Is Prophylactic Hyperthermic Intraperitoneal Chemotherapy Benecial to The Long-Term Survival of Patients After Radical Gastric Cancer Surgery: A Systematic Review and Meta-analysis

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proven to improve the survival rate of gastric cancer and reduce peritoneal recurrence. We aimed to evaluate the effectiveness and safety of prophylactic HIPEC after radical gastric cancer surgery in this study. Methods: Researchers searched for studies published in PubMed, Embase, Web of science, Scopus, Cochrane, Clinicalkey databases and Microsoft Academic databases to identify studies that examine the impact of prophylactic HIPEC on the survival, recurrence and adverse events of patients undergoing radical gastric cancer surgery. RevMan 5.3 was used to analyze the results and risk of bias. The PROSERO registration number is CRD42021262016. Results: This meta-analysis included 19 studies with a total of 2097 patients, 12 of which are RCTs. The results showed that the 1-,3-and 5-year overall survival rate was signicantly favorable to HIPEC (OR=5.10,2.47,1.96 respectively). Compared with the control group, the overall recurrence rate and peritoneal recurrence rate of the HIPEC group were signicantly lower (OR=0.43,0.26 respectively). Signicantly favorable to the control group in terms of renal dysfunction and pulmonary dysfunction complications(OR=2.44,6.03 respectively). Regarding the causes of death due to postoperative recurrence: liver recurrence, lymph node and local recurrence and peritoneal recurrence, the overall effect is not signicantly different (OR=0.81,1.19,0.37 respectively). Conclusions: 1-,3-and 5-year overall survival follow-up can be incremented by the prophylactic HIPEC, and which can signicantly reduce the overall recurrence rate and peritoneal recurrence rate. HIPEC can cause signicant pulmonary dysfunction and renal dysfunction complications. No difference has been found in the deaths due to recurrence after surgery. abstract. The second stage is to screen the studies based on the topic, abstract and keywords. In this process, we use the Rating in EndNote X9 to rank the research. Two investigators marked the studies with “low relevance” as “one star”, “medium credibility” as “2-3 stars”, and “high as “4-5 star”. “The stars” determines the subsequent screening process. “One-star” research will be excluded at this stage, the “2-3 stars” needs to be re-evaluated by all investigators (X.H.Z Y.W.H W.H.M), and the “4-5 stars” can be included in the full text review. The third stage is the full-text review of the included studies. Two researchers excluded the studies of different from inclusion criteria, fail to obtain and protocol. We use Modied methodological subgroup of advanced gastric cancer without peritoneal metastasis, the preventive HIPEC group had 3 years (RR=0.71, 95%CI=0.53-0.96) and 5 years (RR=0.82), 95%CI=0.70-0.96) overall survival rate is better than the control group, but there is no difference in one-year overall survival rate (RR=0.55, 95%CI=0.23-1.30). Chia[47] et al. believe that this is because Desidrio and his colleagues did not evaluate tumor histology grades and chemotherapy regimens. Our study also reported the overall survival rate of patients at 1, 3, and 5 years after surgery. Consistent with our expected results, prophylactic HIPEC is benecial to the survival rate of patients with gastric cancer after radical gastrectomy. And we evaluated the gastric cancer histology grade and HIPEC protocol included in this review. We conducted a subgroup analysis of the overall survival rate at 3-years of patients with different chemotherapy regimens after surgery, and the results arm the role of prophylactic HIPEC in improving the survival rate of patients. Sun[48] et al.’s meta-analysis included ten RCTs and concluded that HIPEC may improve the overall survival rate of patients, but it included four low-quality studies (score < 4). no signicant in of the 141 patients in the HIPEC group and the control group had myelosuppression. literatures to evaluate the occurrence of postoperative myelosuppression, and the results were also without signicantly difference. HIPEC's drugs infused into the patient's abdominal cavity, is different from the conventional intravenous infusion of systemic the leakage results leakage HIPEC group the control group meta-analysis postoperative anastomotic leakage intestinal obstruction signicantly of the organ patients HIPEC. et al.’s out of liver


Introduction
Gastric cancer (GC) is not only one of the most common malignant tumors in the world, but also the malignant tumor with the second highest mortality rate among all kinds of tumors [1,2] . More than 70% of GC occur in developing countries, and more than 50% of cases occur in East Asia [3] .
Liu [4] et al. pointed out in a study published in 2020 that China's annual morbidity and mortality of GC are twice the world average. At present, surgical resection is the only possible cure for gastric cancer [5] , however, the 5-year survival rate is still not satisfactory. Recurrence after GC treatment surgery is quite common, about 10%-46% will have peritoneal recurrence after surgery [6,7] . Peritoneal dissemination is one of the main reasons for gastric cancer recurrence and metastasis in the abdominal cavity. And it will cause peritoneal cancer (PC), which is more complicated and harder to treat than GC.
Although some scholars have proposed in recent years that adjuvant chemotherapy and neoadjuvant chemotherapy can slightly improve the survival rate after radical gastric cancer surgery [7,8] , they have not shown to signi cantly reduce the distant metastasis rate. Despite the use of systemic chemotherapy and other methods, the survival rate of patients with advanced GC is still not ideal. It may be due to the existence of the "plasmaperitoneal barrier" [9,10] that can isolate the abdominal cavity from the effect of intravenous chemotherapy, which leads to the poor response of PC and advanced GC to systemic chemotherapy. Some evidence in the peritoneal dialysis literature indicates that the peritoneal permeability of some hydrophilic anticancer drugs may be much lower than the plasma clearance rate. Pharmacokinetic calculations indicate that the concentration of this intraperitoneal ingested drug is expected to be much higher in the abdominal space than in the plasma [11] . At the same time, hyperthermia has been developed as an anti-cancer therapy. It is one of the most widely studied chemotherapy and radiotherapy sensitizers [12,13] , and it has been proven that it has a direct cytotoxic effect on tumor cells in the abdominal cavity in combination with certain anti-cancer chemotherapy. Therefore, a new combination therapy has been introduced in recent years, namely hyperthermic intraperitoneal perfusion chemotherapy (HIPEC), which is considered to be an effective method to control the peritoneal dissemination of GC patients after the radical GC surgery [2,14,15] . Since HIPEC has been proven effective for PC, peritoneal pseudomyxoma and other diseases, it has been included in the national treatment standards of some EU countries. But the safety and effectiveness of prophylactic HIPEC in patients with advanced gastric cancer and patients after radical gastric cancer surgery is still a hot topic of debates.
Can prophylactic HIPEC really improve the long-term survival rate of patients with radical GC? Effectively control peritoneal transmission? These are still the questions we want to explore. Therefore, this systematic review and meta-analysis will use the results of RCTs and high-quality NRCTs to comprehensively evaluate the effectiveness and safety of prophylactic HIPEC for patients after radical GC surgery in terms of short-term or long-term survival rate (1-,3-and 5-years), recurrence rate, complications and deaths due to recurrence after surgery.

Search strategy
This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines, and we completed the PRISMA checklist according to the guidelines. Two investigators (X.H.Z, Y.W.H) searched for studies published in PubMed, Embase, Web of science, Scopus, Cochrane, and Clinicalkey databases from the inception to June 12, 2021. In addition, X.H.Z searched Microsoft Academic, and all search results are listed in PRISMA_2020_ ow_diagram (Fig. 1). The researcher sets the search conditions as topic keywords and abstracts. There are no language restrictions throughout the search process. The search terms are: (HIPEC OR CHPP OR chemotherapeutic hyperthermic intraperitoneal perfusion OR intraperitoneal hyperthermic perfusion chemotherapy OR Peritoneal thermal perfusion OR Hyperthermic intraperitoneal perfusion OR IHPC OR CCCHP OR Coelom Continued Circulatory Hyperthermia Perfusion OR intraperitoneal chemohyperthermia) AND (gastric carcinoma OR gastric cancer OR stomach cancer OR Carcinoma of stomach OR radical gastrectomy for cancer OR Laparoscopic radical gastrectomy OR radical gastrectomy OR Radical operation of gastric carcinoma OR radical extremital partial gastrectomy OR radical operation for carcinoma of stomach OR radical correction for stomach cancer). We will change the search formula for different databases. In order to avoid omissions, we choose the search formula with the most search results.

Study Selection
The study selection process is carried out in EndNote X9 (Thomson Reuters, NY, USA). The entire retrieval process is divided into three parts. First, X.H.Z saves the respective search results of the two investigators to EndNote X9 and nds duplicates. After deleting all duplicate studies, X.H.Z will exclude studies marked as ineligible by automation tools or other reasons that cannot enter the second stage of screening. Subsequently, we screened out clinical studies and excluded Meta-analysis, Case reports, Reviews, Animal experiments, Letter, Laboratory studies, Guidelines, and conference abstract. The second stage is to screen the studies based on the topic, abstract and keywords. In this process, we use the Rating in EndNote X9 to rank the research. Two investigators marked the studies with "low relevance" as "one star", "medium credibility" as "2-3 stars", and "high credibility" as "4-5 star". "The stars" determines the subsequent screening process. "One-star" research will be excluded at this stage, the "2-3 stars" needs to be reevaluated by all investigators (X.H.Z Y.W.H W.H.M), and the "4-5 stars" can be included in the full text review. The third stage is the full-text review of the included studies. Two researchers excluded the studies of different from inclusion criteria, fail to obtain and protocol. We use Modi ed methodological index for non-randomized studies (MINORS) score [16,17] to evaluate the quality of non-randomized control trails (NRCTs) and exclude studies with a total score of <12. All disputes during the Study Selection process are resolved by the third investigator (W.H.M).

Eligibility Criteria
The purpose of this review is to evaluate the role of prophylactic HIPEC after radical resection of gastric cancer. Therefore, the inclusion criteria of the study are as follows: gastric cancer patients undergoing radical surgery, postoperative prophylactic HIPEC, blank control group or concurrent postoperative chemotherapy. And we excluded gastric cancer palliative surgical treatment, without peritoneal metastases, historical control, nonpostoperative HIPEC, IPEC and non-chemotherapeutic intraperitoneal perfusion. Due to the small number of RCTs, we included some NRCTs and conducted quality assessments. According to the Modi ed methodological index for non-randomized studies (MINORS) score, we will analyze the data included in the NRCT and complete the quality assessment Table 1. In addition, we extracted the characteristics of the studies and patients and summarized them in Table 2.

Risk of Bias Assessment
The contents are as follows: Author, year of publication, Country, RCT/NRCT, Study period, matched factors, and the stage of stomach cancer. The characteristics of the interventions will be summarized in Table 3. MINORS: methodological index for non-randomised studies.

NRCT: Non-Randomized Controlled Trial
Only studies with scores> 12 can be included in the meta-analysis.

Outcomes
The primary outcome of this review is the overall survival at 3 years follow-up. The secondary outcomes are the overall survival at 1-and 5-years follow-up; recurrence rate: overall and peritoneal; complication: myelosuppression, leakage, intestinal obstruction, liver dysfunction; deaths due to recurrence after surgery: liver, lymph node and local and peritoneal recurrence.

Statistical Analysis
All the data that needs to be analyzed are dichotomous data, and we choose to report odds ratio (OR  (Fig. 1).

Intervention characteristics
Two investigators summarized the intervention characteristics of the included studies in

Risk of Bias Assessment and Study Quality
Two investigators used RevMan 5.3 to assess the risk of bias for 12 RCTs. The evaluation result is shown in Fig. 2, Fig. 3 reported blinding the researchers responsible for data statistics, and none of the other studies mentioned blinding. In addition, the simple size is small in two studies [32,36], and there may be a risk of reporting bias.
In two studies, 181 patients reported the deaths due to liver recurrence after surgery [34,35]. Analyzing under the xed effects model, the overall heterogeneity (I 2 =30%) is not signi cant. The overall effect is not signi cantly different (OR=0.81, 95%CI = 0.28-2.31).
Deaths due to recurrence after surgery: lymph node and local recurrence (Fig. 9B).

Discussion
For patients at high risk of peritoneal metastasis, prophylactic HIPEC after radical gastric cancer is a method to reduce peritoneal metastasis and improve the survival rate of patients, but its effect is still controversial. Our study analyzed RCTs and high-quality NRCTs to evaluate the effect of prophylactic HIPEC on long-term survival and safety of patients. This review showed that the prophylactic HIPEC is bene cial to the overall survival rate of patients at 1, 3, and 5 years, and reduces the occurrence of overall and peritoneal metastases. Our results indicate that postoperative pulmonary dysfunction and renal dysfunction are more common in the prophylactic HIPEC group. But it is regrettable that, when we evaluate deaths due to metastatic disease, HIPEC does not have enough advantages.
The overall survival rate after gastric cancer resection is a topic of concern. Many studies have reported the long-term survival rate of patients with HIPEC after surgery. Two studies reported that postoperative use of HIPEC for gastric cancer patients with peritoneal metastasis can signi cantly improve long-term survival [43,45]. With the increase in the incidence of gastric cancer, the effect of prophylactic HIPEC has gradually been paid attention to. In a retrospective study, Liu et al. randomly divided 128 patients into a HIPEC group and a control group. Patients in the HIPEC group received early prophylactic HIPEC + systemic chemotherapy after gastrectomy, and the control group received chemotherapy alone [26]. Through follow-up, the 1, 2, and 5-year overall survival rates of the prophylactic HIPEC group were higher than those of the control group (P<0.05). Fujimura and his colleagues designed an RCT to evaluate the effect of prophylactic HIPEC on the overall survival rate of patients at 1, 2, and 3 years after surgery [34]. Interestingly, the author set up two experimental groups, CHPP and continuous normothermic peritoneal perfusion (CNPP), and the results reported that the overall survival rates of the two study groups were signi cantly different from those of the control group. temperature, etc., we did not evaluate the effects between groups. In addition, prophylactic or therapeutic laparoscopic HIPEC has been mentioned in multiple studies. In the study of Badgwell [45] [49].
The complications of HIPEC after gastrectomy are also worrying [52]. Due to the systemic toxicity of chemotherapy drugs, patients often have complications after HIPEC. We hope that some complications are "acceptable" because they are di cult to avoid [53]. mean that the risk of certain complications can be ignored, especially organ dysfunction. HIPEC is regarded as a radical therapy by many studies, therefore, whether to use HIPEC should be discussed considering the patient's situation [19,43,57].
In order to reduce the occurrence of postoperative adverse events, the selection of patients before surgery should be decided through multidisciplinary consultation, and the appropriate treatment plan should be selected according to the principle of individualization [58].
The metastasis of gastric cancer has a signi cant impact on the survival rate of patients. This review reports the effect of prophylactic HIPEC on the overall metastasis rate and peritoneal metastasis rate, con rming that prophylactic HIPEC reduces the occurrence of gastric cancer metastasis and reduces the risk of death due to peritoneal metastasis. Koemans and his colleagues pointed out in a PERISCOPE I trial that HIPEC can improve the survival rate of patients with gastric cancer, but the control of recurrence rate is not ideal [59]. This is different from our results, which may be due to different inclusion criteria and PERISCOPE I trial. Chia [47]  Coccolini and his colleagues reported that IP improved the overall metastasis rate of patients, and prophylactic IP signi cantly reduced the occurrence of peritoneal metastases. This is consistent with the results of this review. An expert consensus published in 2019 pointed out that the peritoneal metastasis of some cancers should not be regarded as end-stage disease, but localized spread [51]. This suggests that the prevention of gastric cancer peritoneal metastasis should follow the principle of local treatment under the premise of systemic treatment. At the same time, the rise of immunotherapy also provides new ideas for the treatment of gastric cancer. Catumaxomab is currently in Phase III clinical trials in China, mainly for AGC patients with peritoneal metastasis. In the future, the treatment of gastric cancer will be more individualized, so the correct evaluation of patients' treatment methods will be an important part of tumor treatment [49]. Based on the existing evidence, we can basically a rm that preventive HIPEC can reduce the incidence of patients with peritoneal metastasis and the number of deaths due to peritoneal metastasis, but a large sample is still needed, and high-quality RCTs further evaluate the safety and the role of inhibiting disease progression of prophylactic HIPEC for patients.
This systematic review and meta-analysis contain some limitations. First, we included 10 NRCTs. Although they passed the quality assessment, this may affect the accuracy of the results. Second, China and Japan are two countries with a high incidence of gastric cancer, so there are more HIPECrelated clinical studies published [50]. We searched 3 Japanese literatures, but none of them were available. Two investigators searched the Chinese national knowledge infrastructure (CNKI) database, and we did not include them because the studies did not meet the inclusion criteria of this review or did not pass the quality assessment. In addition, there is a certain degree of heterogeneity in our research. For example, differences in patient characteristics, countries, medical levels, treatment plans, chemotherapy drugs, etc. may affect the credibility of the results.

Conclusions
Prophylactic HIPEC helps to improve the survival rate of gastric cancer patients after radical gastrectomy, reduces the risk of gastric cancer metastasis, and effectively prevents peritoneal metastasis. It is recommended to select suitable patients for prophylactic use of HIPEC after     Overall 3-year survival in different HIPEC ways.

Figure 6
Overall recurrence rate (A), Peritoneal recurrence rate (B).   Death due to recurrence after surgery: liver recurrence (A), Death due to recurrence after surgery: lymph node and local recurrence (B), Death due to recurrence after surgery: peritoneum recurrence (C).