Hyperthermic Intraperitoneal Chemotherapy in the Management of Gastric Cancer: A Narrative Review

Gastric cancer (GC) patients with peritoneal metastasis tend to achieve poor clinical outcomes. Until recently, the treatment options were limited mainly to either palliative chemotherapy or radiation therapy in exceptional cases. Currently, these patients benefit from multimodal treatment, such as cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Despite good overall results, this treatment modality is still widely debated. The following study is designed to assess the papers about the possible application and utility of HIPEC in GC. A search in the PubMed, Web of Science, and Scopus databases was performed to assess the papers devoted to the role of HIPEC in GC treatment; a literature search was performed until March 21st; and, finally, 50 studies with a total number of 3946 patients were analyzed. According to the most recent data, it seems to be reasonable to limit the duration of HIPEC to the shortest effective time. Moreover, the drugs used in HIPEC need to have equal concentrations and the same solvent. Perioperative chemotherapy needs to be reported in detail and, furthermore, the term “morbidity” should be defined more clearly by the authors.


Introduction
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a surgical procedure that aims to deliver heated chemotherapy directly to the abdomen after surgery; the procedure was invented and firstly used more than 20 years ago [1]. Currently, HIPEC is an emerging procedure aimed to treat peritoneal metastasis of gastric cancer (GC); unfortunately, data about HIPEC application in locally advanced GC is still scarce. This treatment modality is considered to provide beneficial results in the management of several clinical syndromes within the peritoneum, such as peritoneal mesothelioma, pseudomyxoma peritonei, and peritoneal metastasis (PM), as a result of the metastatic properties mainly of several cancers, including colorectal, ovarian, or gastric cancer [2][3][4][5][6][7]. However, in GC patients, HIPEC is still considered as an innovative way to both prevent and treat PM, which is diagnosed in approximately 30% of patients with advanced GC. PM is characterized by a very poor This observation leads to a further discussion on the possible modifications that can be implemented to improve the utility of this procedure, and this should be primarily based on the results of the independent clinical studies. One of the most prevalent conundra regarding HIPEC therapy worldwide, includes the not yet established proper doses of drugs intraperitoneally administered, which is currently non-evidence-based due to the lack of proper recommendations [11]. However, even a brief analysis of the reports devoted to the application of HIPEC in GC patients shows that they present very difficult material for a comparative analysis, due to a wide spectrum of methodological differences applied in those studies. In order to draw credible and clinically useful conclusions, clinical trials need to be comparably reported. Moreover, the role of HIPEC in the treatment of PM in GC is still evolving and continually modified at all stages of treatment. Firstly, it is more frequently used in neoadjuvant therapy, such as neoadjuvant laparoscopic, heated intraperitoneal chemotherapy (NLHIPEC) after systemic chemotherapy, or neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) in a bidirectional manner (BIPSC), used for both the intraperitoneal (IP) and intravenous (IV) routes of chemotherapy administration before the CRS. Secondly, it is used in the prophylactic treatment (P-HIPEC) and palliative treatment to minimize the risk and reduce the number of the ascites [2,[12][13][14][15]. Apart from HIPEC, other forms of intraperitoneal chemotherapy, such as the early postoperative chemotherapy (EPIC) along with normothermic intra-operative intraperitoneal chemotherapy (NIIC), normothermic intraperitoneal chemotherapy long-term (NIPEC-LT), repeated intraperitoneal chemotherapy (RIPEC) [13,[15][16][17], or pressurized intraperitoneal aerosol chemotherapy (PIPAC), with the relative benefits of delivering aerosolized chemotherapy under pressure into the abdominal cavity, are more frequently used [12,13,16].
The present study assesses the papers about the possible application of HIPEC in the treatment of GC patients, including those with GC and concomitant PM, with regard to the details, guidelines, and recommendations described by the researchers in the studies chosen for this review. Furthermore, we summarize the current state of knowledge regarding the discrepancies of the HIPEC technique applied in GC patients, with an emphasis on the inaccuracies concerning the technique duration as well as the agents, doses, and solvents used in different medical centers. This review will provide an insight into a broad spectrum of potential modifications regarding HIPEC itself, enabling a further exploration of this technique and its possible standardization for a specific group of GC patients who would potentially benefit from this technique.

Search Strategy
The PubMed, Web of Science, and Scopus databases were searched to assess the papers devoted to the role of HIPEC in the treatment of GC with a particular emphasis on the patients with PM present. The search string was as follows: "(gastric cancer) AND (HIPEC) OR (hyperthermic intraperitoneal chemotherapy) AND (peritoneal metastasis)". The time period was restricted to 1 August 1989 and 21 March 2021 (32 years). The search was only restricted to the English language. During the first identification, which was the primary research conducted in March 2021, a total number of 552 papers was retrieved. After the removal of the duplicates, a total of 236 articles was included in the first analysis. Due to the disqualification of case reports, comments to other papers, letters to Editors, and papers devoted to other topics, a total number of 143 papers were assessed for eligibility. Due to the inaccessibility of several papers, and not considering the articles devoted to the tumors other than GC, the final analysis was based on a total number of 50 papers (Appendix A).
In every studied article, information was sought based on the following data: the number of patients; their medium age; agents and doses used in the HIPEC treatment of GC patients with or without PM; volume and kind of solvent for perfusate; duration of HIPEC; the modality of the procedure (open/closed); information about perioperative chemotherapy; the value of mortality and morbidity and their definition and interpretation, according to the authors of the paper; a detailed list of complications; as well as the median survival rates. The results are presented in Table A1 (Appendix A).

Details of the Studied Population
The analyzed reports varied with regards to the population of patients. The largest study included 249 patients, while the smallest was restricted to only 9 patients. The age range of patients was between 47 and 61 years; however, at least 5 papers did not mention this parameter at all, which is one of the limitations of this study.

Intraperitoneal Chemotherapy
Intraperitoneal chemotherapy provides significantly higher local concentrations, which results in a direct anti-tumor effect on free peritoneal cancer cells. Therefore, intraperitoneal chemotherapy facilitates its uptake by cancer cells, by the enhanced drug penetration into them. In terms of the drugs used in HIPEC, mainly four variables differed in the analyzed reports: agents, doses, kind, and volume of the solvents. The most common chemotherapeutic agents used were Mitomycin C and Cisplatin, which were applied in 31 and 32 regimens, respectively. The doses of the applied agents were reported either as the whole dose for the procedure in milligrams (mg) (19 papers) [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36], or in milligrams for the body surface area (mg/m 2 ) (26 papers) [11,35,. One of the latter units was additionally expressed in terms of the volume of solution (mg/m 2 /L) [48]. Two authors did not report the doses of the drugs [61][62][63]; in older studies, the doses were once reported in either µq/mL [64] or once in mg/kg [65]. Several articles lacked information about the volume of perfusate; those were mainly newer reports. In most of the cases, drugs were administered in the saline solution; however, there were single cases where the saline was replaced with 5% dextrose in water (D5W) or dialysis solution.

Median Survival
In some analyses, the patients were divided into the following groups: 1) curative, adjuvant, palliative, 2) patients who underwent CRS and HIPEC or only CRS, 3) patients with PCI < 6, and PCI > 6, and 4) complete cytoreduction, or not complete (Appendix A).

Discussion
HIPEC is a treatment strategy that, combined with surgery, aims to treat advanced cancers within the abdomen, such as colorectal cancer, gastric cancer, ovarian cancer, or peri-toneal mesothelioma. Even though its usefulness was reported in several types of advanced cancers within the abdomen [68][69][70], it should be considered that the application of HIPEC is associated with a risk of several complications, including hematological toxicity, kidney failure, venous thromboembolism, and infections within the venous accesses and urinary tract [71]. Typical side effects include nausea, vomiting, fatigue, or weight loss, but those usually persist up to 3 months after surgery. The other most common complications include fatigue, disturbed sleep pattern, bloating, diarrhea, or constipation; depression is also reported as a side effect. Generally, the occurrence of any adverse events reflects the risks of the whole operation, but distinguishing between surgical and systemic complications can be additionally relevant in further analysis concerning the safest combination of agents and their doses. However, recently, the contemporary safety of HIPEC has significantly improved. Even though the morbidity and mortality rates remain relatively high in both HIPEC and CRS, the associated learning curve is steep and numerous well-structured tutor-based training programs have so far been implemented in Europe, to progressively overcome those drawbacks [72].
The authors of the reports that were directly devoted to HIPEC, usually discussed PM as an independent diagnosis, which, regardless of the origin, has a similar course and prognosis; therefore, it should be treated with the same means. According to the papers included in this narrative review, there are no clear indications as well as recommendations regarding the details of HIPEC, such as the types of agents and solvents (as well as their doses) used, along with the time of HIPEC duration. There are also discrepancies concerning the perioperative systemic chemotherapy applied in GC patients. For these reasons, it can be assumed that even though HIPEC seems to be beneficial for some of the GC patients, this type of therapy should be evaluated further and more standardized amongst the clinical centers; the group of patients who would be most beneficial to this therapy should also be investigated. In Poland, so far, there are only eight medical centers in which HIPEC is applied in GC patients; however, due to a high number of inconsistent data regarding the HIPEC procedure itself, there is no publication on this subject yet.
In our paper, 41 reports were excluded from further analysis, although they contained the required information about HIPEC in GC patients with PM. The reason was that the information about the patients' characteristics (age and profile of chemotherapy, as well as outcomes data), rates of mortality, morbidity, and median survival, were reported together for the patients with PM from tumors of other origins.
Regarding the role of HIPEC in peritoneal carcinomatosis, more randomized trials still need to be conducted in order to select those patients who would constitute good candidates for such therapeutic approaches. In addition to the clinical features, the molecular and pathological features should be investigated in order to select patients for whom HIPEC would be beneficial. Apart from gastric cancer, minimally invasive secondary cytoreduction combined with HIPEC is currently under investigation to be applied in other peritoneal cancers, especially in the case of patients with ovarian cancer [73,74].

Intraperitoneal Chemotherapy
The diversity of regimens used for HIPEC in patients with GC and PM is understandable as, for the time being, the role of this treatment modality is still unsettled and there are no strict restrictions for this matter. The most common chemotherapeutic drugs used in HIPEC include Mitomycin-C and Cisplatin [75]-there were also reports about the potential application of oxaliplatin and doxorubicin; however, those are less common drugs [13]. However, the variability in the reports about the doses of the drugs and the lack of designation of the volume of perfusate during planning procedures, resulted in the situation that, even in the same institutions, the patients are treated with solutions of different concentrations of the drugs. It seems that the rules of treatment with HIPEC can be similar to dialysis therapy. Treating patients incomparably implies that the solutions of the drugs used during treatment need to have equal concentrations, expressed in the unit of mass to the volume of the solution [mg/mL]. The solvent needs to be universal-a saline solution, as in the majority of cases. Then, the volume of the applied drug solution should depend on the body surface area of the patient.

Duration of HIPEC
The duration of HIPEC depends on the used protocol and significantly varies depending on the type of chemotherapeutic agent used along with its pharmacokinetics features. One of the questions that have appeared in this study is whether the duration accuracy of the applied procedure matters. From the pharmacokinetic point of view, the depth of drug penetration is very minimal (up to 1-3 mm), and the prolongation of the treatment time would not increase this [76]. On the other hand, hyperthermia increases blood circulation and the longer the drugs solution remains in the peritoneal cavity, the more the drugs are prone to penetrate the vessels and enter into the blood. However, even if this course of events occurs, it is very limited, as the concentration of drugs in the blood after the application of HIPEC is far below the toxicity threshold [65]. However, the real problem exists from surgical and anesthesiological points of view, as a prolonged operation course increases the rate of postoperative morbidity, blood loss, as well as infection risk [8]. Therefore, some studies suggest that it would be reasonable to limit the duration of HIPEC to the shortest effective time, which means that the desired effects (favorable clinical outcomes with a minimization of the above-mentioned side effects) would be performed in the shortest time possible, without the additional risk of potential intraoperative side effects (either surgical or anesthesia).

Perioperative Chemotherapy
Perioperative chemotherapy (high rates of systemic chemotherapy in the neoadjuvant and adjuvant settings) is a favorable prognostic factor with a positive effect on survival [2,18,19,38]. The aim of this report was not to analyze the details of perioperative chemotherapy, but rather to assess the frequency of reporting this parameter in studies. Based on our analysis, it appears that this issue is generally neglected. In only 17 papers, there was some information about the types of agents used, doses, schedule of regimens, several patients qualified for chemotherapy, and reasons of disqualification; however, in very few, the data was complex. The probable reason is that the analyzed reports were mainly addressed to the surgeons and too much data can lead to information noise. However, from a multidisciplinary point of view, the factor of perioperative chemotherapy is relevant, as it diversifies the treated population.

Mortality
HIPEC is always the complement to severe and extensive CRS and; therefore, "the mortality rate" must be considered throughout the procedure. In most of the studied articles, "mortality" was defined as the number of deaths in 30 postoperative days. However, sometimes the authors redefined this entry and extended the mortality-free period to emphasize the safety of the procedure. In the literature, the careful and rigorous selection of patients qualified for CRS and HIPEC was often underlined as the crucial factor contributing to the effectiveness of treatment [2,38,77].

Morbidity
While "mortality" is an easy and unambiguous event to be defined, and the term "morbidity" is interpreted variously by different authors. It seems that one of the best options is to grade the adverse events related to CRS and HIPEC, according to the "common terminology criteria for adverse events" valid for the time of publication [78]. However, the authors did not always consider the same grades in the final analysis. Most often, they reported grade III-IV, but, in some papers, the less severe grades along with the fatal grade V were also included. Eventually, when analyzing a single paper, the way of reporting a matter of morbidity seemed satisfactory; however, in a wider perspective, the percentage numbers were very misleading, as they could not be compared. Complications are usually graded using the Clavien-Dindo classification system [79]. CRS combined with HIPEC presents significantly lower mortality and morbidity rates, compared with other major gastrointestinal surgical procedures [80].

Median Survival
The estimated median survival rate of patients with GC and concomitant PM is about 6-18 months [81]. Of the analyzed papers, the lowest median survival was mentioned in a study [28] by Hall et al. (2004), while the highest median survival rate was reported by Hamazoe et al. (1994) [64] with the values being equal to 8 months and 77 months, respectively. The appropriate selection of patients using the Peritoneal Carcinomatosis Index (PCI) < 6 and complete cytoreduction, showed promising results in improving overall survival (OS) rates [12,16,82]. The implementation of HIPEC in the case of patients with GC and PM seems to be reasonable, since, even though the median survival rates differ among single-center or prospective registry studies, they are continually improving, not only due to the favorable modifications of the technique itself, but also because of proper surgical training [72].

Conclusions
According to the studies devoted to the application of HIPEC in GC patients, it seems that at least the selected patients can benefit from this type of therapy. Even though similar, the technique itself is continually modified and differs between clinics in terms of the solvents and agents used, as well as the duration of the whole procedure. Further studies, with long-term evaluations, are of major importance to identify the prognostic factors that either positively or negatively affect the overall survival rate of GC patients treated with HIPEC. Numerous studies regarding this matter are currently ongoing, as researchers worldwide try to investigate those factors; e.g., Graziosi et al. indicate the patient-related parameters (pre-operative serum albumin level or platelets-to-lymphocytes ratio) as well as the tumor-related factors (such as the primary tumor site or PCI) as factors strongly associated with the survival of operated patients [83]. Patients with low CC scores present a significant survival advantage [10]. What is crucial, while considering the outcome of HIPEC, is the proper patient selection. Cocollini et al. suggest that the morbidity rate of patients is incremented by intraperitoneal chemotherapy [84]. In the papers devoted to HIPEC in the treatment of PM of any origin, it would be beneficial to distinguish the detailed data of patients and results of the procedures for populations of the same primary neoplasm. To draw credible conclusions and finally settle the role of HIPEC in GC, the reports need to fulfill several conditions:

•
Solutions of the drugs used in HIPEC need to have equal concentrations, expressed in the unit of mass to the volume of solution [mg/mL]; the solvent needs to be universal, and the volume of the solution should depend on the body surface area of the patient, as well as the optimal doses of intraperitoneal administrated chemotherapy agents' doses.

•
The information about perioperative chemotherapy needs to be reported and should contain details about the chemotherapeutic agents used, their doses, the schedule of regimens, how many patients qualified for chemotherapy, and the reasons for disqualification.
The term "morbidity" should be clearly defined. We suggest applying to the observations in the majority of reports the consideration of "morbidity" as grade III-IV adverse events that comes from too common terminology criteria for adverse events [78]. Moreover, it is not enough to specify the number; however, morbid events should be listed. Currently, several randomized clinical trials (RCTs) have been conducted; however, with quite different conclusions regarding the usage of CRS and HIPEC in patients with gastric cancer. The Italian Association of Medical Oncology (AIOM) strongly advises against the application of CRS and HIPEC in patients with PM, while the Peritoneal Surface Oncology Group International (PSOGI) suggests that patients with gastric cancer and PM can strongly benefit from such treatment [85,86]. Such discrepancies once again suggest that RCT, as well as seeking a potential standardization, are of a major necessity.