Safety analysis of intraperitoneal hyperthermic chemotherapy in the treatment of gastrointestinal cancer: a systematic review and meta-analysis

Safety analysis of intraperitoneal hyperthermic chemotherapy in the treatment of gastrointestinal cancer: a systematic review and meta-analysis | 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 Research Article Safety analysis of intraperitoneal hyperthermic chemotherapy in the treatment of gastrointestinal cancer: a systematic review and meta-analysis Yingrong Zhao, Yingxuan Zhang, Weiyu Chen, Changjun Qiu, Litao Xu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7467575/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Mar, 2026 Read the published version in World Journal of Surgical Oncology → Version 1 posted 11 You are reading this latest preprint version Abstract Objective To evaluate the safety of intraperitoneal hyperthermic perfusion chemotherapy in the treatment of gastrointestinal cancer by meta-analysis method. Methods Pubmed, Embase, WOS, Elsevier, ScienceDirect and springer were retrieved by computer. Patients with gastrointestinal malignancies accompanied by peritoneal metastasis were selected as the research subjects, and randomized controlled trials (RCTs) of intraperitoneal hyperthermic perfusion chemotherapy were retrieved. The search time range covers all records in major databases from their establishment to January 2025, and traces the relevant references. Two researchers independently screened the references, extracted the corresponding materials respectively, and managed and extracted the data of the included references using Excel. Data analysis of the included references that met the requirements was conducted using R4.4.2 software. According to the guiding principles of the Cochrane Collaboration, for continuous variables in systematic reviews, weighted mean difference (MD) and its 95% confidence interval (CI) are usually used as effect indicators, while for binary variables, odds ratio (OR) is adopted, and 95% CI is used as the effect indicator. The heterogeneity of the included literature was determined through I2 analysis and Q verification. When P ≥ 0.1 and I2 ≤ 50%, the fixed-effect model was adopted. When P 50%, the random effects model is adopted. The outcome observation indicators were: the incidence of severe adverse reactions, infection, anastomotic leakage, massive hemorrhage, intestinal obstruction, digestive tract adverse reactions (nausea, vomiting, diarrhea), pneumonia, neutropenia, etc. Results A total of 10 RCTs were included, with a total of 1060 patients participating in this study. The number of patients in the experimental group was 540, and the number of patients in the control group was 520. According to the results of the meta-analysis, compared with the control group, after the implementation of HIPEC (hyperthermic intraperitoneal chemotherapy), the incidence of serious adverse events (AE) with Grade ≥ 3 after surgery, intestinal obstruction, massive gastrointestinal bleeding, infection, digestive tract adverse reactions, pneumonia, and neutropenia in the experimental group did not show statistically significant differences. The incidence of adverse reactions related to anastomotic leakage in the experimental group was higher than that in the control group, but the result was not statistically significant (RR = 0.861, 95%CI (0.214, 3.459), Z = 0.21, P = 0.83). Conclusion HIPEC is safe and feasible for gastrointestinal malignancies with PM. The occurrence of postoperative adverse reactions and complications in patients does not increase significantly, and it has good safety. However, the specific efficacy of HIPEC still needs to be further evaluated. Whether it can increase the long-term survival rate of patients and prolong their survival period still requires multi-center, large-sample, and high-quality clinical studies to further demonstrate. Intraperitoneal hyperthermic perfusion chemotherapy Gastric malignant tumors colorectal malignant tumors peritoneal metastatic malignant tumors complications Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Gastrointestinal malignant tumors, especially gastric cancer, occupy a dominant position in digestive system tumors. Their morbidity and mortality are high and increasing year by year. According to data from the World Health Organization’s International Agency for Research on Cancer (IARC) in 2022, there are approximately 1.926 million new cases of colorectal cancer (CRC) and 904 thousands deaths around the world. The morbidity and mortality rates rank third and second in global cancers, respectively. New gastric cancer(GC) cases exceed 968 thousands and the total number of deaths is close to 660 thousands. The morbidity and mortality rates of GC rank fifth and fourth globally, respectively [ 1 ] . Peritoneal metastasis (PM) is one of the main causes of death in patients with gastrointestinal malignant tumors. About 10–30% of GC patients have peritoneal metastasis at the initial diagnosis, and more than 50% of patients with stage II ~ III gastric cancer will develop PM, the prognosis of which is extremely poor, within 5 years after radical gastrectomy [ 2 ] . PM ranks third among CRC metastases. The peritoneal dissemination rate reaches 10% ~ 15% at initial diagnosis, and about 20% ~ 25% of patients have heterogeneous peritoneal metastasis after radical resection [ 3 , 4 ] . Because the plasma-peritoneal barrier prevents most chemotherapeutic drugs from penetrating the peritoneum, or the drugs cannot maintain effective therapeutic concentrations in the abdominal cavity, systemic chemotherapy has a poor response in PM patients [ 5 ] . Hyperthermic intraperitoneal chemotherapy (HIPEC) improves the curative effect through the dual effects of hyperthermia combined with chemotherapy drugs, and prolongs the survival time and improves the of patients’ quality of life [ 6 ] . Although HIPEC has shown positive effects in the treatment of peritoneal malignancies, studies have pointed out that its postoperative complication rate and mortality rate are within acceptable ranges. A study published in Annals of Surgical Oncology showed that HIPEC significantly improved the survival rate of patients with peritoneal metastases of gastric cancer, whose three-year survival rate was about 55%, and most patients received treatment without complications. Meta-analysis was used in this study to evaluate the safety of HIPEC in treating gastrointestinal malignancies, which provided evidence-based evidence on anti-tumor therapy of gastrointestinal malignant tumors with PM and its complications. Materials and Methods 1.1 Database and Retrieval Strategy This study mainly searched English databases, including PubMed, Embase, WOS, Elsevier, ScienceDirect and Springer, and used a free combination of keywords to construct the search strategy. At the same time, the related content of Google Scholar was also searched simultaneously. In order to maintain the linguistic consistency of research data and results and facilitate international communication and publication, an English database was preferred for the search in this study. Literature in Literature from English databases is generally of high quality, and full texts are more readily accessible, which facilitates detailed data extraction and analysis. This study aims to evaluate the application safety of HIPEC worldwide, and the English database has been able to cover most related studies. If the Chinese database is decided to be supplemented in the follow-up research, it will include CNKI, Wanfang Data and VIP, etc., to more comprehensively evaluate the application of HIPEC in the Chinese population. The retrieval strategy will be appropriately adjusted according to the characteristics of the Chinese database. 1.2 Literature Inclusion Criteria 1. Study type: Literature included in this review was all randomized controlled trials (RCTs), and the language was not limited; 2. Research objects: All included study subjects were patients diagnosed with advanced gastrointestinal malignancies with peritoneal metastases (PM), regardless of histological classification of cancer; 3. Test group: Patients treated with hyperthermic intraperitoneal chemotherapy (HIPEC group); 4. Control group: Patients not treated with HIPEC (non-HIPEC group); 5. Outcome measures: Studies must contain relevant data on the incidence of adverse reactions (or complications). 1.3 Literature Exclusion Criteria 1. Patients without gastric cancer and colorectal cancer were excluded; 2. The literature that did not use hyperthermic intraperitoneal chemotherapy (HIPEC) was not included; 3. The following types of studies were excluded: Non-randomized controlled trials, case analyses, review articles, protocols and pilot studies; Single-arm clinical trials, as well as multi-arm trials lacking a control group, were also excluded. 4. If the research results indicators were incomplete, the data could not be obtained, or the data could not be converted, the research would not be taken into consideration. 1.4 Screening of Literature After a literature search, duplicate documents were excluded by software, and two researchers read the title and abstract, screened according to the inclusion and exclusion criteria, and obtained the full text of the remaining documents. If the original text cannot be obtained from the Internet, they contacted the original author and read the full text of the literature for further screening. 1.5 Outcome Measures The primary outcome measures were: 1. The incidence of serious adverse reactions is defined as the number of patients/total cases of all Grade 3-5 adverse reactions occurring during treatment [7] . 2. The incidence of adverse reactions, including infection, anastomotic leakage and massive gastrointestinal bleeding, is defined as the number of patients/total cases of all relevant adverse reactions occurring during treatment. Secondary outcome measures included: The incidence of intestinal obstruction (about 5 in 1,000), gastrointestinal adverse reactions (nausea, vomiting and diarrhea), pneumonia, and the incidence of neutropenia (about 10% in children and adolescents and more than 50% in adults). 1.6 Evaluation of Literature Quality and Assessment of Risk of Bias Cochrane risk of bias V2.0 provided by Cochrane Collaboration was used to assess the risk of bias of the included studies, which included five levels, and each level was given risk assessment using "low", "some concern of risk" and "high". 1.7 Data R etrieval Two researchers independently retrieved literature data from each database, covering literature author, publication date, grouping strategy, sample size of each group, patient age, gender composition, trial protocol, treatment duration, follow-up period, outcome measures and specific data. After completing the data retrieval, the two researchers cross-checked and discussed the different items in depth, managed the included literature and extracted the data using Excel, and finally reached a consensus to determine the data. 1.8 Statistical Methods: (1) Discrete variables used the risk ratio (RR) and its 95% confidence interval (CI) to report the effect size. The calculation of the confidence interval is based on the statistical analysis of a large number of sample data. By comparing the incidence of an event between the experimental group and the control group to evaluate the correlation strength between factors and events. (2) Forest diagram was used to visually show the comparison between different statistics; (3) I 2 statistical analysis and Q test were used to evaluate the heterogeneity among literature, when I 2 >50% or P<0.1, the results were considered to be significantly different; (4) If there was no heterogeneity, the fixed effects model (Mantel-Haenszel) was used for calculation; If heterogeneity existed, it was calculated using the Dersimonian-Laird method. (5) Sensitivity analysis was used to detect the literature with the greatest impact on effect size; (6) Publication bias was detected using Egger's test and Begger's test and showed using a funnel diagram. (7) In this study, R4.4.2 software was used to perform a Meta-analysis on the literature data that met the requirements. The code implementation details were shown in Figure 1. Results 2.1 Results of Literature Screening Figure 1 shows the literature screening process. The initial search results contained 444 documents. After de-duplication and rigorous screening, 10 randomized controlled trial (RCT) articles were finally included in quantitative analysis, involving 1060 patients participating in the study, where 540 patients were in the experimental group and 520 patients were in the control group. Of the 10 RCT articles included, 7 were studied for patients with gastric cancer, while 3 were studied for patients with bowel cancer. Detailed basic characteristics, trial measures, and outcome measures of all literature were presented in Fig. 1 . Table 1 Basic characteristics, trial measures, and outcome measures included in the literature Researchers Year Diseases Number of cases Test measures Outcome measures Test group Control group Test group Control group Rau B [ 8 ] 2024 Gastric cancer 53 52 CRS + HIPEC CRS alone ①②③④⑤ Yang XJ [ 9 ] 2011 Gastric cancer 34 34 CRS + HIPEC CRS alone ②③④⑤ Quénet F [ 10 ] 2021 Colorectal cancer 132 133 CRS + HIPEC + Systemic therapy CRS + Systemic therapy ① Verwaal VJ [ 11 ] 2003 Colorectal cancer 54 51 CRS + HIPEC/ HIPEC + Systemic therapy Systemic therapy ③⑧ Yu P [ 12 ] 2023 Gastric cancer 67 67 CRS + HIPEC + Systemic therapy CRS + Systemic therapy ① Liu L [ 13 ] 2022 Gastric cancer 57 57 CRS + HIPEC + Systemic therapy CRS + Systemic therapy ①⑥⑦ Fan B [ 14 ] 2021 Gastric cancer 33 17 CRS + HIPEC + Systemic therapy CRS + Systemic therapy ④ Huang O [ 15 ] 2015 Gastric cancer 21 21 CRS + HIPEC CRS + Systemic therapy ①②④⑤⑥⑧ Beeharry MK [ 16 ] 2019 Gastric cancer 40 40 CRS + HIPEC + Systemic therapy CRS + Systemic therapy ①②③④⑤⑦ Baratti D [ 17 ] 2020 Colorectal cancer 48 48 CRS + HIPEC + Systemic therapy CRS + Systemic therapy ① Outcome measures: ① Incidence of serious AE at Grade ≥ 3; ② Incidence of infection and sepsis; ③ Incidence of massive intestinal bleeding; ④ Incidence of anastomotic leakage; ⑤ Incidence of intestinal obstruction; ⑥ Incidence of gastrointestinal adverse reactions; ⑦ Neutropenia; ⑧ Pneumonia. 2.2 Literature Quality and Bias Assessment In this study, Cochrane risk of bias (ROB 2.0) was used to evaluate the quality of 10 included randomized controlled trials (RCTs). Overall, random sequence generation and concealed allocation of the included literature were relatively standardized, but some literature has a potential risk of bias in the process of blinded implementation and randomization [ 8 ] , as follows. Literature where blinding was not strictly followed: Rau B (2024) conducted a multicenter randomized controlled open-label study that did not strictly follow the principle of blinding and might have a risk of intervention-related bias [ 13 ] ; The study by Beeharry MK (2019) did not explicitly describe blinding application, and there was a potential risk of bias. Literature may be biased in randomization [ 17 ] . In the study of Baratti D (2020), when describing the sample randomization process, the specific implementation steps of the randomization method were not specified in detail, and there may be bias in randomization process. The remaining included literature (such as Yang XJ 2011, Quénet F 2021, et al.) elaborated on the implementation of the random sequence generation, concealed allocation, and blinding, and recorded the dropped cases in detail. No obvious selective reporting bias or other bias problems were found, and the overall study quality was high. A randomized controlled intervention bias analysis based on ROB 2.0 showed (Fig. 2 ) that the included literature had a low risk of bias in random sequence generation and assignment concealment, but there was a moderate risk during blinded implementation and randomization of several studies. It is recommended that future studies further optimize the blinded design and clarify the specific implementation details of the randomization method to reduce the risk of bias. 2.3 Results of Meta-analysis 2.3.1 Incidence of Serious AE with Grade ≥ 3 : Although all 8 articles reported the incidence of serious adverse reactions between the test group and the control group in the treatment trial, the results showed no statistical difference between the articles (I 2 = 42%, P = 0.10). There was no significant difference in the incidence of adverse reactions between HIPEC and non-HIPEC after comprehensive analysis using the fixed effects model (RR = 1.205, 95% CI: 0.936 to 1.553, Z = 1.44, P = 0.15). However, this contradicts some research results. For example, in a study from 12 HIPEC collaborating centers in the United States, the complication rate of the HIPEC treatment group was almost twice that of the non-HIPEC group. Detailed results were shown in Fig. 3 . 2.3.2 Infection Incidence : All three studies reported the incidence of infection-related adverse reactions during treatment between the test group and the control group, and did not show a statistical difference among studies (I 2 = 0%, P = 0.44). Integrated analysis showed that compared with non-HIPEC, HIPEC had no significant difference in the incidence of infection-related adverse reactions (RR = 1.800, 95% CI (0.391, 8.283), Z = 0.75, P = 0.45), which is consistent with the consensus of gynecologic oncology experts and the progress of clinical practice. The detailed results were shown in Fig. 4 . 2.3. 3 Incidence of Massive Gastrointestinal Bleeding : During the treatment process, the investigator paid special attention to the incidence of massive gastrointestinal bleeding in patients in the experimental group and control group, in view of the possible gastrointestinal adverse reactions and the severity of massive upper gastrointestinal bleeding caused by the drug. According to the three reports, there was no statistical difference among these studies (I 2 = 0%, P = 0.53), and after comprehensive analysis of fixed-effect patterns, it was found that there was no significant difference in the incidence of adverse reactions related to massive gastrointestinal bleeding between HIPEC and non-HIPEC treatment regimens (RR = 1.486, 95% CI (0.524, 4.211), Z = 0.75, P = 0.46). The detailed results were shown in Fig. 5 . Massive gastrointestinal bleeding was a serious symptom, which may be caused by a variety of gastrointestinal diseases, such as peptic ulcer, ruptured esophageal varices and gastrointestinal tumors, etc. Its clinical manifestations included hematemesis, melena, abdominal pain, dizziness, fatigue, palpitations, etc. 2.3.4 Incidence of Anastomotic Leakage : All three studies reported the incidence of adverse reactions related to anastomotic leakage during treatment between the test group and the control group, and no statistical difference between studies was found(I 2 = 0%, P = 0.51). According to the integrated analysis of fixed effects model, compared with non-HIPEC, HIPEC showed unique advantages in preventing and treating peritoneal implant metastasis, although it showed a higher trend in the incidence of adverse reactions related to anastomotic leakage, the result was not statistically significant (RR = 0.861, 95% CI (0.214, 3.459), Z = 0.21, P = 0.83). HIPEC is an effective treatment method, especially in the treatment of middle and advanced abdominal tumors. It can effectively prevent and treat peritoneal implant metastasis and complicated malignant ascites by injecting heated chemotherapeutic drugs into the abdominal cavity for anti-tumor treatment. Detailed results were shown in Fig. 6 . 2.3.5 Other Complication Rates : After a meta-comprehensive analysis of several common adverse reactions, we found that the incidence of specific complications can be significantly reduced by comparing different treatment methods. The specific data and analysis results were detailed in Table 2 . Table 2 Meta-analysis Results of Rate of Other Complications (Test group vs.Control group) Factors Number of literature Analysis mode I 2 C with P value Effect size Pooling value Z.P Value Intestinal obstruction 3 Fixed Effect Mode 0% with 0.5392 RR 0.6921 [0.1115; 4.2953] -0.4, 0.6928 Gastrointestinal adverse reactions 3 Fixed Effect Mode 0% with 0.572 RR 1.1487 [0.9516; 1.3866] 1.4, 0.1489 Pneumonia 2 Fixed Effect Mode 0% with 0.762 RR 1.8000 [0.3904; 8.2998] 0.7, 0.4510 Neutropenia 3 Fixed Effect Mode 0% with 0.774 RR 1.0848 [0.7633; 1.5418] 0.4, 0.6498 2.3.6 Sensitivity Analysis : Fig. 7 shows the results of the sensitivity analysis. After the included documents were eliminated one by one by the "de-one method", the combined effect size was recalculated. The significance of the combined effect size was to evaluate whether the combined effect of the remaining literature changed significantly after the exclusion of a specific literature. It can be seen from the figure that no matter which literature was excluded, the combined effect size remained relatively stable, indicating that the results of this study had good robustness and were not significantly affected by a single literature. = 2.3.7 Publication Bias Analysis: This study evaluated the publication bias of included literature by funnel plot visualization (Fig. 8 ) combined with Egger's test and Begg's test. The results of the Egger test: t = 0.82, p = 0.43 (> 0.1) suggested that there was no significant asymmetry in the distribution of effect size in small sample studies; the results of the Begg test: z = 0.95, p = 0.34 (> 0.1) further supported the conclusion of no publication bias. Funnel graph visualization analysis: showed the funnel plot as a whole presented a symmetrical distribution (Fig. 9), which was consistent with the statistical test results; Subgroup analysis on early studies (sample size < 50 cases) showed a slight scatter deviation at the bottom of the funnel plot without statistical significance (Egger's test p = 0.21), which might be due to random error or inter-study difference rather than systematic publication bias. Based on the double validation of quantitative test (Egger/Begg) and qualitative visualization (funnel plot), this study believed that there was no significant publication bias in the included literature; Scatter deviation of early studies should be interpreted carefully, and it is suggested that future studies should expand the sample size for further verification. Discussion Once peritoneal metastasis occurs in gastrointestinal malignant tumors, it is recognized as an end-stage tumor, with an extremely poor prognosis and limited treatment methods [ 18 , 19 ] . At present, for early peritoneal metastases with small or limited metastatic lesions, postoperative adjuvant chemotherapy is usually the main treatment. For patients with diffuse peritoneal metastases, palliative chemotherapy or symptomatic treatment is usually the main treatment to reduce the tumor burden [ 18 , 19 ] . The conventional chemotherapy route is not effective for peritoneal malignancies due to the presence of the plasma-peritoneal barrier, which limits the penetration of drugs from the systemic circulation into the peritoneum and into the abdominal cavity [ 5 ] . Fujimoto et al. [ 20 ] for the first time used HIPEC technology to treat gastrointestinal malignant tumors with PM in 1988. They directly infused the drugs into the patient’s abdominal cavity, thus significantly increasing the local concentration of the drug in the abdominal cavity and effectively reducing the toxic reaction caused by systemic chemotherapy. At present, HIPEC has become an important research hotspot in the treatment of peritoneal metastatic cancer. However, since HIPEC is an invasive procedure and involves the toxicity of chemotherapeutic drugs, complications inevitably occur during clinical treatment. To further explore the safety of HIPEC in the treatment of gastrointestinal cancer with peritoneal metastasis, this study collected the data of 10 international articles with randomized controlled trials (RCTs) on HIPEC, and used Meta-analysis to comprehensively analyze the postoperative adverse reactions (including incidence of grade 3 or above serious adverse events, gastrointestinal adverse reactions, pneumonia and neutropenia) and postoperative complications (including infection and sepsis, gastrointestinal hemorrhage, anastomotic leakage, and intestinal obstruction) in two groups. The results showed that compared with simple surgery, HIPEC combined surgery can significantly improve the survival rate of patients with peritoneal metastases of gastric cancer from 12–35%, while reducing the recurrence rate, showing higher safety. Through a Meta-study, it was found that the incidence of adverse reactions related to anastomotic leakage in the HIPEC group was higher than that in the non-HIPEC group, but the results were not statistically significant. Pramateftakis et al. [ 21 ] have found that HIPEC immediately after intestinal surgery delays the healing time of colonic anastomosis in rats, resulting in an increased risk of anastomotic leakage, especially in the case of co-perfusion with 5-fluorouracil and irinotecan. Zhang et al. [ 22 ] found through research that although no anastomotic leakage was found in the animals in the experimental group and the control group, the degree of anastomotic inflammatory cell infiltration in the experimental group was significantly higher than that in the control group. There are many factors leading to anastomotic leakage, including excessive anastomotic tension during operation, poor nutritional status, insufficient blood supply to local tissues, excessive obesity, history of hypertension, history of diabetes, and stimulation of chemotherapy drugs to anastomotic leakage [ 23 ] . In clinical operation, the following protective measures should be taken in advance: First, fully isolate the tissues during the operation to reduce the anastomotic tension; Second, ensure sufficient blood supply for local tissues; Third, actively implement nutritional support; Fourth, thoroughly flush the surgical area after surgery. This study found that the HIPEC group did not increase the incidence of infection and pneumonia compared with the non-HIPEC group. The results showed that the risk of infection within 7 days after CRS + HIPEC was 43%, mainly surgical site infection, pneumonia and catheter-related infection. The incidence of infection was positively correlated with the number of organ resections [ 24 ] . A multicenter randomized controlled trial showed that during the treatment for patients in the HIPEC group, a large amount of perfusate was injected into the abdominal cavity, resulting in diaphragm elevation, thoracic dilation, carbon dioxide accumulation, and decreased lung compliance. At the same time, due to the stimulation of chemotherapeutic drugs, reactive pleural effusion can be generated. All of the above factors will increase the risk of postoperative pneumonia [ 25 ] . During high-dose HIPEC, the risk factors for infection and pneumonia cover multiple dimensions, such as long catheter indwelling time, excessive number of drainage tubes, excessive perfusate temperature, local skin lesions caused by chemotherapeutic drugs, insufficient awareness of aseptic procedures during surgical procedures, poor nutritional status of patients, and coexistence with respiratory diseases. For example, studies of ventilator-associated pneumonia in ICU patients have shown that factors such as age, gender, time of admission, and presence or absence of pathogen infection are independent risk factors. Although HIPEC itself does not directly increase the incidence of infection and pneumonia, it is an invasive operation. It is necessary to carefully evaluate the patient's condition in clinical practice, strictly implement aseptic operating procedures, take nursing interventions in time, and apply targeted treatment when necessary. Meta-analysis revealed that the risk of gastrointestinal bleeding and intestinal obstruction was not increased significantly in patients receiving HIPEC; In actual clinical practice, there are still relevant case reports. In clinical studies, the causes of intestinal obstruction related to HIPEC can be attributed to two categories: individual factors of patients and operative factors. A study has pointed out that patients with a history of circulatory system diseases, gastrointestinal surgery, high-grade tumor pathological stage, high PCI (intraperitoneal chemotherapy index), and malnutrition have a significantly higher risk of intestinal obstruction [ 26 ] . Inflammatory reaction is mainly caused by unstable temperature of the perfusate and surface damage of the intestinal tube, which can promote the occurrence of intestinal obstruction [ 27 ] . This study showed that the HIPEC group did not lead to an increase in the incidence of major gastrointestinal bleeding, and it may also be related to the small sample of patients enrolled. Ba et al. [ 28 ] carried out a retrospective analysis, and the results showed that HIPEC alone did not significantly increase the risk of postoperative bleeding in patients. Among the 1200 treated patients, the incidence of bleeding events was extremely low, only 0.7%, which fully demonstrated the relatively low risk of postoperative bleeding. In clinical practice, we should be highly cautious about postoperative complications in patients with a high risk of gastrointestinal malignant tumors and peritoneal metastases. It is recommended to perform postoperative abdominal plain CT review in time and closely monitor the postoperative symptoms of patients. This study found that there was no significant difference in gastrointestinal adverse reactions between the HIPEC group and the non-HIPEC group. HIPEC can stimulate the gastrointestinal wall, lead to gastrointestinal edema, reduce gastrointestinal peristalsis function and secretion and absorption dysfunction [ 29 ] . The results of the study showed no significant difference in gastrointestinal adverse reactions, which may be related to the following factors: The higher heterogeneity of some indicators in the literature, the differences in investigators’ subjective judgments, as well as the induced effect from deliberately asking patients about specific symptoms, can all lead to research bias. In addition, the adverse gastrointestinal reactions of patients after surgery may be closely related to the recovery stage of gastrointestinal function. Considering that all patients included in the study have gastrointestinal malignancies with peritoneal metastases, which inherently have a high risk of gastrointestinal adverse reactions, the statistical results may be subject to some degree of bias. This study revealed that there was no significant difference in the incidence of serious adverse events (AE, Grade ≥ 3) and neutropenia in the patient population receiving HIPEC. This phenomenon may be related to the pharmacokinetic properties of HIPEC. Due to the existence of the plasma-peritoneal barrier, chemotherapeutic drugs can maintain high concentrations in the abdominal cavity and reduce the amount of drugs entering the systemic circulation, which helps to control peritoneal metastasis (PM) while reducing the toxicity and side effects caused by systemic chemotherapy. Conclusions This study evaluated the safety of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of gastrointestinal cancer with peritoneal metastases through a systematic review and Meta-analysis. The 10 randomized controlled trials (RCTs) included showed that HIPEC does not significantly increase the incidence of postoperative serious adverse events with Grade ≥ 3, intestinal obstruction, gastrointestinal bleeding, infection, gastrointestinal adverse reactions, pneumonia and neutropenia. Although the test group is slightly higher than the control group in the incidence of anastomotic leak-related adverse reactions, the difference is not statistically significant (RR = 0.861, 95% CI 0.214–3.459, P = 0.83). These results indicate that HIPEC has a good safety profile in the treatment of gastrointestinal malignant tumors with peritoneal metastasis, but its specific efficacy in improving the long-term survival rate and prolonging the survival of patients still needs to be further verified by more high-quality and large-scale clinical trials. Declarations Ethical approval Not applicable. Declaration of Competing Interest None. Funding None. Author Contribution Conceptualization: Yingrong Zhao,Yingxuan Zhang.Data curation:Yingrong Zhao,Weiyu Chen.Formal analysis: Yingrong Zhao,Yingxuan Zhang.Investigation: Yingrong Zhao,Weiyu Chen.Methodology: Yingrong Zhao,Weiyu Chen,,Yingxuan Zhang.Software: Yingrong ZhaoWriting - original draft: Yingrong ZhaoWriting -review & editing: Litao Xu Data availability The dataset that that support the findings in this study is available fromthe corresponding author upon reasonable request. 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):229–63. 10.3322/caac.21834 . Lei Z, Wang J, Li Z, et al. Hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A multicenter propensity score-matched cohort study. Chin J Cancer Res. 2020;32(6):794–803. Hompes D, Tiek J, Wolthuis A, et al. HIPEC in T4a colon cancer: a defendable treatment to improve oncologic outcome? Ann Oncol. 2012;23(12):3123–9. van Gestel YR, Thomassen I, Lemmens VE, et al. Metachronous peritoneal carcinomatosis after curative treatment of colorectal cancer. Eur J Surg Oncol. 2014;40(8):963–9. Kuramoto M, Shimada S, Ikeshima S, et al. A proposal of a practical and optimal prophylactic strategy for peritoneal recurrence. J Oncol. 2012;2012:340380. Vos LMC, Aronson SL, van Driel WJ, et al. Translational and pharmacological principles of hyperthermic intraperitoneal chemotherapy for ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2022;78:86–102. No author listed. Criteria for acute and subacute toxicity reactions of anticancer drugs (WHO standards)] [J]. (Chinese J Cancer), 1992, (03): 254. Rau B, Lang H, Koenigsrainer A, et al. Effect of Hyperthermic Intraperitoneal Chemotherapy on Cytoreductive Surgery in Gastric Cancer With Synchronous Peritoneal Metastases: The Phase III GASTRIPEC-I Trial. J Clin Oncol. 2024;42(2):146–56. Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011;18(6):1575–81. Quénet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):256–66. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21(20):3737–43. Yu P, Huang X, Huang L, et al. Hyperthermic intraperitoneal chemotherapy (HIPEC) plus systemic chemotherapy versus systemic chemotherapy alone in locally advanced gastric cancer after D2 radical resection: a randomized-controlled study. J Cancer Res Clin Oncol. 2023;149(13):11491–8. Liu L, Sun L, Zhang N, et al. A novel method of bedside hyperthermic intraperitoneal chemotherapy as adjuvant therapy for stage-III gastric cancer. Int J Hyperth. 2022;39(1):239–45. Fan B, Bu Z, Zhang J, et al. Phase II trial of prophylactic hyperthermic intraperitoneal chemotherapy in patients with locally advanced gastric cancer after curative surgery. BMC Cancer. 2021;21(1):216. Published 2021 Mar 2. Huang O, Lu X, Xu X, Shi Y. Fibrin-sealant-delivered cisplatin chemotherapy versus cisplatin hyperthermic intraperitoneal perfusion chemotherapy for locally advanced gastric cancer without peritoneal metastases: a randomized phase-II clinical trial with a 40-month follow-up. Cell Biochem Biophys. 2015;71(2):1171–80. 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 [published correction appears in BMC Cancer. 2019;19(1):1256. 10.1186/s12885-019-6411-9.] . BMC Cancer. 2019;19(1):932. Published 2019 Sep 18. Baratti D, Kusamura S, Azmi N, Guaglio M, Montenovo M, Deraco M. Colorectal Peritoneal Metastases Treated by Perioperative Systemic Chemotherapy and Cytoreductive Surgery With or Without Mitomycin C-Based HIPEC: A Comparative Study Using the Peritoneal Surface Disease Severity Score (PSDSS). Ann Surg Oncol. 2020;27(1):98–106. Cui SZ, Lei ZY, Zhongguo Zhongliu Zhenghe Zhenzhi Zhinan. : Fumo Zhongliu (Weichang Zhongliu Bufen) [Chinese Integrative Guidelines for Diagnosis and Treatment of Tumors: Peritoneal Tumors (Gastrointestinal Tumors Section)] [J]. Xiahua Zhongliu Zazhi (Dianziban) [Journal of Digestive Oncology (Electronic Edition)], 2023, 15(02): 100–108. Tang HS, Ruan Q, Cui SZ. Interpretation of Chinese Integrative Guidelines for Diagnosis and Treatment of Tumors: Peritoneal Tumors [J]. J Dig Oncol (Electronic Edition). 2023;15(02):109–13. Fujimoto S, Shrestha RD, Kokubun M, et al. Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding. Ann Surg. 1988;208(1):36–41. Pramateftakis MG, Kanellos D, Mantzoros I, et al. Intraperitoneally administered irinotecan with 5-fluorouracil impair wound healing of colonic anastomoses in a rat model: an experimental study. Tech Coloproctol. 2011;15(Suppl 1):S121–5. Zhang JY, Ni L, Cao YJ, et al. Experimental study on the effect of intraoperative hypotonic hyperthermic intraperitoneal perfusion chemotherapy on healing of gastrointestinal anastomosis [J]. Mod Oncol. 2013;21(05):1002–5. Xu JP, Ma J, Wang H. Risk factor analysis and prevention of anastomotic leakage after colorectal cancer surgery [J]. Chin J Colorectal Dis (Electronic Edition). 2021;10(01):99–102. Smibert OC, Slavin MA, Teh B, et al. Epidemiology and risks for infection following cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy. Support Care Cancer. 2020;28(6):2745–52. Liu PF, Li TZ, Zhao BJ, et al. Effects of positive end-expiratory pressure on respiratory mechanics and pulmonary function in patients undergoing hyperthermic intraperitoneal perfusion chemotherapy [J]. J Clin Anesthesiology. 2017;33(03):231–5. Lee TC, Wima K, Sussman JJ, et al. Readmissions After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: a US HIPEC Collaborative Study. J Gastrointest Surg. 2020;24(1):165–76. Ye J, Chen L, Zuo J, et al. A precise temperature control during hyperthermic intraperitoneal chemotherapy promises an early return of bowel function. Cancer Biol Ther. 2020;21(8):726–32. Ba M, Cui S, Long H, et al. Safety and Effectiveness of High-Precision Hyperthermic Intraperitoneal Perfusion Chemotherapy in Peritoneal Carcinomatosis: A Real-World Study. Front Oncol. 2021;11:674915. Published 2021 Aug 6. Gu XY, Gao ZQ, Zhang ZJ, et al. Effect of warm acupuncture and moxibustion on gastrointestinal reactions in patients receiving hyperthermic intraperitoneal perfusion chemotherapy after colon cancer surgery [J]. Acupunct Res. 2020;45(04):315–9. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Mar, 2026 Read the published version in World Journal of Surgical Oncology → Version 1 posted Editorial decision: Revision requested 05 Oct, 2025 Reviews received at journal 28 Sep, 2025 Reviews received at journal 25 Sep, 2025 Reviewers agreed at journal 20 Sep, 2025 Reviewers agreed at journal 18 Sep, 2025 Reviews received at journal 12 Sep, 2025 Reviewers agreed at journal 07 Sep, 2025 Reviewers invited by journal 07 Sep, 2025 Editor assigned by journal 06 Sep, 2025 Submission checks completed at journal 28 Aug, 2025 First submitted to journal 26 Aug, 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-7467575","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512769044,"identity":"1a02e722-c7bf-4e50-af1b-0706ae8ceb05","order_by":0,"name":"Yingrong Zhao","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yingrong","middleName":"","lastName":"Zhao","suffix":""},{"id":512769045,"identity":"cfd3254a-f4b9-4dac-9ab1-062797cf80d3","order_by":1,"name":"Yingxuan Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yingxuan","middleName":"","lastName":"Zhang","suffix":""},{"id":512769046,"identity":"d73796dc-0e7e-4a1c-8db2-52fe8eb0112f","order_by":2,"name":"Weiyu Chen","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Weiyu","middleName":"","lastName":"Chen","suffix":""},{"id":512769047,"identity":"7d01e853-b277-4e2d-a141-40afa1c62966","order_by":3,"name":"Changjun Qiu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Changjun","middleName":"","lastName":"Qiu","suffix":""},{"id":512769048,"identity":"704fcda2-bfc4-4de5-8c56-f15be03fc295","order_by":4,"name":"Litao Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAnklEQVRIiWNgGAWjYBAC9oYExgMMFRJy8kRr4TmQwHDgwBkLY8MGkrQcbKtIZDhAtBb2HIPDH+dJJDA2MD98dIMoLTzPEg4c3CaRx87AZmycQ4wWe4nkAyAtxYwNPGzSRGnhkUhsOHBwDogkXgvIlgaStID8cuaYhLFhM7F+AYaY4YOKmjo5efbmh4+J0oIAzKQpHwWjYBSMglGADwAAq9IzT6IbqSQAAAAASUVORK5CYII=","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Litao","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2025-08-27 04:08:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7467575/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7467575/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12957-026-04276-9","type":"published","date":"2026-03-04T15:57:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91198496,"identity":"46e22129-09d5-4e79-b0b7-69e8006831ec","added_by":"auto","created_at":"2025-09-12 15:15:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":158813,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDocument selection flow chart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/805e1b416f318843ddc03a61.png"},{"id":91198495,"identity":"288c9a9c-decf-44c3-a328-b8d83b86e82e","added_by":"auto","created_at":"2025-09-12 15:15:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":25114,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRandomized controlled intervention bias analysis based on ROB 2.0\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/dbbbc2e32bf114806f2aec67.png"},{"id":91201465,"identity":"ccfe9607-1a70-4f72-ad3d-2c935318d0a4","added_by":"auto","created_at":"2025-09-12 15:39:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":98807,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIncidence of Serious AE with Grade ≥ 3\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/7634a718ec33127524ad5f5d.png"},{"id":91198497,"identity":"5c9d61e4-5740-4d63-a586-e71d906e280d","added_by":"auto","created_at":"2025-09-12 15:15:28","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":63692,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInfection Incidence\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/e67de6d5c53a7ca633723922.png"},{"id":91198501,"identity":"9adab63f-7953-4efb-a0ed-4696d6f15abe","added_by":"auto","created_at":"2025-09-12 15:15:28","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67664,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIncidence of Massive Intestinal Bleeding\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/78055110624fffeb64f44fbf.png"},{"id":91199901,"identity":"07e0ae5b-2216-460a-8a66-e2d239aefcf4","added_by":"auto","created_at":"2025-09-12 15:23:28","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":66195,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRate of Anastomotic Leakage\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/3b10c40795b33335128045d3.png"},{"id":91198503,"identity":"3c68330e-838d-40a5-99d2-f632609c73c5","added_by":"auto","created_at":"2025-09-12 15:15:28","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":30604,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSensitivity Analysis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/d926dbccae68dc25ed8d6846.png"},{"id":91199898,"identity":"fa706ece-61b4-4198-8c30-e9f17c84d319","added_by":"auto","created_at":"2025-09-12 15:23:28","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":11994,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel Plot of Outcome Measures\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image8.png","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/11a58fb1dd15e22b9bc2f7c7.png"},{"id":104250892,"identity":"20e8b420-c32b-4dc9-9173-052e38629eeb","added_by":"auto","created_at":"2026-03-09 16:11:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1449143,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7467575/v1/e2e5d120-248f-48e0-8c90-d45b99409ff3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety analysis of intraperitoneal hyperthermic chemotherapy in the treatment of gastrointestinal cancer: a systematic review and meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastrointestinal malignant tumors, especially gastric cancer, occupy a dominant position in digestive system tumors. Their morbidity and mortality are high and increasing year by year. According to data from the World Health Organization\u0026rsquo;s International Agency for Research on Cancer (IARC) in 2022, there are approximately 1.926\u0026nbsp;million new cases of colorectal cancer (CRC) and 904 thousands deaths around the world. The morbidity and mortality rates rank third and second in global cancers, respectively. New gastric cancer(GC) cases exceed 968 thousands and the total number of deaths is close to 660 thousands. The morbidity and mortality rates of GC rank fifth and fourth globally, respectively\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Peritoneal metastasis (PM) is one of the main causes of death in patients with gastrointestinal malignant tumors. About 10\u0026ndash;30% of GC patients have peritoneal metastasis at the initial diagnosis, and more than 50% of patients with stage II\u0026thinsp;~\u0026thinsp;III gastric cancer will develop PM, the prognosis of which is extremely poor, within 5 years after radical gastrectomy\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. PM ranks third among CRC metastases. The peritoneal dissemination rate reaches 10% ~ 15% at initial diagnosis, and about 20% ~ 25% of patients have heterogeneous peritoneal metastasis after radical resection\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Because the plasma-peritoneal barrier prevents most chemotherapeutic drugs from penetrating the peritoneum, or the drugs cannot maintain effective therapeutic concentrations in the abdominal cavity, systemic chemotherapy has a poor response in PM patients\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Hyperthermic intraperitoneal chemotherapy (HIPEC) improves the curative effect through the dual effects of hyperthermia combined with chemotherapy drugs, and prolongs the survival time and improves the of patients\u0026rsquo; quality of life\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Although HIPEC has shown positive effects in the treatment of peritoneal malignancies, studies have pointed out that its postoperative complication rate and mortality rate are within acceptable ranges. A study published in Annals of Surgical Oncology showed that HIPEC significantly improved the survival rate of patients with peritoneal metastases of gastric cancer, whose three-year survival rate was about 55%, and most patients received treatment without complications. Meta-analysis was used in this study to evaluate the safety of HIPEC in treating gastrointestinal malignancies, which provided evidence-based evidence on anti-tumor therapy of gastrointestinal malignant tumors with PM and its complications.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e1.1 Database and Retrieval Strategy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study mainly searched English databases, including PubMed, Embase, WOS, Elsevier, ScienceDirect and Springer, and used a free combination of keywords to construct the search strategy. At the same time, the related content of Google Scholar was also searched simultaneously. In order to maintain the linguistic consistency of research data and results and facilitate international communication and publication, an English database was preferred for the search in this study. Literature in Literature from English databases is generally of high quality, and full texts are more readily accessible, which facilitates detailed data extraction and analysis. This study aims to evaluate the application safety of HIPEC worldwide, and the English database has been able to cover most related studies. If the Chinese database is decided to be supplemented in the follow-up research, it will include CNKI, Wanfang Data and VIP, etc., to more comprehensively evaluate the application of HIPEC in the Chinese population. The retrieval strategy will be appropriately adjusted according to the characteristics of the Chinese database.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.2 Literature Inclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Study type: Literature included in this review was all randomized controlled trials (RCTs), and the language was not limited; 2. Research objects: All included study subjects were patients diagnosed with advanced gastrointestinal malignancies with peritoneal metastases (PM), regardless of histological classification of cancer; 3. Test group: Patients treated with hyperthermic intraperitoneal chemotherapy (HIPEC group); 4. Control group: Patients not treated with HIPEC (non-HIPEC group); 5. Outcome measures: Studies must contain relevant data on the incidence of adverse reactions (or complications).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3 Literature Exclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Patients without gastric cancer and colorectal cancer were excluded; 2. The literature that did not use hyperthermic intraperitoneal chemotherapy (HIPEC) was not included; 3. The following types of studies were excluded: Non-randomized controlled trials, case analyses, review articles, protocols and pilot studies; Single-arm clinical trials, as well as multi-arm trials lacking a control group, were also excluded. 4. If the research results indicators were incomplete, the data could not be obtained, or the data could not be converted, the research would not be taken into consideration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.4 Screening of Literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter a literature search, duplicate documents were excluded by software, and two researchers read the title and abstract, screened according to the inclusion and exclusion criteria, and obtained the full text of the remaining documents. If the original text cannot be obtained from the Internet, they contacted the original author and read the full text of the literature for further screening.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.5 Outcome Measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome measures were:\u0026nbsp;1. The incidence of serious adverse reactions is defined as the number of patients/total cases of\u0026nbsp;all Grade 3-5 adverse reactions occurring during treatment\u003csup\u003e[7]\u003c/sup\u003e. 2. The incidence of adverse reactions, including infection, anastomotic leakage and massive gastrointestinal bleeding, is defined as the number of patients/total cases of all relevant\u0026nbsp;adverse reactions occurring during treatment. Secondary outcome measures included: The incidence of intestinal obstruction (about 5 in 1,000), gastrointestinal adverse reactions (nausea, vomiting\u0026nbsp;and\u0026nbsp;diarrhea), pneumonia, and the incidence of neutropenia (about 10% in children and adolescents and more than 50% in adults).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.6 Evaluation of Literature Quality and Assessment of Risk of Bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCochrane risk of bias V2.0 provided by Cochrane Collaboration was used to assess the risk of bias of the included studies, which included five levels, and each level was given risk assessment using \u0026quot;low\u0026quot;, \u0026quot;some concern of risk\u0026quot; and \u0026quot;high\u0026quot;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.7 Data\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eR\u003c/strong\u003e\u003cstrong\u003eetrieval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo researchers independently retrieved literature data from each database, covering literature author, publication date, grouping strategy, sample size of each group, patient age, gender composition, trial protocol, treatment duration, follow-up period, outcome measures and specific data. After completing the data retrieval, the two researchers cross-checked and discussed the different items in depth, managed the included literature and extracted the data using Excel, and finally reached a consensus to determine the data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.8\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eStatistical Methods:\u003c/strong\u003e (1) Discrete variables used the risk ratio (RR) and its 95% confidence interval (CI) to report the effect size. The calculation of the confidence interval is based on the statistical analysis of a large number of sample data. By comparing the incidence of an event between the experimental group and the control group to evaluate the correlation strength between factors and events.\u0026nbsp;(2) Forest diagram was used to visually show the comparison between different statistics; (3)\u0026nbsp;I\u003csup\u003e2\u003c/sup\u003e statistical analysis and Q test were used to evaluate the heterogeneity among literature, when\u0026nbsp;I\u003csup\u003e2\u003c/sup\u003e\u0026gt;50% or P\u0026lt;0.1, the results were considered to be significantly different; (4) If there was no heterogeneity, the fixed effects model (Mantel-Haenszel) was used for calculation; If heterogeneity existed, it was calculated using the Dersimonian-Laird method. (5) Sensitivity analysis was used to detect the literature with the greatest impact on effect size; (6) Publication bias was detected using Egger\u0026apos;s test and Begger\u0026apos;s test and showed using a funnel diagram. (7) In this study, R4.4.2 software was used to perform a Meta-analysis on the literature data that met the requirements. The code implementation details were shown in Figure 1.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Results of Literature Screening\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the literature screening process. The initial search results contained 444 documents. After de-duplication and rigorous screening, 10 randomized controlled trial (RCT) articles were finally included in quantitative analysis, involving 1060 patients participating in the study, where 540 patients were in the experimental group and 520 patients were in the control group. Of the 10 RCT articles included, 7 were studied for patients with gastric cancer, while 3 were studied for patients with bowel cancer. Detailed basic characteristics, trial measures, and outcome measures of all literature were presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBasic characteristics, trial measures, and outcome measures included in the literature\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eResearchers\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eYear\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDiseases\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eNumber of cases\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eTest measures\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eOutcome measures\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTest group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTest group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRau B\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e①②③④⑤\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYang XJ\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e②③④⑤\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQu\u0026eacute;net F\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eColorectal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e132\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e133\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e①\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVerwaal VJ\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eColorectal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC/ HIPEC\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSystemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e③⑧\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYu P\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e①\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiu L\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e①⑥⑦\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFan B\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e④\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHuang O\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e①②④⑤⑥⑧\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBeeharry MK\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e①②③④⑤⑦\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaratti D\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eColorectal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;HIPEC\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCRS\u0026thinsp;+\u0026thinsp;Systemic therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e①\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOutcome measures: ① Incidence of serious AE at Grade\u0026thinsp;\u0026ge;\u0026thinsp;3; ② Incidence of infection and sepsis; ③ Incidence of massive intestinal bleeding; ④ Incidence of anastomotic leakage; ⑤ Incidence of intestinal obstruction; ⑥ Incidence of gastrointestinal adverse reactions; ⑦ Neutropenia; ⑧ Pneumonia.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Literature Quality and Bias Assessment\u003c/h2\u003e\u003cp\u003eIn this study, Cochrane risk of bias (ROB 2.0) was used to evaluate the quality of 10 included randomized controlled trials (RCTs). Overall, random sequence generation and concealed allocation of the included literature were relatively standardized, but some literature has a potential risk of bias in the process of blinded implementation and randomization\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, as follows. Literature where blinding was not strictly followed: Rau B (2024) conducted a multicenter randomized controlled open-label study that did not strictly follow the principle of blinding and might have a risk of intervention-related bias\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e; The study by Beeharry MK (2019) did not explicitly describe blinding application, and there was a potential risk of bias. Literature may be biased in randomization \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. In the study of Baratti D (2020), when describing the sample randomization process, the specific implementation steps of the randomization method were not specified in detail, and there may be bias in randomization process. The remaining included literature (such as Yang XJ 2011, Qu\u0026eacute;net F 2021, et al.) elaborated on the implementation of the random sequence generation, concealed allocation, and blinding, and recorded the dropped cases in detail. No obvious selective reporting bias or other bias problems were found, and the overall study quality was high.\u003c/p\u003e\u003cp\u003eA randomized controlled intervention bias analysis based on ROB 2.0 showed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) that the included literature had a low risk of bias in random sequence generation and assignment concealment, but there was a moderate risk during blinded implementation and randomization of several studies. It is recommended that future studies further optimize the blinded design and clarify the specific implementation details of the randomization method to reduce the risk of bias.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Results of Meta-analysis\u003c/h2\u003e\u003cp\u003e\u003cb\u003e2.3.1 Incidence of Serious AE with Grade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/b\u003e: Although all 8 articles reported the incidence of serious adverse reactions between the test group and the control group in the treatment trial, the results showed no statistical difference between the articles (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;42%, P\u0026thinsp;=\u0026thinsp;0.10). There was no significant difference in the incidence of adverse reactions between HIPEC and non-HIPEC after comprehensive analysis using the fixed effects model (RR\u0026thinsp;=\u0026thinsp;1.205, 95% CI: 0.936 to 1.553, Z\u0026thinsp;=\u0026thinsp;1.44, P\u0026thinsp;=\u0026thinsp;0.15). However, this contradicts some research results. For example, in a study from 12 HIPEC collaborating centers in the United States, the complication rate of the HIPEC treatment group was almost twice that of the non-HIPEC group. Detailed results were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.3.2 Infection Incidence\u003c/b\u003e: All three studies reported the incidence of infection-related adverse reactions during treatment between the test group and the control group, and did not show a statistical difference among studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, P\u0026thinsp;=\u0026thinsp;0.44). Integrated analysis showed that compared with non-HIPEC, HIPEC had no significant difference in the incidence of infection-related adverse reactions (RR\u0026thinsp;=\u0026thinsp;1.800, 95% CI (0.391, 8.283), Z\u0026thinsp;=\u0026thinsp;0.75, P\u0026thinsp;=\u0026thinsp;0.45), which is consistent with the consensus of gynecologic oncology experts and the progress of clinical practice. The detailed results were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.3. 3 Incidence of Massive Gastrointestinal Bleeding\u003c/b\u003e: During the treatment process, the investigator paid special attention to the incidence of massive gastrointestinal bleeding in patients in the experimental group and control group, in view of the possible gastrointestinal adverse reactions and the severity of massive upper gastrointestinal bleeding caused by the drug. According to the three reports, there was no statistical difference among these studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, P\u0026thinsp;=\u0026thinsp;0.53), and after comprehensive analysis of fixed-effect patterns, it was found that there was no significant difference in the incidence of adverse reactions related to massive gastrointestinal bleeding between HIPEC and non-HIPEC treatment regimens (RR\u0026thinsp;=\u0026thinsp;1.486, 95% CI (0.524, 4.211), Z\u0026thinsp;=\u0026thinsp;0.75, P\u0026thinsp;=\u0026thinsp;0.46). The detailed results were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Massive gastrointestinal bleeding was a serious symptom, which may be caused by a variety of gastrointestinal diseases, such as peptic ulcer, ruptured esophageal varices and gastrointestinal tumors, etc. Its clinical manifestations included hematemesis, melena, abdominal pain, dizziness, fatigue, palpitations, etc.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.3.4 Incidence of Anastomotic Leakage\u003c/b\u003e: All three studies reported the incidence of adverse reactions related to anastomotic leakage during treatment between the test group and the control group, and no statistical difference between studies was found(I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, P\u0026thinsp;=\u0026thinsp;0.51). According to the integrated analysis of fixed effects model, compared with non-HIPEC, HIPEC showed unique advantages in preventing and treating peritoneal implant metastasis, although it showed a higher trend in the incidence of adverse reactions related to anastomotic leakage, the result was not statistically significant (RR\u0026thinsp;=\u0026thinsp;0.861, 95% CI (0.214, 3.459), Z\u0026thinsp;=\u0026thinsp;0.21, P\u0026thinsp;=\u0026thinsp;0.83). HIPEC is an effective treatment method, especially in the treatment of middle and advanced abdominal tumors. It can effectively prevent and treat peritoneal implant metastasis and complicated malignant ascites by injecting heated chemotherapeutic drugs into the abdominal cavity for anti-tumor treatment. Detailed results were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.3.5 Other Complication Rates\u003c/b\u003e: After a meta-comprehensive analysis of several common adverse reactions, we found that the incidence of specific complications can be significantly reduced by comparing different treatment methods. The specific data and analysis results were detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMeta-analysis Results of Rate of Other Complications (Test group vs.Control group)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFactors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of literature\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAnalysis mode\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI\u003csup\u003e2\u003c/sup\u003eC with P value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEffect size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePooling value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eZ.P Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntestinal obstruction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFixed Effect Mode\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0% with 0.5392\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.6921 [0.1115; 4.2953]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e-0.4, 0.6928\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal adverse reactions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFixed Effect Mode\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0% with 0.572\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.1487 [0.9516; 1.3866]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.4, 0.1489\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFixed Effect Mode\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0% with 0.762\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.8000 [0.3904; 8.2998]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.7, 0.4510\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutropenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFixed Effect Mode\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0% with 0.774\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.0848 [0.7633; 1.5418]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.4, 0.6498\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.3.6 Sensitivity Analysis\u003c/b\u003e: Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e shows the results of the sensitivity analysis. After the included documents were eliminated one by one by the \"de-one method\", the combined effect size was recalculated. The significance of the combined effect size was to evaluate whether the combined effect of the remaining literature changed significantly after the exclusion of a specific literature. It can be seen from the figure that no matter which literature was excluded, the combined effect size remained relatively stable, indicating that the results of this study had good robustness and were not significantly affected by a single literature. =\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\u003ch2\u003e2.3.7 Publication Bias Analysis:\u003c/h2\u003e\u003cp\u003eThis study evaluated the publication bias of included literature by funnel plot visualization (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e) combined with Egger's test and Begg's test.\u003c/p\u003e\u003cp\u003eThe results of the Egger test: t\u0026thinsp;=\u0026thinsp;0.82, p\u0026thinsp;=\u0026thinsp;0.43 (\u0026gt;\u0026thinsp;0.1) suggested that there was no significant asymmetry in the distribution of effect size in small sample studies; the results of the Begg test: z\u0026thinsp;=\u0026thinsp;0.95, p\u0026thinsp;=\u0026thinsp;0.34 (\u0026gt;\u0026thinsp;0.1) further supported the conclusion of no publication bias. Funnel graph visualization analysis: showed the funnel plot as a whole presented a symmetrical distribution (Fig.\u0026nbsp;9), which was consistent with the statistical test results; Subgroup analysis on early studies (sample size\u0026thinsp;\u0026lt;\u0026thinsp;50 cases) showed a slight scatter deviation at the bottom of the funnel plot without statistical significance (Egger's test p\u0026thinsp;=\u0026thinsp;0.21), which might be due to random error or inter-study difference rather than systematic publication bias. Based on the double validation of quantitative test (Egger/Begg) and qualitative visualization (funnel plot), this study believed that there was no significant publication bias in the included literature; Scatter deviation of early studies should be interpreted carefully, and it is suggested that future studies should expand the sample size for further verification.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOnce peritoneal metastasis occurs in gastrointestinal malignant tumors, it is recognized as an end-stage tumor, with an extremely poor prognosis and limited treatment methods\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. At present, for early peritoneal metastases with small or limited metastatic lesions, postoperative adjuvant chemotherapy is usually the main treatment. For patients with diffuse peritoneal metastases, palliative chemotherapy or symptomatic treatment is usually the main treatment to reduce the tumor burden\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. The conventional chemotherapy route is not effective for peritoneal malignancies due to the presence of the plasma-peritoneal barrier, which limits the penetration of drugs from the systemic circulation into the peritoneum and into the abdominal cavity\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Fujimoto et al.\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003efor the first time used HIPEC technology to treat gastrointestinal malignant tumors with PM in 1988. They directly infused the drugs into the patient\u0026rsquo;s abdominal cavity, thus significantly increasing the local concentration of the drug in the abdominal cavity and effectively reducing the toxic reaction caused by systemic chemotherapy. At present, HIPEC has become an important research hotspot in the treatment of peritoneal metastatic cancer. However, since HIPEC is an invasive procedure and involves the toxicity of chemotherapeutic drugs, complications inevitably occur during clinical treatment. To further explore the safety of HIPEC in the treatment of gastrointestinal cancer with peritoneal metastasis, this study collected the data of 10 international articles with randomized controlled trials (RCTs) on HIPEC, and used Meta-analysis to comprehensively analyze the postoperative adverse reactions (including incidence of grade 3 or above serious adverse events, gastrointestinal adverse reactions, pneumonia and neutropenia) and postoperative complications (including infection and sepsis, gastrointestinal hemorrhage, anastomotic leakage, and intestinal obstruction) in two groups. The results showed that compared with simple surgery, HIPEC combined surgery can significantly improve the survival rate of patients with peritoneal metastases of gastric cancer from 12\u0026ndash;35%, while reducing the recurrence rate, showing higher safety.\u003c/p\u003e\u003cp\u003eThrough a Meta-study, it was found that the incidence of adverse reactions related to anastomotic leakage in the HIPEC group was higher than that in the non-HIPEC group, but the results were not statistically significant. Pramateftakis et al.\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e have found that HIPEC immediately after intestinal surgery delays the healing time of colonic anastomosis in rats, resulting in an increased risk of anastomotic leakage, especially in the case of co-perfusion with 5-fluorouracil and irinotecan. Zhang et al.\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e found through research that although no anastomotic leakage was found in the animals in the experimental group and the control group, the degree of anastomotic inflammatory cell infiltration in the experimental group was significantly higher than that in the control group. There are many factors leading to anastomotic leakage, including excessive anastomotic tension during operation, poor nutritional status, insufficient blood supply to local tissues, excessive obesity, history of hypertension, history of diabetes, and stimulation of chemotherapy drugs to anastomotic leakage\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. In clinical operation, the following protective measures should be taken in advance: First, fully isolate the tissues during the operation to reduce the anastomotic tension; Second, ensure sufficient blood supply for local tissues; Third, actively implement nutritional support; Fourth, thoroughly flush the surgical area after surgery.\u003c/p\u003e\u003cp\u003eThis study found that the HIPEC group did not increase the incidence of infection and pneumonia compared with the non-HIPEC group. The results showed that the risk of infection within 7 days after CRS\u0026thinsp;+\u0026thinsp;HIPEC was 43%, mainly surgical site infection, pneumonia and catheter-related infection. The incidence of infection was positively correlated with the number of organ resections \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. A multicenter randomized controlled trial showed that during the treatment for patients in the HIPEC group, a large amount of perfusate was injected into the abdominal cavity, resulting in diaphragm elevation, thoracic dilation, carbon dioxide accumulation, and decreased lung compliance. At the same time, due to the stimulation of chemotherapeutic drugs, reactive pleural effusion can be generated. All of the above factors will increase the risk of postoperative pneumonia\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. During high-dose HIPEC, the risk factors for infection and pneumonia cover multiple dimensions, such as long catheter indwelling time, excessive number of drainage tubes, excessive perfusate temperature, local skin lesions caused by chemotherapeutic drugs, insufficient awareness of aseptic procedures during surgical procedures, poor nutritional status of patients, and coexistence with respiratory diseases. For example, studies of ventilator-associated pneumonia in ICU patients have shown that factors such as age, gender, time of admission, and presence or absence of pathogen infection are independent risk factors. Although HIPEC itself does not directly increase the incidence of infection and pneumonia, it is an invasive operation. It is necessary to carefully evaluate the patient's condition in clinical practice, strictly implement aseptic operating procedures, take nursing interventions in time, and apply targeted treatment when necessary.\u003c/p\u003e\u003cp\u003eMeta-analysis revealed that the risk of gastrointestinal bleeding and intestinal obstruction was not increased significantly in patients receiving HIPEC; In actual clinical practice, there are still relevant case reports. In clinical studies, the causes of intestinal obstruction related to HIPEC can be attributed to two categories: individual factors of patients and operative factors. A study has pointed out that patients with a history of circulatory system diseases, gastrointestinal surgery, high-grade tumor pathological stage, high PCI (intraperitoneal chemotherapy index), and malnutrition have a significantly higher risk of intestinal obstruction\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Inflammatory reaction is mainly caused by unstable temperature of the perfusate and surface damage of the intestinal tube, which can promote the occurrence of intestinal obstruction\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. This study showed that the HIPEC group did not lead to an increase in the incidence of major gastrointestinal bleeding, and it may also be related to the small sample of patients enrolled. Ba et al.\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e carried out a retrospective analysis, and the results showed that HIPEC alone did not significantly increase the risk of postoperative bleeding in patients. Among the 1200 treated patients, the incidence of bleeding events was extremely low, only 0.7%, which fully demonstrated the relatively low risk of postoperative bleeding. In clinical practice, we should be highly cautious about postoperative complications in patients with a high risk of gastrointestinal malignant tumors and peritoneal metastases. It is recommended to perform postoperative abdominal plain CT review in time and closely monitor the postoperative symptoms of patients.\u003c/p\u003e\u003cp\u003eThis study found that there was no significant difference in gastrointestinal adverse reactions between the HIPEC group and the non-HIPEC group. HIPEC can stimulate the gastrointestinal wall, lead to gastrointestinal edema, reduce gastrointestinal peristalsis function and secretion and absorption dysfunction\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. The results of the study showed no significant difference in gastrointestinal adverse reactions, which may be related to the following factors: The higher heterogeneity of some indicators in the literature, the differences in investigators\u0026rsquo; subjective judgments, as well as the induced effect from deliberately asking patients about specific symptoms, can all lead to research bias. In addition, the adverse gastrointestinal reactions of patients after surgery may be closely related to the recovery stage of gastrointestinal function. Considering that all patients included in the study have gastrointestinal malignancies with peritoneal metastases, which inherently have a high risk of gastrointestinal adverse reactions, the statistical results may be subject to some degree of bias. This study revealed that there was no significant difference in the incidence of serious adverse events (AE, Grade\u0026thinsp;\u0026ge;\u0026thinsp;3) and neutropenia in the patient population receiving HIPEC. This phenomenon may be related to the pharmacokinetic properties of HIPEC. Due to the existence of the plasma-peritoneal barrier, chemotherapeutic drugs can maintain high concentrations in the abdominal cavity and reduce the amount of drugs entering the systemic circulation, which helps to control peritoneal metastasis (PM) while reducing the toxicity and side effects caused by systemic chemotherapy.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study evaluated the safety of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of gastrointestinal cancer with peritoneal metastases through a systematic review and Meta-analysis. The 10 randomized controlled trials (RCTs) included showed that HIPEC does not significantly increase the incidence of postoperative serious adverse events with Grade\u0026thinsp;\u0026ge;\u0026thinsp;3, intestinal obstruction, gastrointestinal bleeding, infection, gastrointestinal adverse reactions, pneumonia and neutropenia. Although the test group is slightly higher than the control group in the incidence of anastomotic leak-related adverse reactions, the difference is not statistically significant (RR\u0026thinsp;=\u0026thinsp;0.861, 95% CI 0.214\u0026ndash;3.459, P\u0026thinsp;=\u0026thinsp;0.83). These results indicate that HIPEC has a good safety profile in the treatment of gastrointestinal malignant tumors with peritoneal metastasis, but its specific efficacy in improving the long-term survival rate and prolonging the survival of patients still needs to be further verified by more high-quality and large-scale clinical trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical approval\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eDeclaration of Competing Interest\u003c/h2\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eConceptualization: Yingrong Zhao,Yingxuan Zhang.Data curation:Yingrong Zhao,Weiyu Chen.Formal analysis: Yingrong Zhao,Yingxuan Zhang.Investigation: Yingrong Zhao,Weiyu Chen.Methodology: Yingrong Zhao,Weiyu Chen,,Yingxuan Zhang.Software: Yingrong ZhaoWriting - original draft: Yingrong ZhaoWriting -review \u0026amp; editing: Litao Xu\u003c/p\u003e\n\u003ch2\u003eData availability\u003c/h2\u003e\n\u003cp\u003eThe dataset that that support the findings in this study is available fromthe corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\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\u0026ndash;63. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3322/caac.21834\u003c/span\u003e\u003cspan address=\"10.3322/caac.21834\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLei Z, Wang J, Li Z, et al. Hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A multicenter propensity score-matched cohort study. Chin J Cancer Res. 2020;32(6):794\u0026ndash;803.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHompes D, Tiek J, Wolthuis A, et al. HIPEC in T4a colon cancer: a defendable treatment to improve oncologic outcome? Ann Oncol. 2012;23(12):3123\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan Gestel YR, Thomassen I, Lemmens VE, et al. Metachronous peritoneal carcinomatosis after curative treatment of colorectal cancer. Eur J Surg Oncol. 2014;40(8):963\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKuramoto M, Shimada S, Ikeshima S, et al. A proposal of a practical and optimal prophylactic strategy for peritoneal recurrence. J Oncol. 2012;2012:340380.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVos LMC, Aronson SL, van Driel WJ, et al. Translational and pharmacological principles of hyperthermic intraperitoneal chemotherapy for ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2022;78:86\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNo author listed. Criteria for acute and subacute toxicity reactions of anticancer drugs (WHO standards)] [J]. (Chinese J Cancer), 1992, (03): 254.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRau B, Lang H, Koenigsrainer A, et al. Effect of Hyperthermic Intraperitoneal Chemotherapy on Cytoreductive Surgery in Gastric Cancer With Synchronous Peritoneal Metastases: The Phase III GASTRIPEC-I Trial. J Clin Oncol. 2024;42(2):146\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011;18(6):1575\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eQu\u0026eacute;net F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):256\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVerwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21(20):3737\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYu P, Huang X, Huang L, et al. Hyperthermic intraperitoneal chemotherapy (HIPEC) plus systemic chemotherapy versus systemic chemotherapy alone in locally advanced gastric cancer after D2 radical resection: a randomized-controlled study. J Cancer Res Clin Oncol. 2023;149(13):11491\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu L, Sun L, Zhang N, et al. A novel method of bedside hyperthermic intraperitoneal chemotherapy as adjuvant therapy for stage-III gastric cancer. Int J Hyperth. 2022;39(1):239\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFan B, Bu Z, Zhang J, et al. Phase II trial of prophylactic hyperthermic intraperitoneal chemotherapy in patients with locally advanced gastric cancer after curative surgery. BMC Cancer. 2021;21(1):216. Published 2021 Mar 2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang O, Lu X, Xu X, Shi Y. Fibrin-sealant-delivered cisplatin chemotherapy versus cisplatin hyperthermic intraperitoneal perfusion chemotherapy for locally advanced gastric cancer without peritoneal metastases: a randomized phase-II clinical trial with a 40-month follow-up. Cell Biochem Biophys. 2015;71(2):1171\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\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 [published correction appears in BMC Cancer. 2019;19(1):1256. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12885-019-6411-9.]\u003c/span\u003e\u003cspan address=\"10.1186/s12885-019-6411-9.]\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. BMC Cancer. 2019;19(1):932. Published 2019 Sep 18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaratti D, Kusamura S, Azmi N, Guaglio M, Montenovo M, Deraco M. Colorectal Peritoneal Metastases Treated by Perioperative Systemic Chemotherapy and Cytoreductive Surgery With or Without Mitomycin C-Based HIPEC: A Comparative Study Using the Peritoneal Surface Disease Severity Score (PSDSS). Ann Surg Oncol. 2020;27(1):98\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCui SZ, Lei ZY, Zhongguo Zhongliu Zhenghe Zhenzhi Zhinan. : Fumo Zhongliu (Weichang Zhongliu Bufen) [Chinese Integrative Guidelines for Diagnosis and Treatment of Tumors: Peritoneal Tumors (Gastrointestinal Tumors Section)] [J]. Xiahua Zhongliu Zazhi (Dianziban) [Journal of Digestive Oncology (Electronic Edition)], 2023, 15(02): 100\u0026ndash;108.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTang HS, Ruan Q, Cui SZ. Interpretation of Chinese Integrative Guidelines for Diagnosis and Treatment of Tumors: Peritoneal Tumors [J]. J Dig Oncol (Electronic Edition). 2023;15(02):109\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFujimoto S, Shrestha RD, Kokubun M, et al. Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding. Ann Surg. 1988;208(1):36\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePramateftakis MG, Kanellos D, Mantzoros I, et al. Intraperitoneally administered irinotecan with 5-fluorouracil impair wound healing of colonic anastomoses in a rat model: an experimental study. Tech Coloproctol. 2011;15(Suppl 1):S121\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang JY, Ni L, Cao YJ, et al. Experimental study on the effect of intraoperative hypotonic hyperthermic intraperitoneal perfusion chemotherapy on healing of gastrointestinal anastomosis [J]. Mod Oncol. 2013;21(05):1002\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXu JP, Ma J, Wang H. Risk factor analysis and prevention of anastomotic leakage after colorectal cancer surgery [J]. Chin J Colorectal Dis (Electronic Edition). 2021;10(01):99\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSmibert OC, Slavin MA, Teh B, et al. Epidemiology and risks for infection following cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy. Support Care Cancer. 2020;28(6):2745\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu PF, Li TZ, Zhao BJ, et al. Effects of positive end-expiratory pressure on respiratory mechanics and pulmonary function in patients undergoing hyperthermic intraperitoneal perfusion chemotherapy [J]. J Clin Anesthesiology. 2017;33(03):231\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee TC, Wima K, Sussman JJ, et al. Readmissions After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: a US HIPEC Collaborative Study. J Gastrointest Surg. 2020;24(1):165\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYe J, Chen L, Zuo J, et al. A precise temperature control during hyperthermic intraperitoneal chemotherapy promises an early return of bowel function. Cancer Biol Ther. 2020;21(8):726\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBa M, Cui S, Long H, et al. Safety and Effectiveness of High-Precision Hyperthermic Intraperitoneal Perfusion Chemotherapy in Peritoneal Carcinomatosis: A Real-World Study. Front Oncol. 2021;11:674915. Published 2021 Aug 6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGu XY, Gao ZQ, Zhang ZJ, et al. Effect of warm acupuncture and moxibustion on gastrointestinal reactions in patients receiving hyperthermic intraperitoneal perfusion chemotherapy after colon cancer surgery [J]. Acupunct Res. 2020;45(04):315\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\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":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Intraperitoneal hyperthermic perfusion chemotherapy Gastric malignant tumors, colorectal malignant tumors, peritoneal metastatic malignant tumors, complications","lastPublishedDoi":"10.21203/rs.3.rs-7467575/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7467575/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo evaluate the safety of intraperitoneal hyperthermic perfusion chemotherapy in the treatment of gastrointestinal cancer by meta-analysis method.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003ePubmed, Embase, WOS, Elsevier, ScienceDirect and springer were retrieved by computer. Patients with gastrointestinal malignancies accompanied by peritoneal metastasis were selected as the research subjects, and randomized controlled trials (RCTs) of intraperitoneal hyperthermic perfusion chemotherapy were retrieved. The search time range covers all records in major databases from their establishment to January 2025, and traces the relevant references. Two researchers independently screened the references, extracted the corresponding materials respectively, and managed and extracted the data of the included references using Excel. Data analysis of the included references that met the requirements was conducted using R4.4.2 software. According to the guiding principles of the Cochrane Collaboration, for continuous variables in systematic reviews, weighted mean difference (MD) and its 95% confidence interval (CI) are usually used as effect indicators, while for binary variables, odds ratio (OR) is adopted, and 95% CI is used as the effect indicator. The heterogeneity of the included literature was determined through I2 analysis and Q verification. When P\u0026thinsp;\u0026ge;\u0026thinsp;0.1 and I2\u0026thinsp;\u0026le;\u0026thinsp;50%, the fixed-effect model was adopted. When P\u0026thinsp;\u0026lt;\u0026thinsp;0.1 or I2\u0026thinsp;\u0026gt;\u0026thinsp;50%, the random effects model is adopted. The outcome observation indicators were: the incidence of severe adverse reactions, infection, anastomotic leakage, massive hemorrhage, intestinal obstruction, digestive tract adverse reactions (nausea, vomiting, diarrhea), pneumonia, neutropenia, etc.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 10 RCTs were included, with a total of 1060 patients participating in this study. The number of patients in the experimental group was 540, and the number of patients in the control group was 520. According to the results of the meta-analysis, compared with the control group, after the implementation of HIPEC (hyperthermic intraperitoneal chemotherapy), the incidence of serious adverse events (AE) with Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 after surgery, intestinal obstruction, massive gastrointestinal bleeding, infection, digestive tract adverse reactions, pneumonia, and neutropenia in the experimental group did not show statistically significant differences. The incidence of adverse reactions related to anastomotic leakage in the experimental group was higher than that in the control group, but the result was not statistically significant (RR\u0026thinsp;=\u0026thinsp;0.861, 95%CI (0.214, 3.459), Z\u0026thinsp;=\u0026thinsp;0.21, P\u0026thinsp;=\u0026thinsp;0.83).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eHIPEC is safe and feasible for gastrointestinal malignancies with PM. The occurrence of postoperative adverse reactions and complications in patients does not increase significantly, and it has good safety. However, the specific efficacy of HIPEC still needs to be further evaluated. Whether it can increase the long-term survival rate of patients and prolong their survival period still requires multi-center, large-sample, and high-quality clinical studies to further demonstrate.\u003c/p\u003e","manuscriptTitle":"Safety analysis of intraperitoneal hyperthermic chemotherapy in the treatment of gastrointestinal cancer: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 15:15:23","doi":"10.21203/rs.3.rs-7467575/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-06T03:55:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-28T12:17:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-25T08:50:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"299744355650414189015299859943260463741","date":"2025-09-20T04:47:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77430319167474025106538526797301667563","date":"2025-09-18T06:33:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-12T17:55:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"280754156860313933313828932794930748769","date":"2025-09-07T17:53:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-07T15:02:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-06T15:17:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-28T07:53:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Surgical Oncology","date":"2025-08-27T03:56:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9b801066-7e69-4dbc-8d45-9107c92b0e41","owner":[],"postedDate":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-09T16:07:36+00:00","versionOfRecord":{"articleIdentity":"rs-7467575","link":"https://doi.org/10.1186/s12957-026-04276-9","journal":{"identity":"world-journal-of-surgical-oncology","isVorOnly":false,"title":"World Journal of Surgical Oncology"},"publishedOn":"2026-03-04 15:57:23","publishedOnDateReadable":"March 4th, 2026"},"versionCreatedAt":"2025-09-12 15:15:23","video":"","vorDoi":"10.1186/s12957-026-04276-9","vorDoiUrl":"https://doi.org/10.1186/s12957-026-04276-9","workflowStages":[]},"version":"v1","identity":"rs-7467575","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7467575","identity":"rs-7467575","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}