Predictive factors for successful conversion therapy in gastric cancer with peritoneal metastasis: a case-control study

Introduction

Gastric cancer (GC) stands as a formidable challenge within the realm of oncology, ranking fifth in incidence and third in mortality among solid tumors (1). Peritoneal metastasis (PM), a common mode of dissemination, accounts for 53% to 66% of distant metastases (2), often leading to inoperable cases with a dismal prognosis (3). Currently, treatment options for patients with PM from GC remain notably limited.

The study indicates that palliative gastrectomy alone does not improve the survival of patients with PM of GC (4). Despite significant advancements in current systemic chemotherapy, the median survival time for patients with PM of GC remains only 3.1 to 14.1 months (5,6). Conversion therapy, a comprehensive and systematic treatment strategy, aims to downstage tumors to enable R0 resection (6). Although retrospective studies hint at the advantages of conversion surgery (CS), its clinical efficacy and outcomes necessitate further exploration (7).

The success rate of conversion therapy in patients with PM from GC is still unsatisfactory (8,9). Current imaging techniques for evaluating PM lack sufficient accuracy, frequently causing most cases to be detected only during surgical procedures (10). Moreover, research on the ideal conditions for implementing conversion therapy in patients with PM is scant (11). Finding a simple and reliable indicator to identify patients suitable for conversion therapy poses a significant clinical challenge, with far-reaching implications for the development of personalized treatment plans.

In this study, we performed a retrospective analysis of patients with PM of GC who underwent systemic chemotherapy at our institution. The aim of this study was to identify early predictive factors associated with successful R0 resection during CS. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-230/rc).

Methods

Patients

This retrospective case-control study analyzed data from patients diagnosed with PM from GC through laparoscopic exploration, followed by systemic therapy at The First Affiliated Hospital of Xi’an Jiaotong University between January 2019 and December 2023. The participants were stratified into two cohorts on the basis of the receipt of R0 CS: the CS group and the non-CS group.

The study included patients who met the following criteria: (I) a histological diagnosis of primary gastric adenocarcinoma; (II) an age range of 18–85 years; (III) PM confirmed as the sole factor of stage IV disease through laparoscopic findings of macroscopically visible metastatic nodules and intraoperative frozen section; (IV) an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 2 or less; and (V) normal results in routine blood tests, liver and kidney function tests, and electrocardiograms, indicating no contraindications for systemic therapy or surgery.

The exclusion criteria were as follows: (I) the presence of intra-abdominal adhesions or intestinal obstruction; (II) evidence of organ metastases beyond PM; (III) patients who voluntarily discontinued treatment during the study period; (IV) individuals who underwent R1 or R2 resection due to perforation, bleeding, or other complications; and (V) incomplete follow-up records.

This study has been approved by the clinical medical research ethics committee of The First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2024LSYY-230). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was carried out with the written informed consent of the patients or their legal guardians.

Treatment

All patients underwent laparoscopic confirmation of PM, and peritoneal hyperthermic intraperitoneal chemotherapy (HIPEC) catheters were placed on the basis of individual patient requirements. Postoperative systemic therapy and HIPEC treatments were administered in accordance with the guidelines established by the National Comprehensive Cancer Network (NCCN). Tumor assessments were conducted following every three cycles of treatment.

GC patients with PM received HIPEC according to patients’ willingness. In the HIPEC cohort, lobaplatin-based HIPEC was performed under general anesthesia after closure of the incision or within 24 h after first laparoscopic exploration. Two inlet pipes and two outlet pipes were installed. Lobaplatin, at a dosage of 50 mg/m², was dissolved in a heated 5% glucose solution and circulated for a duration of 60 minutes. The perfusion was maintained at a flow rate of 400–500 mL/min, with the circulating temperature consistently held between 42.5 and 43 ℃. After HIPEC, at least 90% of the perfusion fluid was removed. Throughout the HIPEC process, the patients’ vital signs and the color of the drainage fluid were meticulously monitored.

Patients were considered for repeat laparoscopic exploration if they met the following criteria: (I) imaging studies demonstrated either the disappearance or significant reduction of PM; (II) absence of other distant metastases; (III) downstaging of the primary tumor; (IV) improvement in the patient’s generall condition; and (V) consensus from a multidisciplinary team regarding the feasibility of CS.

A radical gastrectomy was conducted during the second laparoscopic examination for patients who met the following criteria: (I) the second laparoscopic examination indicated the absence of PM and negative peritoneal cytology; (II) there were no other distant metastases; (III) the primary tumor was downstaged and was considered completely resectable; and (IV) the patient’s overall condition was adequate to withstand the surgical procedure. Radical gastrectomy referred to the complete removal of tumor in stomach, along with regional lymph nodes (at least a D2 lymphadenectomy) and any adjacent tissues directly invaded by the tumor.

Patients who underwent CS continued with the initial chemotherapy regimen postoperatively until they either developed intolerance or exhibited disease progression (Figure 1).

Figure 1 Flow diagram of treatment. CY1, positive peritoneal lavage cytology; ECOG-PS, Eastern Cooperative Oncology Group performance status; GC, gastric cancer; MDT, multi-disciplinary team; PM, peritoneal metastasis.

Data collection

Data were systematically gathered on a range of patient characteristics, including sex, age, body mass index (BMI), ECOG performance status, PM grading, ascites volume, histopathological type, peritoneal cancer index (PCI), carcinoembryonic antigen (CEA) level, serum carbohydrate antigen 125 (CA125) and 19-9 (CA19-9) level, chemotherapy history, and oophorectomy status, in female patients. Additionally, the types of surgical procedures and extent of resection performed were meticulously documented. Following CS, pathological characteristics, including tumor size, primary tumor location, stage, mismatch repair (MMR) status, human epidermal growth factor receptor 2 (HER2) status, Epstein-Barr virus (EBV) status, and programmed death-ligand 1 (PD-L1) combined positive scores (CPS) status, are documented. The pathological response was evaluated via Becker’s tumor regression grade (TRG) criteria. Postoperative complications were systematically assessed according to the Clavien-Dindo classification (12).

Overall survival (OS) was defined as the interval from diagnosis to death from any cause or the date of the last follow-up.

Statistical analysis

The statistical analysis in this study was performed in SPSS 24.0 (IBM Corp, Armonk, NY, USA). Descriptive statistics and frequency tables were used to summarize the data. Variables with a normal distribution were analysed via Student’s t-test, whereas those exhibiting nonnormal distributions were assessed via the Mann-Whitney U test. Categorical data were evaluated with the Chi-squared test. Survival curves were generated via the Kaplan-Meier method, and their significance was evaluated via the log-rank test. Independent risk factors for failure of conversion therapy were examined by univariate and multivariate logistic regression analyses. Differences were considered statistically significant for a two-sided P value <0.05.

Results

Patient characteristics

In total, 108 patients with PM were enrolled in this study, among whom 21 achieved R0 resection following conversion therapy, resulting in an R0 resection rate of 19.4%. A detailed comparison of the baseline characteristics between the two groups is presented in Table 1. Notably, patients in the CS group exhibited significantly lower PCI scores, as well as reduced levels of CA125 (P=0.003) and CA19-9 (P=0.03). Moreover, the proportion of patients who received chemotherapy according to the FLOT regimen (P=0.03) and combined with programmed death 1 (PD-1) inhibitor (P=0.005) was significantly greater in the CS group than in the non-CS group. No statistically significant differences were observed between the two groups regarding age (P=0.48), sex (P=0.54), BMI (P=0.17), ECOG-PS score (P=0.97), presence of PM (P=0.07), volume of ascites (P=0.27), tumor location (P=0.49), histologic subtype (P>0.99), MMR status (P=0.64), HER2 status (P=0.08), EBV status (P=0.13), PD-L1 CPS status (P=0.18), CEA level (P=0.17), or the proportion of patients who underwent HIPEC (P=0.27).

The details of CS

Table 2 provides a comprehensive summary of the operative details for patients in the CS group. Among these cases, 17 procedures were performed laparoscopically, while 4 were either conducted as open surgeries or converted from laparoscopic to open procedures. A gross radical total gastrectomy was successfully completed in 9 patients, and a radical subtotal gastrectomy was completed in 12 patients. In total, there were 6 females, one of whom underwent ovariectomy during surgery. Postoperative complications occurred in 3 (14.3%) patients. The pathological response assessment of primary tumors showed that 2 (9.5%) patients had a pathologic complete response, 3 (14.3%) patients had a grade 1, 7 (33.3%) patients had a grade 2, and 9 (42.9%) patients had a grade 3 response.

Predictive factors for CS in gastric patients with PM

The median follow-up period was 17.0 months [interquartile range (IQR), 10.5–55.0 months] in the CS group and 12.0 months (IQR, 2.0–42.0 months) in the non-CS group. Notably, patients in the CS group exhibited a significantly longer median OS than those in the non-CS group (P<0.001, Figure 2).

Figure 2 Kaplan-Meier survival analysis for patients who did or did not undergo CS. CS, conversion surgery; OS, overall survival.

We conducted an analysis of the risk factors associated with the failure of CS in GC patients suffering from PM. Univariate logistic regression analysis revealed that PM grade P1c [odds ratio (OR): 4.381, 95% confidence interval (CI): 1.190–16.133, P=0.03) and elevated CA125 levels (OR: 5.864, 95% CI: 1.610–21.355, P=0.007) were risk factors for the failure of CS in GC patients with PM, while treatment with a PD-1 inhibitor (OR: 0.254, 95% CI: 0.094–0.683, P=0.007) was a protective factor against the failure of CS in GC patients with PM. Multivariate analysis further revealed that elevated CA125 levels (OR: 5.449, 95% CI: 1.425–20.830, P=0.01) was a risk factor for the failure of CS in GC patients with PM, and treatment with a PD-1 inhibitor (OR: 0.285, 95% CI: 0.099–0.820, P=0.02) was a protective factor against the failure of CS in GC patients with PM (Table 3).

Discussion

Patients diagnosed with PM secondary to GC typically present a markedly poor prognosis, representing a predominant cause of mortality among individuals with advanced GC (13). For these patients, whether they can successfully undergo conversion therapy to achieve R0 resection is a critical determinant in prolonging survival (6,7). However, following the diagnosis of PM, there is presently an absence of well-defined criteria to ascertain the potential success of conversion therapy owing to the scarcity of literature to guide clinical decisions. Consequently, treatment decisions frequently depend on multidisciplinary deliberations. This scenario may result in certain patients with gastric PM undergoing overtreatment, whereas others may not receive conversion therapy in a timely manner (14,15). Therefore, investigating the factors related to the outcome of conversion therapy for gastric PM that guide subsequent treatment is currently a critical challenge. To address this challenge, we conducted this study via multivariate logistic regression analysis, which revealed that elevated CA125 levels and the absence of a PD-1 inhibitor are correlated with the failure of conversion therapy in GC patients with PM.

Kang, Shinkai and Nakamura et al. reported that the incidence of CS with R0 after conversion therapy in GC patients with PM is about 15.2% to 44.0% in Japan and Korea. Yang et al. reported that the incidence of CS with R0 after conversion therapy in GC patients with PM was approximately 33.6% (6,16-19). In recent years, summary great progress has been made in the conversion therapy of GC with PM through use of targeted therapies, immunotherapy and other treatments, and the incidence of CS with R0 has been increasing. The observed values in previous studies are marginally higher than those reported in our study, which could be attributed to the fact that our center included only grossly visible peritoneal metastases, often associated with a larger tumor burden. In a previous study, patients with obvious shrinkage of the PM also received CS, however, these patients may not receive gastrectomy in our center (6). The stringent criteria employed by our multi-disciplinary team (MDT) for secondary surgical exploration and gastrectomy may result in numerous patients potentially missing the opportunity for CS. Furthermore, research conducted at other institutions has incorporated cases from clinical trials utilizing treatments such as neoadjuvant infusional chemotherapy and targeted therapies, which may potentially enhance the rate of R0 resections (16,17). Consequently, further research is warranted to investigate the factors affecting the outcome of conversion therapy.

Research has demonstrated that intraoperative bleeding and postoperative complications during CS are linked to unfavorable patient outcomes (20-22). This study also investigated the CS process and revealed that all patients, except for a few female patients who required concurrent oophorectomy, did not experience circumstances necessitating extensive lymph node dissection or combined organ resection. Additionally, the findings indicated that intraoperative bleeding and surgical duration remained within acceptable parameters, and no severe postoperative complications exceeding grade IIIa were observed.

Tumor markers are extensively utilized in clinical practice for the assessment of various cancer types, as their levels and trends can provide insights into tumor burden and therapeutic efficacy to some degree (23). Previous research has demonstrated that the levels of CA72-4, CEA, CA19-9, and CA125 are associated with the long-term prognosis of advanced GC patients (24-27). While mesothelial cells of the peritoneum are capable of producing CA125, gastrointestinal cancer cells are relatively rare. Consequently, although CA125 does not directly reflect the tumor burden in GC, it is often employed as a predictive marker for PM (7,28). Prior research has demonstrated a positive correlation between CA125 levels and the volume of ascites in patients with GC, as well as an association with the prognosis of individuals with PM originating from GC (7). Our study further corroborates these findings by identifying elevated CA125 levels as a risk factor for the failure of conversion therapy in GC patients with PM. The prognostic implications of CA125 levels in GC patients with PM may be linked to its effect on the efficacy of conversion therapy, warranting additional investigation for validation.

Research has demonstrated that integrating immunotherapy with first-line chemotherapy regimens can markedly enhance survival outcomes for patients with advanced GC (29-31). Findings from the CheckMate-649 study revealed that the combination of nivolumab with chemotherapy resulted in an approximate 20% increase in the objective response rate across the general population and among individuals with CPS ≥5. Furthermore, there was a significant improvement in disease-free survival, with this enhancement being particularly pronounced in the CPS ≥5 cohort (32). The ORIENT-16 study demonstrated that sintilimab is associated with a reduced risk of mortality in patients with advanced GC (30). Similarly, studies such as KEYNOTE-061, KEYNOTE-062, and KEYNOTE-158 have corroborated the efficacy of immunotherapy in patients with MSI-H/dMMR advanced tumors (18,33,34). Our study also revealed that the combination of sintilimab with chemotherapy serves as a protective factor against the failure of conversion therapy in GC patients with PM. However, our findings did not reveal a significant influence of MMR status on the outcomes of conversion therapy in GC patients with PM. This may be attributed to constraints such as a limited sample size, selection bias in this center, and that we did not undergo multivariable Cox regression analysis. Consequently, further validation through studies with larger sample sizes and more rigorously designed experiments is necessary.

Our study is subject to several limitations. First, as previously noted, the decision to implement CS was made by the MDT, and the criteria for surgical intervention were not standardized. The absence of R1/R2 resections among our patients who underwent CS suggests that our criteria were relatively stringent. Second, throughout the duration of our study, numerous new clinical investigations are underway, potentially leading to continuous changes in clinical practice regarding medications. Our study did not encompass a substantial number of patients participating in clinical trials involving new pharmaceuticals or those who received innovative treatments such as intraperitoneal chemotherapy. Third, individuals who have not received CS with R0 might require additional treatments, including radiation or further chemotherapy, which can affect their overall survival. Finally, owing to the limited sample size and the study’s design, the conclusions drawn from our study necessitate validation through more rigorously designed clinical studies with larger samples. Our study exclusively examined the factors associated with the success of R0 resection. To determine whether CS with R0 might actually have contributed to survival, further multivariable Cox regression analyses are required to ascertain whether R0 resection serves as a prognostic factor for survival.

Conclusions

In conclusion, for GC patients diagnosed with PM via laparoscopic exploration and evaluated for conversion therapy, it is crucial to assess CA125 levels. Patients exhibiting no significant elevation in CA125 should be considered candidates for active first-line therapy in conjunction with immunotherapy as part of the conversion therapy strategy.

Acknowledgments

The authors would like to thank the patients, nurses, and clinicians for their participation in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-230/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-230/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-230/prf

Funding: This work was supported by Shaanxi Province Science Foundation for Youths (No. 2024JC-YBQN-0805).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-230/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study has been approved by the clinical medical research ethics committee of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2024LSYY-230). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was carried out with the written informed consent of the patients or their legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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