Intraperitoneal and intravenous paclitaxel plus S-1 and sintilimab as first-line treatment for gastric cancer with peritoneal metastasis: a single-arm phase 2 trial (DRAGON-09)

ObjectiveTo explore the relationship between flavin-containing monooxygenases (FMOs) and peritoneal metastasis (PM) in gastric cancer (GC).Materials and methodsTIMER 2.0 was used to perform pan-cancer analysis and assess the correlation between the expression of FMOs and cancers. A dataset from The Cancer Genome Atlas (TCGA) was used to analyze the correlation between FMOs and clinicopathological features of GC. PM is well established as the most common mode of metastasis in GC. To further analyze the correlation between FMOs and PM of GC, a dataset was obtained from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database. The results were validated by immunohistochemistry. The relationship between FMOs and PM of GC was explored, and a novel PM risk signature was constructed by least absolute shrinkage and selection operator (LASSO) regression analysis. The regression model’s validity was tested by multisampling. A nomogram was established based on the model for predicting PM in GC patients. The mechanism of FMOs in GC patients presenting with PM was assessed by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses in TCGA and GEO datasets. Finally, the potential relationship between FMOs and immunotherapy was analyzed.ResultsThe pan-cancer analysis in TCGA and GEO datasets showed that FMO1 was upregulated, while FMO2 and FMO4 were downregulated in GC. Moreover, FMO1 and FMO2 correlated positively with the T and N stage of GC in the TCGA dataset. FMO1 and FMO2 expression was a risk factor for GC (hazard ratio: 1.112 and 1.185). The overexpression of FMO1 was significantly correlated with worse disease-free-survival (DFS) and overall survival (OS). However, no relationship was found between FMO2 expression in GC and DFS and OS. PM was highly prevalent among GC patients and typically associated with a worse prognosis. FMO1 was highly expressed in GC with PM. FMO1 and FMO2 were positively correlated with PM in GC. We identified a 12-gene panel for predicting the PM risk signature by LASSO (Area Under Curve (AUC) = 0.948, 95%CI: 0.896–1.000). A 10-gene panel for PM prediction was identified (AUC = 0.932, 95%CI: 0.874–0.990), comprising FMO1 and FMO2. To establish a model for clinical application, a 7-gene panel was established (AUC = 0.927, 95% CI: 0.877–0.977) and successfully validated by multisampling. (AUC = 0.892, 95% CI: 0.878–0.906). GO and KEGG analyses suggest that FMO1 and FMO2 regulate the extracellular matrix and cell adhesion. FMO1 and FMO2 were positively correlated with the immune score of GC, and their expression was associated with the infiltration of immune cells.ConclusionPM in GC is strongly correlated with FMOs. Overall, FMO1 and FMO2 have huge prospects for application as novel diagnostic and therapeutic targets.

Optimising treatment regimens for the management of advanced gastric cancer

BackgroundIntraperitoneal paclitaxel is proved to be efficient for peritoneal metastasis of gastric cancer. It remains uncertain the efficacy and safety of the triplets regimen which combined intraperitoneal high‐dose paclitaxel with systemic SOX in gastric cancer patients with peritoneal metastasis. This study aimed to evaluate the efficacy and safety of intraperitoneal administration of high‐dose paclitaxel, intravenous oxaliplatin and S‐1 in patients with peritoneal metastatic gastric cancer.MethodsThis single‐center, prospective, single‐arm phase II study was conducted between January 2017 and May 2019 in West China Hospital, Sichuan University. Patients diagnosed with primary gastric cancer by histopathology and confirmed synchronous peritoneal metastasis were enrolled. This study aimed to evaluate efficacy and safety of intraperitoneal administration of high‐dose paclitaxel (80 mg/m2, d1), intravenous oxaliplatin (100 mg/m2, d1), and S‐1 (80 mg/m2, d1‐14) of patients. The primary endpoint was 1‐year overall survival rate, and the second endpoints were progression‐free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and adverse events.ResultsIn this single‐arm phase II clinical trial, 49 patients received SOX combined intraperitoneal high‐dose paclitaxel treatment. One‐year survival rate was 81.6% (95% CI, 68.6–90.0%). Median PFS and OS were 6.50 months (95% CI, 2.89–10.11) and 16.9 months (95% CI, 13.58 to 20.22), respectively; ORR was 55.3% (95% CI, 41.3–68.6) and DCR was 76.6% (95% CI, 62.8–86.4). Thirteen patients underwent second laparoscopic detection, but only nine ultimately underwent radical gastrectomy. Subgroup analysis showed that sPCI ≤12 was a good index for a favorable prognosis. The most frequent grade 3/4 toxicities were neutropenia (40.8%), anemia (22.4%), leukopenia (18.4%), nausea (14.3%), and vomiting (12.2%). None of the patients had any intraperitoneal catheter‐related complications.ConclusionsIntraperitoneal high‐dose paclitaxel with systemic SOX is an effective and tolerable first‐line treatment for patients with peritoneal metastatic gastric cancer and patients with sPCI≤12 scores might be recommended crowd for this regimen as conversion therapy.

Peritoneal metastasis (PM) is one of the main causes of a poor prognosis in patients with advanced gastric cancer (GC). lncRNAs have been confirmed to play a very crucial role in the occurrence, development, and metastasis of many human cancers, including gastric cancer. However, the mechanism of lncRNA in PM of GC is rarely studied. We explored the mechanism of PM of GC through lncRNA gene sequencing and protein profiling analysis to detect PM-associated lncRNAs and proteins. A quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to identify the mRNA expression of SEMA3B-AS1 and BGN in GC tissues and adjacent normal tissues. The biological function of SEMA3B-AS1 in the PM of GC was identified through gain- and loss-of-function assays. Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter, and coimmunoprecipitation (co-IP) assays was carried out to demonstrate the potential mechanism between SEMA3B-AS1 and its downstream genes, including HMGB1, FBXW7, and BGN. Finally, the biological function of SEMA3B-AS1 was demonstrated in animal experiments. The mRNA expression level of SEMA3B-AS1 was downregulated in GC and PM tissues compared to normal stomach tissues; however, BGN was highly expressed at the mRNA level. SEMA3B-AS1 was closely related to PM and the overall survival (OS) of GC patients. Functionally, the overexpression of SEMA3B-AS1 was related to GC progression, PM, and prognosis. Mechanistically, SEMA3B-AS1 could combine with HMGB1 to regulate the transcription of FBXW7, thus facilitating the ubiquitination of BGN. In conclusion, our study demonstrated that the SEMA3B-AS1/HMGB1/FBXW7 axis plays an inhibitory role in the PM of GC by regulating BGN protein ubiquitination. It also provides a new biological marker for the diagnosis and treatment of the PM of GC.

Objective: To investigate the safety and short-term efficacy of apatinib combined with oxaliplatin and S-1 in the conversion treatment for gastric cancer with different types of peritoneal metastasis. Methods: A prospective study "one arm exploratory clinical study of conversion therapy of apatinib with S-1 and oxaliplatin in the treatment of advanced gastric cancer" (clinical registration ChiCTR-ONC-17010430) from medical record database was retrospectively analyzed. Patients aged 18-70 years with gastric cancer peritoneal metastasis confirmed by histology and laparoscopic exploration, and had not receive radiotherapy, chemotherapy, targeted therapy or immunotherapy before were enrolled. Before operation, the patients received 6 cycles of S-1 (80-120 mg/d, d1-d14) and oxaliplatin (130 mg/m(2), d1), and 5 cycles of apatinib (500 mg/d, d1-d21) conversion regimen. Three weeks after chemotherapy, whether the operation was performed or not depending on re-evaluation and patient preference. The main outcome were adverse reactions, and the secondary outcome were objective remission rate (ORR), disease control rate (DCR), and overall survival (OS) rate. The follow-up period was up to May 2020. Results: A total of 27 patients with gastric cancer peritoneal metastasis were enrolled in this study. There were 13 males and 14 females, with a median age of 58 (30-68) years old. There were 9 cases of P1a, 5 cases of P1b, and 13 cases of P1c. There were 14 cases with 1-5 scores of PCI (peritoneal cancer index), and 13 cases with 6 scores or above. The incidence of adverse reactions was 100%. The most common adverse reactions were hematological events including leucopenia (70.4%, 19/27) and granulocytopenia (74.1%, 20/27). Non-hematological adverse events included fatigue (51.9%, 14/27) and oral mucositis (37.0%, 10/27). One patient was withdrawn due to grade 4 thrombocytopenia. Among 26 patients with feasible efficacy evaluation, 18 (69.2%) achieved partial remission, 3 (11.5%) achieved stable disease, and 5 (19.2%) disease progression. The objective remission rate was 69.2% (18/26) and the disease control rate was 80.8% (21/26). Fourteen patients underwent surgery, including 6 patients undergoing R0 resection with the R0 resection rate of 42.9% (6/14). The postoperative pathological response rate was 64.3% (9/14). The follow-up time was 12-40 months, and the follow-up rate was 100%. The 1-year OS rate was 65.2% and the survival time was (14.0±1.7) months. The 1-year OS rates of P1a/P1b group and P1c group were 81.8% and 42.0% respectively, whose difference was statistically significant (P=0.041). The 1-year OS rates of PCI 1-5 group and PCI ≥6 group were 67.3% and 38.5% respectively, whose difference was statistically significant (P=0.022). Conclusion: In the conversion treatment of gastric cancer peritoneal metastasis, the safety of apatinib combined with oxaliplatin and S-1 is acceptable, and this regimen shows a good short-term survival efficacy in patients with P1a/P1b and PCI of 1-5.

BackgroundTo investigate the risk factors associated with the development of occult peritoneal metastasis in advanced gastric cancer, and establish and externally validate a nomogram for predicting the occurrence of occult peritoneal metastasis in patients with advanced gastric cancer.MethodsA total of 111 patients with advanced gastric cancer who underwent laparoscopic exploration or peritoneal lavage cytology examination at the Affiliated Drum Tower Hospital of Nanjing University Medical School from August 2014 to December 2021 were retrospectively analyzed. The patients diagnosed between 2019 and 2021 were assigned to the training set (n = 64), while those diagnosed between 2014 and 2016 constituted the external validation set (n = 47). In the training set, patients were classified into two groups based on preoperative imaging and postoperative pathological data: the occult peritoneal metastasis group (OPMG) and the peritoneal metastasis negative group (PMNG). In the validation set, patients were classified into the occult peritoneal metastasis group (CY1P0, OPMG) and the peritoneal metastasis negative group (CY0P0, PMNG) based on peritoneal lavage cytology results. A nomogram was constructed using univariate and multivariate analyses. The performance of the nomogram was evaluated using Harrell’s C-index, the area under the receiver operating characteristic curve (AUC), decision curve analysis (DCA), and calibration plots.ResultsThis study analyzed 22 potential variables of OPM in 111 gastric cancer patients who underwent laparoscopic exploration or peritoneal lavage cytology examination. Logistic regression analysis results showed that Lauren classification, CLDN18.2 score and CA125 were independent risk factors for OPM in patients with gastric cancer. We developed a simple and easy-to-use prediction nomogram of occult peritoneal metastasis in advanced gastric cancer. This nomogram had an excellent diagnostic performance. The AUC of the bootstrap model in the training set was 0.771 and in the validation set was 0.711. This model showed a good fitting and calibration and positive net benefits in decision curve analysis. ConclusionWe have developed a prediction nomogram of OPM for gastric cancer. This novel nomogram has the potential to enhance diagnostic accuracy for occult peritoneal metastasis in gastric cancer patients.

This study aims to investigate the correlation between the tumor-stroma ratio (TSR) and peritoneal metastasis (PM) in gastric cancer (GC) and constructs a diagnostic model based on preoperative examination data. To determine the feasibility of obtaining TSR in GC patients through preoperative examinations, the consistency of TSR between endoscopic biopsy tissues and postoperative histopathological tissues was evaluated. Additionally, the correlation between TSR and PM in GC was analyzed using Gene Expression Omnibus (GEO) datasets. To validate TSR's clinical potential in diagnosing PM, 640 GC patients from two medical centers were enrolled. A training cohort of 330 patients evaluated TSR and synchronous PM correlation, and a validation cohort of 310 patients was used. An additional cohort of 510 patients was established to investigate TSR and metachronous PM. A diagnostic model based on preoperative data was developed and a nomogram constructed. The TSR shows good consistency between endoscopic biopsy tissues and postoperative histopathological tissues. A significant correlation between TSR and PM was observed. The TSR-based model, combined with CA125, CA724 and Borrmann type, exhibited strong diagnostic effectiveness and considerable predictive efficacy, with an Area Under the Curve (AUC) of 0.85 in the training cohort, 0.73 in the external validation cohort, and 0.72 in the metachronous PM cohort. The TSR emerges as a crucial marker for PM in GC, with the developed model, based on TSR and preoperative examination data, demonstrating substantial diagnostic and predictive capabilities.

Objective: Peritoneal Metastases (PM) of Gastric Cancer (GC) are lesions of peritoneal surfaces, which may cause the dissemination throughout the abdominal cavity. The role of laparoscopic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) as neoadjuvant purpose in the management of PM of GC is undefined. Methods: Fifty patients were enrolled into this study with histopathological diagnosis of PM of GC referred to our center between 2012 and 2013 All patients were underwent two cycles of neoadjuvant laparoscopic HIPEC. At the second session of LHIPEC, ascites volume, cytological status and PCI levels were compared with those at the 1st LHIPEC. Results: There was no intraoperative complication and mortality after LHIPEC. Four patients developed mild azotemia of Grade 2. Amount of ascites were completely abolished or decreased in 22 of 34 (64.7%) and positive peritoneal cytology changed to be a negative in 14 of 20 (70%) patients at the 2nd LHIPEC. Complete response was in 6 (12%), and peritoneal cancer indices (PCI) were significantly reduced from 14.3 ± 10.2 at the 1st LHIPEC to 10.8 ± 10.5 at the 2nd LHIPEC (p<0.05). Furthermore, total PCI scores on small bowel mesentery at 1st and 2nd LHIPEC were 6.56 ± 2.92 and 5.25 ± 3.78 (P=0.016). Conclusions: This study identified two outcomes. Diagnostic and therapeutic laparoscopy can be performed safely in patients with PM of GC. Laparoscopic HIPEC can be applied as a neoadjuvant treatment modality in order to reduce the tumor burden and disease control until complete managements to be achieved in patients with PM of GC.

BackgroundImmunotherapy combined with chemotherapy has emerged as the first-line standard treatment for advanced gastric cancer. However, obvious survival benefits in patients with peritoneal metastatic gastric cancer remain elusive. The combination of anti-angiogenic agents and immunotherapy has shown synergistic effects. However, currently there are no relevant reports on the efficacy and safety of immunotherapy combined with anti-angiogenic agents and chemotherapy in patients with gastric cancer peritoneal metastatic.MethodsWe conducted a multicenter, retrospective clinical study in four independent healthcare facilities, enrolling advanced gastric cancer patients with peritoneal metastatic who received immunotherapy in combination with anti-angiogenic agents and chemotherapy between January 2020 and March 2023. All patients were treated with triple combination regimen for at least two and up to eight cycles before being adjusted for immunotherapy and targeted therapy. This study observed overall survival (OS) and time to treatment failure (TTF), as well as an exploratory analysis of the impact of ascites and peritoneal metastases on the prognosis of all patients.ResultsThis study enrolled 30 eligible patients in the final analysis cohort. The median TTF and OS were 7.03 months [95% confidence interval (CI), 4.17–9.89] and 13.33 months (95% CI: 10.96–15.71), respectively. The 6-month and 12-month OS rates were 83.0% and 53.0%, respectively. The objective response rate (ORR) was 58.3%, and the disease control rate (DCR) was 83.3% in 12 patients who were evaluated for response with at least one measurable lesion. Exploratory subgroup analysis revealed that the median TTF and OS in the subgroup without ascites were significantly better than those in the subgroup with ascites, with a median TTF of 9.03 vs. 4.63 months (χ2 = 8.579, P = 0.003), and median OS of 17.83 vs. 11.87 months (χ2 = 6.155, P = 0.013). Conversely, the extent of peritoneal metastasis had little effect on TTF and OS. The common adverse reactions were leukopenia (46.67%), neutropenia (43.33%), fatigue (36.67%), anemia (36.67%), decreased appetite (36.67%), thrombocytopenia (33.33%), and hypertension (33.33%). No new safety signals were observed.ConclusionsThe combination of immunotherapy, anti-angiogenic agents, and chemotherapy demonstrated therapeutic potential with a manageable safety profile in patients with peritoneal metastatic gastric cancer. These findings should be interpreted cautiously due to the inherent limitations of retrospective analyses and need to be validated through prospective randomized controlled trials to establish clinical efficacy and optimize patient selection criteria.

Circulating tumor DNA (ctDNA) is a promising technique for predicting curative effects and monitoring tumor recurrence. The utility of ctDNA for gastric cancer with peritoneal dissemination remains elusive. To assess the feasibility of ctDNA in predicting tumor response to chemotherapy in gastric cancer with peritoneal dissemination. This was a prospective study. We enrolled 30 patients with gastric cancer peritoneal metastasis, treated with intraperitoneal and intravenous paclitaxel plus S-1. Peripheral blood samples of patients were prospectively collected at baseline, after treatment initiation accompanied by computed tomography scan and disease progression. Mutational profiles from ctDNA were analyzed to evaluate its association with chemotherapeutic response. Tumor protein 53 (TP53) was the most frequently altered gene at baseline blood samples. Although baseline TP53 mutation was not related to therapeutic response, patients with TP53 mutation had worse progression-free survival (PFS) and overall survival (OS). Additionally, baseline ctDNA content fraction (CCF) was found to be significantly lower in responders than non-responders. Meanwhile, patients with high CCF had a trend of worse PFS and OS. Combining TP53 alteration and CCF, the prognosis of TP53-wt patients could be further stratified. Patients with CCF-low_TP53-wt had markedly longer survival than those with CCF-high_TP53-wt. Our study highlighted the significance of ctDNA in predicting potential clinical outcomes in gastric cancer patients during chemotherapy. ChiCTR-IIR-16009802 (Chinese Clinical Trial Registry).

PurposeThe purpose of this research was to investigate the efficacy of the CT-based peritoneal cancer index (PCI) to predict the overall survival of patients with peritoneal metastasis in gastric cancer (GCPM) after two cycles of chemotherapy.MethodsThis retrospective study registered 112 individuals with peritoneal metastasis in gastric cancer in our hospital. Abdominal and pelvic enhanced CT before and after chemotherapy was independently analyzed by two radiologists. The PCI of peritoneal metastasis in gastric cancer was evaluated according to the Sugarbaker classification, considering the size and distribution of the lesions using CT. Then we evaluated the prognostic performance of PCI based on CT, clinical characteristics, and imaging findings for survival analysis using multivariate Cox proportional hazard regression.ResultsThe PCI change ratio based on CT after treatment (ΔPCI), therapy lines, and change in grade of ascites were independent factors that were associated with overall survival (OS). The area under the curve (AUC) value of ΔPCI for predicting OS with 0.773 was higher than that of RECIST 1.1 with 0.661 (P < 0.05). Patients with ΔPCI less than −15% had significantly longer OS.ConclusionCT analysis after chemotherapy could predict OS in patients with GCPM. The CT-PCI change ratio could contribute to the determination of an appropriate strategy for gastric cancer patients with peritoneal metastasis.

Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC.

Purpose: There is no standard treatment for peritoneal metastases (PM) from gastric cancer (GC). The aim of this review is to evaluate the clinical trials on cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for GC PM.Materials and methods: The published clinical trials on CRS + HIPEC for GC PM are critically evaluated, and survival and safety are the primary endpoints. In addition, the registered ongoing clinical trials are summarised.Results: The natural course of GC PM is <5 months. CRS + HIPEC could improve the overall survival (OS). In prospective studies, the median OS was 11.0 months in the CRS + HIPEC group vs. 5.4 months in the CRS alone group. In case-control studies, the median OS was 13.3 months in the CRS + HIPEC group vs. 7.9 months in the CRS alone group. In cohort studies, the median OS after CRS + HIPEC was 13.3. The median 1-, 2- and 5-year survival rates after CRS + HIPEC were 50.0%, 35.8% and 13.0%, respectively. There is no statistically significant increase in serious adverse events that are directly attributed to CRS + HIPEC.Conclusions: The combination of CRS and HIPEC is a promising integrated treatment strategy for GC PM that has encouraging initial results, calling for urgent further evaluation of this strategy in randomised control trials (RCTs).

The prognosis of metastasis gastric cancer patients remains poor and the identification of novel molecular markers will improve the management of gastric cancer patients. The present study aimed to investigate the clinical significance and functional role of miR-466 in gastric cancer peritoneal metastasis. miR-466 expression was confirmed by RT-qPCR. The biological functions were examined by MTT assay, Transwell migration, and invasion assays. The Kaplan-Meier survival curve and multivariate Cox regression analysis were used to investigate the clinical role of miR-466. The logistic regression analysis was performed to reveal the risk factors associated with peritoneal metastasis. miR-466 expression was downregulated in gastric cancer cell lines, tumor tissues, and peritoneal metastasis tissues compared with respective controls. Increased miR-466 expression inhibited proliferation, migration, and invasion of gastric cancer cells. Besides, the lower expression of miR-466 in gastric cancer patients was associated with peritoneal dissemination. Furthermore, multivariate Cox proportional hazard regression analyses demonstrated miR-466 expression level as an independent predictor of prognosis of gastric cancer. The present study provides novel evidence for the clinical and biological significance of miR-466 expression as a possible biomarker for the prognosis and identifying patients with peritoneal metastasis, as well as a potential therapeutic target in patients with gastric cancer.

Peritoneal metastasis (PM) is an important metastatic modality of gastric cancer (GC).It is associated with poor prognosis. The underlying molecular mechanism of PM remains elusive. 5-Methylcytosine (m5C), a posttranscriptional RNA modification, involves in the progression of many tumors. However, its role in GC peritoneal metastasis remains unclear. In our study, transcriptome results suggested that NSUN2 expression was significantly upregulated in PM. And patients with high NSUN2 expression of PM predicted a worse prognosis. Mechanistically, NSUN2 regulates ORAI2 mRNA stability by m5C modification, thereby promoting ORAI2 expression and further promoting peritoneal metastasis and colonization of GC. YBX1 acts as a "reader" by binding to the ORAI2 m5C modification site. Following the uptake of fatty acids from omental adipocytes by GC cells, the transcription factor E2F1 was upregulated, which further promoted the expression of NSUN2 through cis-element. Briefly, these results revealed that peritoneal adipocytes provide fatty acid for GC cells, thus contributing to the elevation of E2F1 and NSUN2 through AMPK pathway, and upregulated NSUN2 activates the key gene ORAI2 through m5C modification, thereby promoting peritoneal metastasis and colonization of gastric cancer.