# Management of peritoneal gastric metastasis: An update

Antoine Mariani, Evangelia Triantafyllou, Vahan Kepenekian, Aziz Zaanan, Olivier Glehen, Mehdi Karoui

► To cite this version:

Antoine Mariani, Evangelia Triantafyllou, Vahan Kepenekian, Aziz Zaanan, Olivier Glehen, et al. Management of peritoneal gastric metastasis: An update. EJSO - European Journal of Surgical Oncology, 2025, 51 (6), pp.109731. 10.1016/j.ejso.2025.109731. hal-05106070

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## Review Article

# Management of peritoneal gastric metastasis: An update

<figure><img src="image_2.png" /></figure>

Antoine Mariani<sup>a,1,*</sup> <sup>ID</sup>, Evangelia Triantafyllou<sup>a,1 ID</sup>, Vahan Kepenekian<sup>b</sup>, Aziz Zaanan<sup>c</sup>, Olivier Glehen<sup>b</sup>, Mehdi Karoui<sup>a</sup>

## ABSTRACT

**Importance:** Peritoneal metastases from gastric cancer (PMGC) are associated with poorer median survival and systemic chemotherapy remains the standard of care. This narrative review summarizes the current evidence for medical and surgical treatment of PMGC.

**Observations:** Treatment is moving to local ways of administering chemotherapy, either intraperitoneal normothermic chemotherapy, laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) or even pressurized intraperitoneal aerosol chemotherapy. Furthermore, cytoreductive surgery±HIPEC could also be an alternative in specific situations.

**Conclusions:** and relevance: This review provides an updated summary of existing strategies that can be discussed in the management of patients with PMGC.

## 1. Introduction

Gastric cancer is a frequent and aggressive disease corresponding to the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in the world [1]. Using a Dutch national database, Thomassen et al. showed that 39 % of patients presented metastasis at the moment of diagnosis and peritoneal carcinomatosis was present in 14 %, of whom 9 % had peritoneal metastasis as the only metastatic site [2]. Peritoneal metastases from gastric cancer (PMGC) are associated with poorer median survival, ranging from 4 to 12 months with systemic chemotherapy [2,3]. It has been observed that peritoneal and solid organ (e.g., lung/liver) metastases are often mutually exclusive in gastric cancer patients, reinforcing the concept of peritoneal as a distinct biologic subtype [4,5]. Peritoneal carcinomatosis most probably has to be considered as a locoregional form of the disease, and scientific interest in intraperitoneal therapy is growing.

Another difficult point in assembling and assessing data from all current studies concerning peritoneal carcinomatosis in gastric cancer is discrepancy in the treatment protocols followed in Europe, Asia and the United States, since several strategies are nowadays possible and include not only intravenous chemotherapy, but also intraperitoneal chemotherapy, surgery and surgery combined with intraperitoneal chemotherapy. Systemic chemotherapy remains the standard of care for metastatic disease from gastric cancer [6]. It is remarkable that the

intraperitoneal availability of drugs by systemic chemotherapy is low; consequently, systemic treatment is often ineffective in bulky disease [7]. Furthermore, the cumulative toxicity of repeated intravenous chemotherapeutic regimens is responsible for a progressive decrease in patients' compliance with therapy. In contrast to systemic chemotherapy, intraperitoneal chemotherapy improves drug delivery not only to the tumor but also to the intraperitoneal metastasis, with generally accepted systemic side effects [8]. Ways to administer intraperitoneal chemotherapy include normothermic and hyperthermic intraperitoneal chemotherapy techniques, and also pressurized intraperitoneal aerosol chemotherapy (PIPAC). The current place of surgery is also under investigation since in the exploratory AIO-FLOT3 trial, Al-Batran et al. showed that patients with limited metastatic disease who received neoadjuvant chemotherapy and then underwent surgery showed favorable survival [9]. However, the RENAISSANCE (AIO-FLOT5) trial did not confirm these findings, but was not specifically designed for peritoneal metastases [10]. In this review of the latest treatments for PMGC, we have only included comparative and/or prospective clinical trials that focus on first-line treatment. We also performed a thorough literature search specifically and exclusively, where possible, for terminated clinical trials concerning metastatic gastric cancer patients with peritoneal metastases.

<footnote><sup>a</sup> Department of Digestive Surgery, Université Paris Cité, Assistance Publique Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France</footnote>

<footnote><sup>b</sup> Surgical Oncology Department, Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France</footnote>

<footnote><sup>c</sup> Department of Digestive Oncology, Université Paris Cité, Assistance Publique Hôpitaux de Paris, Georges Pompidou University Hospital, Paris, France</footnote>

<footnote>* Corresponding author. Université Paris Cité, Assistance Publique Hôpitaux de Paris; Department of Digestive and Oncologic Surgery, Hôpital Européen Georges Pompidou, 20 rue Leblanc, PARIS, France.</footnote>

<footnote>E-mail address: antoine.mariani@aphp.fr (A. Mariani).</footnote>

<footnote n="1">¹ these authors contributed equally to this work.</footnote>
## 2. Presentation and diagnosis

According to Rijken et al., the incidence of synchronous peritoneal metastases varies from 2% (observational cohort studies) to 40% (surgical cohort studies), with a frequency of 10–21% in population-based studies [11]. Imaging techniques that can detect peritoneal carcinomatosis include CT scan, MRI and FDG-PET/CT. CT scan is usually the first choice because of its high sensitivity and specificity combined with a short scan time, compared with other techniques [12]. Deposits smaller than 5 mm can be difficult to diagnose with current imaging techniques and indirect signs such as ascites, omental caking and peritoneal thickening are used to diagnose peritoneal metastases [13]. The results of the multicenter prospective Dutch cohort study (PLASTIC) suggested a limited additional value of FDG-PET/CT and a considerable additional value of staging laparoscopy in the detection of peritoneal and nonresectable disease, since in this study diagnostic laparoscopy detected nonresectable and metastatic disease in 20% of patients [14]. In the latest National Comprehensive Cancer Network (NCCN) guidelines of 2024, diagnostic laparoscopy is proposed as an option for the workup of patients with gastric cancer and peritoneal disease [15].

The peritoneal cancer index (PCI) is used to evaluate the extension of peritoneal carcinomatosis and was initially described by Harmon and Sugarbaker [16]. There is evidence that a higher PCI is associated with worse survival, since it reflects a more advanced and disseminated disease. According to Rau et al., in their retrospective analysis of a German database, median survival was 18 months for patients with a PCI between 0 and 6, 12 months for a PCI from 7 to 15 and only 5 months for patients with a PCI higher than 15 [17]. In the Japanese classification system, the degree of peritoneal disease is classified into four grades (P0-P3) [18]. P1 is described as metastasis in the adjacent peritoneum, P2 corresponds to limited metastases to the distant peritoneum and P3 indicates diffuse metastasis to the distant peritoneum. Kawasaki et al. published in 2020 a correlation between the PCI and the P classification of the Japan Society of Coloproctology [19]. They found that the ideal definition for the best alignment between the two scoring systems is: P1 is equivalent to metastases confined to one peritoneal region, P2 to a PCI below 19 and P3 to a PCI above 20.

## 3. Treatment options

### 3.1. Chemotherapy

#### 3.1.1. Systemic chemotherapy alone

Most of the available data concerning systemic treatment of metastatic gastric cancer patients does not concern peritoneal metastases specifically, but rather patients with metastatic disease in general. The principles of systemic chemotherapy may include assessment of the patient's performance status and of the molecular status of the tumor. First-line treatment includes the combination of a fluoropyrimidine with platinum (oxaliplatin and cisplatin have proven equally effective), with a preference for oxaliplatin in patients >65 years old as it appears to have a better safety profile [20,21]. Fluoropyrimidines are either administered as an infusion (5FU) or as an oral treatment (capecitabine or S-1 = tegafur-gimeracil-oteracil in Asian countries). In patients with HER2-negative tumors, addition of the anti-PD1 monoclonal antibody nivolumab to doublet chemotherapy significantly improves survival in patients with a combined positive score (CPS) > 5 for PD-L1 tumors (14.4 months [95% CI, 13.1 to 16.2] vs 11.1 months [95% CI, 10.0 to 12.1], respectively; HR, 0.70 [95% CI, 0.61 to 0.81]) [22]. The most common treatment-related adverse events were nausea, diarrhea, and peripheral neuropathy across both groups, without any new safety signal identified in the nivolumab group. Other new targeted therapies against claudin-18.2 and FGFR2b-overexpressing tumors also showed promising results [23,24].

The combination of fluoropyrimidine, cisplatin and trastuzumab has

<table><caption>**Table 1**

Completed randomized clinical trials concerning peritoneal carcinomatosis from gastric cancer.</caption><thead><tr><th>Study Name, First Author</th><th>Year</th><th>Inclusion criteria</th><th>Groups, number of participants</th><th>Results</th></tr></thead><tbody><tr><td>PHOENIX-GC, Ishigama,</td><td>2018</td><td>Gastric cancer with peritoneal metastasis for patients having received no chemotherapy or short-term chemotherapy (&lt;2 months)</td><td>IP and IV paclitaxel plus S-1 vs S-1 and cisplatin 164 participants</td><td>Median OS was 17.7 months vs 15.2 months respectively (p = 0.8), sensitivity analysis adjusted for baseline ascites: p = 0.008)</td></tr><tr><td>Yang</td><td>2011</td><td>Peritoneal carcinomatosis from gastric cancer</td><td>CRS alone vs CRS + HIPEC (with cisplatin and mitomycin C) 68 participants</td><td>Median OS 6.5 months for CRS group vs 11 months for CRS + HIPEC group (p = 0.046)</td></tr><tr><td>GASTRIPEC, Rau</td><td>2018</td><td>Histologically proven peritoneal carcinomatosis from gastric cancer</td><td>CRS-A group: perioperative chemotherapy and CRS CRS-H group: perioperative chemotherapy, CRS + HIPEC (mitomycin C + cisplatin) 105 participants</td><td>Median OS was the same for both groups 14.4 months (p = 0.1647) MFS: 6.8 months vs 10.2 months p = 0.0286 PFS: 3.5 months vs 7.1 months p = 0.047</td></tr><tr><td>GYMSSA Trial, Rudloff</td><td>2014</td><td>Measurable metastatic disease from gastric cancer adenocarcinoma involving the peritoneum and resectable to "no evidence of disease"</td><td>Systemic chemotherapy (SA) vs multimodality therapy (complete CRP, HIPEC, systemic chemotherapy with FOLFIRI (GYMS)) 16 participants</td><td>Median OS was 11.3 months in the GYMS arm and 4.3 months in the SA arm All patients surviving beyond 12 months in the surgery arm had a complete CRS and initial PCI ≤15.</td></tr></tbody></table>

IP: intraperitoneal, IV: intravenous, OS: overall survival.

CRS: cytoreduction surgery, HIPEC: hyperthermic intraperitoneal chemotherapy.

MFS: metastasis-free survival.

been the standard first-line treatment of HER2-positive tumors since the TOGA trial: 13.8 months survival (95% CI 12–16) with trastuzumab plus chemotherapy compared with 11.1 months (95% CI 10–13) with chemotherapy alone (HR 0.74; 95% CI 0.60–0.91; p = 0.0046) [25]. The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 67% vs chemotherapy alone, vs 63%), vomiting (50% vs 46%), and neutropenia (53% vs 57%). Rates of overall grade 3 or 4 adverse events (68% in both groups) and cardiac adverse events (6% in both groups) did not differ between groups. More recently, the addition of pembrolizumab to chemotherapy and trastuzumab was approved for tumors with a CPS ≥1 (median overall survival was 20.0 months [95% CI 17.8–22.1] versus 16.8 months [95% CI 15–18.7; HR 0.84 [0.70–1.01]]), but did not meet prespecified criteria for significance and will continue to final analysis [26].
<table><caption>**Table 2**
Ongoing randomized clinical trials.</caption><thead><tr><th>Study Name, First Author</th><th>Year</th><th>Inclusion Criteria</th><th>Groups, number of expected participants</th><th>Primary endpoint</th></tr></thead><tbody><tr><td>NCT04222114, LintonPharm Co. Ltd</td><td>2020</td><td>Diagnosed gastric cancer with peritoneal metastases after failure of two standard treatments</td><td>Cetuximab for IP infusion vs localized supportive therapy<br>282 expected participants</td><td>Overall survival</td></tr><tr><td>PERISCOP II, Koemans</td><td>2019</td><td>Peritoneal metastases of gastric cancer with PCI &lt;7</td><td>CRS + HIPEC vs chemotherapy alone<br>106 expected participants</td><td>Overall survival</td></tr><tr><td>PIPAC-VERone, Azienda Ospedaliera Universitaria Integrata di Verona</td><td>2022</td><td>Primary resectable gastric cancer with positive peritoneal cytology and/ or low burden of peritoneal metastases (PCI &lt;6), confirmed by laparoscopy</td><td>Arm A: IV chemotherapy (FOLFOX)<br>Arm B: IV chemotherapy (FOLFOX) + PIPAC with cisplatin and doxorubicin<br>98 expected participants</td><td>Number of patients in the two arms who undergo radical intent surgery (CRP + HIPEC)<br>Timeframe: 3.5 years</td></tr><tr><td>CLASS-05, Liu</td><td>2017</td><td>Stage cT3-T4NxM1 with M1 limited to peritoneum. PCI score &lt;20 evaluated by diagnostic laparoscopy</td><td>CRS + HIPEC vs chemotherapy alone (5-FU-based regimen)<br>220 expected participants</td><td>Overall survival</td></tr></tbody></table>

IP: intraperitoneal, PCI: peritoneal cancer index.

PIPAC: pressurized intraperitoneal aerosol chemotherapy, IV: intravenous.

CRS: cytoreductive surgery, HIPEC: hyperthermic intraperitoneal chemotherapy.

For patients with no positive biomarker, triplet chemotherapy including taxane can be proposed on the basis of preliminary results from the GASTFOX trial comparing FOLFOX alone and FOLFOX with docetaxel (median overall survival: 15.08 vs 12.65 months; HR 0.82 [0.68-0.99], p 0.048) [27]. Most common grade 3 treatment-related adverse events were neuropathy (31.7 vs 19.7 %), diarrhea (14.5 vs 6.4 %) and neutropenia (26.1 vs 18.1 %), respectively, for mFLOT/TFOX and FOLFOX. Irinotecan can be considered as an alternative option for patients who do not tolerate platinum compounds [28].

## 3.2. Intraperitoneal normothermic chemotherapy

The only phase III randomized trial addressing the use of intraperitoneal treatment without surgery is the PHOENIX-GC Trial [29], which compared intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with PMGC (Table 1). The median overall survival was 17.7 and 15.2 months, respectively (p = NS). The 3-year overall survival rate was 21.9 % and 6 %, respectively (p = NS). In the sensitivity analysis adjusted for baseline ascites, the hazard ratio was 0.59 (95 % CI, 0.39 to 0.87; p = 0.008). As far as safety is concerned, there was a statistically significant difference in grade 3 or 4 leukopenia (p = 0.023) and neutropenia (p = 0.028), which were more frequent in the intraperitoneal arm. Eight adverse events related to intraperitoneal ports were observed in 6 % of patients (3 intraperitoneal port infections, 3 catheter obstructions, 1 subcutaneous hematoma and 1 fistula between the catheter and small intestine). There were neither unexpected serious adverse events nor deaths related to the treatment protocol. This trial, although it failed to show statistical superiority of intraperitoneal

paclitaxel plus systemic chemotherapy, suggested possible clinical benefits of intraperitoneal chemotherapy for gastric cancer. The results of other nonrandomized phase II trials have already been published, using intraperitoneal docetaxel or paclitaxel with oral S-1 chemotherapy, and have shown promising results, with a 70 % overall survival at 1 year [30-33].

The concept of neoadjuvant intraperitoneal and systemic (NIPS) treatment was introduced in 2006 by Yonemura et al. who reported intraperitoneal chemotherapy with docetaxel and carboplatin through a peritoneal port system, with simultaneous IV chemotherapy with methotrexate and 5FU, for patients with advanced peritoneal dissemination of primary gastric cancer [34]. Of the 61 patients who were initially enrolled in the study, 39 had positive intraperitoneal cytology and in 22 (56.4 %) of those patients cytology was converted to negative. Thirty patients came to resection and 14 were disease-free at the end of the observational period. For those receiving surgery (gastrectomy and complete cytoreduction) median survival was 20.4 months. In 2014, the same working group proposed a new chemotherapy regimen [30]. In their protocol, S1 was administered orally twice daily at a dose of 60 mg/m²/day for 14 consecutive days, followed by 7 days' rest. Docetaxel and cisplatin were administered intraperitoneally at a dose of 30 mg/m² on day 1. Docetaxel and cisplatin were diluted in 500 mL of normal saline and administered through the implanted peritoneal port system. The same dose of docetaxel and cisplatin was administered intravenously on day 8 after standard premedication. The treatment course was repeated every 3 weeks 3 times. Complete cytoreduction was achieved in 28 (64 %) of 44 patients. Complete histologic disappearance of peritoneal metastases was observed in 10 (22.7 %) of 44 patients. Median survival time was 12.2 months, with one- and two-year survival rates of 62.4 %, and 44.0 %, respectively.

A phase 3 trial designed in 2020 in China by LintonPharm Co. Ltd compared the efficacy and safety of intraperitoneal infusion of capecitabine combined with chemotherapy left to the investigator's choice vs chemotherapy alone in patients with PMGC [35]. This trial is still in the recruitment stage and 297 patients are expected to enroll (Table 2). The primary endpoint is overall survival.

## 3.3. Laparoscopic hyperthermic intraperitoneal chemotherapy

HIPEC is usually delivered after cytoreductive surgery. Based on the results for intraperitoneal chemotherapy, an original technique for the administration of HIPEC drugs was used during laparoscopy, in order to achieve optimal distribution of heat and of cytotoxic drugs without performing cytoreductive surgery, while also avoiding postoperative morbidity.

There are no randomized trials concerning laparoscopic HIPEC in the literature. In a prospective noncomparative study including 19 patients, 38 laparoscopic HIPEC procedures, using 60-min perfusion of cisplatin (200 mg) and mitomycin-C (30 mg), were performed [36]. The complication rate was 11 % and the median length of hospital stay was 3 days. Median follow-up was 18.9 months, median overall survival from the date of diagnosis of metastatic disease was 30.2 months, and median overall survival from the first laparoscopic HIPEC was 20.3 months. Absence of peritoneal disease was demonstrated in 5 patients, who were able to undergo gastrectomy. In a 2019 retrospective review of results from the same team concerning the efficacy of laparoscopic HIPEC with mitomycin C and cisplatin, Newhook et al. reported that 71 procedures were performed between 2014 and 2017 [37]. Of the patients concerned, 32 % (n = 14) had isolated peritoneal disease. In the 71 procedures, no conversion to laparotomy was required. One Clavien-Dindo grade III surgical complication was noted and 7 postoperative adverse hematologic events (> CTCAE 2) were observed in 5 patients (11 %). Eleven patients (25 %) underwent secondary gastrectomy following resolution of peritoneal cytology. This retrospective review illustrated the repeatability and feasibility of neoadjuvant laparoscopic HIPEC as part of a standardized treatment algorithm for patients with advanced
gastric cancer [38,39].

Laparoscopic HIPEC was also part of the Dragon II randomized trial protocol which compared surgery (R0 resection and D2 lymphadenectomy) followed by 8 cycles of SOX regimen (doxorubicin and oxaliplatin with S1) with neoadjuvant laparoscopic HIPEC with paclitaxel followed by 3 cycles of SOX regimen and surgery [40]. Even though the inclusion criteria for this study included locally advanced disease, it is speculated that the proposed regimen will be able to control occult peritoneal carcinomatosis or peritoneal free cancer cells.

## 3.4. PIPAC

Another recent approach for intraperitoneal chemotherapy is pressurized intraperitoneal aerosol chemotherapy (PIPAC). The scientific idea behind PIPAC is a combination of the theoretical pharmacokinetic advantages of low-dose intraperitoneal chemotherapy with the characteristics of aerosols, which allow homogenous intraperitoneal distribution and deeper tissue penetration [41].

The first evidence of the efficacy of the PIPAC procedure was reported by the German team of Solass et al. [42]. In 2016, Khomyakov et al. reported the results of the phase 2 study PIPAC-GA2 [43]. The protocol that included staging laparoscopy or laparotomy, 3–4 courses of systemic chemotherapy (XELOX) followed by PIPAC procedures every 6 weeks until progression of disease or death. Fifty-six PIPAC procedures were performed in a total of 31 patients with a mean PCI of 13.8. An objective histological regression was seen in 60 % of patients, and median overall survival was 13 months. Using a bidirectional approach, Di Giorgio et al. performed 46 PIPAC procedures in 28 consecutive patients [44]. A pathological response was recorded in 61.5 % of patients (one with complete and seven with partial regression). Median overall survival was 12.3 months in the overall population and 15.0 months in patients undergoing more than one PIPAC procedure. CTCAE grade 1–2 complications (mild abdominal pain, vomiting, nausea), which are common following laparoscopy, occurred postoperatively in ten patients. Two patients experienced serious liver toxicity (CTCAE grades 3 and 4); one patient recovered with medical therapy and resumed systemic chemotherapy, while the other patient died 45 days after the procedure due to hepatic failure. Both patients already presented slight liver impairment before PIPAC treatment. Surgical complications (Clavien-Dindo > grade III) were observed in 1/46 patients (2 %). In 2020, Struller et al. published the results of another phase II trial, which used PIPAC low-dose cisplatin and doxorubicin for patients with recurrent peritoneal metastases from gastric cancer [45]. Of 25 patients enrolled, 10 (40 %) had a complete radiological response or stable disease. Median overall survival was 67 months. Complete or major histological regression was observed in 9 patients.

The PIPAC EstoK 01 trial, which started in 2018, was a randomized phase II study evaluating the effects of PIPAC with doxorubicin (2.1 mg/m²) and cisplatin (10.5 mg/m²) on patients with peritoneal carcinomatosis with PCI >8, treated with systemic chemotherapy between two PIPAC procedures [46]. This trial was closed before the end of enrollment and the results are pending. The ongoing PIPAC VEROOne trial is a prospective randomized phase III trial studying the role of PIPAC in multimodal treatment for gastric cancer patients with positive cytology and/or limited peritoneal metastasis [47].

## 3.5. Cytoreductive surgery + HIPEC

The first results from a phase III randomized trial studying the overall survival of patients with PMGC were published in 2011 by Yang et al. [48]. Sixty-eight patients were randomized to cytoreduction alone vs cytoreduction with HIPEC with cisplatin and mitomycin C. Median survival was 6.5 months for the group with cytoreductive surgery alone vs 11 months for the group with surgery + HIPEC (p = 0.046). The authors concluded that the addition of HIPEC with mitomycin C and cisplatin may improve survival, with acceptable morbidity. In the

CYTO-ChIP study, propensity score analysis for patients with PMGC identified a total of 277 patients, 180 of whom underwent surgery + HIPEC and 97 surgery alone [49]. Median overall survival was 18.6 months for the surgery + HIPEC group, vs 11.1 months (p = 0.002). A statistically important between-group difference was found for 3- and 5-year overall survival (p = 0.005) and also for the 3- and 5-year recurrence-free survival rate (p = 0.001), with better results in the group with HIPEC. This aggressive approach was also challenging since the 30- and 90-day mortality rates were 3.2 % and 8.4 %, respectively, with no significant difference between groups. The major 90-day morbidity rates were similar with cytoreductive surgery + HIPEC and cytoreductive surgery alone (53.7 % vs 55.3 %, respectively; p = 0.496), as were surgical complications rates (37.1 % vs 38.8 %, respectively; p = 0.921). As a result, and since no additional morbidity or mortality was seen in this study, Bonnot et al. stress the importance of performing HIPEC when complete cytoreduction can be performed. Selection of candidates for surgery is also a critical issue and should include response to initial systemic treatment and a low burden of peritoneal disease.

More recently, The phase III GASTRIPEC-I study by Rau et al. was designed to explore the potential benefit in overall survival of adding HIPEC with mitomycin C and cisplatin after cytoreductive surgery in patients with isolated PMGC in comparison with cytoreductive surgery alone [50]. One hundred and five patients were included in this trial, which was prematurely terminated because of slow recruitment. Median overall survival was the same for both groups (14.9 months). Overall survival rates at 1, 2 and 3 years were 60.5 %, 15.4 % and 0 % for the cytoreduction alone group, and 58.4 %, 25.5 % and 13.6 % for the cytoreductive surgery and HIPEC group. There was a statistically significant difference in progression-free survival (3.5 months for the surgery alone group vs 7.1 months for the surgery plus HIPEC group; p = 0.047). The incidence of severe adverse events (> grade 3) was the same for the two groups. The authors concluded that even though there was no statistical difference in the overall survival, the addition of HIPEC to cytoreductive surgery improved the progression-free rate and the metastasis-free survival rate.

Another important question in the treatment of patients with peritoneal carcinomatosis from gastric cancer is whether a surgical approach including cytoreductive surgery ± HIPEC provides better overall survival and progression-free survival than exclusively medical treatment. The GYMSSA trial was the first phase III study that attempted to answer this question. In this prospective trial, patients were randomized to gastrectomy, metastasectomy and HIPEC plus systemic chemotherapy vs systemic chemotherapy alone, with inclusion of only 17 of the 140 patients initially planned [51]. Median overall survival was 11.3 months vs 4.3 months, respectively. In the surgery + HIPEC + systemic chemotherapy arm, all patients survived beyond 12 months and had an initial PCI <15. In the chemotherapy alone arm, no patient survived for more than 11 months. This was the first randomized trial to yield promising results for prolonged survival with surgery in patients with limited disease burden.

Concerning ongoing trials, the CLASS-05 and PERISCOPE II trial will compare cytoreductive surgery and HIPEC with systemic chemotherapy vs systemic chemotherapy alone for patients with limited metastatic disease to the peritoneum [52,53].

## 4. Discussion

The treatment of patients with isolated PMGC is a rather complex subject and systemic chemotherapy remains the standard of care. Recent advances in chemotherapy drugs and in the different routes of administration of chemotherapy have offered several new possibilities to find the right combination of treatments that offers patients longer progression-free and/or overall survival. These different ways of administering chemotherapy, focused on the peritoneum, have a good safety profile and have also given promising results. However, the main question was the potential interest of a surgical treatment. The role of
<figure><img src="image_3.png" /><figcaption>Figure 1. Proposed management algorithm of PMGC</figcaption></figure>

<caption>Fig. 1. Proposed management algorithm of PMGC.</caption>

conversion surgery in PMGC remains undefined, particularly in patients with good disease response or control with first-line systemic therapy. With multiple trials demonstrating effective novel systemic therapy and potential control/treatment of disease, there is true equipoise as to whether or not surgical resection will be beneficial in these patients compared to continuing systemic therapy. While conversion surgery has been reported to potentially offer a durable response and disease control, it has not been confirmed in the setting of a phase III prospective randomized trial. Moreover, the potential benefits of conversion surgery for gastric cancer in particular need to be weighed against significant risk of morbidity following gastrectomy with cytoreductive surgery, where the 90-day mortality rate may reach 8% and the major complication rate 54%. In 2024, the updated NCCN guidelines proposed a management algorithm specifically for peritoneal metastatic disease [15]. It consists of systemic therapy for a minimum of 6 months, restaging with a CT scan and diagnostic laparoscopy. If the PCI is less than 10, the possibility of cytoreductive surgery should be discussed in a multidisciplinary meeting. In any case, the NCCN believes that the best management of any patient with cancer is in a clinical trial, and participation is especially encouraged. Here, we propose a sequential management algorithm (Fig. 1).

Quality of life in such a disease of poor prognosis is another important issue. Palliative chemotherapy may prolong life and alleviate symptoms, but its benefits vary, and side effects can occur. A review of clinical trials shows that before treatment, patients report poor health-related quality of life (HRQoL), particularly because of anxiety, fatigue, and appetite loss. During first-line chemotherapy, improvements in symptoms like pain, appetite, and emotional well-being are observed. These findings emphasize the importance of discussing treatment options, survival, side effects, and HRQoL in shared decision-making between doctors and patients [54]. Intraperitoneal chemotherapy has a good safety profile, with acceptable hematologic and nonhematologic toxicity [29], and PIPAC is a well-tolerated option [55] in a palliative setting. The impact of cytoreductive surgery + HIPEC on QoL is totally different since this approach is often proposed as a curative option and candidates for such treatment have better general and functioning status than palliative patients. The performance status of patients as well as their quality of life are also two important factors to be taken into consideration when planning future research. Moreover, new advances in biomarker development for personalized medicine are appearing rather rapidly in the literature. We believe that multicenter studies with strict inclusion criteria should be performed and quality of life should be added a secondary endpoint of the research. We also believe that earlier detection of peritoneal carcinomatosis in gastric cancer patients through

noninvasive methods can lead to the inclusion of more patients in research in the field and consequently to the proposal of more active research in this direction, using circulating tumor DNA, for example [56, 57].

## 5. Limitations

Our narrative review of the current literature on peritoneal metastasis from gastric cancer and decision making for the treatment of patients with this specific disease has several limitations. First, the lack of a systematic approach worldwide prevents comparison of the different treatment modalities, but here we wanted to summarize the results of the different approaches. Second, the choice of only high-level evidence might result in bias through exclusion of pilot studies or promising exploratory studies. Third, there is also a temporal limitation since there are some phase III trials for which results have not yet been published. Fourth, quality of life data concerning the different treatments are scarce since most studies have been focused on survival or complications.

## 6. Conclusion

Patients with peritoneal carcinomatosis from gastric cancer are a difficult subgroup to examine, since peritoneal disease has not long been considered a different entity from other metastatic sites. Taking into consideration the number of phase II and phase III clinical trials that address the problem of patients with isolated PMGC, in the next few years we expect the emergence of important results that might change our treatment options.

## Author contribution

AMETVKAZOGMK

## Declaration of competing interest

No further conflicts of interest.

## Acknowledgement

The authors thank David Marsh, PhD, for manuscript editing.
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