic Gastrectomy with D2 Lymphadenectomy: A Phase III Multicentre Prospective Randomized Controlled Clinical Trial (HIPEC-09) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Study Protocol for Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Gastric Cancer after Laparoscopic or Robotic Gastrectomy with D2 Lymphadenectomy: A Phase III Multicentre Prospective Randomized Controlled Clinical Trial (HIPEC-09) Xiaodong Liu, Yulong Tian, Shougen Cao, Zequn Li, Quan Wang, Han Liang, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6957503/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2026 Read the published version in BMC Cancer → Version 1 posted 5 You are reading this latest preprint version Abstract Background Although some prospective clinical studies have shown comparable oncological outcomes between laparoscopic and open surgery for advanced gastric cancer, the 3-year recurrence-free survival rate of patients who undergo laparoscopic radical gastrectomy is lower than that of patients who undergo open radical gastrectomy. Animal experiments have also shown that laparoscopic surgery may increase the risk of peritoneal metastasis during carbon dioxide pneumoperitoneum. Previous single-centre clinical trials have confirmed that HIPEC can effectively eliminate free cancer cells, thereby improving the survival rate of patients with advanced gastric cancer. In this study, we aimed to investigate the safety and efficacy of the combination of laparoscopic gastrectomy with HIPEC in advanced gastric cancer to reduce the incidence of peritoneal metastasis. Methods A total of 616 patients will be randomly divided into 2 groups at a 1:1 ratio using central randomization after laparoscopic exploration in this prospective, randomized, controlled, open, multicentre clinical trial. The experimental arm will receive laparoscopic or robotic D2 surgery with 2 cycles of HIPEC treatment followed by 6–8 cycles of adjuvant chemotherapy, whereas the control group will undergo laparoscopic or robotic D2 surgery followed by 6–8 cycles of systemic chemotherapy. The primary endpoint for this study is 5-year recurrence-free survival. The secondary endpoints are the 5-year overall survival rate, peritoneal metastasis rate, peritoneal metastasis-free survival, regional recurrence rate, distant metastasis rate, toxicity and side effects of the treatment program. Discussion This is the first multicentre randomized controlled clinical study exploring whether HIPEC can prevent peritoneal metastasis after laparoscopic or robotic radical gastrectomy under carbon dioxide pneumoperitoneum for advanced gastric cancer. Minimally invasive surgery under carbon dioxide pneumoperitoneum can cause tremendous changes in the peritoneal microenvironment, increasing the risk of gastric cancer cell peritoneal dissemination and metastasis. In previous studies, the roles of HIPEC and laparoscopic gastrectomy for advanced gastric cancer have been confirmed. The innovation of this study lies in observing whether the combination of HIPEC can decrease the risk of peritoneal metastasis and recurrence in patients with advanced gastric cancer after laparoscopic or robotic gastrectomy under carbon dioxide pneumoperitoneum. Trial registration: The trial was registered on 14/05/2023 under clinicaltrials.gov (Identifier: NCT05871099). Advanced gastric cancer HIPEC Laparoscopic or robotic gastrectomy Randomized clinical trial Figures Figure 1 Figure 2 Background The epidemiology of gastric cancer Globally, the incidence of gastric cancer (GC) is the fifth most common type of malignant tumour, with the fourth highest cancer-related mortality [ 1 , 2 ] . Currently, the treatment of gastric cancer relies primarily on comprehensive approaches, including surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, nutritional therapy and other means to achieve radical resection or maximum tumour growth inhibition to improve patients' quality of life and prolong survival time. However, despite receiving the best available treatment plan, the 5-year survival rate for advanced gastric cancer remains below 40%, with a high recurrence rate [ 3 – 5 ] . Minimally invasive surgery for gastric cancer With continuous advancements in medical technology, minimally invasive surgeries have rapidly developed, such as laparoscopic and robotic surgery. Professor Kitano from Japan first reported the application of laparoscopic surgery in the treatment of early gastric cancer in 1994 [ 6 ] , followed by Goh's performance of laparoscopic D2 radical gastrectomy for advanced gastric cancer patients in 1997 [ 7 ] . Professors Minhua Zheng and Peiwu Yu were the first to perform laparoscopic radical gastrectomy for gastric cancer in China in 1999. Robot-assisted gastrectomy was first introduced by Hashizume et al. in 2002 [ 8 ] . Since 2006, more than 10000 cases of robotic radical gastrectomy for gastric cancer have been reported in China. At present, the clinical application of laparoscopic and robotic surgery for early gastric cancer has been confirmed by many RCTs, but high-quality evidence and consensus on the treatment of advanced gastric cancer remain lacking. RCTs conducted in China (CLASS-01 [ 9 ] ), Korea (KLASS-02 [ 10 ] ) and Japan (JLSSG0901 [ 11 ] ) compared laparoscopic versus open D2 radical gastrectomy for locally advanced distal gastric cancer, revealing favourable short-term clinical outcomes with no significant increase in complications between the two groups. The oncological controversy of laparoscopic or robotic gastrectomy Although some prospective clinical studies have demonstrated comparable oncological outcomes between laparoscopic and open surgery approaches, it is important to note that patients who undergo laparoscopic radical gastrectomy exhibit a lower 3-year recurrence-free survival rate compared to those who undergo open radical gastrectomy. Further discussion is warranted to explore the underlying factors contributing to this disparity [ 9 , 10 ] . The JLSSG0901 study from Japan revealed that the incidence of peritoneal metastasis was 4.3% (11/254) in open surgery and 7.7% (19/248) in laparoscopic surgery; although, the difference was not statistically significant [ 11 ] . Laparoscopic surgery for advanced gastric cancer has not yet been incorporated into the Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition) [ 12 ] . Furthermore, animal experiments have also indicated an increased risk of peritoneal metastasis associated with laparoscopic surgery [ 13 , 14 ] . Open surgery contributes to peritoneal metastasis in gastric cancer through three mechanisms: first, infiltration of the serosa by tumours results in tumour cell dissemination during growth or traumatic procedures; second, the involvement of lymph nodes and lymphatic vessels around the stomach, which may be damaged during lymph node dissection, results in cancer cell escape; and third, tumour invasion of blood vessels causes bleeding during resection or separation, leading to leakage of cancer cells from blood vessels [ 15 ] . In addition to the same mechanism as open surgery for the occurrence of peritoneal metastasis, the inherent characteristics of laparoscopic surgery under carbon dioxide pneumoperitoneum might increase the risk of peritoneal metastasis through a number of unique pathways. First, the application of CO2 pneumoperitoneum in minimally invasive surgery, where dry CO2 dehumidifies the peritoneum and damages the abdominal cortex, increases the probability of tumour cells adhering to the peritoneum [ 13 , 14 , 16 ] . Although humidified CO2 pneumoperitoneum has been employed in clinical practice, its benefits remain ambiguous. Second, in contrast to open surgery, it is challenging to utilize a large volume of liquid for abdominal lavage after laparoscopic surgery. The stirring and absorption of the lavage liquid under laparoscopy are relatively difficult, which could more readily result in the residual presence of free cancer cells in the abdominal cavity. Third, laparoscopic surgery is more likely to involve contact with tumours through squeezing, which causes tumour cells to detach, leading to iatrogenic dissemination. Other factors, such as smog, body fluids, and the leakage of tumour cells from lymphatic and blood during lymph node dissection using electrical energy devices such as ultrasonic and electric scalpels, can cause dissemination within the enclosed abdominal cavity, especially the trocar hole chimney effect [ 17 – 19 ] . We designed a device capable of collecting smog and tissue exudates generated during carbon dioxide pneumoperitoneum via laparoscopic or robotic radical gastrectomy throughout the entire surgery. By detecting CEA mRNA levels and monitoring postoperative abdominal metastasis, we aim to determine the causal relationship between the two parameters. We hope that this ongoing clinical study can provide us with new evidence and clarify the relevant mechanisms of abdominal metastasis in gastric cancer laparoscopic surgery [NCT06076265]. Peritoneal metastasis of gastric cancer Peritoneal metastasis is the most prevalent form of recurrence after gastric cancer surgery. The prognosis of patients with peritoneal metastases is very poor, and the median survival time is only 3 ~ 6 months [ 20 ] . Peritoneal-free cancer cells (FCCs) are the primary cause of peritoneal metastasis. The Japanese Gastric Cancer Society (JGCA) defined cancer cells found in the abdominal cavity as stage IV, and the 8th edition of TNM staging also defined positive abdominal cytology as tumour stage M1. Approximately 30%-50% of gastric cancer patients with subserosal or serosal involvement already have FCCs [ 21 , 22 ] . Ikeguchi et al. [ 23 ] reported that the five-year survival rate of patients without FCCs who underwent radical gastrectomy was 49.3%, but the survival rate of patients with FCCs was significantly reduced (15.4%, P < 0.01). Kuromoto et al. [ 24 ] reported that, in patients with tumour invasion into the subserosa and serosa, peritoneal lavage fluid had FCCs in 14.3% and 26.7% of cases, respectively. FCCs initiate fibrin retention followed by cellular implantation, which subsequently promotes inflammatory cell infiltration, leading to the release of growth factors and cytokines that facilitate tumour growth, invasion, and dissemination. Therefore, preventing the peritoneal implantation of tumour cells during or shortly after surgery is crucial for increasing the five-year survival rate of advanced gastric cancer patients. The role of HIPEC in advanced gastric cancer HIPEC enhances the efficacy of drugs against tumour cells mainly on the basis of the differential sensitivity of normal tissue and tumours to temperature. Studies have shown that normal tissue cells can remain healthy at a temperature of 47°C for 1 hour, whereas irreversible damage occurs to tumour cells at a critical temperature of 43°C for 1 hour. HIPEC induces ultrastructural changes in tumour cells, increasing the permeability of the cell membrane to chemotherapy drugs and facilitating the uptake of drugs by tumour cells. Moreover, it inhibits the repair mechanisms of tumour cells, promotes the absorption of antitumour drugs, improves patient immunity, and effectively suppresses the expression of multidrug resistance genes in tumour cells. HIPEC has shown remarkable clinical efficacy in preventing the recurrence and metastasis of gastric cancer, colorectal cancer, ovarian cancer, and other malignant tumours [ 25 – 29 ] . Relevant studies have indicated that HIPEC prolongs the survival time of patients with peritoneal metastasis of gastric cancer by approximately 2 years, confirming its positive effect on improving patient prognosis [ 30 – 32 ] . Over time, scholars worldwide have continuously improved the technology and methods related to HIPEC. From simple direct infusion heating to precise celiac perfusion chemotherapy techniques using innovative equipment, this approach has evolved into highly precise and accurate temperature-controlled, constantly circulating celiac perfusion technology solutions [ 33 , 34 ] . The "BR-TRG-I-type coelomic hyperthermic perfusion therapy system" employed in this study provides temperature measurement and control accuracy as fine as ± 0.1 ℃ as well as ± 5% perfusion speed control accuracy while being user friendly with stable performance. In terms of the primary technical indicators, the BR-TRG-I system significantly outperforms other perfusion therapy equipment in terms of temperature control and temperature measurement accuracy. Some previous single-centre clinical studies have shown that prophylactic HIPEC is quite effective in eliminating FCCs and peritoneal metastasis, thereby improving the 5-year survival rate of advanced cancer patients [ 35 , 36 ] . However, multicentre high-quality randomized controlled trials (RCTs) are currently lacking. We are eagerly awaiting the results of HIPEC-01 study on whether prophylactic HIPEC treatment after radical surgery for locally advanced gastric cancer can reduce the abdominal metastasis rate. Evidence regarding the combination of laparoscopic or robotic D2 radical gastrectomy under carbon dioxide pneumoperitoneum and HIPEC for preventing peritoneal metastasis of gastric cancer remains scarce. Therefore, it is necessary to determine its effectiveness, safety, and oncological control outcomes, such as peritoneal metastasis, through prospective multicentre randomized controlled trials, thereby providing high-level evidence-based medical evidence for clinical practice. Methods/design HIPEC-09 is a prospective, randomized, controlled, open-label, multicentre clinical trial with the aim to evaluate the effect of HIPEC on 5-year recurrence-free survival after CO2 pneumoperitoneum laparoscopic or robotic D2 surgery for advanced gastric cancer. In accordance with the CONSORT statement, eligible patients from 12 large-volume university teaching hospitals in China will be randomly divided into the experimental group receiving laparoscopic or robotic D2 surgery plus 2 sessions of HIPEC and 6‒8 cycles of systemic chemotherapy or the control group receiving laparoscopic or robotic D2 surgery plus 6‒8 cycles of systemic chemotherapy (Fig. 1 - study flow chart).. Measures of outcomes Primary endpoint 5-year recurrence-free survival. Secondary endpoints (1) 5-year overall survival rate, (2) peritoneal metastasis rate, (3) peritoneal metastasis-free survival rate, (4) regional recurrence rate (local recurrence after radical gastrectomy refers to the recurrence in the anastomosis, duodenal stump, tumour bed, or residual stomach, including recurrence in regional lymph nodes), (5) distant metastasis rate, and (6) toxicity and side effects of the program. Patient eligibility Inclusion criteria (1) Newly treated patients who did not receive chemotherapy, radiotherapy or other antitumor therapy before the start of the clinical trial, (2) Aged 18–80 years, (3) male or non-pregnant or lactating female, (4)Gastric adenocarcinoma was pathologically confirmed, and laparoscopic (robotic) radical gastrectomy was planned, (5) Patients with T stage of T3 or T4a, no distant metastasis, and feasible criteria for laparoscopic D2 radical resection (AJCC 6th edition), (6) The estimated survival time is more than 6 months, (7) History of nonabdominal surgery (except laparoscopic cholecystectomy), (8) The bone marrow reserve function was good, and the blood routine met the following conditions: white blood cell count (WBC) ≥ 3.5×109/L, neutrophil ≥ 1.5×109/L, platelet count(Plt) ≥ 100×109/L, hemoglobin(Hb) ≥ 90g/L, (9) Organ function was good, and biochemical examination met the following conditions: glutamate aminotransferase (ALT) ≤ 2.5×upper limit of normal value (ULN), aspartate aminotransferase (AST) ≤ 2.5×ULN, serum total bilirubin(BUN) ≤ 1.5×ULN, serum creatinine(Cr) ≤ 1.5×ULN, (10) Eastern Cooperative Oncology Group(ECOG) score: 0–1, (11) Preoperative American Society of Anesthesiologists(ASA) grade: I-III; (12) Voluntarily sign the informed consent. Exclusion criteria (1) Lymph node bulky N2 status diagnosed by abdominal CT/MRI, that is, at least one lymph node meridian ≥ 3 cm or three consecutive lymph nodes, each meridian ≥ 1.5 cm; (2) patients with other malignant tumours within the past 5 years; (3) preoperative temperature ≥ 38°C or complicated with infectious diseases requiring systematic treatment; (4) patients with serious mental illness; (5) patients with severe respiratory diseases with FEV1 < 50%; (6) patients with history of unstable angina pectoris or myocardial infarction within the past 6 months; (7) patients with a history of cerebral infarction or cerebral haemorrhage within the past 6 months, except for old infarcts; (8) patients who had systemic glucocorticoid therapy within the past month; (9) patients with gastric cancer complications (bleeding, perforation, obstruction) requiring emergency surgery; (10) patients who have participated in or were currently participating in other clinical studies (within the past 6 months); or (11) patients with confirmed intraperitoneal implantation and metastasis by the way of laparoscopic exploration, biopsy and cytology. Discharge criteria (1) Patients with stage IV disease after the operation; (2) patients for whom R0 resection could not be achieved during the operation; (3) patients for whom simultaneous surgical treatment of other diseases was required (except gallstones); (4) patients who were not suitable for or unable to implement the treatment plan of the study due to sudden severe comorbidities (inability to tolerate surgery or anaesthesia) during the perioperative period; (5) after entering the study, the need for emergency surgery was confirmed by the doctor in charge due to changes in the patient's condition; and (6) at any stage after entering the study, the patient voluntarily requested to withdraw from the study or discontinue treatment for personal reasons rather than for reasons of efficacy. Randomization and grouping In this study, a minimization-based central dynamic randomization method will be employed. Stratification factors considered will include age (< 60 or ≥ 60), intraoperative T stage (T3 or T4a), histopathological type (signet-ring cell carcinoma or not), and study centre. After each patient is enrolled, researchers at each participating centre will record relevant information (age, intraoperative T stage and histopathological type) in the central randomization system. The system will promptly provide randomized results back to the research centre. Sample size estimate The primary endpoint of this study is 5-year recurrence-free survival. Sample size estimation utilized survival analysis based on a log-rank test, with an estimated rate of 65.4% in the laparoscopic-only group and 75.4% in the laparoscopic combined with HIPEC group. The projected recruitment time for all the subjects was 36 months, with cases assigned a 1:1 ratio of α = 0.05 and β = 0.2 (power = 80%). Considering an overall dropout rate of 10% (including dropouts and loss to follow-up), both the laparoscopic surgery-only group and the laparoscopic combined with HIPEC group would consist of 308 patients each, for a total of 616 patients. Statistical analysis Categorical variables will be described in terms of frequency distribution (number of cases and percentage). Continuous variables will be described as the mean, median, minimum, maximum, first quartile and third quartile. The confidence intervals for all the parameters will be considered significant if α ≤ 0.05(i.e., 95% confidence interval). Epitaxial analysis of the data will be performed properly. All analyses will be performed using SAS. The overall survival and disease-free survival rates of the two groups will be analysed using the log-rank test and described with Kaplan‒Meier curves. A Cox proportional hazards model will be used to analyse the risk coefficients and 95% confidence intervals considering race, age, and disease progression. Subsets of time and event analyses will be performed according to intraperitoneal tumour status. A modified intention-to-treat analysis (mITT) and per-protocol (PP) analysis will be used to compare outcomes, but the conclusion will be drawn from mITT analysis. Treatments Laparoscopic and Robotic D2 radical gastrectomy Laparoscopic and robotic D2 radical gastrectomy involves several crucial steps. After laparoscopic or Da Vinci robot exploration, measurements of the lesion infiltration area and tumour size, as well as intraoperative T staging, should be performed. Enrolment and randomization should be based on the presence or absence of peritoneal carcinoma. The surgical resection scope for different types of localized gastric cancer should be more than 3 cm from the tumour, whereas invasive gastric cancer requires a distance of more than 5 cm. For esophagogastric junction cancer, the oesophageal resection margin must be at least 2 cm away from the tumour. An examination of frozen pathological sections is necessary when suspicious findings are present. In cases where tumours invade the pyloric canal, a duodenal margin greater than 3 cm from the tumour is needed. The extent of D2 lymphadenectomy for various tumour regions is based on the Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition) [ 12 ] . First, the veins and arteries will be ligated at the base of the vessel while the lymph nodes are simultaneously dissected. The samples will be carefully separated and excised. During the procedure, gentle handling is recommended, and blunt separation should be minimized. In addition, direct contact with the tumour should be avoided to prevent damage to the lymph nodes that may lead to cancer cell spread or local implantation. The serosal layer can be protected by covering it. Before and after the operation, 500 mL of normal saline was used to thoroughly rinse, stir and collect the area near the gastric cancer lesion. During the irrigation process, patients will be positioned with their head high and feet low. A total of 500 mL of normal saline should be injected into the right upper abdomen, avoiding the cancer site, followed by aspiration of at least 200 ml of rinse solution from the pelvic cavity. The peritoneal rinsing fluid will be collected and anticoagulated with 1 ml of heparin before being centrifuged at 1000 × g for 10 minutes. The nucleated cell layer will then be obtained for smear preparation, and tumour cells will be detected using HE staining by two senior pathologists. In the case of any disagreement between two pathologists regarding the conclusion, a senior pathologist designated by the research committee will be consulted to confirm the diagnosis. Photographs will be taken and archived following the surgical procedure. For photographic documentation, the distal subtotal gastrectomy will be captured, which includes the ligation of the left gastroepiploic artery, the common hepatic artery, the proper hepatic artery, the ligation of the left gastric artery, the ligation of both the left and right gastric veins, the proximal splenic artery, the arteriovenous ligation of the right gastroepiploic vessel, and the bare proximal minor curvature. In the case of proximal gastrectomy, photographs should include images showing ligation of the left gastric artery and coronary vein stump, common hepatic artery, proximal splenic artery, celiac trunk (depending on individual centre protocols), and splenic hilum. Total gastrectomy requires the capture of images displaying ligation points of both the left gastric arteries and veins along with those for the right gastric arteries and veins. In addition, the common hepatic artery should be documented along with the celiac trunk (based on centre-specific conditions), splenic hilum (if applicable), splenic artery, proper hepatic artery and ligation points for both right gastro-omental vessels. The entire surgical procedure must be documented comprehensively, and unaltered video recordings must be retained. HIPEC (1) Location of the drainage tube: Two perfusion tubes will be positioned in the upper abdomen. Their openings will be placed under the left diaphragm and in the liver and kidney crypts. After HIPEC is completed, the left diaphragm can serve as the postoperative abdominal drainage tube. Two outflow tubes will be located in the lower abdomen. The openings will be placed on both sides of the pelvic floor. Each drainage tube was generally positioned in the front axillary plane. It is important to ensure that the perfusion tube is placed near the tumour while maintaining a distance from the tumour area for optimal placement of outflow tubes. (2) Temperature setting: 43°C. (3) Perfusion time: 60 min. (4) Dosage of perfusion fluid: The principle of perfusion fluid is abdominal cavity filling and unimpeded circulation. (5) The perfusion solution: Normal saline. (6) Drug selection and dose: First HIPEC, 75 mg/m 2 paclitaxel; second HIPEC, 100 mg/m 2 paclitaxel. (7) Timing of treatment: The first HIPEC should be conducted within 48 hours after surgery, and the time interval between the second HIPEC and the first HIPEC should be no less than 24 hours (within one week after the operation). (8) Treatment course: 2 times. (9) Intraoperative medication: Intravenous sedation was performed as needed, with the dosage adjusted on the basis of the patient's response, and fluid rehydration was performed according to vital sign monitoring. (10) Temperature control: The entry temperature for HIPEC should be maintained at 43.0 ± 0.5°C, while the body temperature should be kept constant within the range of 39.0–42.0°C. (11) Intraoperative monitoring: During HIPEC treatment, blood pressure, body temperature, pulse rate, urine volume, respiration rate, and oxygen saturation levels were continuously monitored. Additionally, any blockage in the perfusion tube and smoothness of the effusion were checked regularly. These parameters will be recorded on the CRF at 0 minutes, 30 minutes, and 60 minutes after HIPEC initiation and one hour after HIPEC completion. If symptoms such as profuse sweating or a heart rate exceeding 100 beats per minute occur during treatment, measures must be taken to address potential hypovolemia by strengthening fluid replacement. Any abnormal respiration or decrease in blood oxygen saturation will require careful evaluation of anaesthetic drug dosage and perfusate administration. If necessary, treatment may be discontinued for that patient. Postoperative adjuvant chemotherapy After 4 to 6 weeks post-surgery when the patient's condition has recovered, 6 to 8 cycles of postoperative systemic adjuvant chemotherapy will be initiated. The Xelox regimen comprises 130 mg/m 2 oxaliplatin administered on Day 1 and 1 g/m 2 capecitabine twice a day from Day 1 to Day 14, with cycles repeated every 3 weeks. Alternatively, the SOX regimen could be considered, which involves 130 mg/m 2 oxaliplatin on Day 1 and tegafur/gimeracil/oteracil (Teggio) at a dosage of 40–60 mg twice a day from Days 1 to 14, with cycles repeated every 3 weeks. Researcher qualifications To maintain the standard of the study and ensure patient safety, certain fundamental principles must have been fulfilled prior to a surgeon's involvement in the research. Laparoscopic (robot-assisted) D2 gastrectomy must have been performed on a minimum of 50 patients. In addition, the unedited surgical videos will also be subject to blind review by two senior experts from the HIPEC 09 research committee. Data collection and management Evaluation prior to enrolment will require completion of the following procedures within one week after admission: (1) detailed personal information, including complete medical history data; (2) current treatment status; (3) physical examination; (4) routine blood tests (Hb, Plt, WBC, and NEUT) and liver and kidney function tests measuring ALT, AST, BUN, total protein albumin, globulin, BUN, and serum creatinine levels; (5) tumour marker levels, including CEA, CA199, CA724, and CA125; and (7) electrocardiogram, B-ultrasound, chest CT, gastroscopy, and imaging examinations of tumour lesions (CT or endoscopic ultrasound). Evaluation during HIPEC: Short-term adverse reactions to HIPEC should be assessed 24 hours after each hyperthermic infusion. Additionally, the evaluation should be conducted on the 7th day postoperation or prior to discharge for a total of three assessments. The assessment should include the following: (1) routine blood tests (Hb level, Plt, WBC, and NEUT) and liver and kidney function analysis (ALT, AST, total bilirubin, total protein, albumin, globulin, BUN, and Cr); (2) assessment of complications and abdominal conditions; and (3) evaluation of anastomotic fistula. Chemotherapy monitoring included pre- and posttreatment laboratory tests. These include routine blood examinations (Hb, WBC, Plt, and NEUT), liver and kidney function assessments and other routine biochemical indicators (ALT, AST, total protein, albumin, BUN, and Cr). Additionally, the observation and evaluation of chemotherapy toxicity, such as decreased appetite, nausea, vomiting, oral mucosa, diarrhoea, abdominal pain, dizziness, headache, infection fever, hair loss, and allergy, were performed during each cycle of chemotherapy. If patients experienced adverse reactions, treatment should be adjusted or discontinued according to the indications for dose adjustment or withdrawal in the XELOX systemic adjuvant chemotherapy protocol. The effectiveness of this treatment will be evaluated by tumour efficacy indicators including tumour recurrence (site and time), metastasis (site and time), and death (cause and time). Patient survival benefit will be evaluated on the basis of (1) relapse-free survival (RFS), defined as the time from randomization to relapse onset or the end of follow-up; (2) overall survival (OS), which is commonly considered the primary efficacy endpoint in cancer trials and refers to the time from randomization to death from any cause. Accurate records were maintained throughout the entire follow-up period; and the observation endpoint was 5-year recurrence-free survival. This study employed a network-based electronic case report form (eCRF) to transmit research data and information. Data can be recorded from source files, or the eCRF can be utilized as the primary source file. In any case, data must always be under the control of the investigator, and systems and procedures must be in place to guarantee the quality and safety of the data and not be altered or manipulated. A closed-loop management system for data transmission, electronic universal reporting formats, electronic data, raw data, and source data will be established. To improve the quality of the trial, an independent data monitoring committee (DMC) composed of surgeons, statisticians and ethics experts was established. This committee has no affiliation with the project research team and is responsible for objectively evaluating the effectiveness and safety of the trial. When the expected number of participants reaches half (n = 308), an interim analysis will be conducted. The results of the interim analysis will be announced to all researchers. Furthermore, the DMC will conduct data audits monthly based on the eCRF. Adverse events (AEs) Emergence or exacerbation of any signs, symptoms, syndromes, or diseases impacting the subject's health from the time of informed consent and study enrolment until their final visit will be assessed. This will include clinically relevant conditions identified using laboratory tests or other diagnostic procedures. AEs included new diseases, worsening of treatment-related symptoms/signs or concomitant deterioration of preexisting conditions, effects of control drugs, events unrelated to trial participation, or a combination thereof. The term AE does not imply causality with the trial. The primary chemotherapy agents utilized in this study included paclitaxel, oxaliplatin, and capecitabine. The major nonhaematological adverse reactions include nausea, vomiting, and diarrhoea. Neurotoxicity from these drugs primarily presents as peripheral neuritis, occasionally accompanied by spasms and sensory disturbances in the oral cavity, upper respiratory tract, and upper digestive tract. In the HIPEC group, specific thermoperfusion duct components must be utilized and may increase risks such as anastomotic fistula, delayed recovery of exhaust function, and intestinal adhesion development leading to obstruction. Follow-up A specialized team is responsible for the follow-up, and the first follow-up review began 3 months after the operation. Once every 3 months for 2 years, once every half a year after 2 years, once a year after 5 years, long-term follow-up review will be performed. Each follow-up visit should include the following: (1) Routine blood tests (Hb, Plt, WBC, and NEUT) and liver and kidney function tests (ALT, AST, total bilirubin, total protein, albumin, globulin, and serum urea levels); (2) examination of the tumour marker levels of CEA, CA199, CA724, and CA125; and (3) evaluation of the tumour status using tumour marker, CT and gastroscopy. CT examination should be performed when the patient has physical abnormalities or when the tumour marker levels are elevated. CT examination (enhanced CT is recommended, and plain CT is acceptable) is recommended once every six months within three years and once yearly after three years. The upper abdomen should be examined, and full abdominal CT is recommended. Gastroscopy will be performed six months after surgery and annually thereafter until the completion of the follow-up. Tumour markers are recommended to be assessed every 3 months for 2 years, semiannually after 2 years, and once yearly after 5 years. If the CT scan highly suspects peritoneal metastasis, after discussion with the MDT, fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET)-CT and laparoscopic exploration can be employed for diagnosis. Discussion To the best of our knowledge, this is the first multicentre randomized controlled clinical study that seeks to determine whether HIPEC can prevent peritoneal metastasis via laparoscopic or robotic radical gastrectomy for gastric cancer under carbon dioxide pneumoperitoneum. The aim of this clinical trial was to explore the efficacy of HIPEC in improving the 5-year overall survival rate and reducing peritoneal metastases in patients with locally advanced gastric cancer who have undergone laparoscopic or robotic gastrectomy with D2 lymphadenectomy. Gastric cancer is a prevalent malignancy worldwide and is characterized by high incidence and mortality rates [ 1 , 2 ] . The peritoneum is the most common site of recurrence and metastasis in advanced gastric cancer patients [ 37 , 38 ] . Approximately 20% of patients are diagnosed with peritoneal metastasis before or during surgery, and more than 50% of patients with T3 and T4 disease have peritoneal metastasis after radical surgery. Patients with advanced peritoneal metastasis have a median survival time of only 3–6 months, with a five-year survival rate of less than 2% [ 20 ] . Effective prevention and treatment of peritoneal metastasis are crucial for improving the prognosis of postsurgical gastric cancer patients, with a particular emphasis on proactive preventive measures. Laparoscopic exploration for tissue pathological examination is regarded as the gold standard for diagnosing peritoneal metastasis following gastrectomy; however, its widespread acceptance is hindered by its invasive nature. Enhanced CT is commonly employed for postoperative follow-up in clinical practice. The sensitivity of thin-slice enhanced CT in diagnosing peritoneal metastasis of gastric cancer is 50%, with a specificity ranging from 95–99%, surpassing that of ultrasound and PET-CT examinations. The use of FAPI as an innovative metabolic imaging agent for PET-CT can increase the diagnostic accuracy of detecting peritoneal metastasis in patients with gastric cancer [ 39 ] . For this study follow-up examinations will be conducted using abdominal thin-slice enhanced CT combined with serum tumour markers, and additional (PET)-CT (FAPI) or laparoscopic exploration was performed as needed. This study will establish a standardized operating procedure (SOP) for the treatment of peritoneal metastasis, which will stipulate that systemic treatments such as chemotherapy, immunotherapy, and targeted therapy combined with HIPEC treatment be implemented under the guidance of an MDT group. Despite the rapid advancement of laparoscopic gastric cancer surgery, numerous problems are still encountered in the promotion of the standardization of laparoscopic gastric cancer surgery and clinical practice, and confirmation and support through more high-quality clinical research is needed to provide high-level evidence-based medical evidence. The CLASS-01 study from China [ 9 ] , the KLASS-02 study from Korea [ 10 ] , and the JLSSG0901 study from Japan [ 11 ] indicate that the tumour prognosis is not inferior to that of open surgery, providing evidence-based medical evidence for laparoscopic surgery in the treatment of advanced gastric cancer. However, when meticulously interpreting the details of these studies, some limitations and certain risk factors related to tumour prognosis are noted. First, some patients included in these studies were in the early stage of gastric cancer (pathological stage I), which may affect the generalizability of the study results and the inability to offer a more precise assessment of the postoperative prognosis for patients with advanced gastric cancer. On the other hand, the study revealed that the RFS of laparoscopic surgery patients was lower than that of open surgery patients. Although the difference was not statistically significant, the underlying cause requires further investigation. The characteristics of laparoscopic surgery, such as pneumoperitoneum, inadequate irrigation, tumour manipulation, and the generation of smoke by electrical energy instruments, also raise concerns that it may further increase the risk of postoperative gastric cancer metastasis, especially peritoneal metastasis, compared with open surgery. Huang et al. [ 40 ] also reported that in patients with cT4a tumours and tumours > 5cm, the number of peritoneal recurrences was significantly greater in the LDG group than in the ODG group, and the peritoneal recurrence time and multiple-site recurrence time were both earlier in the LDG group. Thus, it remains controversial whether laparoscopic surgery for gastric cancer can increase the incidence of postoperative metastasis, especially peritoneal metastasis. In this context, a single-centre study (SMOG01 study, NCT06076265) initiated by our centre on whether laparoscopic and robotic radical gastrectomy for gastric cancer performed under a carbon dioxide pneumoperitoneum state increases the risk of intra-abdominal tumour dissemination is ongoing. We anticipate the release of the results of this study. Since the initial report by Spratt et al. in 1980 [ 41 ] , researchers have continuously improved HIPEC technology. The International Collaborative Group for Peritoneal Surface Malignancies (PSOGI) employs HIPEC technology characterized by high-dose single-drug administration (primarily oxaliplatin 360 ~ 460 mg/m 2 or bleomycin 30 ~ 50 mg/m 2 ), open or closed infusion (up to 30 or 60‒90 minutes), and treatment temperatures ranging from 41 to 43°C [ 42 – 44 ] . These diverse techniques and infusion methods lead to varying clinical outcomes due to imprecise temperature control. Chinese specialists have developed China Hyperthermic Intraperitoneal Chemotherapy (C-HIPEC) technology along with a high-precision, large-capacity continuous circulation system for the constant-temperature infusion method within C-HIPEC standards. This study utilized C-HIPEC technology for intraperitoneal infusion, which requires the infusion fluid to be maintained at a temperature of 43.0 ± 0.5°C. The treatment protocol consisted of 2 sessions. In this study, paclitaxel was utilized as the infusion drug, with an initial infusion dosage of 75 mg/ m 2 and a subsequent infusion dosage of 100 mg/m 2 . During HIPEC, chemotherapy drugs are directly injected into the abdominal cavity, bypassing the blood‒peritoneal barrier and enabling direct contact with the lesion to exert an antitumour effect. The selection criteria for peritoneal drugs include sensitivity to primary tumours, enhanced penetration capacity, high molecular weight, low peritoneal absorption rate, minimal irritation to the peritoneum and potential synergistic effects with thermal treatment. Common abdominal chemotherapy drugs include paclitaxel, docetaxel, cisplatin, and oxaliplatin. Paclitaxel has a high molecular weight and fat solubility and is slowly absorbed through the lymphatic system. Moreover, it has potent anti-proliferative activity but rarely causes intraperitoneal adhesion postadministration. Additionally, its ability for repeated intraperitoneal administration makes it relatively ideal as an intraperitoneal chemotherapy drug. Nevertheless, there are disparities in terms of dosage, type and frequency of intraperitoneal drug use among different studies. To date, several retrospective studies have indicated that the addition of HIPEC during surgery in conjunction with standard adjuvant chemotherapy may significantly decrease the risk of peritoneal recurrence [ 45 – 47 ] . A meta-analysis evaluating the role of HIPEC in preventing peritoneal recurrence in patients with advanced gastric cancer without peritoneal metastasis demonstrated a significant reduction in the rate of peritoneal recurrence compared with simple gastrectomy (RR = 0.63) [ 48 ] . Nevertheless, HIPEC is also associated with a substantial increase in postoperative complications, such as respiratory failure and renal dysfunction. Thus, it is essential to conduct clinical studies with robust designs adhering to current treatment standards. Currently, prophylactic HIPEC is not recommended as a routine postoperative treatment for advanced gastric cancer. Ongoing studies such as the GASTRICHIP (NCT01882933) [ 49 ] and PREVENT (FLOT9) trials (NCT04447352) [ 50 ] will further assess the safety and survival advantages of HIPEC, and the HIPEC-01 study (NCT02356276), a prospective, multicentre, randomized controlled phase III trial investigating adjuvant HIPEC after D2 radical surgery for locally advanced gastric cancer in China, has ended. The results of the 3-year follow-up will be published shortly [ 51 ] . The vast majority of the aforementioned studies focused on the role of HIPEC in preventing peritoneal metastasis after open surgery for gastric cancer. However, unlike open surgery, minimally invasive surgery under carbon dioxide pneumoperitoneum can cause sudden alterations in the intra-abdominal microenvironment, which may become an inducer and high-risk factor for intra-abdominal metastasis of gastric cancer. To date, strictly designed high-quality multicentre RCT study specifically focused on the role of HIPEC in preventing peritoneal metastasis in laparoscopic and robotic minimally invasive gastric cancer surgery under carbon dioxide pneumoperitoneum are lacking. Ensuring the reliability of results in an RCT depends on standardizing treatment across all research centres. To achieve this goal, we have taken several measures. First, all participating centres are major medical facilities in China with a high volume of minimally invasive gastric cancer surgeries and HIPEC treatments performed independently by researchers annually. Second, we require the retention of surgical videos and the uploading of operative field photos, specimen images, and HIPEC treatment curves for regular evaluation by the HIPEC-09 Research Committee. Finally, we will conduct regular data entry monitoring to guarantee the completeness and reliability of the research data. In light of the major challenges and clinical issues such as tumour safety faced in the current rapid development of laparoscopic and robotic surgeries for gastric cancer, we have devised this multicentre randomized controlled clinical trial in line with international conventions and standards. The aim of the study is to assess the potential of HIPEC in reducing and preventing peritoneal metastasis after laparoscopic or robotic gastrectomy under carbon dioxide pneumoperitoneum for advanced gastric cancer. We anticipate that the results of this study will be capable of providing high-level evidence-based medical evidence for the future clinical practice of minimally invasive surgery for gastric cancer. Trial status The recruitment for this study officially began when ethics approval was granted. The protocol version was revised to V2.0 on March 3, 2022. The trial will last from November 23, 2022, to November 30, 2030. Abbreviations HIPEC: hyperthermic intraperitoneal chemotherapy; RCT: randomized controlled trial; CRF: case report form; FCCs: Peritoneal-free cancer cells; JGCA: The Japanese Gastric Cancer Society; ALT: glutamate aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; Cr: blood creatinine; ULN: upper limit of normal value; Hb : haemoglobin ; WBC : white blood cell count；Plt: platelet count; NEUT: neutrophil count; RFS: relapse-free survival; OS: overall survival; AEs: Adverse events; PSOGI: The International Collaborative Group for Peritoneal Surface Malignancies; ECOG: Eastern Cooperative Oncology Group; ASA: American Society of Anesthesiologists; FAPI: fibroblast-activating protein inhibitor; PET: positron emission tomography; DMC: data monitoring committee. Declarations Ethics approval and consent to participate The study has been approved by the Ethics Committee of the Affiliated Hospital of Qingdao University and has already been registered at ClinicalTrial.gov with Registration ID NCT05871099. The HIPEC-09 study complies with the Declaration of Helsinki rules, the principles of the Good Clinical Practice guidelines and the Data Protection Act. The trial will also be performed in accordance with local legal and regulatory requirements. Each patient recruited to the study will provide written informed consent after receiving extensive information about the intent of the study, the study regimen, potential associated risks and side effects as well as potential alternative therapies. The investigator will not undertake any diagnostic measures specifically required for the clinical trial until valid consent has been obtained. Monitoring will be conducted throughout the trial. We have purchased insurance for this research. If subject suffers any damage related to this study or experiences a serious adverse event, appropriate compensation will be provided. Consent for publication Not applicable. Availability of data and materials The original data from the study are available for dissemination to other researchers upon request at the time of publication. Access can be arranged by contacting the corresponding author via email ( [email protected] ). Competing interests The authors declare that they have no competing interests. Funding The present trial is supported by Wu Jieping Medical Foundation (320.6750.2024-17-24). The sponsor is not involved in the aspects of trial design, data collection and analysis and manuscript writing. Authors' contributions YZ, XL and JW conceived and designed the study. XL and YZ drafted the manuscript and developed the protocol. YZ, YT and GL contributed to the study coordination. XL, QW, HL, SC, TZ, YL, XS, WH, PG, KT, TL, LL and YZ contributed to the patient recruitment. XL, YT, SC, ZL and YZ contributed to the data management and statistical analysis. YZ contributed to funding acquisition and study supervision. All authors have read and approved the version to be published and have agreed to be responsible for all aspects of the work. Acknowledgements We thank all the participants and their families for their participation and support in this study. We thank Professor Xiaobin Zhou from School of Public Medicine of Qingdao University for practical suggestions to the study's design, data analysis, and interpretation. References Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. 74(3): 229-263. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022. 135(5): 584-590. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012. 379(9813): 315-21. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007. 357(18): 1810-20. Xu W, Liu W, Wang L, et al. Is D2 Lymphadenectomy Alone Suitable for Gastric Cancer With Bulky N2 and/or Para-Aortic Lymph Node Metastases After Preoperative Chemotherapy. Front Oncol. 2021. 11: 709617. Kitano S, Iso Y, Moriyama M, Sugimachi K. Laparoscopy-assisted Billroth I gastrectomy. Surg Laparosc Endosc. 1994. 4(2): 146-8. Goh PM, Khan AZ, So JB, et al. Early experience with laparoscopic radical gastrectomy for advanced gastric cancer. Surg Laparosc Endosc Percutan Tech. 2001. 11(2): 83-7. Hashizume M, Sugimachi K. Robot-assisted gastric surgery. Surg Clin North Am. 2003. 83(6): 1429-44. Huang C, Liu H, Hu Y, et al. Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer: Five-Year Outcomes From the CLASS-01 Randomized Clinical Trial. JAMA Surg. 2022. 157(1): 9-17. Hyung WJ, Yang HK, Park YK, et al. Long-Term Outcomes of Laparoscopic Distal Gastrectomy for Locally Advanced Gastric Cancer: The KLASS-02-RCT Randomized Clinical Trial. J Clin Oncol. 2020. 38(28): 3304-3313. Etoh T, Ohyama T, Sakuramoto S, et al. Five-Year Survival Outcomes of Laparoscopy-Assisted vs Open Distal Gastrectomy for Advanced Gastric Cancer: The JLSSG0901 Randomized Clinical Trial. JAMA Surg. 2023. 158(5): 445-454. Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer. 2023. 26(1): 1-25. Volz J, Köster S, Spacek Z, Paweletz N. The influence of pneumoperitoneum used in laparoscopic surgery on an intraabdominal tumor growth. Cancer. 1999. 86(5): 770-4. Carpinteri S, Sampurno S, Bernardi MP, et al. Peritoneal Tumorigenesis and Inflammation are Ameliorated by Humidified-Warm Carbon Dioxide Insufflation in the Mouse. Ann Surg Oncol. 2015. 22 Suppl 3(Suppl 3): S1540-7. Tustumi F, Bernardo WM, Dias AR, et al. Detection value of free cancer cells in peritoneal washing in gastric cancer: a systematic review and meta-analysis. Clinics (Sao Paulo). 2016. 71(12): 733-745. Binda MM, Molinas CR, Mailova K, Koninckx PR. Effect of temperature upon adhesion formation in a laparoscopic mouse model. Hum Reprod. 2004. 19(11): 2626-32. Neuhaus SJ, Watson DI. Pneumoperitoneum and peritoneal surface changes: a review. Surg Endosc. 2004. 18(9): 1316-22. Wittich P, Marquet RL, Kazemier G, Bonjer HJ. Port-site metastases after CO(2) laparoscopy. Is aerosolization of tumor cells a pivotal factor. Surg Endosc. 2000. 14(2): 189-92. Koninckx PR, Fernandes R, Ussia A, et al. Pathogenesis Based Diagnosis and Treatment of Endometriosis. Front Endocrinol (Lausanne). 2021. 12: 745548. Thomassen I, van Gestel YR, van Ramshorst B, et al. Peritoneal carcinomatosis of gastric origin: a population-based study on incidence, survival and risk factors. Int J Cancer. 2014. 134(3): 622-8. De Andrade JP, Mezhir JJ. The critical role of peritoneal cytology in the staging of gastric cancer: an evidence-based review. J Surg Oncol. 2014. 110(3): 291-7. Mori N, Oka M, Hazama S, et al. Detection of telomerase activity in peritoneal lavage fluid from patients with gastric cancer using immunomagnetic beads. Br J Cancer. 2000. 83(8): 1026-32. Ikeguchi M, Oka A, Tsujitani S, Maeta M, Kaibara N. Relationship between area of serosal invasion and intraperitoneal free cancer cells in patients with gastric cancer. Anticancer Res. 1994. 14(5B): 2131-4. Shimada S, Kuramoto M, Marutsuka T, Yagi Y, Baba H. Adopting extensive intra-operative peritoneal lavage (EIPL) as the standard prophylactic strategy for peritoneal recurrence. Rev Recent Clin Trials. 2011. 6(3): 266-70. Wang W, Tan G, Skanthakumar T, Chia CS, Soo KC, Teo M. Exploring the trend in referrals for consideration of CRS and HIPEC to understand the attitudes of clinicians in the development of a national cancer centre programme in peritoneal disease. Int J Hyperthermia. 2018. 34(5): 551-558. Kwakman R, Schrama AM, van Olmen JP, et al. Clinicopathological Parameters in Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer Metastases: A Meta-analysis. Ann Surg. 2016. 263(6): 1102-11. Chia CS, You B, Decullier E, et al. Patients with Peritoneal Carcinomatosis from Gastric Cancer Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Is Cure a Possibility. Ann Surg Oncol. 2016. 23(6): 1971-9. Sgarbura O, Al Hosni M, Petruzziello A, et al. Complete pathologic response after two-stage cytoreductive surgery with HIPEC for bulky pseudomyxoma peritonei: proof of concept. Int J Hyperthermia. 2020. 37(1): 585-591. van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018. 378(3): 230-240. Beeharry MK, Zhu ZL, Liu WT, Yao XX, Yan M, Zhu ZG. Prophylactic HIPEC with radical D2 gastrectomy improves survival and peritoneal recurrence rates for locally advanced gastric cancer: personal experience from a randomized case control study. BMC Cancer. 2019. 19(1): 932. Desiderio J, Chao J, Melstrom L, et al. The 30-year experience-A meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer. Eur J Cancer. 2017. 79: 1-14. Yonemura Y, Ishibashi H, Hirano M, et al. Effects of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy and Neoadjuvant Intraperitoneal/Systemic Chemotherapy on Peritoneal Metastases from Gastric Cancer. Ann Surg Oncol. 2017. 24(2): 478-485. Gwee YX, Chia D, So J, et al. Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis. J Clin Oncol. 2022. 40(24): 2830. Zhao JJ, Ong CJ, Srivastava S, et al. Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases. Gastroenterology. 2024. 167(7): 1384-1398.e4. Zhu ZG, Tang R, Yan M, et al. Efficacy and safety of intraoperative peritoneal hyperthermic chemotherapy for advanced gastric cancer patients with serosal invasion. A long-term follow-up study. Dig Surg. 2006. 23(1-2): 93-102. Foster JM, Zhang C, Rehman S, Sharma P, Alexander HR. The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future. CA Cancer J Clin. 2023. 73(1): 49-71. Yang R, Su YD, Ma R, Li Y. Clinical epidemiology of peritoneal metastases in China: The construction of professional peritoneal metastases treatment centers based on the prevalence rate. Eur J Surg Oncol. 2023. 49(1): 173-178. Chen D, Liu Z, Liu W, et al. Predicting postoperative peritoneal metastasis in gastric cancer with serosal invasion using a collagen nomogram. Nat Commun. 2021. 12(1): 179. Mori Y, Dendl K, Cardinale J, Kratochwil C, Giesel FL, Haberkorn U. FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease. Radiology. 2023. 306(2): e220749. Huang ZN, Ma Y, Chen QY, et al. Potential survival benefits of open over laparoscopic radical gastrectomy for gastric cancer patients beyond three years after surgery: result from multicenter in-depth analysis based on propensity matching. Surg Endosc. 2022. 36(2): 1456-1465. Spratt JS, Adcock RA, Muskovin M, Sherrill W, McKeown J. Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res. 1980. 40(2): 256-60. Elias D, Goéré D, Dumont F, et al. Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases. Eur J Cancer. 2014. 50(2): 332-40. Prada-Villaverde A, Esquivel J, Lowy AM, et al. The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery. J Surg Oncol. 2014. 110(7): 779-85. Klaver C, Wisselink DD, Punt C, et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol. 2019. 4(10): 761-770. Yarema RR, Ohorchak MA, Zubarev GP, et al. Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: results of a single-centre retrospective study. Int J Hyperthermia. 2014. 30(3): 159-65. Kang LY, Mok KT, Liu SI, et al. Intraoperative hyperthermic intraperitoneal chemotherapy as adjuvant chemotherapy for advanced gastric cancer patients with serosal invasion. J Chin Med Assoc. 2013. 76(8): 425-31. Hultman B, Lundkvist J, Glimelius B, Nygren P, Mahteme H. Costs and clinical outcome of neoadjuvant systemic chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from gastric cancer. Acta Oncol. 2012. 51(1): 112-21. Desiderio J, Chao J, Melstrom L, et al. The 30-year experience-A meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer. Eur J Cancer. 2017. 79: 1-14. Glehen O, Passot G, Villeneuve L, et al. GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study. BMC Cancer. 2014. 14: 183. Götze TO, Piso P, Lorenzen S, et al. Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma - the phase III "PREVENT"- (FLOT9) trial of the AIO /CAOGI /ACO. BMC Cancer. 2021. 21(1): 1158. Lui S, Liang H, Li Y, et al. PILGRIM: Phase III clinical trial in evaluating the role of hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer patients after radical gastrectomy with D2 lymphadenectomy (HIPEC-01) [J]. J Clin Oncol, 2020,38 Suppl 15:S4538-S4538. DOI: 10.1200/JCO.2020. 38.15_suppl. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Mar, 2026 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 23 Feb, 2026 Reviewers invited by journal 12 Sep, 2025 Editor assigned by journal 23 Jun, 2025 Submission checks completed at journal 23 Jun, 2025 First submitted to journal 23 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6957503","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":514853142,"identity":"8671f962-e315-4aa3-b62a-31d9a5ecdda2","order_by":0,"name":"Xiaodong Liu","email":"","orcid":"","institution":"Affiliated Hospital of Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Xiaodong","middleName":"","lastName":"Liu","suffix":""},{"id":514853143,"identity":"07b5f9ff-8e7f-4e3f-bd91-c0a52f4ccf61","order_by":1,"name":"Yulong Tian","email":"","orcid":"","institution":"Affiliated Hospital of Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Yulong","middleName":"","lastName":"Tian","suffix":""},{"id":514853144,"identity":"903798cc-2cdb-4dcf-ad8e-6b4a1a6dab65","order_by":2,"name":"Shougen Cao","email":"","orcid":"","institution":"Affiliated Hospital of Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Shougen","middleName":"","lastName":"Cao","suffix":""},{"id":514853145,"identity":"f4b90668-853a-460f-a848-8cf2cf7508ea","order_by":3,"name":"Zequn Li","email":"","orcid":"","institution":"Affiliated Hospital of Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Zequn","middleName":"","lastName":"Li","suffix":""},{"id":514853146,"identity":"3344d38a-9f3f-4f6f-b880-84e9162f370d","order_by":4,"name":"Quan Wang","email":"","orcid":"","institution":"First Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Quan","middleName":"","lastName":"Wang","suffix":""},{"id":514853147,"identity":"fef2ec84-cefb-4308-a8c5-185dc153282d","order_by":5,"name":"Han Liang","email":"","orcid":"","institution":"Tianjin Medical University Cancer Institute and Hospital","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Liang","suffix":""},{"id":514853148,"identity":"d2e556bb-1c5e-4edc-b9e4-ca1bb117cd0f","order_by":6,"name":"Shuzhong Cui","email":"","orcid":"","institution":"Affiliated Cancer Hospital \u0026 Institute of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shuzhong","middleName":"","lastName":"Cui","suffix":""},{"id":514853149,"identity":"fa2aeb57-1b56-4e82-91d7-1038fc31e7e4","order_by":7,"name":"Tao Zhang","email":"","orcid":"","institution":"Liaoning Cancer Hospital \u0026 Institute","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Zhang","suffix":""},{"id":514853150,"identity":"a9f9571f-0963-4730-8832-b35802b4a90f","order_by":8,"name":"Yong Li","email":"","orcid":"","institution":"The Fourth Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Li","suffix":""},{"id":514853151,"identity":"29ea575f-5e26-41b4-8202-c7c864cf0378","order_by":9,"name":"Xuejun Sun","email":"","orcid":"","institution":"First Affiliated Hospital of Xi'an Jiaotong University","correspondingAuthor":false,"prefix":"","firstName":"Xuejun","middleName":"","lastName":"Sun","suffix":""},{"id":514853152,"identity":"b9a852de-dfc7-4b26-9f03-8f1493d3977b","order_by":10,"name":"Wen qing Hu","email":"","orcid":"","institution":"Changzhi People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"qing","lastName":"Hu","suffix":""},{"id":514853153,"identity":"f7b514e9-a786-4425-aee3-75928b644eec","order_by":11,"name":"Peiming Guo","email":"","orcid":"","institution":"Jinan Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peiming","middleName":"","lastName":"Guo","suffix":""},{"id":514853154,"identity":"ce52b958-891e-4bee-8dbd-a8d8a73d7423","order_by":12,"name":"Kaixiong Tao","email":"","orcid":"","institution":"Union Hospital of Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Kaixiong","middleName":"","lastName":"Tao","suffix":""},{"id":514853155,"identity":"3567b7c0-d5e5-427d-8bf9-924e967ca5b4","order_by":13,"name":"Taiyuan Li","email":"","orcid":"","institution":"First Affiliated Hospital of Nanchang University","correspondingAuthor":false,"prefix":"","firstName":"Taiyuan","middleName":"","lastName":"Li","suffix":""},{"id":514853156,"identity":"00d1fd22-7468-4e16-a4ae-8bcfa72fad71","order_by":14,"name":"Leping Li","email":"","orcid":"","institution":"Shandong Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Leping","middleName":"","lastName":"Li","suffix":""},{"id":514853157,"identity":"3367f1a4-7cb9-4a41-be99-ed28bef00d13","order_by":15,"name":"Jiping Wang","email":"","orcid":"","institution":"Brigham and Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiping","middleName":"","lastName":"Wang","suffix":""},{"id":514853158,"identity":"62814bfd-1cce-4901-8b02-f5bd3c8dfd86","order_by":16,"name":"Yanbing Zhou","email":"data:image/png;base64,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","orcid":"","institution":"Affiliated Hospital of Qingdao University","correspondingAuthor":true,"prefix":"","firstName":"Yanbing","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-06-23 13:53:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6957503/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6957503/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-026-15899-2","type":"published","date":"2026-03-26T16:11:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91936506,"identity":"5a55950c-72c8-4e1c-b425-0cafa3badda1","added_by":"auto","created_at":"2025-09-23 02:50:09","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":227466,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/6de85c866ed3b61bd9243890.docx"},{"id":91935007,"identity":"4c5772d3-72e7-4b65-95c3-610a13c3b698","added_by":"auto","created_at":"2025-09-23 02:42:09","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16982,"visible":true,"origin":"","legend":"","description":"","filename":"cdaa9a4b764f4a089e322f0470f67bc8.json","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/cbf1460050a3fc95cd9dddb6.json"},{"id":91935009,"identity":"be9460d8-a435-4cfa-bb65-8e1aed8983b4","added_by":"auto","created_at":"2025-09-23 02:42:09","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":139061,"visible":true,"origin":"","legend":"","description":"","filename":"cdaa9a4b764f4a089e322f0470f67bc81enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/d1d7cb09b5c24f178aaab8a3.xml"},{"id":91932239,"identity":"bbbd1902-2238-4b45-96d6-8c270e5251d1","added_by":"auto","created_at":"2025-09-23 02:34:09","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62367,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/91544c5815d6dee1179149e9.png"},{"id":91935005,"identity":"0b5c9292-5f47-40ac-94f6-57aeef491153","added_by":"auto","created_at":"2025-09-23 02:42:09","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49635,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/273ab6fa8faff2726cd93a08.png"},{"id":91932243,"identity":"d9991edf-8a65-46a1-b630-85117d865e9f","added_by":"auto","created_at":"2025-09-23 02:34:09","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20393,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/4dbec42173b719d91a462808.png"},{"id":91932245,"identity":"21915100-c1d6-4b62-9ef9-f9ca49837761","added_by":"auto","created_at":"2025-09-23 02:34:09","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22619,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/0a9708d9ccde2eba50608524.png"},{"id":91932246,"identity":"8039828b-693f-4eef-95f9-b32eb9370963","added_by":"auto","created_at":"2025-09-23 02:34:09","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":134364,"visible":true,"origin":"","legend":"","description":"","filename":"cdaa9a4b764f4a089e322f0470f67bc81structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/414246e55b9606886021c8c3.xml"},{"id":91932248,"identity":"bc6e8293-39bf-4177-acfd-3bd6bb1a4947","added_by":"auto","created_at":"2025-09-23 02:34:09","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":149201,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/3dc01aae91e0a8ab31117ccc.html"},{"id":91932237,"identity":"e7895892-1b82-493c-8345-25911bcbe808","added_by":"auto","created_at":"2025-09-23 02:34:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61162,"visible":true,"origin":"","legend":"\u003cp\u003eHIPEC-09 study flow chart\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/f0da05e395aaabd5bfc827fe.png"},{"id":91936507,"identity":"864cbf2a-6c7c-4403-ad63-7d5caa4cfa29","added_by":"auto","created_at":"2025-09-23 02:50:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":49635,"visible":true,"origin":"","legend":"\u003cp\u003eThe items of enrolment, interventions and assessments\u003c/p\u003e\n\u003cp\u003eThe items of enrolment, interventions and assessments in the flowchart. The symbol of × represent that the program needs to be collected.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e1. Blood test\u003c/strong\u003e\u003c/em\u003e includes routine blood examinations (haemoglobin Hb, white blood cell count (WBC), platelet count (Plt), and neutrophil count (NEUT)), liver and kidney function assessments and other routine biochemical indicators (glutamate aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), and blood creatinine (Cr) levels).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e2.\u003c/strong\u003e\u003c/em\u003e \u003cem\u003e\u003cstrong\u003eChemotherapy toxicity\u003c/strong\u003e\u003c/em\u003e includes decreased appetite, nausea, vomiting, oral mucosa, diarrhea, abdominal pain, dizziness, headache, infection fever, hair loss, and allergy, were performed during each cycle of chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e3. Tumour markers\u003c/strong\u003e\u003c/em\u003e are recommended to be assessed every 3 months for 2 years, semiannually after 2 years, and once yearly after 5 years.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e4. CT examination\u003c/strong\u003e\u003c/em\u003e (enhanced CT is recommended, and plain CT is acceptable) is recommended once every six months within three years and once yearly after three years.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e5.\u003c/strong\u003e\u003c/em\u003e \u003cem\u003e\u003cstrong\u003eGastroscopy\u003c/strong\u003e\u003c/em\u003e will be performed six months after surgery and annually thereafter until the completion of the follow-up. Thereafter, gastroscopy will be performed annually.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003e6. Tumour status \u003c/strong\u003e\u003c/em\u003eincludes tumour recurrence (site and time), metastasis (site and time), and death (cause and time).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. \u003c/strong\u003eThe first follow-up review began 3 months after the operation. Once every 3 months for 2 years, once every half a year after 2 years, once a year after 5 years, long-term follow-up review will be performed.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/1f892b44ef8722fb70e169e3.png"},{"id":105755022,"identity":"993ccdc0-46db-4808-8cdd-a338f90788cd","added_by":"auto","created_at":"2026-03-30 16:24:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1073610,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6957503/v1/27f972ef-0bf1-48ef-a1c7-531aecf22077.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Study Protocol for Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Gastric Cancer after Laparoscopic or Robotic Gastrectomy with D2 Lymphadenectomy: A Phase III Multicentre Prospective Randomized Controlled Clinical Trial (HIPEC-09)","fulltext":[{"header":"Background","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eThe epidemiology of gastric cancer\u003c/h2\u003e\u003cp\u003eGlobally, the incidence of gastric cancer (GC) is the fifth most common type of malignant tumour, with the fourth highest cancer-related mortality \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Currently, the treatment of gastric cancer relies primarily on comprehensive approaches, including surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, nutritional therapy and other means to achieve radical resection or maximum tumour growth inhibition to improve patients' quality of life and prolong survival time. However, despite receiving the best available treatment plan, the 5-year survival rate for advanced gastric cancer remains below 40%, with a high recurrence rate\u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMinimally invasive surgery for gastric cancer\u003c/h2\u003e\u003cp\u003eWith continuous advancements in medical technology, minimally invasive surgeries have rapidly developed, such as laparoscopic and robotic surgery. Professor Kitano from Japan first reported the application of laparoscopic surgery in the treatment of early gastric cancer in 1994\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, followed by Goh's performance of laparoscopic D2 radical gastrectomy for advanced gastric cancer patients in 1997\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Professors Minhua Zheng and Peiwu Yu were the first to perform laparoscopic radical gastrectomy for gastric cancer in China in 1999. Robot-assisted gastrectomy was first introduced by Hashizume et al. in 2002\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Since 2006, more than 10000 cases of robotic radical gastrectomy for gastric cancer have been reported in China. At present, the clinical application of laparoscopic and robotic surgery for early gastric cancer has been confirmed by many RCTs, but high-quality evidence and consensus on the treatment of advanced gastric cancer remain lacking. RCTs conducted in China (CLASS-01\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e), Korea (KLASS-02\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e) and Japan (JLSSG0901\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e) compared laparoscopic versus open D2 radical gastrectomy for locally advanced distal gastric cancer, revealing favourable short-term clinical outcomes with no significant increase in complications between the two groups.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eThe oncological controversy of laparoscopic or robotic gastrectomy\u003c/h3\u003e\n\u003cp\u003eAlthough some prospective clinical studies have demonstrated comparable oncological outcomes between laparoscopic and open surgery approaches, it is important to note that patients who undergo laparoscopic radical gastrectomy exhibit a lower 3-year recurrence-free survival rate compared to those who undergo open radical gastrectomy. Further discussion is warranted to explore the underlying factors contributing to this disparity\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The JLSSG0901 study from Japan revealed that the incidence of peritoneal metastasis was 4.3% (11/254) in open surgery and 7.7% (19/248) in laparoscopic surgery; although, the difference was not statistically significant\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Laparoscopic surgery for advanced gastric cancer has not yet been incorporated into the Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition)\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Furthermore, animal experiments have also indicated an increased risk of peritoneal metastasis associated with laparoscopic surgery\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOpen surgery contributes to peritoneal metastasis in gastric cancer through three mechanisms: first, infiltration of the serosa by tumours results in tumour cell dissemination during growth or traumatic procedures; second, the involvement of lymph nodes and lymphatic vessels around the stomach, which may be damaged during lymph node dissection, results in cancer cell escape; and third, tumour invasion of blood vessels causes bleeding during resection or separation, leading to leakage of cancer cells from blood vessels\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn addition to the same mechanism as open surgery for the occurrence of peritoneal metastasis, the inherent characteristics of laparoscopic surgery under carbon dioxide pneumoperitoneum might increase the risk of peritoneal metastasis through a number of unique pathways. First, the application of CO2 pneumoperitoneum in minimally invasive surgery, where dry CO2 dehumidifies the peritoneum and damages the abdominal cortex, increases the probability of tumour cells adhering to the peritoneum\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Although humidified CO2 pneumoperitoneum has been employed in clinical practice, its benefits remain ambiguous. Second, in contrast to open surgery, it is challenging to utilize a large volume of liquid for abdominal lavage after laparoscopic surgery. The stirring and absorption of the lavage liquid under laparoscopy are relatively difficult, which could more readily result in the residual presence of free cancer cells in the abdominal cavity. Third, laparoscopic surgery is more likely to involve contact with tumours through squeezing, which causes tumour cells to detach, leading to iatrogenic dissemination. Other factors, such as smog, body fluids, and the leakage of tumour cells from lymphatic and blood during lymph node dissection using electrical energy devices such as ultrasonic and electric scalpels, can cause dissemination within the enclosed abdominal cavity, especially the trocar hole chimney effect\u003csup\u003e[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. We designed a device capable of collecting smog and tissue exudates generated during carbon dioxide pneumoperitoneum via laparoscopic or robotic radical gastrectomy throughout the entire surgery. By detecting CEA mRNA levels and monitoring postoperative abdominal metastasis, we aim to determine the causal relationship between the two parameters. We hope that this ongoing clinical study can provide us with new evidence and clarify the relevant mechanisms of abdominal metastasis in gastric cancer laparoscopic surgery [NCT06076265].\u003c/p\u003e\n\u003ch3\u003ePeritoneal metastasis of gastric cancer\u003c/h3\u003e\n\u003cp\u003ePeritoneal metastasis is the most prevalent form of recurrence after gastric cancer surgery. The prognosis of patients with peritoneal metastases is very poor, and the median survival time is only 3\u0026thinsp;~\u0026thinsp;6 months\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Peritoneal-free cancer cells (FCCs) are the primary cause of peritoneal metastasis. The Japanese Gastric Cancer Society (JGCA) defined cancer cells found in the abdominal cavity as stage IV, and the 8th edition of TNM staging also defined positive abdominal cytology as tumour stage M1. Approximately 30%-50% of gastric cancer patients with subserosal or serosal involvement already have FCCs\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Ikeguchi et al.\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e reported that the five-year survival rate of patients without FCCs who underwent radical gastrectomy was 49.3%, but the survival rate of patients with FCCs was significantly reduced (15.4%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Kuromoto et al.\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e reported that, in patients with tumour invasion into the subserosa and serosa, peritoneal lavage fluid had FCCs in 14.3% and 26.7% of cases, respectively. FCCs initiate fibrin retention followed by cellular implantation, which subsequently promotes inflammatory cell infiltration, leading to the release of growth factors and cytokines that facilitate tumour growth, invasion, and dissemination. Therefore, preventing the peritoneal implantation of tumour cells during or shortly after surgery is crucial for increasing the five-year survival rate of advanced gastric cancer patients.\u003c/p\u003e\n\u003ch3\u003eThe role of HIPEC in advanced gastric cancer\u003c/h3\u003e\n\u003cp\u003eHIPEC enhances the efficacy of drugs against tumour cells mainly on the basis of the differential sensitivity of normal tissue and tumours to temperature. Studies have shown that normal tissue cells can remain healthy at a temperature of 47\u0026deg;C for 1 hour, whereas irreversible damage occurs to tumour cells at a critical temperature of 43\u0026deg;C for 1 hour. HIPEC induces ultrastructural changes in tumour cells, increasing the permeability of the cell membrane to chemotherapy drugs and facilitating the uptake of drugs by tumour cells. Moreover, it inhibits the repair mechanisms of tumour cells, promotes the absorption of antitumour drugs, improves patient immunity, and effectively suppresses the expression of multidrug resistance genes in tumour cells. HIPEC has shown remarkable clinical efficacy in preventing the recurrence and metastasis of gastric cancer, colorectal cancer, ovarian cancer, and other malignant tumours\u003csup\u003e[\u003cspan additionalcitationids=\"CR26 CR27 CR28\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. Relevant studies have indicated that HIPEC prolongs the survival time of patients with peritoneal metastasis of gastric cancer by approximately 2 years, confirming its positive effect on improving patient prognosis\u003csup\u003e[\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Over time, scholars worldwide have continuously improved the technology and methods related to HIPEC. From simple direct infusion heating to precise celiac perfusion chemotherapy techniques using innovative equipment, this approach has evolved into highly precise and accurate temperature-controlled, constantly circulating celiac perfusion technology solutions\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. The \"BR-TRG-I-type coelomic hyperthermic perfusion therapy system\" employed in this study provides temperature measurement and control accuracy as fine as \u0026plusmn;\u0026thinsp;0.1 ℃ as well as \u0026plusmn;\u0026thinsp;5% perfusion speed control accuracy while being user friendly with stable performance. In terms of the primary technical indicators, the BR-TRG-I system significantly outperforms other perfusion therapy equipment in terms of temperature control and temperature measurement accuracy.\u003c/p\u003e\u003cp\u003eSome previous single-centre clinical studies have shown that prophylactic HIPEC is quite effective in eliminating FCCs and peritoneal metastasis, thereby improving the 5-year survival rate of advanced cancer patients\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. However, multicentre high-quality randomized controlled trials (RCTs) are currently lacking. We are eagerly awaiting the results of HIPEC-01 study on whether prophylactic HIPEC treatment after radical surgery for locally advanced gastric cancer can reduce the abdominal metastasis rate. Evidence regarding the combination of laparoscopic or robotic D2 radical gastrectomy under carbon dioxide pneumoperitoneum and HIPEC for preventing peritoneal metastasis of gastric cancer remains scarce. Therefore, it is necessary to determine its effectiveness, safety, and oncological control outcomes, such as peritoneal metastasis, through prospective multicentre randomized controlled trials, thereby providing high-level evidence-based medical evidence for clinical practice.\u003c/p\u003e"},{"header":"Methods/design","content":"\u003cp\u003eHIPEC-09 is a prospective, randomized, controlled, open-label, multicentre clinical trial with the aim to evaluate the effect of HIPEC on 5-year recurrence-free survival after CO2 pneumoperitoneum laparoscopic or robotic D2 surgery for advanced gastric cancer. In accordance with the CONSORT statement, eligible patients from 12 large-volume university teaching hospitals in China will be randomly divided into the experimental group receiving laparoscopic or robotic D2 surgery plus 2 sessions of HIPEC and 6‒8 cycles of systemic chemotherapy or the control group receiving laparoscopic or robotic D2 surgery plus 6‒8 cycles of systemic chemotherapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e - study flow chart)..\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eMeasures of outcomes\u003c/h2\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003ePrimary endpoint\u003c/h2\u003e\u003cp\u003e5-year recurrence-free survival.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eSecondary endpoints\u003c/h3\u003e\n\u003cp\u003e(1) 5-year overall survival rate, (2) peritoneal metastasis rate, (3) peritoneal metastasis-free survival rate, (4) regional recurrence rate (local recurrence after radical gastrectomy refers to the recurrence in the anastomosis, duodenal stump, tumour bed, or residual stomach, including recurrence in regional lymph nodes), (5) distant metastasis rate, and (6) toxicity and side effects of the program.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePatient eligibility\u003c/h2\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003eInclusion criteria\u003c/h2\u003e\u003cp\u003e(1) Newly treated patients who did not receive chemotherapy, radiotherapy or other antitumor therapy before the start of the clinical trial, (2) Aged 18\u0026ndash;80 years, (3) male or non-pregnant or lactating female, (4)Gastric adenocarcinoma was pathologically confirmed, and laparoscopic (robotic) radical gastrectomy was planned, (5) Patients with T stage of T3 or T4a, no distant metastasis, and feasible criteria for laparoscopic D2 radical resection (AJCC 6th edition), (6) The estimated survival time is more than 6 months, (7) History of nonabdominal surgery (except laparoscopic cholecystectomy), (8) The bone marrow reserve function was good, and the blood routine met the following conditions: white blood cell count (WBC)\u0026thinsp;\u0026ge;\u0026thinsp;3.5\u0026times;109/L, neutrophil\u0026thinsp;\u0026ge;\u0026thinsp;1.5\u0026times;109/L, platelet count(Plt)\u0026thinsp;\u0026ge;\u0026thinsp;100\u0026times;109/L, hemoglobin(Hb)\u0026thinsp;\u0026ge;\u0026thinsp;90g/L, (9) Organ function was good, and biochemical examination met the following conditions: glutamate aminotransferase (ALT)\u0026thinsp;\u0026le;\u0026thinsp;2.5\u0026times;upper limit of normal value (ULN), aspartate aminotransferase (AST)\u0026thinsp;\u0026le;\u0026thinsp;2.5\u0026times;ULN, serum total bilirubin(BUN)\u0026thinsp;\u0026le;\u0026thinsp;1.5\u0026times;ULN, serum creatinine(Cr)\u0026thinsp;\u0026le;\u0026thinsp;1.5\u0026times;ULN, (10) Eastern Cooperative Oncology Group(ECOG) score: 0\u0026ndash;1, (11) Preoperative American Society of Anesthesiologists(ASA) grade: I-III; (12) Voluntarily sign the informed consent.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eExclusion criteria\u003c/h2\u003e\u003cp\u003e(1) Lymph node bulky N2 status diagnosed by abdominal CT/MRI, that is, at least one lymph node meridian\u0026thinsp;\u0026ge;\u0026thinsp;3 cm or three consecutive lymph nodes, each meridian\u0026thinsp;\u0026ge;\u0026thinsp;1.5 cm; (2) patients with other malignant tumours within the past 5 years; (3) preoperative temperature\u0026thinsp;\u0026ge;\u0026thinsp;38\u0026deg;C or complicated with infectious diseases requiring systematic treatment; (4) patients with serious mental illness; (5) patients with severe respiratory diseases with FEV1\u0026thinsp;\u0026lt;\u0026thinsp;50%; (6) patients with history of unstable angina pectoris or myocardial infarction within the past 6 months; (7) patients with a history of cerebral infarction or cerebral haemorrhage within the past 6 months, except for old infarcts; (8) patients who had systemic glucocorticoid therapy within the past month; (9) patients with gastric cancer complications (bleeding, perforation, obstruction) requiring emergency surgery; (10) patients who have participated in or were currently participating in other clinical studies (within the past 6 months); or (11) patients with confirmed intraperitoneal implantation and metastasis by the way of laparoscopic exploration, biopsy and cytology.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eDischarge criteria\u003c/h2\u003e\u003cp\u003e(1) Patients with stage IV disease after the operation; (2) patients for whom R0 resection could not be achieved during the operation; (3) patients for whom simultaneous surgical treatment of other diseases was required (except gallstones); (4) patients who were not suitable for or unable to implement the treatment plan of the study due to sudden severe comorbidities (inability to tolerate surgery or anaesthesia) during the perioperative period; (5) after entering the study, the need for emergency surgery was confirmed by the doctor in charge due to changes in the patient's condition; and (6) at any stage after entering the study, the patient voluntarily requested to withdraw from the study or discontinue treatment for personal reasons rather than for reasons of efficacy.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eRandomization and grouping\u003c/h2\u003e\u003cp\u003eIn this study, a minimization-based central dynamic randomization method will be employed. Stratification factors considered will include age (\u0026lt;\u0026thinsp;60 or \u0026ge;\u0026thinsp;60), intraoperative T stage (T3 or T4a), histopathological type (signet-ring cell carcinoma or not), and study centre. After each patient is enrolled, researchers at each participating centre will record relevant information (age, intraoperative T stage and histopathological type) in the central randomization system. The system will promptly provide randomized results back to the research centre.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eSample size estimate\u003c/h2\u003e\u003cp\u003eThe primary endpoint of this study is 5-year recurrence-free survival. Sample size estimation utilized survival analysis based on a log-rank test, with an estimated rate of 65.4% in the laparoscopic-only group and 75.4% in the laparoscopic combined with HIPEC group. The projected recruitment time for all the subjects was 36 months, with cases assigned a 1:1 ratio of α\u0026thinsp;=\u0026thinsp;0.05 and β\u0026thinsp;=\u0026thinsp;0.2 (power\u0026thinsp;=\u0026thinsp;80%). Considering an overall dropout rate of 10% (including dropouts and loss to follow-up), both the laparoscopic surgery-only group and the laparoscopic combined with HIPEC group would consist of 308 patients each, for a total of 616 patients.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eCategorical variables will be described in terms of frequency distribution (number of cases and percentage). Continuous variables will be described as the mean, median, minimum, maximum, first quartile and third quartile. The confidence intervals for all the parameters will be considered significant if α\u0026thinsp;\u0026le;\u0026thinsp;0.05(i.e., 95% confidence interval). Epitaxial analysis of the data will be performed properly. All analyses will be performed using SAS. The overall survival and disease-free survival rates of the two groups will be analysed using the log-rank test and described with Kaplan‒Meier curves. A Cox proportional hazards model will be used to analyse the risk coefficients and 95% confidence intervals considering race, age, and disease progression. Subsets of time and event analyses will be performed according to intraperitoneal tumour status.\u003c/p\u003e\u003cp\u003eA modified intention-to-treat analysis (mITT) and per-protocol (PP) analysis will be used to compare outcomes, but the conclusion will be drawn from mITT analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eTreatments\u003c/h2\u003e\u003cdiv id=\"Sec19\" class=\"Section3\"\u003e\u003ch2\u003eLaparoscopic and Robotic D2 radical gastrectomy\u003c/h2\u003e\u003cp\u003eLaparoscopic and robotic D2 radical gastrectomy involves several crucial steps. After laparoscopic or Da Vinci robot exploration, measurements of the lesion infiltration area and tumour size, as well as intraoperative T staging, should be performed. Enrolment and randomization should be based on the presence or absence of peritoneal carcinoma.\u003c/p\u003e\u003cp\u003eThe surgical resection scope for different types of localized gastric cancer should be more than 3 cm from the tumour, whereas invasive gastric cancer requires a distance of more than 5 cm. For esophagogastric junction cancer, the oesophageal resection margin must be at least 2 cm away from the tumour. An examination of frozen pathological sections is necessary when suspicious findings are present. In cases where tumours invade the pyloric canal, a duodenal margin greater than 3 cm from the tumour is needed. The extent of D2 lymphadenectomy for various tumour regions is based on the Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition)\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFirst, the veins and arteries will be ligated at the base of the vessel while the lymph nodes are simultaneously dissected. The samples will be carefully separated and excised. During the procedure, gentle handling is recommended, and blunt separation should be minimized. In addition, direct contact with the tumour should be avoided to prevent damage to the lymph nodes that may lead to cancer cell spread or local implantation. The serosal layer can be protected by covering it.\u003c/p\u003e\u003cp\u003eBefore and after the operation, 500 mL of normal saline was used to thoroughly rinse, stir and collect the area near the gastric cancer lesion. During the irrigation process, patients will be positioned with their head high and feet low. A total of 500 mL of normal saline should be injected into the right upper abdomen, avoiding the cancer site, followed by aspiration of at least 200 ml of rinse solution from the pelvic cavity. The peritoneal rinsing fluid will be collected and anticoagulated with 1 ml of heparin before being centrifuged at 1000 \u0026times; g for 10 minutes. The nucleated cell layer will then be obtained for smear preparation, and tumour cells will be detected using HE staining by two senior pathologists. In the case of any disagreement between two pathologists regarding the conclusion, a senior pathologist designated by the research committee will be consulted to confirm the diagnosis.\u003c/p\u003e\u003cp\u003ePhotographs will be taken and archived following the surgical procedure. For photographic documentation, the distal subtotal gastrectomy will be captured, which includes the ligation of the left gastroepiploic artery, the common hepatic artery, the proper hepatic artery, the ligation of the left gastric artery, the ligation of both the left and right gastric veins, the proximal splenic artery, the arteriovenous ligation of the right gastroepiploic vessel, and the bare proximal minor curvature. In the case of proximal gastrectomy, photographs should include images showing ligation of the left gastric artery and coronary vein stump, common hepatic artery, proximal splenic artery, celiac trunk (depending on individual centre protocols), and splenic hilum. Total gastrectomy requires the capture of images displaying ligation points of both the left gastric arteries and veins along with those for the right gastric arteries and veins. In addition, the common hepatic artery should be documented along with the celiac trunk (based on centre-specific conditions), splenic hilum (if applicable), splenic artery, proper hepatic artery and ligation points for both right gastro-omental vessels.\u003c/p\u003e\u003cp\u003eThe entire surgical procedure must be documented comprehensively, and unaltered video recordings must be retained.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eHIPEC\u003c/h2\u003e\u003cp\u003e(1) Location of the drainage tube: Two perfusion tubes will be positioned in the upper abdomen. Their openings will be placed under the left diaphragm and in the liver and kidney crypts. After HIPEC is completed, the left diaphragm can serve as the postoperative abdominal drainage tube. Two outflow tubes will be located in the lower abdomen. The openings will be placed on both sides of the pelvic floor. Each drainage tube was generally positioned in the front axillary plane. It is important to ensure that the perfusion tube is placed near the tumour while maintaining a distance from the tumour area for optimal placement of outflow tubes.\u003c/p\u003e\u003cp\u003e(2) Temperature setting: 43\u0026deg;C.\u003c/p\u003e\u003cp\u003e(3) Perfusion time: 60 min.\u003c/p\u003e\u003cp\u003e(4) Dosage of perfusion fluid: The principle of perfusion fluid is abdominal cavity filling and unimpeded circulation.\u003c/p\u003e\u003cp\u003e(5) The perfusion solution: Normal saline.\u003c/p\u003e\u003cp\u003e(6) Drug selection and dose: First HIPEC, 75 mg/m\u003csup\u003e2\u003c/sup\u003e paclitaxel; second HIPEC, 100 mg/m\u003csup\u003e2\u003c/sup\u003e paclitaxel.\u003c/p\u003e\u003cp\u003e(7) Timing of treatment: The first HIPEC should be conducted within 48 hours after surgery, and the time interval between the second HIPEC and the first HIPEC should be no less than 24 hours (within one week after the operation).\u003c/p\u003e\u003cp\u003e(8) Treatment course: 2 times.\u003c/p\u003e\u003cp\u003e(9) Intraoperative medication: Intravenous sedation was performed as needed, with the dosage adjusted on the basis of the patient's response, and fluid rehydration was performed according to vital sign monitoring.\u003c/p\u003e\u003cp\u003e(10) Temperature control: The entry temperature for HIPEC should be maintained at 43.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u0026deg;C, while the body temperature should be kept constant within the range of 39.0\u0026ndash;42.0\u0026deg;C.\u003c/p\u003e\u003cp\u003e(11) Intraoperative monitoring: During HIPEC treatment, blood pressure, body temperature, pulse rate, urine volume, respiration rate, and oxygen saturation levels were continuously monitored. Additionally, any blockage in the perfusion tube and smoothness of the effusion were checked regularly. These parameters will be recorded on the CRF at 0 minutes, 30 minutes, and 60 minutes after HIPEC initiation and one hour after HIPEC completion. If symptoms such as profuse sweating or a heart rate exceeding 100 beats per minute occur during treatment, measures must be taken to address potential hypovolemia by strengthening fluid replacement. Any abnormal respiration or decrease in blood oxygen saturation will require careful evaluation of anaesthetic drug dosage and perfusate administration. If necessary, treatment may be discontinued for that patient.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003ePostoperative adjuvant chemotherapy\u003c/h2\u003e\u003cp\u003eAfter 4 to 6 weeks post-surgery when the patient's condition has recovered, 6 to 8 cycles of postoperative systemic adjuvant chemotherapy will be initiated. The Xelox regimen comprises 130 mg/m\u003csup\u003e2\u003c/sup\u003e oxaliplatin administered on Day 1 and 1 g/m\u003csup\u003e2\u003c/sup\u003e capecitabine twice a day from Day 1 to Day 14, with cycles repeated every 3 weeks. Alternatively, the SOX regimen could be considered, which involves 130 mg/m\u003csup\u003e2\u003c/sup\u003e oxaliplatin on Day 1 and tegafur/gimeracil/oteracil (Teggio) at a dosage of 40\u0026ndash;60 mg twice a day from Days 1 to 14, with cycles repeated every 3 weeks.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003eResearcher qualifications\u003c/h2\u003e\u003cp\u003eTo maintain the standard of the study and ensure patient safety, certain fundamental principles must have been fulfilled prior to a surgeon's involvement in the research. Laparoscopic (robot-assisted) D2 gastrectomy must have been performed on a minimum of 50 patients. In addition, the unedited surgical videos will also be subject to blind review by two senior experts from the HIPEC 09 research committee.\u003c/p\u003e\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\u003ch2\u003eData collection and management\u003c/h2\u003e\u003cp\u003eEvaluation prior to enrolment will require completion of the following procedures within one week after admission: (1) detailed personal information, including complete medical history data; (2) current treatment status; (3) physical examination; (4) routine blood tests (Hb, Plt, WBC, and NEUT) and liver and kidney function tests measuring ALT, AST, BUN, total protein albumin, globulin, BUN, and serum creatinine levels; (5) tumour marker levels, including CEA, CA199, CA724, and CA125; and (7) electrocardiogram, B-ultrasound, chest CT, gastroscopy, and imaging examinations of tumour lesions (CT or endoscopic ultrasound).\u003c/p\u003e\u003cp\u003eEvaluation during HIPEC: Short-term adverse reactions to HIPEC should be assessed 24 hours after each hyperthermic infusion. Additionally, the evaluation should be conducted on the 7th day postoperation or prior to discharge for a total of three assessments. The assessment should include the following: (1) routine blood tests (Hb level, Plt, WBC, and NEUT) and liver and kidney function analysis (ALT, AST, total bilirubin, total protein, albumin, globulin, BUN, and Cr); (2) assessment of complications and abdominal conditions; and (3) evaluation of anastomotic fistula.\u003c/p\u003e\u003cp\u003eChemotherapy monitoring included pre- and posttreatment laboratory tests. These include routine blood examinations (Hb, WBC, Plt, and NEUT), liver and kidney function assessments and other routine biochemical indicators (ALT, AST, total protein, albumin, BUN, and Cr). Additionally, the observation and evaluation of chemotherapy toxicity, such as decreased appetite, nausea, vomiting, oral mucosa, diarrhoea, abdominal pain, dizziness, headache, infection fever, hair loss, and allergy, were performed during each cycle of chemotherapy. If patients experienced adverse reactions, treatment should be adjusted or discontinued according to the indications for dose adjustment or withdrawal in the XELOX systemic adjuvant chemotherapy protocol.\u003c/p\u003e\u003cp\u003eThe effectiveness of this treatment will be evaluated by tumour efficacy indicators including tumour recurrence (site and time), metastasis (site and time), and death (cause and time). Patient survival benefit will be evaluated on the basis of (1) relapse-free survival (RFS), defined as the time from randomization to relapse onset or the end of follow-up; (2) overall survival (OS), which is commonly considered the primary efficacy endpoint in cancer trials and refers to the time from randomization to death from any cause. Accurate records were maintained throughout the entire follow-up period; and the observation endpoint was 5-year recurrence-free survival.\u003c/p\u003e\u003cp\u003eThis study employed a network-based electronic case report form (eCRF) to transmit research data and information. Data can be recorded from source files, or the eCRF can be utilized as the primary source file. In any case, data must always be under the control of the investigator, and systems and procedures must be in place to guarantee the quality and safety of the data and not be altered or manipulated. A closed-loop management system for data transmission, electronic universal reporting formats, electronic data, raw data, and source data will be established.\u003c/p\u003e\u003cp\u003e To improve the quality of the trial, an independent data monitoring committee (DMC) composed of surgeons, statisticians and ethics experts was established. This committee has no affiliation with the project research team and is responsible for objectively evaluating the effectiveness and safety of the trial. When the expected number of participants reaches half (n\u0026thinsp;=\u0026thinsp;308), an interim analysis will be conducted. The results of the interim analysis will be announced to all researchers. Furthermore, the DMC will conduct data audits monthly based on the eCRF.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003eAdverse events (AEs)\u003c/h2\u003e\u003cp\u003eEmergence or exacerbation of any signs, symptoms, syndromes, or diseases impacting the subject's health from the time of informed consent and study enrolment until their final visit will be assessed. This will include clinically relevant conditions identified using laboratory tests or other diagnostic procedures. AEs included new diseases, worsening of treatment-related symptoms/signs or concomitant deterioration of preexisting conditions, effects of control drugs, events unrelated to trial participation, or a combination thereof. The term AE does not imply causality with the trial.\u003c/p\u003e\u003cp\u003eThe primary chemotherapy agents utilized in this study included paclitaxel, oxaliplatin, and capecitabine. The major nonhaematological adverse reactions include nausea, vomiting, and diarrhoea. Neurotoxicity from these drugs primarily presents as peripheral neuritis, occasionally accompanied by spasms and sensory disturbances in the oral cavity, upper respiratory tract, and upper digestive tract. In the HIPEC group, specific thermoperfusion duct components must be utilized and may increase risks such as anastomotic fistula, delayed recovery of exhaust function, and intestinal adhesion development leading to obstruction.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003eFollow-up\u003c/h2\u003e\u003cp\u003e A specialized team is responsible for the follow-up, and the first follow-up review began 3 months after the operation. Once every 3 months for 2 years, once every half a year after 2 years, once a year after 5 years, long-term follow-up review will be performed. Each follow-up visit should include the following: (1) Routine blood tests (Hb, Plt, WBC, and NEUT) and liver and kidney function tests (ALT, AST, total bilirubin, total protein, albumin, globulin, and serum urea levels); (2) examination of the tumour marker levels of CEA, CA199, CA724, and CA125; and (3) evaluation of the tumour status using tumour marker, CT and gastroscopy. CT examination should be performed when the patient has physical abnormalities or when the tumour marker levels are elevated. CT examination (enhanced CT is recommended, and plain CT is acceptable) is recommended once every six months within three years and once yearly after three years. The upper abdomen should be examined, and full abdominal CT is recommended. Gastroscopy will be performed six months after surgery and annually thereafter until the completion of the follow-up. Tumour markers are recommended to be assessed every 3 months for 2 years, semiannually after 2 years, and once yearly after 5 years. If the CT scan highly suspects peritoneal metastasis, after discussion with the MDT, fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET)-CT and laparoscopic exploration can be employed for diagnosis.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first multicentre randomized controlled clinical study that seeks to determine whether HIPEC can prevent peritoneal metastasis via laparoscopic or robotic radical gastrectomy for gastric cancer under carbon dioxide pneumoperitoneum. The aim of this clinical trial was to explore the efficacy of HIPEC in improving the 5-year overall survival rate and reducing peritoneal metastases in patients with locally advanced gastric cancer who have undergone laparoscopic or robotic gastrectomy with D2 lymphadenectomy.\u003c/p\u003e\u003cp\u003eGastric cancer is a prevalent malignancy worldwide and is characterized by high incidence and mortality rates\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The peritoneum is the most common site of recurrence and metastasis in advanced gastric cancer patients\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. Approximately 20% of patients are diagnosed with peritoneal metastasis before or during surgery, and more than 50% of patients with T3 and T4 disease have peritoneal metastasis after radical surgery. Patients with advanced peritoneal metastasis have a median survival time of only 3\u0026ndash;6 months, with a five-year survival rate of less than 2%\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Effective prevention and treatment of peritoneal metastasis are crucial for improving the prognosis of postsurgical gastric cancer patients, with a particular emphasis on proactive preventive measures.\u003c/p\u003e\u003cp\u003eLaparoscopic exploration for tissue pathological examination is regarded as the gold standard for diagnosing peritoneal metastasis following gastrectomy; however, its widespread acceptance is hindered by its invasive nature. Enhanced CT is commonly employed for postoperative follow-up in clinical practice. The sensitivity of thin-slice enhanced CT in diagnosing peritoneal metastasis of gastric cancer is 50%, with a specificity ranging from 95\u0026ndash;99%, surpassing that of ultrasound and PET-CT examinations. The use of FAPI as an innovative metabolic imaging agent for PET-CT can increase the diagnostic accuracy of detecting peritoneal metastasis in patients with gastric cancer\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. For this study follow-up examinations will be conducted using abdominal thin-slice enhanced CT combined with serum tumour markers, and additional (PET)-CT (FAPI) or laparoscopic exploration was performed as needed. This study will establish a standardized operating procedure (SOP) for the treatment of peritoneal metastasis, which will stipulate that systemic treatments such as chemotherapy, immunotherapy, and targeted therapy combined with HIPEC treatment be implemented under the guidance of an MDT group.\u003c/p\u003e\u003cp\u003eDespite the rapid advancement of laparoscopic gastric cancer surgery, numerous problems are still encountered in the promotion of the standardization of laparoscopic gastric cancer surgery and clinical practice, and confirmation and support through more high-quality clinical research is needed to provide high-level evidence-based medical evidence. The CLASS-01 study from China\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e, the KLASS-02 study from Korea\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, and the JLSSG0901 study from Japan\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e indicate that the tumour prognosis is not inferior to that of open surgery, providing evidence-based medical evidence for laparoscopic surgery in the treatment of advanced gastric cancer. However, when meticulously interpreting the details of these studies, some limitations and certain risk factors related to tumour prognosis are noted. First, some patients included in these studies were in the early stage of gastric cancer (pathological stage I), which may affect the generalizability of the study results and the inability to offer a more precise assessment of the postoperative prognosis for patients with advanced gastric cancer. On the other hand, the study revealed that the RFS of laparoscopic surgery patients was lower than that of open surgery patients. Although the difference was not statistically significant, the underlying cause requires further investigation. The characteristics of laparoscopic surgery, such as pneumoperitoneum, inadequate irrigation, tumour manipulation, and the generation of smoke by electrical energy instruments, also raise concerns that it may further increase the risk of postoperative gastric cancer metastasis, especially peritoneal metastasis, compared with open surgery. Huang et al.\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e also reported that in patients with cT4a tumours and tumours\u0026thinsp;\u0026gt;\u0026thinsp;5cm, the number of peritoneal recurrences was significantly greater in the LDG group than in the ODG group, and the peritoneal recurrence time and multiple-site recurrence time were both earlier in the LDG group. Thus, it remains controversial whether laparoscopic surgery for gastric cancer can increase the incidence of postoperative metastasis, especially peritoneal metastasis. In this context, a single-centre study (SMOG01 study, NCT06076265) initiated by our centre on whether laparoscopic and robotic radical gastrectomy for gastric cancer performed under a carbon dioxide pneumoperitoneum state increases the risk of intra-abdominal tumour dissemination is ongoing. We anticipate the release of the results of this study.\u003c/p\u003e\u003cp\u003eSince the initial report by Spratt et al. in 1980\u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e, researchers have continuously improved HIPEC technology. The International Collaborative Group for Peritoneal Surface Malignancies (PSOGI) employs HIPEC technology characterized by high-dose single-drug administration (primarily oxaliplatin 360\u0026thinsp;~\u0026thinsp;460 mg/m\u003csup\u003e2\u003c/sup\u003e or bleomycin 30\u0026thinsp;~\u0026thinsp;50 mg/m\u003csup\u003e2\u003c/sup\u003e), open or closed infusion (up to 30 or 60‒90 minutes), and treatment temperatures ranging from 41 to 43\u0026deg;C\u003csup\u003e[\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e. These diverse techniques and infusion methods lead to varying clinical outcomes due to imprecise temperature control. Chinese specialists have developed China Hyperthermic Intraperitoneal Chemotherapy (C-HIPEC) technology along with a high-precision, large-capacity continuous circulation system for the constant-temperature infusion method within C-HIPEC standards. This study utilized C-HIPEC technology for intraperitoneal infusion, which requires the infusion fluid to be maintained at a temperature of 43.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u0026deg;C. The treatment protocol consisted of 2 sessions.\u003c/p\u003e\u003cp\u003eIn this study, paclitaxel was utilized as the infusion drug, with an initial infusion dosage of 75 mg/ m\u003csup\u003e2\u003c/sup\u003e and a subsequent infusion dosage of 100 mg/m\u003csup\u003e2\u003c/sup\u003e. During HIPEC, chemotherapy drugs are directly injected into the abdominal cavity, bypassing the blood‒peritoneal barrier and enabling direct contact with the lesion to exert an antitumour effect. The selection criteria for peritoneal drugs include sensitivity to primary tumours, enhanced penetration capacity, high molecular weight, low peritoneal absorption rate, minimal irritation to the peritoneum and potential synergistic effects with thermal treatment. Common abdominal chemotherapy drugs include paclitaxel, docetaxel, cisplatin, and oxaliplatin. Paclitaxel has a high molecular weight and fat solubility and is slowly absorbed through the lymphatic system. Moreover, it has potent anti-proliferative activity but rarely causes intraperitoneal adhesion postadministration. Additionally, its ability for repeated intraperitoneal administration makes it relatively ideal as an intraperitoneal chemotherapy drug. Nevertheless, there are disparities in terms of dosage, type and frequency of intraperitoneal drug use among different studies.\u003c/p\u003e\u003cp\u003eTo date, several retrospective studies have indicated that the addition of HIPEC during surgery in conjunction with standard adjuvant chemotherapy may significantly decrease the risk of peritoneal recurrence \u003csup\u003e[\u003cspan additionalcitationids=\"CR46\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e. A meta-analysis evaluating the role of HIPEC in preventing peritoneal recurrence in patients with advanced gastric cancer without peritoneal metastasis demonstrated a significant reduction in the rate of peritoneal recurrence compared with simple gastrectomy (RR\u0026thinsp;=\u0026thinsp;0.63) \u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, HIPEC is also associated with a substantial increase in postoperative complications, such as respiratory failure and renal dysfunction. Thus, it is essential to conduct clinical studies with robust designs adhering to current treatment standards. Currently, prophylactic HIPEC is not recommended as a routine postoperative treatment for advanced gastric cancer. Ongoing studies such as the GASTRICHIP (NCT01882933)\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e and PREVENT (FLOT9) trials (NCT04447352)\u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e will further assess the safety and survival advantages of HIPEC, and the HIPEC-01 study (NCT02356276), a prospective, multicentre, randomized controlled phase III trial investigating adjuvant HIPEC after D2 radical surgery for locally advanced gastric cancer in China, has ended. The results of the 3-year follow-up will be published shortly \u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e. The vast majority of the aforementioned studies focused on the role of HIPEC in preventing peritoneal metastasis after open surgery for gastric cancer. However, unlike open surgery, minimally invasive surgery under carbon dioxide pneumoperitoneum can cause sudden alterations in the intra-abdominal microenvironment, which may become an inducer and high-risk factor for intra-abdominal metastasis of gastric cancer. To date, strictly designed high-quality multicentre RCT study specifically focused on the role of HIPEC in preventing peritoneal metastasis in laparoscopic and robotic minimally invasive gastric cancer surgery under carbon dioxide pneumoperitoneum are lacking.\u003c/p\u003e\u003cp\u003eEnsuring the reliability of results in an RCT depends on standardizing treatment across all research centres. To achieve this goal, we have taken several measures. First, all participating centres are major medical facilities in China with a high volume of minimally invasive gastric cancer surgeries and HIPEC treatments performed independently by researchers annually. Second, we require the retention of surgical videos and the uploading of operative field photos, specimen images, and HIPEC treatment curves for regular evaluation by the HIPEC-09 Research Committee. Finally, we will conduct regular data entry monitoring to guarantee the completeness and reliability of the research data.\u003c/p\u003e\u003cp\u003eIn light of the major challenges and clinical issues such as tumour safety faced in the current rapid development of laparoscopic and robotic surgeries for gastric cancer, we have devised this multicentre randomized controlled clinical trial in line with international conventions and standards. The aim of the study is to assess the potential of HIPEC in reducing and preventing peritoneal metastasis after laparoscopic or robotic gastrectomy under carbon dioxide pneumoperitoneum for advanced gastric cancer. We anticipate that the results of this study will be capable of providing high-level evidence-based medical evidence for the future clinical practice of minimally invasive surgery for gastric cancer.\u003c/p\u003e\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e\u003ch2\u003eTrial status\u003c/h2\u003e\u003cp\u003e The recruitment for this study officially began when ethics approval was granted. The protocol version was revised to V2.0 on March 3, 2022. The trial will last from November 23, 2022, to November 30, 2030.\u003c/p\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHIPEC: hyperthermic intraperitoneal chemotherapy; RCT: randomized controlled trial; CRF: case report form; FCCs: Peritoneal-free cancer cells; JGCA: The Japanese Gastric Cancer Society; ALT: glutamate aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; Cr: blood creatinine; ULN: upper limit of normal value; Hb : haemoglobin ; WBC : white blood cell count；Plt: platelet count; NEUT: neutrophil count; RFS: relapse-free survival; OS: overall survival; AEs: Adverse events; PSOGI: The International Collaborative Group for Peritoneal Surface Malignancies; ECOG: Eastern Cooperative Oncology Group; ASA: American Society of Anesthesiologists; FAPI: fibroblast-activating protein inhibitor; PET: positron emission tomography; DMC: data monitoring committee.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study has been approved by the Ethics Committee of the Affiliated Hospital of Qingdao University and has already been registered at ClinicalTrial.gov with Registration ID NCT05871099. The HIPEC-09 study complies with the Declaration of Helsinki rules, the principles of the Good Clinical Practice guidelines and the Data Protection Act. The trial will also be performed in accordance with local legal and regulatory requirements. Each patient recruited to the study will provide written informed consent after receiving extensive information about the intent of the study, the study regimen, potential associated risks and side effects as well as potential alternative therapies. The investigator will not undertake any diagnostic measures specifically required for the clinical trial until valid consent has been obtained. Monitoring will be conducted throughout the trial. We have purchased insurance for this research.\u0026nbsp;If subject suffers any damage related to this study or experiences a serious adverse event, appropriate compensation will be provided.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original data from the study are available for dissemination to other researchers upon request at the time of publication. Access can be arranged by contacting the corresponding author via email ([email protected]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present trial is supported by\u0026nbsp;Wu Jieping Medical Foundation (320.6750.2024-17-24). The sponsor is not involved in the aspects of trial design, data collection and analysis and manuscript writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYZ, XL and JW conceived and designed the study. XL and YZ drafted the manuscript and developed the protocol. YZ, YT and GL contributed to the study coordination. XL, QW, HL, SC, TZ, YL, XS, WH, PG, KT, TL, LL and YZ contributed to the patient recruitment. XL, YT, SC, ZL and YZ contributed to the data management and statistical analysis. YZ contributed to funding acquisition and study supervision. All authors have read and approved the version to be published and have agreed to be responsible for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants and their families for their participation and support in this study. We thank Professor Xiaobin Zhou from School of Public Medicine of Qingdao University for practical suggestions to the study\u0026apos;s design, data analysis, and interpretation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. 74(3): 229-263.\u003c/li\u003e\n\u003cli\u003eXia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022. 135(5): 584-590.\u003c/li\u003e\n\u003cli\u003eBang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012. 379(9813): 315-21.\u003c/li\u003e\n\u003cli\u003eSakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007. 357(18): 1810-20.\u003c/li\u003e\n\u003cli\u003eXu W, Liu W, Wang L, et al. Is D2 Lymphadenectomy Alone Suitable for Gastric Cancer With Bulky N2 and/or Para-Aortic Lymph Node Metastases After Preoperative Chemotherapy. Front Oncol. 2021. 11: 709617.\u003c/li\u003e\n\u003cli\u003eKitano S, Iso Y, Moriyama M, Sugimachi K. Laparoscopy-assisted Billroth I gastrectomy. Surg Laparosc Endosc. 1994. 4(2): 146-8.\u003c/li\u003e\n\u003cli\u003eGoh PM, Khan AZ, So JB, et al. Early experience with laparoscopic radical gastrectomy for advanced gastric cancer. Surg Laparosc Endosc Percutan Tech. 2001. 11(2): 83-7.\u003c/li\u003e\n\u003cli\u003eHashizume M, Sugimachi K. Robot-assisted gastric surgery. Surg Clin North Am. 2003. 83(6): 1429-44.\u003c/li\u003e\n\u003cli\u003eHuang C, Liu H, Hu Y, et al. Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer: Five-Year Outcomes From the CLASS-01 Randomized Clinical Trial. JAMA Surg. 2022. 157(1): 9-17.\u003c/li\u003e\n\u003cli\u003eHyung WJ, Yang HK, Park YK, et al. Long-Term Outcomes of Laparoscopic Distal Gastrectomy for Locally Advanced Gastric Cancer: The KLASS-02-RCT Randomized Clinical Trial. J Clin Oncol. 2020. 38(28): 3304-3313.\u003c/li\u003e\n\u003cli\u003eEtoh T, Ohyama T, Sakuramoto S, et al. Five-Year Survival Outcomes of Laparoscopy-Assisted vs Open Distal Gastrectomy for Advanced Gastric Cancer: The JLSSG0901 Randomized Clinical Trial. JAMA Surg. 2023. 158(5): 445-454.\u003c/li\u003e\n\u003cli\u003eJapanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer. 2023. 26(1): 1-25.\u003c/li\u003e\n\u003cli\u003eVolz J, K\u0026ouml;ster S, Spacek Z, Paweletz N. The influence of pneumoperitoneum used in laparoscopic surgery on an intraabdominal tumor growth. Cancer. 1999. 86(5): 770-4.\u003c/li\u003e\n\u003cli\u003eCarpinteri S, Sampurno S, Bernardi MP, et al. Peritoneal Tumorigenesis and Inflammation are Ameliorated by Humidified-Warm Carbon Dioxide Insufflation in the Mouse. Ann Surg Oncol. 2015. 22 Suppl 3(Suppl 3): S1540-7.\u003c/li\u003e\n\u003cli\u003eTustumi F, Bernardo WM, Dias AR, et al. Detection value of free cancer cells in peritoneal washing in gastric cancer: a systematic review and meta-analysis. Clinics (Sao Paulo). 2016. 71(12): 733-745.\u003c/li\u003e\n\u003cli\u003eBinda MM, Molinas CR, Mailova K, Koninckx PR. Effect of temperature upon adhesion formation in a laparoscopic mouse model. Hum Reprod. 2004. 19(11): 2626-32.\u003c/li\u003e\n\u003cli\u003eNeuhaus SJ, Watson DI. Pneumoperitoneum and peritoneal surface changes: a review. Surg Endosc. 2004. 18(9): 1316-22.\u003c/li\u003e\n\u003cli\u003eWittich P, Marquet RL, Kazemier G, Bonjer HJ. Port-site metastases after CO(2) laparoscopy. Is aerosolization of tumor cells a pivotal factor. Surg Endosc. 2000. 14(2): 189-92.\u003c/li\u003e\n\u003cli\u003eKoninckx PR, Fernandes R, Ussia A, et al. Pathogenesis Based Diagnosis and Treatment of Endometriosis. Front Endocrinol (Lausanne). 2021. 12: 745548.\u003c/li\u003e\n\u003cli\u003eThomassen I, van Gestel YR, van Ramshorst B, et al. Peritoneal carcinomatosis of gastric origin: a population-based study on incidence, survival and risk factors. Int J Cancer. 2014. 134(3): 622-8.\u003c/li\u003e\n\u003cli\u003eDe Andrade JP, Mezhir JJ. The critical role of peritoneal cytology in the staging of gastric cancer: an evidence-based review. J Surg Oncol. 2014. 110(3): 291-7.\u003c/li\u003e\n\u003cli\u003eMori N, Oka M, Hazama S, et al. Detection of telomerase activity in peritoneal lavage fluid from patients with gastric cancer using immunomagnetic beads. Br J Cancer. 2000. 83(8): 1026-32.\u003c/li\u003e\n\u003cli\u003eIkeguchi M, Oka A, Tsujitani S, Maeta M, Kaibara N. Relationship between area of serosal invasion and intraperitoneal free cancer cells in patients with gastric cancer. Anticancer Res. 1994. 14(5B): 2131-4.\u003c/li\u003e\n\u003cli\u003eShimada S, Kuramoto M, Marutsuka T, Yagi Y, Baba H. Adopting extensive intra-operative peritoneal lavage (EIPL) as the standard prophylactic strategy for peritoneal recurrence. Rev Recent Clin Trials. 2011. 6(3): 266-70.\u003c/li\u003e\n\u003cli\u003eWang W, Tan G, Skanthakumar T, Chia CS, Soo KC, Teo M. Exploring the trend in referrals for consideration of CRS and HIPEC to understand the attitudes of clinicians in the development of a national cancer centre programme in peritoneal disease. Int J Hyperthermia. 2018. 34(5): 551-558.\u003c/li\u003e\n\u003cli\u003eKwakman R, Schrama AM, van Olmen JP, et al. Clinicopathological Parameters in Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer Metastases: A Meta-analysis. Ann Surg. 2016. 263(6): 1102-11.\u003c/li\u003e\n\u003cli\u003eChia CS, You B, Decullier E, et al. Patients with Peritoneal Carcinomatosis from Gastric Cancer Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Is Cure a Possibility. Ann Surg Oncol. 2016. 23(6): 1971-9.\u003c/li\u003e\n\u003cli\u003eSgarbura O, Al Hosni M, Petruzziello A, et al. Complete pathologic response after two-stage cytoreductive surgery with HIPEC for bulky pseudomyxoma peritonei: proof of concept. Int J Hyperthermia. 2020. 37(1): 585-591.\u003c/li\u003e\n\u003cli\u003evan Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018. 378(3): 230-240.\u003c/li\u003e\n\u003cli\u003eBeeharry MK, Zhu ZL, Liu WT, Yao XX, Yan M, Zhu ZG. Prophylactic HIPEC with radical D2 gastrectomy improves survival and peritoneal recurrence rates for locally advanced gastric cancer: personal experience from a randomized case control study. BMC Cancer. 2019. 19(1): 932.\u003c/li\u003e\n\u003cli\u003eDesiderio J, Chao J, Melstrom L, et al. The 30-year experience-A meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer. Eur J Cancer. 2017. 79: 1-14.\u003c/li\u003e\n\u003cli\u003eYonemura Y, Ishibashi H, Hirano M, et al. Effects of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy and Neoadjuvant Intraperitoneal/Systemic Chemotherapy on Peritoneal Metastases from Gastric Cancer. Ann Surg Oncol. 2017. 24(2): 478-485.\u003c/li\u003e\n\u003cli\u003eGwee YX, Chia D, So J, et al. Integration of Genomic Biology Into Therapeutic Strategies of Gastric Cancer Peritoneal Metastasis. J Clin Oncol. 2022. 40(24): 2830.\u003c/li\u003e\n\u003cli\u003eZhao JJ, Ong CJ, Srivastava S, et al. Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases. Gastroenterology. 2024. 167(7): 1384-1398.e4.\u003c/li\u003e\n\u003cli\u003eZhu ZG, Tang R, Yan M, et al. Efficacy and safety of intraoperative peritoneal hyperthermic chemotherapy for advanced gastric cancer patients with serosal invasion. A long-term follow-up study. Dig Surg. 2006. 23(1-2): 93-102.\u003c/li\u003e\n\u003cli\u003eFoster JM, Zhang C, Rehman S, Sharma P, Alexander HR. The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future. CA Cancer J Clin. 2023. 73(1): 49-71.\u003c/li\u003e\n\u003cli\u003eYang R, Su YD, Ma R, Li Y. Clinical epidemiology of peritoneal metastases in China: The construction of professional peritoneal metastases treatment centers based on the prevalence rate. Eur J Surg Oncol. 2023. 49(1): 173-178.\u003c/li\u003e\n\u003cli\u003eChen D, Liu Z, Liu W, et al. Predicting postoperative peritoneal metastasis in gastric cancer with serosal invasion using a collagen nomogram. Nat Commun. 2021. 12(1): 179.\u003c/li\u003e\n\u003cli\u003eMori Y, Dendl K, Cardinale J, Kratochwil C, Giesel FL, Haberkorn U. FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease. Radiology. 2023. 306(2): e220749.\u003c/li\u003e\n\u003cli\u003eHuang ZN, Ma Y, Chen QY, et al. Potential survival benefits of open over laparoscopic radical gastrectomy for gastric cancer patients beyond three years after surgery: result from multicenter in-depth analysis based on propensity matching. Surg Endosc. 2022. 36(2): 1456-1465.\u003c/li\u003e\n\u003cli\u003eSpratt JS, Adcock RA, Muskovin M, Sherrill W, McKeown J. Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res. 1980. 40(2): 256-60.\u003c/li\u003e\n\u003cli\u003eElias D, Go\u0026eacute;r\u0026eacute; D, Dumont F, et al. Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases. Eur J Cancer. 2014. 50(2): 332-40.\u003c/li\u003e\n\u003cli\u003ePrada-Villaverde A, Esquivel J, Lowy AM, et al. The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery. J Surg Oncol. 2014. 110(7): 779-85.\u003c/li\u003e\n\u003cli\u003eKlaver C, Wisselink DD, Punt C, et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol. 2019. 4(10): 761-770.\u003c/li\u003e\n\u003cli\u003eYarema RR, Ohorchak MA, Zubarev GP, et al. Hyperthermic intraperitoneal chemoperfusion in combined treatment of locally advanced and disseminated gastric cancer: results of a single-centre retrospective study. Int J Hyperthermia. 2014. 30(3): 159-65.\u003c/li\u003e\n\u003cli\u003eKang LY, Mok KT, Liu SI, et al. Intraoperative hyperthermic intraperitoneal chemotherapy as adjuvant chemotherapy for advanced gastric cancer patients with serosal invasion. J Chin Med Assoc. 2013. 76(8): 425-31.\u003c/li\u003e\n\u003cli\u003eHultman B, Lundkvist J, Glimelius B, Nygren P, Mahteme H. Costs and clinical outcome of neoadjuvant systemic chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from gastric cancer. Acta Oncol. 2012. 51(1): 112-21.\u003c/li\u003e\n\u003cli\u003eDesiderio J, Chao J, Melstrom L, et al. The 30-year experience-A meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer. Eur J Cancer. 2017. 79: 1-14.\u003c/li\u003e\n\u003cli\u003eGlehen O, Passot G, Villeneuve L, et al. GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study. BMC Cancer. 2014. 14: 183.\u003c/li\u003e\n\u003cli\u003eG\u0026ouml;tze TO, Piso P, Lorenzen S, et al. Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma - the phase III \u0026quot;PREVENT\u0026quot;- (FLOT9) trial of the AIO /CAOGI /ACO. BMC Cancer. 2021. 21(1): 1158.\u003c/li\u003e\n\u003cli\u003eLui S, Liang H, Li Y, et al. PILGRIM: Phase III clinical trial in evaluating the role of hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer patients after radical gastrectomy with D2 lymphadenectomy (HIPEC-01) [J]. J Clin Oncol, 2020,38 Suppl 15:S4538-S4538. DOI: 10.1200/JCO.2020. 38.15_suppl.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Advanced gastric cancer, HIPEC, Laparoscopic or robotic gastrectomy, Randomized clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-6957503/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6957503/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAlthough some prospective clinical studies have shown comparable oncological outcomes between laparoscopic and open surgery for advanced gastric cancer, the 3-year recurrence-free survival rate of patients who undergo laparoscopic radical gastrectomy is lower than that of patients who undergo open radical gastrectomy. Animal experiments have also shown that laparoscopic surgery may increase the risk of peritoneal metastasis during carbon dioxide pneumoperitoneum. Previous single-centre clinical trials have confirmed that HIPEC can effectively eliminate free cancer cells, thereby improving the survival rate of patients with advanced gastric cancer. In this study, we aimed to investigate the safety and efficacy of the combination of laparoscopic gastrectomy with HIPEC in advanced gastric cancer to reduce the incidence of peritoneal metastasis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 616 patients will be randomly divided into 2 groups at a 1:1 ratio using central randomization after laparoscopic exploration in this prospective, randomized, controlled, open, multicentre clinical trial. The experimental arm will receive laparoscopic or robotic D2 surgery with 2 cycles of HIPEC treatment followed by 6\u0026ndash;8 cycles of adjuvant chemotherapy, whereas the control group will undergo laparoscopic or robotic D2 surgery followed by 6\u0026ndash;8 cycles of systemic chemotherapy. The primary endpoint for this study is 5-year recurrence-free survival. The secondary endpoints are the 5-year overall survival rate, peritoneal metastasis rate, peritoneal metastasis-free survival, regional recurrence rate, distant metastasis rate, toxicity and side effects of the treatment program.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e\u003cp\u003eThis is the first multicentre randomized controlled clinical study exploring whether HIPEC can prevent peritoneal metastasis after laparoscopic or robotic radical gastrectomy under carbon dioxide pneumoperitoneum for advanced gastric cancer. Minimally invasive surgery under carbon dioxide pneumoperitoneum can cause tremendous changes in the peritoneal microenvironment, increasing the risk of gastric cancer cell peritoneal dissemination and metastasis. In previous studies, the roles of HIPEC and laparoscopic gastrectomy for advanced gastric cancer have been confirmed. The innovation of this study lies in observing whether the combination of HIPEC can decrease the risk of peritoneal metastasis and recurrence in patients with advanced gastric cancer after laparoscopic or robotic gastrectomy under carbon dioxide pneumoperitoneum.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eThe trial was registered on 14/05/2023 under clinicaltrials.gov (Identifier: NCT05871099).\u003c/p\u003e","manuscriptTitle":"Study Protocol for Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Gastric Cancer after Laparoscopic or Robotic Gastrectomy with D2 Lymphadenectomy: A Phase III Multicentre Prospective Randomized Controlled Clinical Trial (HIPEC-09)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:34:04","doi":"10.21203/rs.3.rs-6957503/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-23T14:07:20+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-12T14:48:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-23T23:42:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-23T23:41:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-06-23T13:49:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4b1cbc8a-b85d-499c-9597-fd4655170bc4","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:19:26+00:00","versionOfRecord":{"articleIdentity":"rs-6957503","link":"https://doi.org/10.1186/s12885-026-15899-2","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2026-03-26 16:11:52","publishedOnDateReadable":"March 26th, 2026"},"versionCreatedAt":"2025-09-23 02:34:04","video":"","vorDoi":"10.1186/s12885-026-15899-2","vorDoiUrl":"https://doi.org/10.1186/s12885-026-15899-2","workflowStages":[]},"version":"v1","identity":"rs-6957503","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6957503","identity":"rs-6957503","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}